Netherlands Journal. E.J. Lust, W.K. Lagrand, M. van der Ent, A.P.W.M. Maat, M.L. Simoons

Netherlands NetherlandsJournal Journal o o ff cCrr ii ttiiccaall Ccaarree

b i - m o n t h ly o f f i c i a l j o u r n a l

o f t h e d u t c h s o c i e t y o f i n t e n s i v e care (nvic)

Volume 10, No. 5 October 2006

In this issue

c l i n i c a l i m age

Incomplete circle of Willis

530

H.R.H. de Geus, J. Bakker c a s e r e p o rts

Ventricular septal rupture as an early and fatal complication of acute myocardial infarction: case-report

531

E.J. Lust, W.K. Lagrand, M. van der Ent, A.P.W.M. Maat, M.L. Simoons

Syphilis-associated Guillain- Barré Syndrome

534

M. Hijmering, C. Hoedemaekers, A. Oude Lashof and J. van der Hoeven

Fatal Invasive Aspergillosis in an Apparently Immunocompetent Host

536

W.M. Dijkman, B.H. Postma

Polychemotherapy with bleomycin for metastasized choriocarcinoma of the testis in a ventilated patient

538

M. de Bruin, T. Müller, N. Foudraine, S. Wouda, P. ter Horst, F. Nooteboom reviews

Intensive Care and Recombinant Factor VIIa Use: A Review

542

R. Sherrington, A. Tillyard, A. Rhodes and R.M. Grounds

Fluids for protection from renal failure in the Intensive Care Unit

548

J. Kountchev and M. Joannidis

Volatile anaesthetics and the heart

554

R.A. Bouwman, R.J.P. Musters, J.J. de Lange, C. Boer guideline

Guidelines for timing, dose, and mode of continuous renal replacement therapy for acute renal failure in the critically ill

561

C.S.C. Bouman, H.M. Oudemans-van Straaten NVICatern r o u n d tab l e Nederlandse Vereniging

voor

Intensive Care (NVIC)

New perspectives in the treatment of severe yeast- and fungal infections in critically ill patients: the role of Mycograb®

587

K.H. Polderman, A.R.H. van Zanten

V 2006 NJCC_05 omslag 01.indd 2

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TOTAL PERFORMANCE SPEED STRENGTH ENDURANCE 06.tyg.6.8 Productinformatie zie elders in dit blad.

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Voor productinformatie zie elders in dit blad

2006 NJCC_05 omslag 01.indd 3

12-10-2006 09:20:18

n eth e rlan ds jou rnal of critical care

Colophon Executive editorial board AB Johan Groeneveld, Editor in Chief Arthur RH van Zanten, Managing Editor Kees H Polderman, Internet Editor Peter HJ van der Voort, Correspondence Editor

ournal Netherlands J of critical care Vol. 10, No. 5, October 2006

Publisher Netherlands Journal of Critical Care issn: 1569-3511 nvic Stationsweg 73C 6711 PL Ede (Gld) Telephone: +31-318-69 33 37 Fax: +31-318-69 33 38 KvK Utrecht V30149527 Production Interactie, Ede Design v i l l a y, The Hague

Information for authors

429

Clinical image Incomplete circle of Willis H.R.H. de Geus, J. Bakker

530

•

Case reports Ventricular septal rupture as an early and fatal complication of acute myocardial infarction: case-report E.J. Lust, W.K. Lagrand, M. van der Ent, A.P.W.M. Maat, M.L. Simoons

•

531

• Syphilis-associated Guillain- Barré Syndrome

534

• Fatal Invasive Aspergillosis in an Apparently Immunocompetent Host

536

• Polychemotherapy with bleomycin for metastasized choriocarcinoma

538

Layout Unit-1, The Hague Printing Perfect DM Groep, Rotterdam Advertising-exploitation/ Business contacts Eldering Studio BV Thomas Eldering Communication and media-specialists Zijlweg 12 2051 BA Overveen Telephone: +31-23-52 59 332 Fax: +31-23-52 53 265 E-mail: [email protected] Internet address Dutch IC society: www.nvic.nl Bankaccount ABN AMRO Ede 52.45.61.893 IBAN

NL 55ABNA0524561893

BIC

ABNANL 2 A

NVIC membership and subscriptions One year NVIC-membership costs € 165 (for registered intensivist) or € 110(otherwise). These costs include a subscrition for the Neth J Crit Care. Separate issues are available for € 27,50 excluding 6% VAT. Prices subject to change without notice. Further information can be obtained by telephone at +31-318-69 33 37 or by fax at +31-318-69 33 38 Copyright © 2006 nvic All information contained in this issue is the property of the NVIC. Reproduction in any kind is prohibited without prior written permission by the NVIC.

M. Hijmering, C. Hoedemaekers, A. Oude Lashof and J. van der Hoeven W.M. Dijkman, B.H. Postma

of the testis in a ventilated patient M. de Bruin, T. Müller, N. Foudraine, S. Wouda, P. ter Horst, F. Nooteboom

Reviews Intensive Care and Recombinant Factor VIIa Use: A Review R. Sherrington, A. Tillyard, A. Rhodes and R.M. Grounds

•

542

• Fluids for protection from renal failure in the Intensive Care Unit

548

• Volatile anaesthetics and the heart

554

J. Kountchev and M. Joannidis

R.A. Bouwman, R.J.P. Musters, J.J. de Lange, C. Boer

Guidelines Guidelines for timing, dose, and mode of continuous renal replacement therapy for acute renal failure in the critically ill C.S.C. Bouman, H.M. Oudemans-van Straaten

•

NVICatern

• Commissies en Afgevaardigden • Verenigingsnieuws • Agenda • Round Table: New perspectives in the treatment of severe yeast- and fungal

571 573 573 587

infections in critically ill patients: the role of Mycograb® K.H. Polderman, A.R.H. van Zanten

• Interne indicatoren voor Intensive Care afdelingen:

595

• Inschrijvingsformulier

603

een continue nationale registratie ten behoeve van kwaliteitsverbetering De commissie kwaliteitsindicatoren van de NVIC

n eth j crit care • volume 10 • no 5 • octobe r 2006

2006 NJCC_05 binnenwerk 01.indd 525

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(advertenties)

Productinformatie Samenstelling en farmaceutische vorm: Pantozol ® 20 en Pantozol ® 40 maagsapresistente tabletten bevatten respectievelijk 22,6 mg en 45,1 mg pantoprazolnatriumsesquihydraat overeenkomend met respectievelijk 20 mg en 40 mg pantoprazol. Indicaties: Pantozol ® 20: onderhoudsbehandeling bij refluxoesofagitis, behandeling milde refluxziekte en daaraan gerelateerde symptomen, preventie van ulcera bij chronisch NSAID-gebruik. Pantozol ® 40: eradicatie van Helicobacter pylori in combinatie met twee geschikte antibiotica, ulcus duodeni, ulcus ventriculi en/of matige tot ernstige refluxoesofagitis, Zollinger-Ellison syndroom (ZES) en andere aandoeningen die gepaard gaan met pathologische hypersecretie. Dosering: Afhankelijk van de indicatie éénmaal daags één tablet Pantozol ® 20 of Pantozol ® 40. On demand gebruik van Pantozol ® 20 is mogelijk wanneer symptoomverlichting is bereikt. Doseerschema voor eradicatietherapie is opvraagbaar. Bij leverfunctiestoornissen maximaal 20 mg per dag. Ouderen en patiënten met verslechterde nierfunctie maximaal 40 mg pantoprazol per dag (met uitzondering van eradicatietherapie). Voor ZES: starten met 80 mg per dag, daarna aanpassen aan de klinische behoefte, tijdelijke verhoging boven 160 mg is mogelijk. Contra-indicaties: Overgevoeligheid voor pantoprazol of andere bestanddelen. De combinatietherapie voor eradicatie van Helicobacter pylori niet bij patiënten met matig tot ernstige nierof leverfunctiestoornissen. Waarschuwingen: Maligniteiten dienen uitgesloten te worden in verband met mogelijke maskering. Over gebruik bij kinderen zijn geen gegevens bekend. Bij patiënten met ernstige leverfunctiestoornissen moeten regelmatig leverenzymwaarden bepaald worden tijdens langdurige behandeling. Interacties: pH-afhankelijke absorptie van stoffen kan worden beïnvloed. Er zijn geen interacties waargenomen met antacida, carbamazepine, cafeïne, diazepam, diclofenac, digoxine, ethanol, glibenclamide, meto prolol, naproxen, nifedipine, piroxicam, fenytoïne, theofylline en orale contraceptiva. Daarnaast zijn er geen klinisch relevante interacties met metronidazol, amoxicilline en claritromycine. In de postmarketing periode is een aantal geïsoleerde gevallen van toename van INR-tijd waargenomen bij gelijktijdig gebruik met fenprocoumon en warfarine. Monitoring van de prothrombinetijd / INR wordt aanbevolen bij patiënten die behandeld worden met anticoagulantia uit de coumarinederivatengroep, na initiatie, beëindigen of gedurende onregelmatig gebruik van pantoprazol. Zwangerschap en borstvoeding: Er zijn onvoldoende gegevens bekend. Rijvaardigheid: Pantozol ® heeft geen invloed op de rijvaardigheid of het vermogen machines te bedienen. Bijwerkingen: Vaak maagdarmklachten en hoofdpijn. Soms allergische huidreacties, jeuk, duizeligheid en visusstoornissen. Zelden artralgie en droge mond. In enkele gevallen perifeer oedeem, leverbeschadiging, koorts, myalgia, leukopenie, thrombocytopenie, depressie, interstitiële nefritis en anafylactische reacties. Overige informatie: Verpakkingsgrootte: blisterverpakkingen met 15 of 30 tabletten en E.A.V. verpakking 50 stuks. Kanalisatie: UR. Vergoedingsstatus: volledig vergoed. Volledige informatie op aanvraag beschikbaar. Pantozol ® 20 RVG 23513; Pantozol ® 40 RVG 18300. (Augustus 2005) ALTANA Pharma bv, Postbus 31, 2130 AA Hoofddorp, www.altanapharma.nl

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Verkorte productinformatie Tygacil Tygacil 50 mg poeder voor oplossing voor infusie. Samenstelling: Elke 5 ml flacon Tygacil bevat 50 mg tigecycline. Na reconstitutie bevat 1 ml 10 mg tigecycline. Indicatie: Tygacil is geïndiceerd voor de behandeling van gecompliceerde huidinfecties en infecties van weke delen en voor de behandeling van gecompliceerde intra-abdominale infecties. Er dient rekening gehouden te worden met de officiële richtlijnen over het juiste gebruik van antibacteriële middelen. Contra-indicaties: Overgevoeligheid voor het actieve bestanddeel of voor één van de hulpstoffen. Patiënten die overgevoelig zijn voor tetracycline-klasse antibioticakunnen overgevoelig zijn voor tigecycline. Waarschuwingen/voorzorgsmaatregelen: Tigecycline kan dezelfde bijwerkingen als tetracycline-klasse antibiotica hebben. Er is beperkte ervaring met het gebruik van tigecycline voor de behandeling van infecties bij patiënten met ernstige onderliggende aandoeningen. Daarom is voorzichtigheid geboden bij het behandelen van zulke patiënten. Het gebruik van antibacteriële combinatietherapie dient steeds overwogen te worden wanneer tigecycline zal worden toegediend bij ernstig zieke patiënten met gecompliceerde intraabdominale infecties die secundair zijn aan een klinisch manifeste, intestinale perforatie of patiënten met beginnende sepsis of shock. Patiënten die cholestase vertonen moeten nauwkeurig gecontroleerd worden. Protrombinetijd of een andere geschikte anticoagulatietest dient gebruikt te worden om patiënten te controleren als tigecycline samen met anticoagulantia wordt toegediend. Pseudomembraneuze colitis is gemeld bij bijna alle antibacteriële geneesmiddelen en kan in ernst variëren van mild tot levensbedreigend. Het is daarom belangrijk deze diagnose te overwegen bij patiënten waarbij zich diarree voordoet tijdens toediening of nadat enig antibacterieel middel is toegediend. Het gebruik van tigecycline kan resulteren in overmatige groei van niet-gevoelige , waaronder schimmels. Patiënten dienen nauwkeurig gecontroleerd te worden gedurende de therapie. Als superinfectie optreedt, dienen passende maatregelen genomen te worden. Tygacil dient niet te worden gebruikt bij kinderen jonger dan 8 jaar vanwege het risico op verkleuring van de tanden en het wordt niet aanbevolen bij adolescenten jonger dan 18 jaar vanwege het gebrek aan gegevens met betrekking tot veiligheid en effectiviteit bij die leeftijdsgroep. Bijwerkingen: In klinische studies, waren de meest voorkomende, aan het geneesmiddel gerelateerde uit de behandeling voortkomende bijwerkingen reversibele misselijkheid en braken, wat gewoonlijk vroeg voorkwam (op behandelingsdagen 1-2) en over het algemeen mild tot matig in hevigheid was. Andere bijwerkingen die voorkwamen waren abcessen, infecties, sepsis/septische shock, verlengde geactiveerde partiële tromboplastinetijd (aPTT), verlengde protrombinetijd (PT), duizeligheid, flebitis, tromboflebitis, diarree, acute pancreatitis, verhoogd aspartaat-aminotransferase (AST) in serum en verhoogd alanine-aminotransferase (ALT) in serum, bilirubinemie, pruritus, uitslag, hoofdpijn, buikpijn, dyspepsie, anorexie, verhoogd amylase in het serum, verhoogd ‘blood urea nitrogen’ (BUN). Registratiehouder: Wyeth Europa Ltd., Verenigd Koninkrijk. U.R. April 2006

Tijd en energie over? De Intensivisten-pool!

Nederland heeft voorlopig nog een tekort aan intensivisten. Veel ziekenhuizen proberen er het beste van te maken, maar kunnen de zorg op hun IC afdeling niet altijd op het gewenste niveau leveren. Er wordt aan gewerkt, maar in de tussesntijd is er vraag naar intensivisten met interesse, tijd en energie om de nood te lenigen. ViaMedica is een gerenommeerd intermediair voor medisch specialisten in elke discipline. Op IC gebied verzorgt ViaMedica werving en selectie van vaste/interim medewerkers alsmede het onderhouden van een IC pool met intensivisten die in overleg ‘losse’ waarnemingen doen op andere ICU afdelingen in Nederland. Voor deze pool zoekt ViaMedica intensivisten die worden aangesproken door: • • • • •

Kijkje in -en proeven van- een andere “keuken” Uitstekende verdiensten Nieuwe mensen ontmoeten in een andere omgeving Direct in de patiëntenzorg werkzaam en geen bestuurlijke problemen Na de dienst naar huis…

Indien u interesse heeft om in de ViaMedica IC pool te worden opgenomen kunt u een email met uw CV sturen naar: [email protected]. Voor meer informatie kunt u bellen met een van onze medisch specialist/consultants 035-524 78 26 of bezoek onze website www.ViaMedica.nl.

Voor de volledige SmPC zie wyeth.nl Conform de gedragscode van de CGR is dit promotiemateriaal uitsluitend bestemd voor artsen en apothekers. Wyeth Pharmaceuticals bv Postbus 255, 2130 AG Hoofddorp, www.wyeth.nl

06.tyg.6.8.

Leading the way to a healthier world


12-10-2006 09:05:19


Editorial Board of the Netherlands Journal of Critical Care A.B. Johan Groeneveld, Editor in Chief Dept. of Intensive Care Medicine VU University Medical Center PO box 7057 1007 MB Amsterdam Arthur van Zanten, Managing Editor Dept. of Intensive Care Medicine Gelderse Vallei Hospital PO box 9025 6710 HN Ede

Kees Polderman, Internet Editor/ Section Editor Neuro University Medical Center Utrecht PO Box 85500 3508 GA Utrecht

Jan Bakker, Section Editor Hemodynamics Dept. of Intensive Care Medicine Erasmus Medical Center Rotterdam PO Box 2040 3000 CA Rotterdam

Armand Girbes, Section Editor General Dept. of Intensive Care Medicine VU University Medical Center PO box 7057 1007 MB Amsterdam

Johan Damen, Section Editor Anesthesiology Dept. of Cardiothoracic Anesthesiology and Intensive Care Medicine UMC St. Radboud, PO Box 9101, 6500 HB Nijmegen

Jan Hazelzet, Section Editor Pediatrics Pediatric Intensive Care Unit; Sophia Children’s Hospital; Erasmus Medical Center Rotterdam PO Box 2060 3000 CB Rotterdam Hans van der Hoeven, Section Editor Mechanical Ventilation Dept. of Intensive Care Medicine UMC St. Radboud PO Box 9101 6500 HB Nijmegen

Paul van den Berg Dept. of Intensive Care Medicine Leids University Medical Center PO Box 9600 2300 RC Leiden Alexander Bindels Dept. of Internal Medicine Catharina Hospital Michelangelolaan 2 5623 EJ Eindhoven Reinier Braams Dept. of Intensive Care Medicine University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Can Ince Dept. of Physiology Academic Medical Center, University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam

Anton van Kaam Dept. of Neonatal Intensive Care Emma Children’s Hospital Academic Medical Centre University of Amsterdam, Meibergdreef 9 1105 AZ Amsterdam Jozef Kesecioglu Division of Perioperative Medicine and Emergency Care, Cardiothoracic and Neurosurgical Intensive Care University Medical Center Utrecht Mail stop E03-511; PO Box 85500 3508 GA Utrecht Michael Kuiper Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box 888 8901 BR Leeuwarden

Peter van der Voort, Correspondence Editor Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box 888 8901 BR Leeuwarden

Evert de Jonge, Section Editor Scoring and quality assessment Dept. of Intensive Care Medicine Academic Medical Center, University of Amsterdam Mail stop G3-206 Meibergdreef 9 1105 AZ Amsterdam Heleen Oudemans-van Straaten, Section Editor Nephrology Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box 95500 1090 HM Amsterdam

Peter Pickkers, Section Editor Sepsis and inflammation Dept. of Intensive Care Medicine UMC St. Radboud PO Box 9101 6500 HB Nijmegen Dick Tibboel, Section Editor Pediatrics Pediatric Intensive Care Unit; Sophia Children’s Hospital; Erasmus Medical Center Rotterdam PO Box 2060 3000 CB Rotterdam

Andrew Maas Dept. of Neurosurgery Erasmus Medical Center Rotterdam PO Box 2060 3000 CB Rotterdam

Peter Spronk Dept. of Intensive Care Medicine Gelre Hospital, location Lukas PO Box 9014 7300 DS Apeldoorn

Manu Malbrain Dept. of Intensive Care Medicine Academic Hospital Stuivenberg Lange Beeldekenstraat 267 B-2060 Antwerpen, Belgium

Tjip van der Werf Intensive and Respiratory Care Unit Dept. of Internal Medicine Groningen University Hospital PO Box 30001 9700 RB Groningen

Gerrit-Jan Scheffer Dept. of Anaesthesiology UMC St. Radboud PO Box 9101 6500 HB Nijmegen Marcus Schultz Dept. of Intensive Care Medicine Academic Medical Center, University of Amsterdam Mail stop G3-206 Meibergdreef 9 1105 AZ Amsterdam



Saskia Peerderman, Section Editor Neuro Dept. of Neurosurgery Intensive Care VU University Medical Center PO box 7057 1007 MB Amsterdam

Durk Zandstra Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box 95500 1090 HM Amsterdam

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L ce aat l o de ng hu em m oe ane id

Fungal Cell Wall

Fungal Cell Wall

CANCIDAS

Cell Membrane

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Precursors to ß(1,3)-D-glucan

Precursors to ß(1,3)-D-glucan

Normal Cell-Wall Synthesis

Synthesis Inhibited by CANCIDAS

• Invasieve candidiasis • Invasieve aspergillose • Empirische antifungale therapie 1

CANDIDA ALBICANS

3

C. C . rugo C. gla b s a C. pararata C. trop p s i l o C. krusicali sis s C . gui l e i l l i C. i p o e r m l C. d u b y t i c o n d l a ii C. kefy inie lu r ns is sit an A. iae A. flav u A . f um s i A. terr gat u e A . nige u s s ni r du lan s

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Referenties: 1. Duarte P.N.: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Eng J Med 347;2020-9, 2002. 2. Maertens J.: Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant for conventional antifungal therapy. CID 2004;39:000-000. 3. Walsh T.J.: Caspofungin versus Liposomal Amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Eng J Med 2004; 351:1391-402. 4. David W. Denning: Echinocandin antifungal drugs. The Lancet 362: 1142-51, 2003. Raadpleeg eerst de volledige productinformatie alvorens CANCIDAS voor te schrijven CANCIDAS is een geregistreerd handelsmerk van Merck & Co., Inc., Whitehouse Station, NJ, USA

M Merck Sharp & Dohme BV, Postbus 581, 2003 PC Haarlem, Tel. 023-5153153, www.msd.nl, www.univadis.nl

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Evidence. Experience. Confidence. 09-06-2006 12-10-2006 11:21:37 09:05:21


Information for authors The Netherlands Journal of Critical Care (Neth J Crit Care) is the official journal of the Dutch Society of Intensive Care (‘Nederlandse Vereniging voor Intensive Care-NVIC’). Reports of research related to any aspect of the field of intensive care, whether laboratory, clinical, or epidemiological, will be considered for publication in Neth J Crit Care. All manuscripts will be subject to an independent reviewing process managed by the executive board.

S

Major Articles. Major articles report the results

S

of original investigations that have been brought to an acceptable degree of completion. They should contain a maximum of 4,000 words and 50 references. Manuscript should be clear in outline (with subheadings) for maximum clarity. There is no fixed limit to the number of figures and tables; However, duplication of data from the text of the manuscript should be avoided. The first page of the manuscript should include: The title of the article, the names of all authors, footnotes to the title, complete address of all authors with identification of the corresponding author, and running title (for page heading). The text should contain the following sections: an Abstract, Introduction, Materials and Methods, Results, Discussion and Conclusion. An abstract should not exceed 250 words. In addition, writers are encouraged to write one or more short key-messages. For major articles the abstract should be divided into the following sections: Objective - Setting and Patients – Interventions - Measurements and Main Results - Conclusions.

(Systemic) reviews. Review articles are usually submitted after prior consultation with the editors, and are subject to the peer review process. They should contain a maximum of 4,000 words and 50 references. Systemic reviews should be focused: state the question to be addressed, the methods by which potential materials (original articles, published and unpublished abstracts, etc) have been selected, and the methods through which they are subsequently appraised. The text should contain an Abstract, Introduction, Search Results, Discussion and Conclusion section. An abstract should not exceed 250 words. For reviews it should be divided into the following sections: Objective - Search strategy – Summary of findings - Conclusions.

Editorials. Editorials may deal with any aspect of intensive care medicine. They are generally invited, but occasionally unsolicited editorials may be considered.

Clinical notes, images in intensive care medicine, and case reports Clinical notes should describe a specific intensive care medicine-related entity; images in intensive care medicine are photographic pictures in intensive care medicine, noteworthy for their scientific, emotional and/or challenging content; case reports are short presentations on cases that merit special attention. Clinical notes, images in

e. 11:21:37

intensive care medicine, and case reports should include an abstract and must be limited to no more than 2000 words of text, a maximum of two inserts (tables or figures), and 15 references. In addition, writers are encouraged to write one or more short key-messages

Letters. Only correspondence submitted in reference to a previous publication in NJCC will be considered. Letters should be submitted within 8 weeks of publication of the paper to which it refers. Please prepare the letter in manuscript format, including a title page. Letters are limited to a maximum of 500 words of text, one table or figure, and a maximum of 5 references.

Guidelines. Guidelines, which are produced by the NVIC guideline committee (‘commissie richtlijnontwikkeling’) will be published in our Journal. Guidelines are usually preceded by a review on the topic of the guideline; these reviews should be in English, and are subject to the peer review process. Guidelines themselves will be published in both English and Dutch.

General information. Manuscripts should be submitted by e-mail (as attachments) to: [email protected]. The manuscript should be accompanied by a cover letter stating the following: the complete mailing address, E-mail address, telephone number and fax number of the corresponding author. Receipt of the manuscript will be acknowledged by E-mail within 14 days. If this should not be the case, authors are requested to check with the editor. Please submit your manuscript as a Word Perfect® or Microsoft Word® text-file. The language of the journal is English. Authors who are not fluent in the Englsih language should have their manuscript checked by a native English speaker. Tables. Tables should be numbered independently of the figures, with Arabic numerals, with headings, and kept separate from the text.

Figures. Figures should also be numbered using

be considered for publication, except for review articles, provided written permission from the original authors has been obtained and the source is clearly indicated. Colour figures are encouraged. Short, clear legends make additional description in the text unnecessary. The preferred location for figures and tables may be marked in the margins of the manuscript sheets. During the final lay-out process these remarks will be taken into account.

References. Only articles cited in the text should be listed. These should be arranged in order of appearance in the text […] and numbered sequentially. Only the reference number should appear in the text. The maximum number of listed authors is six; if there are more than six authors please list the first six and add et al. Article in journals: Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. Books or book-sections: Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent JL (eds) Clinical trials for the treatment of sepsis. (Update in intensive care and emergency medicine, volume 19). Berlin Heidelberg New York, Springer 1995: pp 167-190.

Proofs. The corresponding author will receive

proofs by E-mail as a pdf-file (Adobe®-Acrobat®file). Corrected proofs must be returned by fax within 48 hours of receipt.

Production process. Decisions of the editors are final. All materials accepted for publication are subject to editing. The original manuscript will be discarded one month after publication unless the author requests the return of these original materials. The Neth J Crit Care reserves the right to edit manuscripts to conform to the journal style, and to improve clarity, precision of expression, and grammar. Authors may review these changes at the proof stage, but should limit any alterations in the proofs to correction of errors and clarification of misleading statements.

Arabic numerals, and kept separate from the text. Legends should be provided on a separate sheet. Schematic line drawings are preferred. Figures previously published elsewhere will generally not



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n eth e rlan ds jou rnal of critical care Copyright ©2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved.

c l i n i c a l

Received August 2006; accepted in revised form September 2006

i m a g e

Incomplete circle of Willis H.R.H. de Geus, J. Bakker Department of Intensive Care, Erasmus University Medical Centre Rotterdam, The Netherlands

Abstract. A 60-year-old woman presented with acute headache and loss of consciousness. On admission her Glasgow coma scale score was 6. She was intubated in order to secure the airway. The computer tomography scan (CT-scan) showed a huge amount of subarachnoidal blood probably due to an aneurysmal haemorrhage. Further CT-angiography and image reconstruction identified the aneurysm as being situated in the anterior communicating artery (Figure 1). Furthermore there was an incomplete circulus arteriosus cerebri (circle of Willis) with an absent posterior communicating artery on both sides and the right anterior cerebral artery originating in the left carotid artery with absence of communication between the right anterior cerebral artery and the right middle cerebral artery. There were no neurosurgical or endovascular treatment options. Despite optimal management by preventing vasospasm with excessive fluid infusion, calcium channel blockers and dobutamine she developed frontal lobe ischaemia (Figure 2) and cardiac failure with acute pulmonary oedema. After a fulminant re-bleed our patient was brain-dead and further medical treatment was discontinued. Merkkola et al studied 87 post-mortem patients identifying missing posterior communicating arteries in 46% and missing or incomplete anterior communicating arteries in 22%. (1) The developmental absence of both communicating systems is rare and proved fatal in this case of subarachnoidal haemorrhage. Because of the high risk of ischaemia during neurosurgical or endovascular intervention the treatment of the aneurysm in these cases is suboptimal, thus increasing the risk of a fatal re-bleed.

Figure 1b. Normal circle of Willis; 1=anterior communicating artery, 2=anterior cerebral artery, 3=middle cerebral artery, 4=carotid artery, 5=posterior communicating artery, 6=posterior cerebral artery, 7=basilar artery.

Figure 1a. Reconstruction image showing the anterior communicating artery aneurysm. The right anterior cerebral artery originates in the left carotid artery. There is no connection between the right anterior cerebral artery and the right middle cerebral artery. Both posterior communicating arteries are absent, there is no communication between the basilar blood flow and the blood flow of the carotid arteries.

Figure 2. Left and right frontal lobe ischaemia due to vasospasm of the anterior cerebral arteries and inadequate blood supply due to the incomplete circulus arteriosus cerebri. Visible blood in posterior horn of the left lateral ventricle.

Correspondence:

References

H.R.H. de Geus E-mail: [email protected]

1. Merkkola P, Tulla H, Ronkainen A, Soppi V, Oksala A, Koivisto T et al. Incomplete circle of Willis and right axillary artery perfusion. Ann Thorac Surg 2006; 82(1):74-79.

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Received January 2006; accepted in revised form July 2006

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Ventricular septal rupture as an early and fatal complication of acute myocardial infarction: case-report E.J. Lust1 *, W.K. Lagrand1, M. van der Ent1, A.P.W.M. Maat2, M.L. Simoons1 1Departments of Cardiology and 2Cardiothoracic Surgery Intensive Care Thorax Centre, University Medical Centre Rotterdam, The Netherlands Key words: acute myocardial infarction, ventricular septal rupture

Abstract. This article presents the history of a patient who developed ventricular septal rupture (VSR) after acute myocardial infarction (AMI). Clinical presentation, diagnostic work-up and treatment are described. The literature on this subject is also discussed.

Introduction Ventricular septal rupture is a feared and potentially lethal complication of AMI. Occurrence of VSR has declined over the years due to improved coronary reperfusion treatment (1). For this reason, clinicians are nowadays less often confronted with VSR and experience of this complication is declining. Symptoms of VSR include chest pain, shortness of breath, and those commonly associated with low cardiac output and shock. At physical examination a harsh, loud holosytolic murmur can be heard along the left sternal border, radiating toward the base, apex and right parasternal area. A palpable parasternal thrill is present in half of the patients. With cardiogenic shock and a low-output state complicating VSR, there is rarely a thrill, and the murmur is difficult to identify because flow across the defect is reduced. Right and left ventricular S3 are common. Doppler echocardiography is generally diagnostic and can distinguish between VSR, rupture of ventricular free wall and papillary muscle rupture. Pulmonary artery catheterisation may be helpful. In patients with a VSR, an increase in oxygen saturation occurs within the right ventricle. Medical therapy consists of mechanical support with an intra-aortic balloon pump, afterload reduction, diuretics and usually inotropic agents. Most patients, however, need immediate surgical intervention. The aim of this case report is to discuss VSR after AMI and to examine the early recognition, diagnostic features and prompt treatment of the condition.

Case history A 65year-old male was admitted to our hospital with a 16 hour history of severe chest pain. The patient’s medical history revealed Buerger’s Disease, resulting in severely diminished arterial perfusion of the limbs. On admission, the chest pain had resolved and he denied shortness of breath. At physical examination he appeared moderately ill, with a blood pressure of 90/60 mmHg and sinus tachycardia of 120/min. Auscultation revealed normal heart sounds with no extra sounds or murmurs. No signs of left- or right-sided

Correspondence: E.J. Lust Email: [email protected]

heart failure were observed. On electrocardiography a recent anterior wall myocardial infarction was detected, with ST-segment elevation in leads V1 to V5, I and aVL in combination with QS formation in leads V1 to V4. Treatment with aspirin, clopidogrel and a statin was initiated. Because of progressive haemodynamic deterioration, it was decided to perform an immediate coronary angiography, which revealed single vessel disease of the ramus descendens anterior (RDA). Despite several attempts to revascularize the RDA, including stenting, only a greatly reduced flow (TIMI flow 1-2) could be obtained. Considering the no-reflow state at the end of the procedure abciximab was added to the initial medical therapy. Inotropic support was started by means of dobutamine 3 µg/kg/min and noradrenalin 0.012 µg/kg/min. Because of the compromised peripheral arterial vessels it was decided not to insert an intra-aortic balloon pump (IABP). During his stay in the Intensive Care Unit, inotropic support could not be reduced. Repeat echocardiographic examination showed progressive aneurysmal widening of the apex of the left ventricle. Left ventricular function was severely compromised. Other than mitral valve regurgitation grade II/IV, no additional valvular abnormalities were seen. Pericardial effusion was absent. Laboratory examination revealed normal values for haemoglobulin, thrombocytes, leucocytes, and liver- and renal function parameters. Troponin-T and CK-MB increased to maximal values of 16.8 mg/l and 247 U/l, respectively. In the early hours of the next morning,36 hours after onset of chest pain, his clinical condition suddenly deteriorated. The chest pain recurred, accompanied by progressive dyspnoea and nausea. On physical examination blood pressures were lower (70/30 mmHg) with increased heart rates up to 128/min (sinus tachycardia). Central venous pressure (CVP) was elevated. On auscultation a continuous murmur, grade III-IV/VI, was heard with a mid-sternal maximum accompanied by rales at both lung fields. Echocardiographic examination demonstrated a ventricular septal rupture (VSR) (Figure 1) with a maximum velocity over the septum of a minimum of 3 m/s. Mitral valve regurgitation and left ventricular function were unchanged. No tricuspid valve regurgitation was seen. Pulmonary artery catheterisation revealed an oxygen saturation jump from 62 % in the right atrium to 82 % in the pulmonary artery (aortic saturation 99%), resulting in a left to right shunt calculated



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Figure 1: Apical, 4-chamber, trans-thoracic echocardiographic view showing VSR (arrow). (MV = mitral valve, TV = tricuspid valve, IVS = interventricular septum, RV = right ventricle)

Figure 2: Per-operative image showing massive hemorrhagic anterior wall myocardial infarction), and VSR (at the tip of suction device / speculum).

to be 1: 2.2. Emergency surgery was performed immediately. After sternotomy the anterior wall of the left ventricle was seen to be haemorrhagic and infarcted. This extended into the right ventricular wall and there was blood in the pericardium indicating imminent ventricular free wall rupture (Figure 2). By means of ventriculotomy in the infarcted anterior region, both the impending ventricular free wall rupture and the VSR were covered by an autologous pericardial patch. mitral valve annuloplasty was not performed because of moderate mitral valve regurgitation. Temporary epicardial atrial and ventricular pacemaker leads were attached although the patient had persistent sinus tachycardia without any conduction disturbances. Transoesophageal echocardiography performed directly after surgery showed no signs of pericardial effusion but there was still a minor residual VSR. Both left ventricular function and mitral valve regurgitation remained unchanged. Postoperatively, however, mixed venous oxygen saturation progressively increased, indicating progressive VSR with a calculated shunt fraction up to 1: 2.9, indicating patch dehiscence Because of hypotension, progressive renal failure and ongoing myocardial ischaemia it was decided that further surgical intervention was not feasible. Active treatment was suspended and the patient died soon after. Permission for autopsy was refused.

though reducing infarct size and VSR occurrence rate, may promote haemorrhagic dissection in the myocardium, thereby accelerating the onset of VSR. The effects of percutaneous coronary intervention (PCI) with respect to the occurrence of VSR after AMI are not well established. However, Yip et al report a significantly lower occurrence rate of VSR after AMI in PCI-treated patients, although in this study no data are available with respect to final angiographic results [3]. Mortality rates among patients with VSR who do not have surgery are approximately 24% in the first 24 hours, 46% in the first week, and 67 to 82% over two months. However, the 30-day mortality of medically and surgically treated patients with VSR was 76 and 53% respectively, indicating the potential benefit of surgical treatment [4]. In the study of Lemery and co-workers it was shown that in patients who go into cardiogenic shock after VSR, the prognosis was uniformly fatal unless they undergo prompt surgery. In the same study it was found that a higher age correlated with an adverse outcome. So, early surgery should be considered for every patient with VSR after AMI in the knowledge that elderly patients in cardiogenic shock have the worst prognosis [4]. The operation involves excluding rather than excising the infarcted septum and ventricular wall. A left ventriculotomy is made through the infarcted area of muscle and a pericardial patch is sewn over the endocardium of the left ventricle around the infarcted area of myocardium. The ventriculotomy is then closed over the pericardial patch.[5] Patients with VSR are regularly treated with an IABP which improves survival by augmenting coronary blood flow as well as reducing left ventricular afterload and wall tension. Indeed, IABP support results in lower immediate postoperative mortality rates, although IABP treatment was not found to be associated with improved longterm survival [6]. In our patient it was decided not to insert an IABP because of severe atherosclerosis of the femoral arteries. Alternative insertion sites (e.g. intra-thoracic) were not feasible because of severe atherosclerosis and elongation of the aorta. The development of residual or recurrent VSR is reported in up to 28% of patients who survive surgical repair, and is associated with high mortality [7]. Nowadays VSR is an extremely rare complication of AMI. VSR should be considered in all patients who deteriorate rapidly after an

Discussion VSR after AMI is associated with female gender, advanced age, anterior wall myocardial infarction, one-vessel coronary artery disease, absence of collateral circulation and no coronary reperfusion [1,2]. Our patient, although a man, fulfilled most of these risk factors for VSR. We do not have any clinical indication or data from literature that Buerger’s Disease is involved in the occurrence of VSR after AMI. With the advent of the more appropriate reperfusion treatment the incidence of VSR has declined over the years. In the era before thrombolytic therapy, VSR complicated 1 to 3 percent of cases of AMI, occurring within one day or after 3 to 5 days [1]. In the GUSTO-I trial the incidence of VSR was 0.2 percent [2]. Remarkably, most of the VSR occurred in the first 24 hours after onset of AMI. It was concluded from these observations that thrombolysis, al-

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AMI despite receiving optimal treatment. Patients with one-vessel coronary heart disease without any collateral coronary circulation and no adequate reperfusion are at particular risk. Early diagnosis of VSR is extremely important. When the diagnosis has been confirmed, IABP support and immediate surgical treatment should be considered. References 1.

Birnbaum Y, Fishbein MC, Blanche C, Siegel RJ. Ventricular septal rupture after acute myocardial infarction. N Engl J Med. 2002;347:1426-32. 2. Crenshaw BS, Granger CB, Birnbaum Y, Pieper KS, Morris DC, Kleiman NS, Vahanian A, Califf RM, Topol EJ. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) Trial Investigators. Circulation. 2000;101(1):27-32.

3. Yip HK, Fang CY, Tsai KT, Chang HW, Yeh KH, Fu M, Wu CJ. The potential impact of primary percutaneous coronary intervention on ventricular septal rupture complicating acute myocardial infarction. Chest. 2004;125:1622-8. 4. Lemery R, Smith HC, Giuliani ER, Gersh BJ. Prognosis in rupture of the ventricular septum after acute myocardial infarction and role of early surgical intervention. Am J Cardiol. 1992;70:147-51. 5. David ET, Dale L, Sun Z. Postinfarction ventricular septal rupture: repair by endocardial patch with infarct exclusion. J Thorac Cardiovasc Surg 1995;110:1315-1322.

6. Blanche C, Khan SS, Matloff JM, Chaux A, DeRobertis MA, Czer LS, Kass RM, Tsai TP. Results of early repair of ventricular septal defect after an acute myocardial infarction. J Thorac Cardiovasc Surg. 1992;104(4):961-5. 7. Blanche C, Khan SS, Chaux A, Matloff JM. Postinfarction ventricular septal defect in the elderly: analysis and results. Ann Thorac Surg. 1994;57:1244-7.



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Received June 2006; accepted in revised form September 2006

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Syphilis-associated Guillain- Barré Syndrome M. Hijmering1, C. Hoedemaekers1, A. Oude Lashof 2 and J. van der Hoeven1 1Department of Intensive Care, 2Department of Internal Medicine Radboud University Hospital Nijmegen, the Netherlands

Abstract. Guillain-Barré Syndrome (GBS) is the most common cause of acute flaccid paralysis in previously healthy adults. It is

strongly associated with several bacterial and viral infections, with C. jejuni, CMV, EBV, HIV, Mycoplasma pneumoniae and H. influenzae being the most common infecting micro-organisms. We present a case in which a previously healthy male developed GBS syndrome that did not respond to the standard treatment with immunoglobulins and plasmapheresis. An infection with treponema pallidum was proven both by serological testing and histological investigations . After treatment for syphilis, the patient made a remarkable recovery.

Case Report

Discussion

A 47 year-old, previously healthy Dutch male, was admitted with a three day history of progressive symmetrical weakness in his arms and legs, accompanied by abnormal sensations in his hands and feet. He reported no fever, chills, diarrhoea, or other signs of infection in the weeks prior to admission. He denied IV drug abuse. On examination, the patient had moderate quadriparesis, no deep tendon reflexes, and distal paraesthesia/hypoesthesia in all extremities. A non-tender solitary lymph node was palpated in the supraclavicular region. No other abnormalities were found on general clinical examination. Laboratory investigations revealed a slightly raised sedimentation rate of 49 mm/h and a C-reactive protein concentration of 39 mg/l. The cerebrospinal fluid had normal protein levels but an increased IgG concentration of 54 mg/dl (normal 10-29 mg/dl), without pleiocytosis. Nerve conduction studies and electromyography (EMG) findings identified clear evidence of demyelination with secondary axonal damage compatible with Guillain-Barré Syndrome (GBS). The patient was treated with intravenous immunoglobulin (0.4 g/kg/day) for seven days. Forced vital capacity was lowered and showed a downward trend. On the third day respiratory failure occurred and the patient required intubation and mechanical ventilation. After completion of immunoglobulin treatment the patient underwent plasmapheresis, but neither treatment had any apparent clinical effect. Serological examination revealed no recent infection with Campylobacter, Mycoplasma, Cytomegalovirus, Epstein-Barr virus, hepatitis C virus, influenza virus, para-influenza virus, or Borrelia. Serological testing and PCR for HIV was negative, but VDRL [1:8], TPPA and FTA-ABS testing was positive for syphilis. Histological examination revealed Treponema pallidum in the supraclavicular lymph node (photo). Treponema pallidum antigen was not detected in the cerebrospinal fluid by PCR, VDRL, TPPA and FTA-ABS. Clinical signs of primary or secondary syphilis were not detected. The patient was treated with benzylpenicillin for two weeks, which led to a dramatic clinical improvement, with a return of muscle strength and normal sensibility. The patient was discharged from the intensive care unit five weeks after admission.

GBS is the most common cause of acute flaccid paralysis in previously healthy adults, with an average incidence of approximately 1.5 per 100,000 (1). Several subtypes can be defined depending on the clinical and electrophysiological characteristics, with acute demyelinating neuropathy (AIDP), being the most frequent subtype. Although our patient showed clear signs of axonal involvement of both motor and sensory fibres, the phenotype is still compatible with AIDP, because a variable degree of axonal degeneration is universal in severe cases of GBS. The exact cause of the autoimmune reaction that leads to inflammatory demyelination is unknown. The association with numerous infectious diseases suggests that the autoimmune response in GBS may be triggered by molecular mimicry between the infectious organism and peripheral nerve antigens. GBS is strongly associated with several bacterial and viral infections, with C. jejuni, CMV, EBV, HIV, Mycoplasma pneumoniae and H. influenzae being the most common infecting micro-organisms. Although review of the literature

Correspondence: M. Hijmering E-mail: [email protected]

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Table 1. Results of a Pubmed search based on the search terms “Guillain Barré and infection”. Micro-organisms that were reported in at least 20 patients were qualified as frequent. Frequent reports Anecdotal reports C. jejuni M. neisseria Mycoplasma pneumoniae Y. enterocolitica H. influenzae S. typhy Helicobacter pylori Chl. pneumoniae Herpes virusses Hanta virus HIV Parvo virus B19 West-Nile virus Para-infuenza virus Hepatitis A, B, C virusses Barmah Forest virus Enterovirus 71 Coxsackie B-5 Rocky Mountain spotted fever Japanese encephalitis virus Treponema pallidum Rickettsia conorii Plasmodium falciparum, vivax Toxoplasma Leptospira interrogans Cyclospora Borrelia burgdorferi


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(Pubmed search of literature published in English language using Guillain-Barré and infection as search terms) identified numerous case reports of other infections (Table 1), it is uncertain whether these infections had a causative role or represented chance associations. Our patient was diagnosed with syphilis on the basis of serological tests and the detection of Treponema pallidum in a lymph node. We found one case report of syphilis associated with GBS in a 24yearold African-American female diagnosed by positive serological testing [2]. In that case, plasmapheresis alone resulted in clinical and electrophysiological improvement. In contrast, both clinical signs and electrophysiological parameters showed our patient to have deteriorated despite immunoglobulin therapy and plasmapheresis. There was, however, a dramatic improvement on administration of penicillin. This suggests that the immune response in our patient was actively triggered by living micro-organisms. The lymphatic system is the primary reservoir of facultative anaerobic treponemes. Generalized inflammatory lymph node hyperplasia is a characteristic feature of early syphilis, including latent syphilis. In the absence of dermatological and mucosal changes, the lymph nodes may be the only infected tissues accessible for detection of T pallidum .[3]. The incidence of primary and secondary syphilis in Europe and North America is increasing, especially among people with high-risk sexual behaviour [4-6]. In this population there is a high rate of HIV co-infection [7]. Clinicians examining patients who have an infec-

Figure 1. Spirochetes in a supraclavicular lymph node.

tious process underlying GBS should be aware of the possibility of syphilis infection. In our case, penicillin treatment resulted in rapid clinical improvement and restoration of electrophysiological variables.

References 1. Govoni V, Granieri E. Epidemiology of the Guillain-Barre syndrome. Curr Opin Neurol 2001; 14(5):605-613. 2. Weisenberg E, Baron BW. Syphilis-associated GuillainBarre syndrome: response to plasmapheresis. J Clin Apher 1994; 9(3):200-201. 3. Kouznetsov AV, Prinz JC. Molecular diagnosis of syphilis: the Schaudinn-Hoffmann lymph-node biopsy. Lancet 2002; 360(9330):388-389.

4. Ciesielski CA. Sexually Transmitted Diseases in Men Who Have Sex with Men: An Epidemiologic Review. Curr Infect Dis Rep 2003; 5(2):145-152. 5. Doherty L, Fenton KA, Jones J, Paine TC, Higgins SP, Williams D et al. Syphilis: old problem, new strategy. BMJ 2002; 325(7356):153-156.

6. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003; 290(11):15101514. 7. Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis 2004; 4(7):456-466.



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Received and accepted: oktober 2006

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Fatal Invasive Aspergillosis in an Apparently Immunocompetent Host W.M. Dijkman1, B.H. Postma2

1dept. intensive care medicine, Máxima Medisch Centrum. 2Laboratory for Medical Microbiology, Veldhoven.

Abstract. A 51-year-old woman was admitted to the ICU because of perforation of the stomach. In spite of initial recovery following abdominal surgery, she succumbed from an invasive pulmonary infection with Aspergillus fumigatus. There were no signs or symptoms of an underlying immunodeficiency. Although rare, Aspergillus spp. is able to overcome seemingly normal pulmonary defences giving rise to a devastating and lethal infection.

Introduction

Discussion

Aspergillus spp, a genus of mitosporic fungi commonly present in the environment, can cause a variety of conditions, ranging from superficial colonisation and allergic reactions to deep penetration of tissues like invasive pneumonia. These invasive infections are a major cause of morbidity and mortality in immunosuppressed patients. Although unusual, Aspergillus spp can cause pneumonia in the absence of an apparent predisposing immunodeficiency. In spite of advances made with azole therapy the outcome of invasive aspergillosis remains poor [1]. We describe a case to exemplify that critically ill patients without a known history of abnormal immune function can develop this severe opportunistic infection.

Our patient died of invasive pulmonary aspergillosis after a prolonged stay in the intensive care unit, during which she sustained a period of severe abdominal sepsis and multiple organ failure. In the course of her illness Aspergillus fumigatus was cultured several times from various clinical samples (Table 1). The first two positive cultures were considered to be due to contamination, but because of the combination of clinical findings and the abnormalities found at bronchoscopy antifungal treatment was started anyway and continued until she died. At the time of her admission renovation works were being carried out both at her home and in the hospital. Two circumstances may have triggered the development of invasive pulmonary aspergillosis in our patient. First, a period of severe abdominal sepsis and multiple organ failure, leading to a temporary state of acquired immunodeficiency, and second, inhalation of spores of Aspergillus. No Aspergillus spp. was found in multiple air samples taken during the construction period in the hospital. No samples were taken in the patient’s home. Although there is no evidence for inhalation of a heavy inoculum, the first option has only been postulated [2] and therefore cannot be proven. An explanation for this rare infection remains uncertain. The diagnosis ‘invasive pulmonary aspergillosis’ is usually based on a combination of clinical, microbiological, radiographical and histopathological findings, with clinical suspicion being of paramount importance. Two laboratory methods are of value to help establishing a diagnosis: direct microscopic examination of bronchoalveolar lavage BAL fluid for the presence of branched hyphae [3] and monitoring serum samples for Aspergillus galactomannan (GM), a specific cell wall component circulating during infection [4]. Previously described series of patients are small and mention a mortality of up to 100% [5]. In one study [6] the latex agglutination test for Aspergillus antigen yielded positive results only in advanced stages of infection in most patients suspected of having invasive aspergillosis and consequently did not contribute to early diagnosis. When Aspergillus was found for the first time in BAL fluid, our patient was not neutropenic and there were no other known risk factors for an invasive opportunistic infection. Therefore, she was not considered to be immunosuppressed or at risk for invasive aspergillosis and so here was no reason to monitor GM levels. Considering the increasing incidence of invasive aspergillosis in intensive care units and a mortality of over 90% in patients without a malignancy [7] our current concept of immune competence might be inadequate. The anti-inflammatory response in sepsis may be seen as

Case history A 51-year-old woman with no medical history presented at the emergency ward after several days of abdominal pain. On examination she was hypotensive and barely responsive. The abdomen was tender and an ultrasound examination showed intra-abdominal free fluid. On laparotomy there was perforation of the stomach with extensive spill of contents. After apparently successful closure of the defect several re-laparotomies were needed to control persistent leakage. Initially she suffered from severe septic shock with multiple organ failure, and as the abdominal outflow decreased her situation improved slowly. Cultures of sputum, blood, peritoneal fluid and indwelling catheters yielded Enterobacter cloacae, Enterococcus faecium and Candida albicans. Antibiotic treatment consisted of cefuroxim, ciprofloxacin, metronidazole and fluconazole, either alone or in various combinations. After two weeks, respiratory support had to be increased because of rapidly diminishing compliance. Chest X-ray and computed tomography (Figure 1) showed progressive infiltrative abnormalities and pleural effusion. No cavities were observed. Bronchoscopy revealed extensive bumpy irregularities with a tattered surface extending through all visible parts of the bronchial tree (Figure 2). Bronchial alveolar lavage (BAL) fluid yielded Aspergillus fumigatus. A diagnosis of invasive aspergillosis was confirmed by pathological analysis of bronchus biopsies. No Aspergillus was found in specimens taken previously during abdominal surgery. In spite of treatment with voriconazole, itraconazole and caspofungin her condition progressively deteriorated and she died 48 days after admission. Autopsy was not permitted. Correspondence: W.M. Dijkman E-mail: [email protected]

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Table 1. results of microscopy and culture for A. fumigatus Day in ICU Sample Method / Result 14 BAL Microscopy: hyphae Culture: A. fumigatus 15 Sputum Microscopy: hyphae Culture: A. fumigatus 20 Sputum Microscopy: no hyphae Culture: A. fumigatus 23 BAL Microscopy: no hyphae Culture: A. fumigatus Biopsy Microscopy: hyphae Culture: A. fumigatus 44 Sputum Microscopy: no hyphae Culture: A. fumigatus BAL = bronchoalveolar lavage fluid.

a temporary acquired immunodeficiency, facilitating opportunistic infections to develop in apparently immunocompetent patients [2]. Conditions like, chronic lung disease, non-haematological malignancy, HIV infection, diabetes mellitus, liver failure, chronic alcohol abuse, malnutrition and extensive burns have been reported in association with invasive aspergillosis [8] and the interpretation of finding ubiquitous, branched hyphae in a culture taken from a nonsterile site remains difficult. In the absence of large epidemiological studies there are no known risk factors, single or in combination, for the acquisition of an invasive Aspergillus infection. Polymerase chain reaction (PCR) allows detection of the equivalent of 10-100 colonyforming units (CFU) of Aspergillus fumigatus per sample in serum or plasma. The combined use of PCR for A. fumigatus DNA and ELISA for galactomannan should provide a definitive diagnosis of invasive aspergillosis, even in the absence of obvious clinical signs [9]. As long as these methods are not generally available, direct microscopic examination of BAL fluid remains the first and most important clue to a potentially lethal mycosis. Retrospectively, there were no known predisposing factors for invasive aspergillosis or indications of reduced pulmonary host defences in our patient other than sepsis. For immunocompromised patients with cancer and hematopoietic stem cell transplants definitions of invasive fungal infections and the best methods for establishing the diagnosis are published as an international consensus [10]. However regarding immune competent hosts there remains much uncertainty. A diagnostic algorithm for patients without a malignancy as proposed by van de Woude et al. [8] should trigger physicians not to take a culture containing Aspergillus spp. too easily for contamination.

Figure 1, CT scan of the thorax showing infiltrative abnormalities, mainly in the right upper lobe, and pleural effusion. No cavities were found.

Figure 2, Bronchoscopic view of the carina showing extensive irregularities with a ragged surface. Biopsies confirmed the diagnosis of invasive aspergillosis.

References 1.

Hope WW, Denning DW: Invasive aspergillosis: current and future challenges in diagnosis and therapy. Clin Microbiol Infect 2004, 10(1):2-4. 2. Hartemink KJ, Paul MA, Spijkstra JJ, Girbes AR, Polderman KH: Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003, 29(11):20682071. 3. Richardson MD WD: Fungal Infection. Diagnosis and treatment, 3 edn: Blackwell 2003. 4. Verweij PE, Dompeling EC, Donnelly JP, Schattenberg AV, Meis JF: Serial monitoring of Aspergillus antigen in the early diagnosis of invasive aspergillosis. Preliminary investigations with two examples. Infection 1997, 25(2):86-89.

5. Clancy CJ, Nguyen MH: Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease. Chest 1998, 114(2):629-634. 6. Verweij PE, Rijs AJ, De Pauw BE, Horrevorts AM, Hoogkamp-Korstanje JA, Meis JF: Clinical evaluation and reproducibility of the Pastorex Aspergillus antigen latex agglutination test for diagnosing invasive aspergillosis. J Clin Pathol 1995, 48(5):474-476. 7. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E: Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004, 170(6):621-625.

8. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D: Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care 2006, 10(1):R31. 9. Richardson MD K, M: Aspergillus. Philadelphia: Churchill Livingstone; 2003 10. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z et al: Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002, 34(1):7-14.



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Received June 2006; accepted September 2006

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Polychemotherapy with bleomycin for metastasized choriocarcinoma of the testis in a ventilated patient M. de Bruin1, T. Müller, N. Foudraine1, S. Wouda3, P. ter Horst2, F. Nooteboom4 1Department of Intensive Care, 2Department of Clinical Pharmacy, 3Department of Pathology, VieCuri Medisch Centrum voor Noord-Limburg, The Netherlands 4 Department of Intensive Care, Laurentius ziekenhuis Roermond, Roermond, The Netherlands Key words: Bleomycin – Mechanical ventilation - Pulmonary fibrosis - Chemotherapy - Choriocarcinoma

Abstract. A 25 year-old Caucasian male was admitted to the ICU with respiratory failure after one cycle of BEP (45 International Units (IU) (=30 mg) bleomycin, 200 mg etoposide and 40 mg cisplatin) chemotherapy. He had pulmonary metastases from stage IV choriocarcinoma and was given the first BEP cycle while on a non-rebreathing mask (FiO2 = 60%). Chemotherapy was continued during mechanical ventilation. He developed end-stage pulmonary fibrosis after the fourth cycle with a cumulative dosage of 180 IU (120 mg) bleomycin and died on the 38th day after his admission to the ICU. Post-mortem examination revealed no active metastases in the lungs but extensive pulmonary fibrosis, probably secondary to administration of bleomycin. This case history illustrates that standard chemotherapy including bleomycin is potentially lethal. Bleomycin treatment should be stopped in patients who develop acute pulmonary toxicity and respiratory failure.

Introduction Germ cell tumours originating in the testis can be grouped according to prognosis. Choriocarcinoma, a non-seminomatous germ cell cancer (NSGCC), is very rare in its pure form and by definition its prognosis can be classified as poor risk. Additionally, even in better-risk histological entities, poor risk is recognized in metastasized NSGCC if pulmonary metastases exceed 20 in number[1], are present outside the lungs (brain, liver or bone marrow) or the human chorionic gonadotropin (HCG) tumour marker is elevated beyond 10.000 IU/ml [2]. The role of bleomycin in standard polychemotherapy regimens for poor risk patients has been established as cure rates have increased from 40% to 60 %[2]. Our patient had both histologically confirmed NSGCC and advanced disease with more than 40 pulmonary metastases and total HCG exceeding 800.000 IU/L. He was treated with the standard four-cycle BEP regimen [ 1,2] for advanced disease as established by the Indiana group [2] and the results of EORTC/MRC protocol 30974[6]. Bleomycin, antineoplastic amide, first extracted from Streptomyces vertillicus by Umezawa and colleagues in the 1960s, is known to have side effects including interstitial pneumonitis and pulmonary fibrosis[1]. Little is known about the administration of bleomycin to the critically ill, who are frequently ventilated with high oxygen fractions. We present a patient who was treated in accordance with standard polychemotherapy regimen for advanced disease [1,2,3,4]. This included bleomycin, etoposide and cisplatin (PEB) for grossly disseminated choriocarcinoma (HCG above 800.000 IU/l) at the same time as being treated with high oxygen fractions. Bleomycin may have contributed to the fatal outcome for this patient.

Case report A 25 year-old Caucasian male was admitted to our hospital in respiratory distress. His medical history had been unremarkable up to Correspondence: Martha de Bruin E-mail: [email protected]

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that point, when he developed back pain, shortness of breath, bloodtinged sputum and night sweats. A chest X-ray showed bilateral interstitial lung defects. Bronchoscopy was performed but was unremarkable. Computed tomography of the thorax showed extensive (more than 30) dense, coin-shaped lesions in both lungs, measuring up to 4x5x2 cm each (Figure 1), with a bulky retroperitoneal tumour measuring 20x12x10 cm. The differential diagnosis included sarcoidosis, tuberculosis, yeast infection and metastases from testicular carcinoma. A thoracotomy and open lung biopsy revealed a stage IV,grossly metastasized, choriocarcinoma but no evidence of further intrinsic lung pathology (Fig. 2). Serum tumour markers, measured for the first time following thoracotomy, and GFR are shown in Table 1. Polychemotherapy following EORTC guidelines and comprising the BEP scheme with 45 IU bleomycin (30 mg), etoposide (200 mg) and cisplatin (40 mg) was initiated on the second postoperative day. On the sixth postoperative day, four days after his first cycle of BEP, he developed severe respiratory insufficiency (Table 1). The patient was sedated, relaxed, intubated and mechanically ventilated. His APACHE II score on ICU admission was 22. Pressure controlled ventilation with 30 cm H2O and 14 cm H2O of PEEP and a FiO2 of 60% resulted in a paO2 7.3 kPa (paO2 /FiO2 = 12.2). In order to maximize the chance of cure, BEP chemotherapy was continued by means of non-bolus infusion on ICU days 4, 12 and 19, totalling 180 IU (120 mg) bleomycin. Markers (AFP, ß-HCG) decreased significantly (Table 1) chemotherapy. The clinical course of the patient, however, involved multiple and severe complications including a pneumothorax treated by chest tube insertion on ICU day six, severe exudative pericarditis treated with pericardiocentesis on ICU day twelve, and fever thereafter. Bronchial secretion cultures revealed Candida spec., E. coli, Enterococcus faecalis and Stenotrophomonas maltophilia which were treated with intravenous and oral antibiotics according to pattern of resistance. Persistent leucopenia with a nadir of 0.9*109 leucocytes /l meant the patient had to be put in isolation for his protection on day 29. His worsening respiratory and clinical condition necessitated pressure-controlled ventilation with peak pressures of 66 cm H20 (including up to 8 cm H2O PEEP) and a FiO2


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Table 1 – Respiratory parameters and laboratory results Respiratory parameters ICU d –5 ICU d -4 before bleomycin after 1st cycle Blood gas analysis (in kPa)

pH paCO2 paO2 HCO3BE SaO2 FiO2

Respiration parameters Pressures in cm H2O Mode Peak pressure above PEEP PEEP PaO2/FIO2 ratio Tumour markers AFP HCG LDH GFR

7.38 6.3 13.9 27.3 2 98% NRBM 60% Spontaneous NA

7.40 6.6 10.3 29.7 5 96% NRBM 60%

24 36 889.356 1911 112

21 45 1.625.764 4550

On Intake ICU ICU d 4 ICU d 12 day 0 after 2nd cycle after 3rd cycle 7.38 7.29 7.45 7.5 9.2 6.2 7.2 19.4 10.8 32.2 32.2 31.5 6 5 7 89% 98% 97% NRBM 0.75 0.4 60% PC PS 24 18 14

80

14 26 30 295.000 2016 84

8 27 15 12.604 1821 119

ICU d 19 after 4th cycle 7.40 7.8 9.2 35.8 10 94% 0.4

ICU d38 premortum 7.16 22.0 5.8 57.0 24 76% 1.0

PS 10

PC 54

6 23 27 2.919 934 146

6 6 14 210 612 215

Figure 1. CT morphology of lung pathology on admission

Figure 2. (50x, HE) open lung biopsy (intraoperative) with metastatic choriocarcinoma. The lung tissue shows no sign of fibrosis or other damage due to cytotoxic agents.

of 100%, resulting in peak paO2 of 8.8 kPa (paO2 /FiO2= 8.8). The patient was placed in the prone position on day 34, unfortunately without appropriate improvement in oxygenation and an essentially unchanged paO2 /FiO2 of 9.5. Despite treatment with 16 mg dexamethasone [1] IV daily, acetylcysteine 12 g IV daily [4] (prescribed as potential oxygen radical scavenger) no improvement of lung function or overall patient status was achieved. The patient’s situation continued to deteriorate tremendously, and day 27, E. faecalis and S. maltophilia appeared in blood cultures. Antibiotics were prescribed; however, colonization with multi-drug resistant S. maltophilia persisted. Despite our best efforts fever and poor blood oxygenation were not resolved. The patient died on day 38 due to respiratory insufficiency accompanied by a clinical picture of severe ARDS. Blood gas analysis two hours prior to his demise revealed pH 7.16, pCO2 22.0 kPa, paO2 5.8 kPa and an arterial saturation of 76% (Table 1). Autopsy was performed and showed a scar in the left testis with a diameter of 0.5 cm probably indicating the primary site of the choriocarcinoma. There was no viable tumour tissue. Burnt-out metastases were found retroperitoneally, and in the lung. The lung showed a picture of extensive interstitial and

intra-alveolar fibrosis (Fig.3). accompanied by scarce granulocytous infiltrates and multiple thrombosed small vessels, indicating bleomycin toxicity [7].Histological examination of the lung (Fig. 4) showed regenerating type II pneumocytes lining the alveolar spaces with atypia indicating bleomycin toxicity. These cells are large and contain nuclei with large eosinophilic inclusions or clear vacuoles. [1] Histological changes in the lung due to treatment with cytotoxic agents like bleomycin are seen as diffuse alveolar damage: hyaline membranes lining the alveolar spaces, alveolar oedema and an influx of polymorphic neutrophilic granulocytes.

Discussion: The incidence of non-seminomateus germ cell cancer (NSGCC) is 4 per 107 per year or only 1% of malignancies in male in the Netherlands[2,21]. Mortality rate is 0.3 per 100.000 men per year. According to the nationwide guidelines issued by the Dutch Urological Tumours Working Group, NSGCC is staged by TNM classification, clinical staging and classification by prognostic groups [21]. According to these classifications our patient’s diagnosis was stage IV choriocarcinoma, with a poor prognosis. The prognosis for



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Figure 3. (400X HE) postmortem lung microscopy showing characteristic signs of lung fibroses.

Figure 4. (400x, HE) postmortem lung microscopy showing characteristic signs of cytotoxic therapy: atypical type II pneumocyte (arrow).

this patient’s group is poor, with a 5 year progression-free survival of 40% [20,21] and a 5 year-survival of 48 %[20,21]. Because of its infrequent occurrence and often complicated multidisciplinary treatments, the best results are obtained in specialized centres [21]. Bleomycin therapy is associated with Bleomycin Induced Pneumonitis (BIP) which can lead to potentially lethal pulmonary fibrosis [3]. The incidence of BIP is, depending on the criteria used for the diagnosis, 0-46% [1], the mortality of all the patients treated with bleomycin is 3%. Clinical diagnosis of BIP is difficult due to its resemblance to other conditions such as pneumonia and pulmonary metastases. Clinical signs are non-productive cough, exert ional dyspnoea and fever. Physical examination is not conclusive, and chest radiographs often show bilateral infiltrates and/or lobar consolidations[1,2]. Lung function changes are found in half of the patients treated with bleomycin [3], but it is not possible to use these symptoms to accurately predict patients likely to develop BIP [1,3,6]. The diagnosis of BIP is therefore only made by the exclusion of other diseases. The pathogenesis of BIP has mainly been investigated in animals. The antitumour effect of bleomycin works through inhibition of tumour angiogenesis and induction of tumour cell death. The mechanisms of the toxic effect are not known in detail, but the formation of free radicals and cytokines may lead to endothelial damage. Free radicals that are produced directly after oxidation of the BleomycinFe II complex cause dysfunction of the antioxidant system activity and subsequently lead to DNA damage from unopposed endogenous super oxide production [1,3,14]. Bleomycin also has some potential for direct DNA-cleaving [1,5,15] and this damaging effect on DNA might be involved in late-onset, previously asymptomatic lung damage following bleomycin administration[1]. A five fold increase has been shown with 70% supplemental oxygen versus ambient air in animal studies [8]. However in humans, clear data showing an increased risk of BIP with concomitant oxygen supplementation are lacking [1]. Bleomycin is mainly eliminated by the kidneys and deactivated by the enzyme bleomycin hydrolase, which is produced in the liver, spleen, bone marrow and intestine, but not in the lungs or skin. This

is why toxicity occurs mainly in these organs [1,3,8,12]. Genetic variance in the enzyme setup may partially explain individual difference in susceptibility [12,19]. Risk factors for development of BIP are: cumulative doses of bleomycin (> 400 U), age >40 years, a creatinine clearance <35 ml/min, concomitant radiotherapy, extent of lung metastases, prior lung disease, and bolus drug delivery.[1,2,5,8,11,12,16,18,20]. Many agents have been tested for the prevention or attenuation of BIP, n-acetyl cysteine (Fluimicil®), corticosteroids [1,7] have been used without proven benefit, Fas antigen, IL-1-receptor antagonist, cyclosporine, tacrolimus, iron chelators such as dexrazoxane or amifostine are being tested.

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Conclusion In this patient the presumptive diagnosis was based on the radiographic findings of the chest X-ray and CT scan. Because of his poor condition, broncho-alveolar lavage and later thoracotomy were performed to get material for the diagnosis. The primary treatment consisted of a four-cycle BEP course, after consultation with a consultant oncologist at a specialized regional centre. The prognosis of this man with NSGCC was poor because of the extent of lung metastases, the high levels of HSG (see Table 1), the existing oxygenation problems prior to the bleomycin treatment and the diagnostic thoracotomy he underwent. In spite of international recommendations [20,21] to withhold further bleomycin administration in cases of BIP or if it is suspected, we decided not to withhold bleomycin treatment in this patient because of his good response to the first cycle (see Table 1: tumour markers). After two cycles of BEP we decided to stop bleomycin because of his deteriorating respiratory state but unfortunately this brought about no improvement. The patient died of hypoxia due to bleomycin-induced pulmonary fibrosis. Autopsy revealed burnt-out metastases in the lungs and abdomen and signs of BIP in the lungs. Retrospectively, we think that clinical signs should have prompted us not to treat this critically ill patient with bleomycin.


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References 1. 2. 3.

4.

5.

6. 7. 8.

9.

Sleijfer S, Bleomycin-induced Pneumonitis; Chest 2001; 120; 617-624. Einhorn L.H., Curing metastatic testicular cancer; PNAS; 2002 April 2; vol 99; no 7; 4592-4595. O’Sullivan J.M., Huddart R.A., Norman A.R., Nicholls J., Dearnaley D.P., Hrowich A.; Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours; annals of oncology 2003; 14: 91-96. Kaye S., Mead G., Fossa S., Cullen M., de Wit R., Bodrogi I., Intensive induction sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor prognosis metastatic non-seminomateus germ cell tumor: a randomised MRC/EORTC study; J.Clin. Oncol 1998; 16: 692-701. Azambuja E., Fleck J.F., Batista R.G., Menna Barreto S.S.; Bleomycin lung toxicity: who are the patients with increased risk?; Pulm.Pharmacol. Ther. 2005; 18 ( 5 ): 363366. Maher J., Daly P., Severe bleomycin lung toxicity: reversal with high dose corticosteroids; Thorax 1993; 48 : 92-94. Joselson R., Warnock M., Pulmonary veno-occlusive disease after chemotherapy. Hum. Pathol> 1983; ( 14 ):88-91. Tryka A., Godleski J., Brain J., Differences in effects of immediate and delayed hyperoxia exposure on bleomycin- induced pulmonary injury. Cancer treatment reports 1984; 68 ( 5): 759-764. Holoye P., Luna M., Mackay B., Bleomycin hypersensitivity pneumonitus. Ann Intern. Med. 1978; 88: 47-49.

10. Bakowska J., Adamson I., Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury. J. Pathol. 1998; 185 ( 3 ): 319-323. 11. Phan S, Armstrong G, Sulavik M, Schrier D, Johnson K, Ward P. A Comparative Study of Pulmonary Fibrosis Induced by Bleomycin and an O2 Metabolite Producing Enzyme System. Chest 1983; 83(5):44-45. 12. Sogal R, Gottlieb A, Boutros A, Ganapathi R, Tubbs R, Satariano P et al. Effect of oxygen on bleomycininduced lung damage. Cleve Clin J Med 1987; 54:503509. 13. Cooper J, White D, Matthay R. Drug-induced pulmonary disease. Am Rev Respir Dis 1986; 133:321-340. 14. Chandler D. Possible Mechanisms of Bleomycin-Induced Fibrosis. Clin Chest Med 1990; 11(1):21-30. 15. Iacovino J, Leitner J, Abbas A, Lokich J, Snider G. Fatal Pulmonary Reaction from low doses of bleomycin : an idiosyncratic tissue response. JAMA 1976; 235(12):12531255. 16. Cersosimo R, Matthews S, Hong W. Bleomycin pneumonitis potentiated by oxygen administration. Drug Intelligence and Clinical Pharmacy 1985; 19:921-923. 17. Borzone G, Moreno R, Urrea R, Meneses M, Oyarzun M, Lisboa C. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 7(163):1648-1653. 18. Krakoff I, Cvitkovic E, Currie V. Clinical pharmacologic and therapeutic studies of bleomycin given by continuous infusion. Cancer 1977;(40):2027-2037.

19. Dunsmore S, Roes J, Chua F, Segal A, Mutsaers S, Laurent G. Evidence that neutrophil elastase-deficient mice are resistant to bleomycin-induced fibrosis. Chest 2001;(120):35-36. 20. www.cancernet.nci.nih.gov. 21. Hinton S, Catalano P, Einhorn L. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors; final analysis of an intergroup trial. Cancer 2003, 97; 1869-75.



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Received March 2006; accepted in revised form August 2006

r e v i e w

Intensive Care and Recombinant Factor VIIa Use: A Review R. Sherrington1, A. Tillyard1, A. Rhodes2 and R.M. Grounds2 1Specialist Registrar in Intensive Care, St Georges Hospital, London, UK. 2Consultant in Intensive Care, St Georges Hospital, London, UK.

Abstract. Objective – Currently recombinant factor VIIa (rFVIIa) is licensed only for use in the management of haemorrhage in patients with congenital and acquired haemophilia, congenital factor VII deficiency and Glanzmann’s thrombasthenia that is refractory to platelet transfusion. However, there has recently been a profusion of case reports and a number of randomised controlled trials regarding the use of rFVIIa in the setting of life-threatening bleeding in patients without specific coagulopathies. The purpose of this review is to examine its mechanism of action, use and efficacy in these ‘non-licensed’ conditions that often require intensive care support. Search Strategy – A Pubmed and Medline search in November 2005 was used with the keywords ‘recombinant activated factor VIIa’ and ‘critical care’. Any appropriate referenced articles from this search were also retrieved. Summary of findings – In the majority of clinical settings there is a lack of prospective randomised controlled trials of rFVIIa. The few that have been performed have shown minimal mortality and morbidity benefit. Conclusion – Further, well-performed, randomised controlled trials are recommended. Until this time, rFVIIa should be reserved for clinical trials and patients with life-threatening surgical bleeding where all conventional treatments have at least been initiated, and shown to have failed.

Introduction Factor VIIa is not a new agent. Following reports of the use of prothrombin complex concentrate on patients with haemophilia and antibodies to Factor VIII, Hedner and Kisiel first reported, in 1983, the successful use of plasma-derived activated Factor VIIa (FVIIa) in controlling haemorrhage in two patients with Factor VIII antibodies [1]. The development of recombinant human Factor VIIa - rFVIIa – (‘eptacog alpha’ - NovoSeven by Novo Nordisk A/S, Bagsvaerd, Denmark) using transfected baby hamster cells led to the widespread licence in many countries for the treatment of spontaneous and surgical bleeding in patients with inhibitors against FVIII or Factor IX. There have now been over 700,000 doses administered to patients with haemophilia [2]. In 1999 Kenet et al reported the first use of rFVIIa in a patient without a specific factor deficiency who had a high velocity gunshot wound to the inferior vena cava [3]. In 2002, O’Neill et al [4] achieved haemorrhagic control with a single dose of rFVIIa in a victim of multiple stab wounds who had inadequate haemostasis despite 100 units of blood products. Currently rFVIIa is licensed for use in the management of haemorrhage in patients with congenital and acquired haemophilia, congenital factor VII deficiency and Glanzmann’s thrombasthenia that is refractory to platelet transfusion. However, since the publication by Kenet et al, interest in the application of this treatment to other medical and surgical conditions has rapidly increased. The purpose of this paper is to review rFVIIa’s efficacy from the published results in conditions that are seen in the intensive care unit (ITU). To achieve this, we conducted a Pubmed and Medline search

in November 2005 using the keywords ‘recombinant activated factor VIIa’ and ‘critical care’, and retrieved any appropriate referenced articles.

Coagulation and Factor VIIa Pharmacological doses of rFVIIa increase thrombin generation locally without systemic activation. In order to understand the mechanism by which this occurs we must first understand the process of coagulation in vivo. The traditional model of coagulation includes the intrinsic and extrinsic or tissue factor (TF) pathways. However, it is now believed that the TF pathway has the greatest importance to normal haemostasis [5]. In 2001, Hoffmann and colleagues [6] proposed a cellbased model of coagulation, which emphasises the cellular control of coagulation in vivo, based on the expression of tissue factor. They describe three overlapping phases, which occur on different cell surfaces. The phases are called initiation, amplification and propagation. Initiation

TF is present in the sub-endothelium and other tissues that are not normally exposed to blood [7,8]. Damage to the vascular endothelium exposes this TF and is the primary physiological initiator of coagulation [5]. Both Factor VII and activated Factor VII (1% of the total circulating FVII) bind to TF. This FVIIa/TF complex inturn activates both factors X and IX [9]. This generation of a small amount of factor Xa initiates a cascade process leading to the further generation of factor Xa and thrombin [9,10]. The initiation of coagulation also leads to the inhibition of fibrinolytic activity.

Correspondence:

Amplification

Andrew Tillyard E-mail: [email protected]

This starts with vascular disruption and exposure of tissue factor bearing cells to platelets, Von Willebrand factor and Factor VIII. The

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thrombin generated in the initiation phase activates the platelets forming a platelet plug and their surface is primed with factors Va, VIIIa and XIa. Factor IX is activated by both tissue-factors—factor VIIa complex and factor XIa, so the coagulation cascade has moved to the platelet surface where all the necessary factors are assembled ready for the propagation stage [10]. Propagation

Factor IXa produced in both the initiation and amplification phases, binds to the platelet surface and combines with FVIIIa to form the tenase complex (FIXa/FVIIIa/calcium). This activates FX which combines with FVa to form prothrombinase complex leading to the large scale production of thrombin. Thrombin cleaves fibrinogen to fibrin monomers, which polymerise to consolidate the initial platelet plug and form a stable clot. This thrombin generation also exerts positive feedback into the coagulation process by activating factors V, VIII, XI and Thrombin Activatable Fibrinolysis Inhibitor (TAFI). This process is localised to the site of injury by localised exposure of TF causing localised binding and activation of FVII and platelets.

Factor VIIa Mechanism of Action Normal circulating levels of FVII and FVIIa are in the ratio of 100:1 (10nmol/l and 0.10nmol/l respectively). Administration of rFVIIa increases the circulating concentration of activated factor 100 fold (to 3-20nmol/l) [11]. Although it is widely agreed that rFVIIa acts by local activation of thrombin production there is disagreement regarding the exact mechanism by which this is achieved. There are two principal pathways – TF-dependent and TF-independent [12]. However both require the initial interaction of rFVIIa with TF, which leads to the activation of FX and thrombin formation. In the TF-dependent pathway, higher concentrations of FVIIa/TF complex go on to enhance FXa production and subsequent thrombin formation [13]. In the TF-independent pathway, rFVIIa itself activates FX on the platelet surface. As platelets accumulate at the site of injury, FXa production is independent of TF [10,14]. Although this reaction is less efficient than activation by the FVIIa/TF complex, the pharmacological concentration of factor offsets this inefficiency. The continuation of both pathways requires the combination of FXa with FVa on the platelet surface to form the prothrombinase complex, which converts prothrombin to thrombin. This localised generation of large amounts of thrombin may carry the additional benefits of enhanced platelet adhesion and aggregation [15] as well as producing thinner, more tightly packed fibrin fibres and increased activation of thrombin activatable fibrinolysis inhibitor (TAFI) making the clots more resistant to fibrinolysis [16,17]. It is worth noting, that since the process of haemostasis involves both coagulation and anti-fibrinolysis (as stimulated in the propagation phase described above), rFVIIa will never replace the rational use of appropriately dosed antifibrinolytic drugs. The authors believe the use of tranexamic acid should be considered in conjunction with rFVIIa administration.

Laboratory Monitoring of the Effects of Factor VIIa There is no definitive laboratory test that is satisfactory for monitoring the efficacy of rFVIIa treatment. The use of Prothrombin Time (PT) is recommended but a reduction in PT does not predict clinical haemostasis. The improved clotting time reflects only the enzymatic activity

of FVIIa. It is not a marker of the therapeutic efficacy of FVIIa [18]. It can only be suggested that the correction of the PT to within a normal range is an indicator that the drug was administered and therefore may be beneficial [11]. The failure to reduce PT may also predict non-responders. Thromboelastography has been used to assess the effect of rFVIIa [19]. It was found that the speed of clot formation and the physical properties of the clot are improved, both of which cannot be detected by routine coagulation tests. This correlates with the mechanism of action being most probably dependant on the presence of activated platelets which are localised to the site of the injury [20]. This would also explain why there is little systemic activation of coagulation because the maximum effect of rFVIIa occurs at the site of injury. The best test of efficacy remains the observation of haemostasis.

Blood Product Management. There are no universal guidelines or evidence for the efficacy of a particular regime for fresh frozen plasma (FFP), platelets, fibrinogen and cryoprecipitate replacement [21]. There is also very little information to guide the use of rFVIIa outside its licensed indications. Due to rFVIIa’s mechanism of action, severe thrombocytopaenia (<5000/mcl) or zero levels of thrombin or fibrinogen are likely to grossly impair the pro-thrombotic effect of VIIa. [22]. Therefore, the use of rFVIIa should be in close consultation with the haematologists to facilitate the coordination of this and blood product administration. The Israeli Multidisciplinary rFVIIa Task Force have published guidelines for its use in uncontrolled bleeding secondary to trauma [23]. These include the preconditions of a fibrinogen level greater than 0.5gm/lt and a platelet count greater than 5000/mcl. However, these recommendations were based on study of 36 patients and they have subsequently stated that “as a result of the lack of controlled trials, our guidelines should be considered as suggestive rather than conclusive” [24].

Factor VIIa and Dose It has been shown that single doses can normalise the International Normalised Ratio (INR) and coagulation profile and increasing the dose prolongs the duration of normalisation despite the half-life being unchanged [25]. The recommended dose for patients with haemophilia following major surgery is a 90mcg/kg bolus every 2 hours. The frequency of dosing reduces to four hourly and continues until the 7th post-operative day [26]. Such large doses are necessary because rFVIIa undergoes linear pharmacokinetics and has a half-life of 2.3 hours in actively bleeding patients [27]. It must be emphasised that these are huge cumulative doses and are only appropriate for haemophiliacs undergoing major surgery. The correct dose for patients with normal coagulation profiles who have a temporary, short lived massive bleeding diathesis has yet to be established. Case reports and two randomised controlled trials have described single doses as low as 20mcg/kg to 45mcg/kg being effective [28-31]. Doses as large as 160mcg/kg have also been used [31]. Overall, there is insufficient data to suggest an optimal dose for a particular clinical scenario. Pragmatically, if a particular dose proves to be ineffective at controlling bleeding, it can be repeated. This is in part because all the trials that have been conducted so far, there has been an excellent safety profile.



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There have only been some non-significant trends towards an increased incidence of thromboembolic complications in the treatment arm. There is also little evidence describing the existence of a dose-response effect. However, there did appear to be a dose-response effect for the treatment of intracerebral haemorrhage (ICH) with doses of 160mcg/kg producing better outcomes than 40mcg/kg [31]. This may be due to the unique mechanism that damage is produced by ICH, which will be discussed later.

The Israeli Multidisciplinary rFVIIa Task Force reported a decline in clinical response to rFVIIa in trauma patients at a pH below 7.2, but the effect was only significant below 7.0 [23]. Thus, based on information available there does appear to be a reduction in efficacy with declining pH but acidosis can not be used as an absolute indicator of the likely effectiveness of treatment. The Israeli Taskforce has recommended a correction of pH to ≥ 7.2 prior to administration to improve chances of effectiveness.

Factor VIIa and reversal of oral anticoagulants

Under experimental conditions, TF dependent activity of rFVIIa has been shown to reduce by 20% with a decline in temperature from 37 to 33 degrees Celsius. However TF independent activity rises with the fall in temperature [44]. Activity of the TF independent pathway alone is likely to be limited by the lack of platelet activation under hypothermic conditions [48]. Martinowitz and Michaelson [23] reported efficacy in trauma patients with an average core temperature of 34.1 degrees. One study reports efficacy at a body temperature as low as 30 degrees. Current information suggests that rFVIIa can be expected to be useful for the control of non-surgical bleeding under hypothermic conditions encountered in trauma (e.g. 33 degrees C) but loss of TF activity and decreased platelet function are likely to lead to reduced rFVIIa efficacy as the temperature approaches 30 degrees [11].

The level of factor VII, one of the vitamin K-dependent coagulation factors, decreases during oral anticoagulant therapy leading to an increased prothrombin time. This can be reversed with factor VIIa without producing systemic coagulation [32]. The lowest dose (5 microgram/kg) has been shown to normalize the INR for 12 h and doses > 120 micro/kg normalized INR for 24 h [32]. Although only one small study, this rapid reversal could be of benefit in the setting of oral anti-coagulated patient that requires emergency surgery [32]. Recombinant FVIIa has also been shown to have some effect on the newer anticoagulants. There is one case report of its efficacy in reversing the effect of low molecular weight heparin [33]. There is also evidence showing its benefit reversing the anticoagulant effect of the pentasaccharide anticoagulants idraparinux and fondaparinux [34-36]. However, drugs used to maintain anticoagulation after the diagnosis of heparin-induced thrombocytopaenia – the direct acting thrombin inhibitors - have been less successfully reversed by rFVIIa [37].

Factor VIIa and Trauma In civilian and military trauma, exsanguination accounts for 40% of the mortality [38,39]. Blood transfusion in trauma is associated with late complications and has been shown to be an independent risk factor for the development of infection [40] and multiple organ failure [41,42]. The coagulopathy associated with trauma is mutifactorial including acidosis, hypothermia, haemodilution and consumption – referred to as the ‘bloody vicious cycle’. If a patient develops the lethal triad of hypothermia, acidosis and coagulopathy, then surgical control alone is less likely to be effective [43]. These factors must all be considered when assessing the use of rFVIIa in a trauma setting. Acidosis

Acidosis affects enzyme activity [44] and platelet function [45,46]. In vitro, a reduction in pH from 7.4 to 7.0 resulted in a 90% reduction in TF independent activity of rFVIIa and a 60% reduction in TF dependent activity [44]. However, as rFVIIa administration increases circulating FVIIa concentrations by 100 fold, it is not known how the interaction of low pH and high rFVIIa concentration effects coagulation. Given that the relative importance of TF independent and dependant activity may vary according to the exact clinical situation, the effect of acidosis becomes more difficult to quantify. Impaired platelet function due to acidosis would also be expected to have a detrimental affect on rFVIIa efficacy. A retrospective analysis of 81 coagulopathic trauma patients treated with rFVIIa, found that the mean pH in trauma patients responding to rFVIIa treatment was 7.29 compared to a mean pH of 7.02 in non-responders [47]. However, six out of twenty non-responders had a pH > 7.1 whilst 5 patients with pH ≤ 7.1 did respond to treatment.

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Hypothermia

Haemodilution / consumption

Changes in the concentrations of various components of the system can greatly alter thrombin generation and the clotting process as a whole [49]. In the absence of FX or FV, rFVIIa does not shorten in vitro clotting times [50]. In a study of 13 patients receiving rFVIIa, the responders had a better coagulation status as measured by fibrinogen and platelet concentrations, PT and APTT at the time of administration than the non-responders [51]. In order to optimise the opportunity for rFVIIa to be effective, it is recommended that coagulation factors and platelets be replaced as far as possible prior to administration [23, 52-54]. The direct loss of clotting factors through haemorrhage rapidly reduces the body’s small stores of fibrinogen and platelets and resuscitation that includes blood components can still cause further dilution [55]. Haemodilution and consumption can reach a point where a component other than FVIIa becomes a rate limiting step and the benefit of rFVIIa is lost. Overall efficacy

To date there is only one published RCT of the use of rFVIIa in trauma. Boffard and colleagues [56] ran two parallel clinical trials for victims of blunt (n=143) or penetrating trauma (n=134). Patients receiving six units of blood in the initial 4 hours of hospital treatment were randomised to receive 3 doses of rFVIIa (200, 100 and 100 mcg/kg) or placebo following transfusion of the eighth unit of blood. These were exceedingly large doses (see section above on dosing) and probably unnecessarily so in patients with normal coagulation prior to injury. In blunt trauma, RBC transfusion requirements were significantly reduced, with the need for massive transfusion (>20 units) in only 14% compared to 33% of patients in placebo group. In penetrating trauma there was a non-significant trend towards a reduction in RBC and massive transfusion. There was a trend in both groups towards a reduction in critical complications (acute respiratory distress syndrome, multiple organ


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dysfunction syndrome and sepsis) and in mortality. There was no observed increased incidence in thrombi-embolic complications in treatment groups compared to placebo. Most importantly, however, there was not a statistically significant reduction in mortality in either of the study arms. This may suggest that in many cases the rFVIIa was given earlier than necessary.

Factor VIIa and Surgery It is hypothesised that patients undergoing major surgery develop intra-operative down-regulation of the coagulation system leading to suboptimal thrombin generation. Therefore, patients may benefit from rFVIIa treatment [57]. There are a number of isolated reports and small case series supporting the use of rFVIIa in surgical patients. These reports describe the benefits of rFVIIa used in patients with coagulopathy undergoing surgery [58-60] and when used as salvage treatment for patients with intractable haemorrhage following cardiac [61,62], vascular [63], orthopaedic [64,65] and renal [66,67] surgery. However, case reports are subject to positive reporting bias and evidence from randomised controlled trials is sparse. Cardiac surgery

Aggarwal and colleagues [68] report on a series of eight patients with intractable bleeding following cardiac surgery, seven of whom responded to a single bolus of 90 mcg/kg with the eighth patient requiring a second bolus. Al Douri and colleagues also reported the efficacy of rFVIIa in the management of severe uncontrolled haemorrhage following cardiac surgery in a pilot study of five patients undergoing heart valve replacement surgery [69]. In a retrospective analysis of matched patients suffering intractable bleeding following cardiac surgery, 51 patients received rFVIIa compared with 51 who did not [70]. Karkouti and colleagues concluded that rFVIIa at a dose of 35 to 70 mcg/kg was effective in reducing intractable haemorrhage [70]. Despite the obvious theoretical concern that rFVIIa may lead to thrombosis at the site of vessel grafting, in this study there was no significant increase in thromboembolic events. Elective pre-operative administration

Evidence for the pre-emptive use of rFVIIa in high risk patients is contradictory. A large, multi-centre trial of 204 non-cirrhotic patients undergoing major liver resection, randomised to receive pre-surgical injection of placebo, 20 mcg/kg or 80mcg/kg dose of rFVIIa , showed no significant differences in peri-operative blood loss or transfusion requirements [57]. There was no increased incidence of thrombo-embolic complications in the treatment groups in this study. A further study of pre-surgical rFVIIa administration in patients undergoing orthotopic liver transplantation again showed no significant effect on intra-operative blood loss or transfusion [71]. Similarly, in a recent RCT [72] of patients with normal haemostasis undergoing pelvic reconstruction, there was no significant difference in peri-operative blood loss or transfusion requirements for the placebo group or the treatment group receiving rFVIIa at a dose of 90 mcg/kg prior to surgery. However, a prospective, double-blind randomised study [73] of 36 patients undergoing retropubic transabdominal prostatectomy did show that rFVIIa given at a dose of 40 mcg/kg at an early phase of surgery did significantly reduce blood loss (from a mean blood loss from 2688 mls to 1089 mls) and the need for transfusion. It is possible that the observed efficacy in the prostatectomy group may be attributable to factors specific to this patient population, notably age, and the nature and site of surgery [72].

Factor VIIa and Medicine Haematological

32% of patients having haematopoetic stem-cell transplants develop critical illness of which 46% do not survive [74]. In one double-blind randomised- controlled trial, patients with bleeding complications following stem cell transplantation were randomised to receive placebo or differing doses of Factor VIIa every 6 hours for 36 hours [75]. All patients received standard haemostatic management. Bleeding complications included moderate to severe pulmonary, cerebral and gastrointestinal bleeding. Patients receiving 80mcg/kg had a significant improvement in bleeding compared to those receiving placebo. However, in the same study, patients receiving 40mcg/kg or 160ucg did not show any improvement. Perhaps understandably, the study did not look at survival as an outcome measure. At present, there is insufficient evidence to recommend the use of rFVIIa in this group of patients. Disseminated intravascular coagulation is relatively common in the setting of sepsis with its incidence increasing with the severity of sepsis and with an associated effect on mortality and morbidity [76]. During sepsis circulating monocytes are activated and express tissue factor as part of the inflammatory response [77]. Theoretically therefore, there is the potential for rFVIIa to exacerbate systemic activation of coagulation in the setting of sepsis, although there has not been any cases recorded thus far. Variceal bleeding

Coagulation factors including factor VII are commonly low in liver disease [25]. In patients with advanced liver disease who were not actively bleeding, single doses of rFVIIa can normalise prothrombin time [25]. Variceal bleeding has a high mortality rate [78]. A multicentre double-blind randomised-controlled trial including 242 patients known to have cirrhosis who presented with haematemasis were randomised to receive placebo or 100mcg/kg of rFVIIa before the first endoscopy and then a further 7 doses at set intervals over the next 30 hours following the first dose [79]. Overall, 67% of these patients with haematemasis had oesophageal varices. Recombinant FVIIa failed to show any outcome benefit in terms of ICU or hospital length of stay or 5-day mortality. It also failed to control active bleeding, reduce rebleeding or reduce red blood cell transfusion requirements despite normalising the INR. Overall there was no significant difference in thrombotic complications. More evidence is required before rFVIIa can be recommended in this group of patients. Intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is a devastating event that has a profound effect on an individual’s mortality and morbidity. The larger the haematoma, the greater the loss of functional ability [80]. In one study, 26% of patients had a greater than 33% increase in the size of the parenchymal haematoma within 1 hour of the first CT scan and a further 12% of patients also had an increase of 33% or over the next 20 hours [81]. Larger haematomas will produce greater surrounding oedema. This will combine to produce a more significant mass effect within the fixed cranial space leading to more pronounced disability. Any agent that could halt this process – by limiting the size of the original haematoma – would be anticipated to reduce the residual disability. In a prospective double-blind randomised controlled trial of 399 patients with ICH and a Glasgow Coma Score of greater than 5 were randomised to receive placebo or 40, 80 or 160mcg/kg of rFVIIa with-



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in one hour of an initial CT scan, both of which occurred within 4 hours of symptom onset [31]. The end points of the study were the change in volume of the haematoma as assessed by repeat CT scans and clinical outcome. Patients receiving rFVIIa had significantly less increase in the haematoma volume. The placebo group had a 29% increase in the haematoma at 24 hours compared to an increase of 16%, 14% and 11% for the 40, 80 and 160mcg/kg groups respectively. Overall, pooled data for all doses resulted in a 52% relative reduction in haematoma volume compared with placebo. Patients receiving rFVIIa had significantly less disability at three months compared to patients receiving placebo, and there was a 38% relative reduction in mortality. Finally, there was a trend to suggest that earlier administration and larger doses produced improved end points. However, there was an increase in thromboembolic events including seven patients with myocardial infarction and nine with cerebral infarction in the treatment groups. Overall there were two serious thromboembolic events in the placebo group and 21 in the treatment group. This difference was significant although the number of fatal or disabling thromboembolic events was not significantly increased. On the basis of this study, rFVIIa will probably become a useful therapeutic agent although the ideal dose and patient population at high risk of ischaemic complications is yet to be identified.

Thromboembolic Complications A recent article has reviewed the number of thromboembolic complications (TECs) that have been voluntarily reported to the American federal Drug Administration following rFVIIa use over a five year period [82]. During this time, there were 168 reports that were deemed to be true TECs secondary to rFVIIa, 28 of which were in patients with haemophilia. This compares with 4 520 patients who received rFVIIa in the year 2004 alone. Of the 168 TEC’s, there were 39 cerebro-vascular events, 34 acute myocardial infarctions, 32 pulmonary emboli and 42 deep vein thromboses.

There were also splenic, retinal vein, femoral and renal artery thromboses. Eighteen percent occurred within two hours of the last dose of rFVIIa (compatible with the elimination half-life of 2.3 hours for rFVIIa) and 52% of TECs occurred within 24 hours. There were 36 deaths that were thought to be due to the TEC. However only 102 cases of the 168 included a causality assessment of which 81 were deemed to be probably or possibly secondary to the rFVIIa. Finally there were also 193 reports pertaining to a lack of benefit following administration.

Conclusion There is a significant body of evidence to suggest that rFVIIa is safe with only minimal thrombo-embolic complications. There are also many ‘last-ditch’ case reports illustrating a beneficial effect of rFVIIa in a number of life-threatening surgical and non-surgical clinical settings. And if this drug is present within the hospital, it becomes emotionally and ethically difficult not to use it as a rescue therapy in lifethreatening haemorrhage. However, there is undoubtedly a degree of positive bias reporting in the literature when describing rFVIIa in this clinical scenario. Also, in an era of increasing concern regarding the rapidly expanding public health expenditure, rFVIIa remains a very costly therapy whose non-evidenced based, off-licence use may impact on the provision of other therapies. In those areas where clinical efficacy has been relatively established such as in patients with haemophilia or patients with a recent intracerebral haemorrhage, we would recommend the use of rFVIIa as described by the trials. In the majority of clinical settings though, there is a lack of prospective randomised-controlled trials of rFVIIa. Thus far, the few that have been performed have shown minimal mortality benefit. Without a body of well performed, randomisedcontrolled trials, we would recommend that the use of this agent is reserved for last ditch salvage situations where all conventional treatments have at least been initiated, and shown to have failed in patients with life-threatening surgical bleeding.

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19. Hendricks HG, Meijer K, Dewdt JT, Porte RJ, Klompmaker IJ, Lip H et al. Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Coagulation and Fibrinolysis 2002;13:309-13 20. Hoffman M. Laboratory monitoring of high dose factor VIIa therapy. Annals of Internal Medicine 2003;139:791 21. Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in trauma. British Journal of Anaesthesia 2005;95:130-9 22. Grounds RM, Bolan C. Clinical experiences and current evidence for therapeutic recombinant factor VIIa treatment in nontrauma settings. Critical Care 2005;9(Suppl 5):S29-36 23. Martinowitz U, Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding : a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost 2005;3:640-648 24. www.hemophilia.org/News/medicalnews/mn_06_09_ 05.htm 25. Bernstein DE, Jeffers L, Erhardtsen E et al. Recombinant Factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study. Gastroenterology 1997;113:1930-7 26. Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104: 3858-3864T18 27. Lindley CM, Sawyer TW, Macik BG, Lusher J, Harrison JF, Baird-Cox K et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clinical Pharmacology and Therapy 1994;55:638-48


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28. Zietkiewicz M, Garlick M, Domagala J, Wierzbicki K, Drwila R, Pfitzner R et al. Successful use of activated recombinant factor VII to control bleeding abnormalities in a patient with a left ventricular assist device. J of Thoracic and Cardiovascular Surgery 2002;123:384-5 29. Tunak KA, Waly AA, Cooper WA, Levy JH. Treatment of excessive bleeding in Jehovah’s Witness patients after cardiac surgery with recombinant factor VIIa (Novoseven). Anesthesiology 2003;98:1513-5 30. Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, Kurth K-H et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: A double-blind placebocontrolled randomised trial. The Lancet 2003;361:201-5 31. Mayer SA, Brun NC, Begtrup K et al. Recoæmbinant activated factor VII for acute intracerebral hemorhage. N Engl J Med 2005;352:777-85 32. Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood, Coagulation and Fibrinolysis1998;9(8):741-8. 33. Hu Q and Brady JO. Recombinant activated factor VII for treatment of enoxaparin –induced bleeding. Mayo Clinic Proceedings 2004;79:827 34. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002;106(20):2550-4. 35. Bijsterveld NR, Vink R, van Aken BE, Fennema H, Peters RJ, Meijers JC, Buller HR, Levi M. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br .J. Haematology 2004;124(5):653-8 36. Lisman T, Bijsterveld NR, Adelmeijer J et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thrombosis and Haemostasis 2003;1:2368-73 37. Malherbe S, Tsui BCH, Stobart K, Koller J. Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anaesthesiology 2004;100: 443-5 38. Sauaia A, Moore FA, Moore EE et al. Epidemiology of trauma deaths : a reassessment. J Trauma 1995;38:185193 39. Bellamy RF. The causes of death in conventional land warfare : implications for combat casualty care research. Mil Med 1984;149:55-62 40. Claridge JA, Sawyer RG, Schulman AM, McLemore EC, Young JS. Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Am Surg 2002;68:566-572 41. Sauaia A, Moore FA, Moore EE et al. Early predictors of postinjury multiple organ failure. Arch Surg 1994;129:3945 42. Moore FA, Moore EE, Sauaia A. Blood transfusion : an independent risk factor for postinjury multiple organ failure. Arch Surg 1997;132:620-625 43. Ferrara A, MacArthur JD, Wright HK, Modlin IM, McMillen MA. Hypothermia and acidosis worsen coagulopathy in the patient requiring massive transfusion. Am J Surg 1990;160:515-518 44. Meng ZH, Wolberg AS, Monroe DM III, Hoffman M. The effect of temperature and pH on the activity of factor VIIa:implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma 2003;55:886-891 45. Gende OA. Capacitative calcium influx and intracellular pH cross-talk in human platelets. Platelets 2003;14:9-14 46. Marumo M, Suehiro A, Kakishita E, Groschner K, Wakabayashi I. Extracellular pH affects platelet aggregation associated with modulation of store-operated Ca2+ entry. Thromb Res 2001;104:353-360 47. Dutton RP, McCunn M, Hyder M, D’Angelo M, O’Connor J, Hess JR et al. Factor VIIa for correction of traumatic coagulopathy. J Trauma 2004;57:709-718

48. Kermode JC, Zheng Q, Milner EP. Marked temperature dependence of the platelet calcium signal induced by human von Willebrand factor. Blood 1999;94:199-207 49. Jones KC, Mann KG. A model for the tissue factor pathway to thrombin. II. A mathematical Simulation. J Biol Chem 1994;269:23367-23373 50. Telgt DS, Macik BG, McCord DM, Monroe DM, Roberts HR. Mechanism by which recombinant factor VIIa shortens the apt : activation of factor X in the absence of tissue factor. Thromb Res 1989;56:603-609 51. Mayo A, Misgav M, Kluger Y, Greenberg R, Pauzner D, Klausner J et al. Recombinant activated factor VII (NovoSeven) : addition to replacement therapy in acute, uncontrolled and life-threatening bleeding. Vox Sang 2004;87:34-40 52. Armand R, Hess JR. Treating coagulopathy in trauma patients. Transfus Med Rev 2003;17:223-231 53. Martinowitz U, Kenet G, Lubetski A, Luboshitz J, Segal E. Possible role of recombinant activated factor VII (rFVIIa) in the control of haemorrhage associated with massive trauma. Can J Anaesth 2002;49:S15-S20 54. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion 2004;44:1325-1331 55. Armand R, Hess JR. Treating coagulopathy in trauma patients. Transfus Med Rev 2003;17:223-231 56. Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R et al; NovoSeven Trauma Study Group. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients : two randomised, placebo-controlled, double-blind clinical trials. J Trauma 2005;59(1):8-15 57. Lodge JP, Jonas S, Oussoultzoglou E, Malago M, Jayr C, Cherqui D et al. Recombinant coagulation factor VIIa in major liver resection : a randomised, placebocontrolled, double-blind clinical trial. Anesthesiology 2005;102(2):269-275 58. Slappendel R, Huvers FC, Benraad B et al. Use of recombinant factor VIIa (NovoSeven) to reduce postoperative bleeding after total hip arthroplasty in a patient with cirrhosis and thrombocytopenia. Anesthesiology 2002;96:1525-1527 59. Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 2002;96:1522-1525 60. Park P, Fewel ME, Garton HJ et al. Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophiliac neurosurgical patients. Neurosurgery 2003;53:34-39 61. Kogan A, Berman M, Stein M, Vidne BA, Raanani E. Recombinant factor VIIa use in cardiac surgery – expanding the arsenal therapy for intractable bleeding? J Cardiovasc Surg 2004;45:569-571 62. Stratmann G, Russell IA, Merrick SH. Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair. Ann Thoraci Surg 2003;76:2094-2097 63. Manning BJ, Hynes N, Courtney DF, Sultan S. Recombinant factor VIIa in the treatment of intractable bleeding in vascular surgery. Eur J Vasc Endovasc Surg 2005;30:525-527 64. Kaw LL Jr, Coimbra R, Potenza BM, Garfin SR, Hoyt DB. The use of recombinant factor VIIa for severe intractable bleeding during spine surgery. Spine 2004;29:1384-1387 65. Danilos J, Goral A, Paluszkiewicz P, Przesmycki K, Kotarski J. Successful treatment with recombinant factor VIIa for intractable bleeding at pelvic surgery. Obstet Gynecol 2003;101:1172-1173 66. Gielen-Wijffels SE, van Mook WN, van der Geest S, Ramsay G. Successful treatment of severe bleeding with recombinant factor VIIa after kidney transplantation. Intensive Care Med 2004;30:1232-1234 67. Dunkley SM, Mackie F. Recombinant factor VIIa used to control massive haemorrhage during renal transplantation surgery; vascular graft remained patent. Hematology 2003;8:263-264

68. Aggarwal A, Catlett J, Alcorn K. The use of recombinant factor VIIa in the management of intractable bleeding in surgical and trauma patients. American Society of Haematology Presentation, 43rd Annual Meeting, Orlando; Dec 2001 (Abstract 3883) 69. Al Douri M, Shafi T, Al Khudairi D et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S121-S127 70. Karkouti K, Beattis WS, Wijeysundera DN et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery : a propensity score-matched case control analysis. Transfusion 2005;45:26-34 71. Lodge JP, Jonas S, Jones RM, Olausson M, Mir-Pallardo J, Soefelt S et al: rFVIIa OLT Study Group. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11:973-979 72. Raobaikady R, Redman J, Ball JAS, Maloney G, Grounds RM. Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum : a double-blind, randomised, placebo-controlled trial. BJA 2005;94(5):586-591 73. Friederich PW, Henny CP, Messelink EJ et al. The effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy : a double-blind placebo controlled randomised trial. Lancet 2003;361:201-205 74. Gordon AC, Oakervee HE, Kaya B, Thomas JM, Barnett MJ, Rohatiner AZ et al. Incidence and outcome of critical illness amongst hospitalised patients with haematological malignancy: a prospective observational study of ward and intensive care unit based care. Anaesthesia 2005;60(4):340-7. 75. Brenner B, Pihusch M, Bacigalupo A, Szer J, von Depka Prondzinski, Gasper-Blaudschun B et al. Activated recombinant factor VII (rFVVIa/Novoseven) in the treatment of bleeding complications following hematopoetic stem cell transplantation (HSCT). Blood 2004;104:321a 76. Kinasewitz GT, Zein JG, Lee GL, Nazir SA, Taylor FB Jr. Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis. Crit Care Med 2005;33:2214-21 77. Guha M, Mackman N. The phosphatidylinositol 3-kinaseAkt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem. 2002;277(35):32124-32. 78. Harry R and Wendon J. Management of variceal bleeding. Current Opinion in Critical Care 2002;8:164-70 79. Bosch J, Thabut D, Bendtsen F, D’Amico G, Albillos A, Abraldes JG et al. Recombinant Factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: A randomised double-blind trial. Gastroenterology 2004;127:1123-30 80. Diamond P, Gale S, Stewart K. Primary intracerebral haemorrhage--clinical and radiologic predictors of survival and functional outcome Disabil Rehabil 2003;25(13):689-98 81. Brott T, Broderick J, Kothari R et al. Early haemorrhage growth in patients with intracerebral haemorrhage. Stroke 1997;28:1-5 82. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-8



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Received October 2005; accepted in revised form September 2006

r e v i e w

Fluids for protection from renal failure in the Intensive Care Unit J. Kountchev and M. Joannidis Medical Intensive Care Unit, Division of General Internal Medicine, Department of Internal Medicine, Medical University Innsbruck, Austria Key words: acute renal failure (ARF), hypovolaemia, crystalloids, colloids Running Title: fluids for prevention of renal failure

Abstract. Volume expansion by fluid administration is the most frequently suggested protective measure in acute renal failure. In this review we discuss the types of fluid given in different clinical settings when impairment of renal function is to be anticipated. Further, we discuss the risks and benefits associated with various fluid resuscitation regimens and summarise the main evidencebased findings on this topic.

Introduction Hypovolaemia is a major risk factor in many forms of acute renal failure. The majority of cases of renal failure in the ICU are considered to have pre-renal aetiology or at least be precipitated by relative hypovolaemia. This is confirmed by several investigations into the incidence of acute renal failure (ARF) in the ICU, which found ischaemic renal failure to be the most frequent cause, followed by pre-renal azotaemia. [1-9]. Consequently, early and vigorous fluid administration is a preventive measure which should be effective in many patients. The aim of this review is to describe the role of different types of fluids administered to prevent ARF.

Physiological rationale for giving fluids Volume expansion is performed to: • increase cardiac output and effective circulating volume, • improve oxygen delivery and microcirculatory perfusion, and • ensure adequate colloid oncotic pressure (COP). Volume expansion by intravenous fluids increases preload and via the Frank-Starling mechanism cardiac output, as well as effective circulating volume. There is ample physiological evidence that sufficient cardiac output is the basis for adequate renal perfusion as long as severe disparities in resistance of perfusion beds does not occur [10]. Volume expansion diminishes the activity of compensatory mechanisms stimulated by hypovolaemia such as the sympathetic nervous system, vasopressin, endothelin and renin-angiotensin-aldosterone, mediating renal vasoconstriction and increasing the kidney’s susceptibility to hypoperfusion [11]. Further renal effects of hydration may be attributed to the associated diuresis. Animal and human experiments indicate decreased oxygen demand especially in the outer medulla, during water and solute diuresis [12]. Additionally, augmented diuresis results in the removal of increased amounts of urea associated with critical illness. Volume expansion is also used to decrease the renal toxicity of various drugs as well as radio-contrast media and heme molecules. The attributable protective mechanisms are improved renal perfuCorrespondence: M. Joannidis E-Mail: [email protected]

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sion, diuresis promoting intratubular dilution of toxins and antagonising formation of tubular casts and decreasing renal metabolic demand. According to Starling’s equation ensuring COP should increase intravascular volume and reduce interstitial fluid. Due to the huge compensatory capacity of lymphatic drainage, however, arbitrary increase of COP appears to be warranted only in situations of severe hypoproteinaemia and haemorrhagic shock. In case of capillary leakage the colloids administered may escape into the extravascular space and promote interstitial oedema formation.

Type of hydration fluid Generally three types of solution may be given: glucose 5% (i.e. free water), crystalloids (isotonic, half isotonic) and colloids. Crystalloids

Whereas glucose is mainly used to correct hyperosmolar states and as a substitute for free water, isotonic crystalloids remain the mainstay of solutions used for hydration. They help to improve sodium depletion as well as to restore solute and water diuresis. On the other hand, isotonic saline must be considered an unbalanced solution containing much higher chloride concentration than normal serum. Thus, larger amounts of isotonic saline (>30ml/kg/h) may result in hyperchloraemic acidosis possibly associated with renal vasoconstriction and altered perfusion of other organs like the gut [13]. Crystalloids expand plasma volume by 25% of the infused volume and produce about a threefold increase in interstitial fluid volume. Though more crystalloids have to be infused to achieve the same expansion of plasma volume, they are significantly cheaper than colloids. An alternative to normal saline is lactated Ringer’s solution.. Its use results in less hyperchloraemia and it is well tolerated as long as lactate metabolism is intact. Hypertonic saline may be detrimental for renal function [31]. Colloids

Colloids are generally thought to improve COP and help to improve vascular filling in severe hypovolaemia. Infusion of crystalloids results in plasma volume expansion at least equal to the volume infused with an equivalent increase of interstitial space. On the other hand colloids bear the danger of hyperoncotic impairment of glomerular


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Table 1: Characteristics of HES products HES 70/0,5 Concentration in % 6 Volume Effect in % 80 Effect duration in hours 1-2 Mean mol. weight in kD 70 Degree of substitution 0,5 C2/C6 ration 4:1 Table 2: Fluids for true hypovolemia Author/Trial name Number of patients London MJ et al. 94 Stockwell MA et al. 475 Vogt NH et al. 41 Beyer R 46 Kumle B et al. 60 Allison KP et al. 45 Boldt J et al 20 Dehne MJ et al. 60 Sedrakyan A et al. 19578 Winkelmayer W. et al 238 Neff TA et al. 31

HES 130/0,4 6 100 2-3 130 0,4 9:1

Design RCT RCT RCT RCT RCT RCT RCT RCT retrospective retrospective RCT

HES 200/0,5 6 100 3-4 200 0,5 6:1

HES 200/0,5 10 140 3-4 200 0,5 6:1

Kind of fluid used 10% HES vs. 5% albumin albumin vs. polygelin HES vs. albumin HES vs.3% gelatine LMW HES vs. MMW HES vs. Gelatine HES vs. Gelatine HES 130/0,4 vs. HES 200/0,5 lactated ringer vs. 3 different HES albumin vs. non-protein colloids HES 670/0.75 vs. no HES HES 130/0,4 vs. HES 200/0,5 + albumin

filtration as well as osmotic nephrosis (osmotic tubular damage) if insufficient free water accompanies administration.Four types of colloids are used: albumin, gelatins and hydroxy-ethyl starch. Human albumin (HA)

Human albumin (HA) is the natural colloid present in human circulation and therefore may appear to be the ideal substitution in hypo-oncotic hypovolaemia. Furthermore albumin decreases inflammatory cytokine expression after haemorrhagic shock [14;15] and is necessary for delivery of furosemide to the thick ascending limb of Henle for effective diuresis [16]. However, albumin is expensive, and due to its relative small size (69 kD) its intravascular effect may be reduced in states of endothelial damage and capillary leakage. Albumin is derived from pooled plasma and potentially carries the risk of infection. Despite earlier concerns about safety a recent large multicentre RCT using 4% albumin did not show any difference in either outcome parameter including renal function when compared to normal saline [17]. Gelatins

Gelatins usually have an average molecular weight around 30 kD which is even smaller than albumin. Thus, its intravascular volume effect is even shorter at around 2 hours. The advantage of this substance is absence of adverse effects on renal function [18;19]. Problems associated with gelatin, however, are the possibility of prion transmission, their capacity to release histamine and their negative influence on the coagulation system [20;21]. Dextrans

Dextrans are single chain polysaccharides with a size comparable to albumin (40 , 60 or 70 kD) and a reasonably high volume effect. However, main disadvantages include anaphylactic reactions and serious interference with coagulation system at doses higher than 1.5 g/kg/day [22;23]. Additionally, case reports on the occurrence of ARF after dextran administration have been published [24;25]. Hydroxyethyl starch (HES)

Hydroxyethyl starches (HES) are highly polymerised sugar mol-

HES 450/0,7 6 100 5-6 450 0,7 4,5:1

Renal outcome no difference no difference no difference no difference no difference HES better no difference no difference albumin renders survival benefit reduced GFR no difference

Evidence level I level I level II level II level II level II level II level II level III level III level III

ecules. They are characterised by their molecular weight, grade of substitution, concentration and C2/C6 ratio. Their volume effect is significantly longer than that of albumin especially when larger size HES are used (Table 1). Degradation occurs by hydrolytic cleavage which results in smaller molecules which will finally be eliminated by the reticular endothelial system or filtered and eliminated by the kidney. In this way these degradation products may be reabsorbed and contribute to osmotic nephrosis and probably to medullary hypoxia [26;27]. Another problem associated with administration of HES is pruritus [28]. Recently there was a review of fourteen studies investigating the use of various colloids on renal function [29]. Although no statistical analysis was performed in this study owing to the heterogeneity of the studies selected, the authors stated that rapidly degradable HES preparations (degree of substitution (DS) 0.4 or 0.5) appear to have less risk for impairing renal function than HES with a high DS (0.62 or 0.7). Whereas albumin appears to be safe [17], recent data indicate possible impairment of renal function by HES [19]. This is further supported by a cohort study in patients undergoing coronary artery bypass graft surgery (CABG and demonstrating moderate reduction of glomerular filtration rate (GFR) after administration of HES [30]

Clinical situations in which renal protection/renal recovery by volume expansion appears feasible and supported by clinical studies

We performed a systematic MEDLINE search for randomised controlled trials (RCT) addressing the use of different types of hydration regimens to prevent deterioration of renal function in adult patients at risk for ARF. • The following clinical conditions were considered: major surgery, sepsis, shock, use of potentially nephrotoxic drugs, radiocontrast media and renal transplantation. • The following terms and text words were used: kidney failure, acute, kidney failure, acute/prevention and control, renal, cardiac surgery, sepsis, contrast, shock, liver cirrhosis, normal saline, hydroyethyl starch, colloids, crystalloids, gelatine, human albumin.



HES 200/0,62 6 100 5-6 200 0,62 9:1

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Table 3: Fluids in sepsis Author/Trial name Schortgen F. et al. SAFE Study Stockwell MA et al.

Number of patients 129 6997 475

Table 4: Fluids in relative hypovolemia Author/Trial name Number of patients Sort P et al. 126 Gines P et al. 105 Gines A et al. 289

Design RCT RCT RCT Design RCT RCT RCT

Kind of fluid used 6% HES vs. 3% gelatine albumin vs. saline albumin vs. polygeline Kind of fluid used albumin or no fluid albumin or no albumin albumin vs. dextran vs. polygeline

Table 5: Fluids for prevention of contrast nephropathy Author Number of patients Design Kind of fluid used Merten GJ et al. 119 RCT bicarbonate-containing 5% glucose (1) vs. saline (2) Mueller C et al. 1620 RCT isotonic vs. half-isotonic Solomon R et al. 78 RCT 0,45 % saline (1) alone vs. 1+ mannitol vs. 1 + furosemide Trivedi HS et al. 53 RCT normal saline I.V. vs. deliberate oral fluid intake

• The following endpoints were extracted: Physiological endpoints: - Creatinine clearance (CrCl), glomerular filtration rate (GFR), increase in serum creatinine (∆SCr) Clinical endpoints: - Need for renal replacement therapy (RRT) - Mortality Studies were graded using the five level system described by Dellinger and co-workers [32]. In this study, the cut-off for a large and a small randomised controlled trial was arbitrarily set at 50 patients per group and a meta-analysis was graded as Level I. True hypovolaemia (surgery, trauma)

Several studies have investigated the effects of volume expansion in hypovolaemia or expected hypovolaemia during various kinds of surgery (Table 2). A small RCT compared lactated Ringers´ solution to three different forms of HES in patients with normal renal function undergoing middle ear surgery. Neither fluid was found to have any effect on renal function [33]. The same lack of effect on renal function was found in a large RCT comparing saline to 4% albumin [17]. Most studies compared different colloids (i.e. mainly HES vs gelatin, albumin or dextrans)[18;34-39] without showing any particular benefit on renal function from any of the solutions. However, a retrospective study, reported reduced mortality in patients undergoing coronary artery bypass surgery and receiving albumin in comparison to synthetic colloids (level III) [40].On the other hand, in a recent large retrospective study on 238 cardiac surgery patients, perioperative administration of HES (670/0.75) was associated with significant decrease of glomerular filtration rate (GFR) of an estimated magnitude of 14 ml/min/1.73m2 per every 2 HES units given (level III) [30]. The degree of renal impairment associated with different forms of HES seems to be related to their molecular weight as well as to the degree of molar substitution, although adverse renal effects have been reported with all commercially available HES forms. Only one study compared volume replacement versus no volume replacement- that of Bickel and co-authors (level III) [41]. In this RCT studying hypotensive patients with penetrating torso injuries, delay of aggressive fluid resuscitation until operative intervention significantly reduced mortality when compared to early volume resuscitation. Additionally a trend towards a lower incidence of renal failure was found in the delayed group.

550


renal outcome gelatine better no difference no difference renal outcome better with albumin better with albumin no difference

Evidence level I level I level I Evidence level I level I level I

renal outcome 1 better than 2 isotonic hydration better 0,45% saline best I.V. saline better

Evidence level II level I level I level II

Taking the existing evidence, normal saline, although it has less effect on volume, clearly cannot be classified as inferior to colloids. Among the colloids, it seems prudent to avoid HES, especially large molecular weight containing HES, in patients with pre-existing renal impairment. Sepsis

Beneficial effects of volume replacement in sepsis have been investigated in several trials (Table 3). In a rat model of sepsis [42] fluid resuscitation was successful in restoring the glomerular filtration rate if it was initiated at the moment that the bacterial inoculum was present, but not if it was started at the moment endotoxaemia was induced. Similar findings in humans were obtained by a prospective study (level III)[43] which showed that in deteriorating renal function, further fluid loading is not likely to reverse ARF in patients in whom the septic cascade has already started. Early volume resuscitation, however, along with other measures applied in sepsis to reach certain targets of oxygen delivery, results in less organ failure and reduced mortality (level I)[44]. In this study both colloids and crystalloids were given depending on physician’s preference. Schortgen and co-workers compared 6% HES 130/0.62 (n=65) to gelatin (n=64) and showed lower serum creatinine levels in the group receiving gelatin with no effect on RRT or outcome (level I)[19]. In a recent multicentre RCT, albumin was compared to isotonic sodium chloride in various situations including sepsis and without finding any difference in impact on renal function (level I)[17]. A single centre RCT of ICU patients comparing volume substitution with 5% HA or gelatin could not find any difference in renal function despite significant differences in serum albumin (level I) [35] . Finally, a comparison of several forms of HES in ICU patients did not demonstrate differences in renal function (level II) [45]. Relative or unrecognized hypovolaemia

Relative or unrecognised hypovolaemia (with respect to effective circulating volume) are clinical situations which are often missed and occur for example in diuretic therapy in the elderly, liver cirrhosis, heart failure and positive pressure mechanical ventilation. In an earlier study on the effect of diuretics on ICU patients with renal failure, renal function recovered in about 25% of patients after simple fluid replacement, indicating the presence of unrecognised pre-renal failure (level III) [46]. Therefore, many authors recom-


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mend a fluid challenge in ICU patients with deteriorating renal function [47]. Unfortunately, no randomised trial has ever evaluated the impact of fluid loading as a single intervention in this patient group. Mechanical ventilation per se is known to be a risk factor for ARF and application of positive end-expiratory pressure (PEEP) in mechanically ventilated patients induces a decrease in glomerular filtration rate, renal blood flow and free water clearance, and the effect may be worsened by concurrent volume depletion [51]. The effect of volume substitution in this setting however has not been investigated in a controlled trial. An earlier RCT in patients with liver cirrhosis undergoing paracentesis, found a highly significant reduction of the incidence of renal failure after albumin substitution (level I, Table 4) [48]. If either 20% HA, dextrans or gelatin were substituted as volume replacement (level I) [49], no difference in either creatinine clearance, the incidence of ARF or outcome was observed in any of these three substitution groups. Furthermore, a trial in patients with liver cirrhosis and spontaneous bacterial peritonitis (SBP) showed improved outcome with intravenous HA (level I) [50]. Prevention of nephrotoxic renal injury

Hypovolaemia is a major risk factor for most forms of drug-induced renal failure [52]. On the other hand, it has been shown to be preventable in some instances by adequate hydration. No trials exist that systematically investigate the ideal solution and the amount to be administered. However, clinical reports /studies mainly document the use of normal saline. Prophylaxis by volume expansion has been demonstrated for amphotericin B [53], antiviral drugs like foscarnet [54], cidofovir and adefovir [55] as well as drugs inducing crystal nephropathy, i.e. indinavir, acyclovir, and sulfadiazine [56]. Furthermore this effect has been shown for cisplatin [57] and for tumour lysis syndrome [58]. At best available studies only reach level IV and only one study can be classified as level II [54]. Contrast nephropathy

Hydration appears to be the most effective preventive measure for contrast nephropathy (Table 5). Initial studies investigating the protective role of hydration in contrast nephropathy used historical controls [59]. Nearly all studies investigating potentially protective drugs like N-acetyl-cysteine or theophylline in this setting use hydration with normal saline in their control groups. Intravenous 0.45% saline was shown to be superior to both mannitol and furosemide in a larger RCT [60]. Another RCT (n= 1383) patients showed that normal saline is superior to half normal saline in reducing the incidence of contrast nephropathy in patients undergoing coronary angiography (0.7% vs. 2%) (level I) [61]. Additionally, intravenous normal saline (1 ml/kg/h) was found to be superior to oral fluid administration in a small trial (n=53) (level II) [62]. In a recent prospective observational study the incidence of contrast nephropathy was kept very low (1.4%) simply by keeping patients well hydrated, both intravenously and orally [63]. A recent trial suggests it is beneficial to use isotonic sodium-bicarbonate instead of normal saline (level I) [64]. Colloids were not investigated. Myoglobinuria - Crush injury

normal saline (level III) [65] [66;67]. Sodium bicarbonate in combination with mannitol did not significantly contribute to improved outcome (level III) [68].

Potential problems of volume expansion As already noted, there may be situations where further fluid loading may even cause outcomes to deteriorate. Clearly fluid loading is contraindicated in patients with severe heart failure and lung oedema. Furthermore in a prospective observational trial of 2 442 patients admitted to the ICU, it was shown that in deteriorating renal function further fluid loading is not likely to reverse ARF if the septic cascade has already started [43] (level III). Furthermore, they found no evidence that hypovolaemia was a cause of ARF in patients with normal renal function who developed sepsis. Aggressive fluid loading does not seem to prevent further evolution to ARF, and may potentially induce tissue oedema, particularly in the lung and gut mucosa [69]. Thus, fluid loading must be initiated to achieve well-defined endpoints such as central venous pressure (8-12 mmHg) and SvO2 (>70%) in septic shock or hypovolaemia [70]. A minimal urinary output (e.g. 100-150 ml/h) is often recommended to avoid potential nephrotoxic renal injury.

Final recommendations • Volume expansion by fluids is generally recommended as the primary and most effective measure for prevention of acute renal failure in states of true or suspected hypovolaemia and sepsis (Grade A). • Volume expansion using isotonic saline is recommended for protection in certain instances of drug induced nephrotoxicity (amphotericin B, foscarnet, cidofovir, adefovir, indinavir, acyclovir, sulfadiazine (Grade D, E), and cisplatin (Grade B). • Intravenous normal saline is recommended for prevention of contrast nephropathy (Grade A). Bicarbonate containing solutions may be a better option. (Grade B) • Given the still unresolved debate regarding the influence of HES on renal function, HES can not be recommended as a first-line option for volume resuscitation in a broad range of patients (Grade B). • If HES is given, it is recommended that low-molecular HES preparations be used. (Grade C). • If HES is given, sufficient quantity of free water must be co-administered to minimize the risk of renal dysfunction (Grade E). • In large volume paracentesis in patients with liver cirrhosis, application of colloids and in particular albumin, is more effective in preserving renal function than crystalloids (Grade A). • Uncontrolled volume substitution may result in oedema as well as abdominal compartment syndrome and should be avoided (Grade C). • In hypotensive patients with penetrating torso injuries, aggressive fluid resuscitation may be delayed until operative intervention (Grade B) • Fluid loading should be performed to achieve well-defined end points of resuscitation such as SvO2, CVP, cardiac output and urinary output.

Renal failure due to crush injury is a consequence of both hypovolaemia due to volume loss into the third space (e.g. injured limb) and toxic injury due to myoglobinuria/haemoglobinuria. Reports from larger case series show significantly improved outcome and reduced rate of ARF in patients with crush injury who were hydrated with



551

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Conclusion Fluids are commonly given to prevent deterioration of renal function in hypovolaemia, sepsis, contrast nephropathy and administration of nephrotoxins. Summarising the current evidence, no clear highgrade recommendation can be given regarding the type of hydration regimen. Crystalloids appear to be safe in many settings, but exert

less volume effect and may aggravate extravascular oedema. On the other hand, HES exerts larger volume effect, but caution is warranted when using high molecular weight HES with a higher degree of substitution as they may impair renal function. Albumin appears to be safe with regard to renal function.

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54. Cheung TW, Jayaweera,DT, Pearce,D, Benson,P, Nahass,R, Olson,C, Wool,GM. Safety of oral versus intravenous hydration during induction therapy with intravenous foscarnet in AIDS patients with cytomegalovirus infections. Int J STD AIDS 2000;11:640-647. 55. Safrin S, Cherrington,J, Jaffe,HS. Cidofovir. Review of current and potential clinical uses. Adv Exp Med Biol 1999;458:111-20.:111-120. 56. Perazella MA. Crystal-induced acute renal failure. Am J Med 1999;106:459-465. 57. Santoso JT, Lucci,JA, III, Coleman,RL, Schafer,I, Hannigan,EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol 2003;52:13-18. 58. Davidson MB, Thakkar,S, Hix,JK, Bhandarkar,ND, Wong,A, Schreiber,MJ. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 2004;116:546-554. 59. Eisenberg RL, Bank,WO, Hedgock,MW. Renal failure after major angiography can be avoided with hydration. AJR Am J Roentgenol 1981;136:859-861. 60. Solomon R, Werner,C, Mann,D, D’Elia,J, Silva,P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:1416-1420. 61. Mueller C, Buerkle,G, Buettner,HJ, Petersen,J, Perruchoud,AP, Eriksson,U, Marsch,S, Roskamm,H. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:329-336. 62. Trivedi HS, Moore,H, Nasr,S, Aggarwal,K, Agrawal,A, Goel,P, Hewett,J. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003;93: C29-C34.

63. Mueller C, Seidensticker,P, Buettner,HJ, Perruchoud,AP, Staub,D, Christ,A, Buerkle,G. Incidence of contrast nephropathy in patients receiving comprehensive intravenous and oral hydration. Swiss Med Wkly 2005;135:286-290. 64. Merten GJ, Burgess,WP, Gray,LV, Holleman,JH, Roush,TS, Kowalchuk,GJ, Bersin,RM, Van Moore,A, Simonton,CA, III, Rittase,RA, Norton,HJ, Kennedy,TP. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328-2334. 65. Gunal AI, Celiker,H, Dogukan,A, Ozalp,G, Kirciman,E, Simsekli,H, Gunay,I, Demircin,M, Belhan,O, Yildirim,MA, Sever,MS. Early and vigorous fluid resuscitation prevents acute renal failure in the crush victims of catastrophic earthquakes. J Am Soc Nephrol 2004;15:18621867. 66. Better OS, Stein,JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med 1990;322:825-829. 67. Homsi E, Barreiro,MF, Orlando,JM, Higa,EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997;19:283-288. 68. Brown CV, Rhee,P, Chan,L, Evans,K, Demetriades,D, Velmahos,GC. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma 2004;56:1191-1196. 69. Kreimeier U, Peter,K. Strategies of volume therapy in sepsis and systemic inflammatory response syndrome. Kidney Int Suppl 1998;64:S75-9.:S75-S79. 70. Rivers E, Nguyen,B, Havstad,S, Ressler,J, Muzzin,A, Knoblich,B, Peterson,E, Tomlanovich,M. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.



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Received March 2006; accepted in revised form July 2006

r e v i e w

Volatile anaesthetics and the heart R.A. Bouwman1, R.J.P. Musters2, J.J. de Lange1, C. Boer3 1Department Of Anaesthesiology, 2Laboratory for Physiology, Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU) VU University Medical Center (VUmc), Amsterdam, The Netherlands. 3Abbott B.V., Hoofddorp,Tthe Netherlands

Abstract. During surgical procedures and in intensive care units anaesthetics are widely used to induce and maintain anaesthesia and to sedate patients. Most anaesthetics negatively affect the haemodynamic profile by their negative inotropic effects on cardiac function. These effects could be detrimental to patients with cardiovascular pathology. However, at clinically relevant concentrations volatile anaesthetics were recently reported to exert beneficial effects during ischaemia and reperfusion, and were able to improve post-ischaemic contractile function and reduce infarct size. These beneficial effects rely on a cardioprotective signalling cascade dependent on several mediators such as protein kinase C, reactive oxygen species and adenosine triphosphate-sensitive K+channels in analogy to ischaemic preconditioning. These cardioprotective properties may alter the importance of volatile anaesthetics in the development of clinical cardioprotective strategies and become an important therapeutic tool. However, the cellular mechanisms of this phenomenon have not been elucidated and the purpose of this review is to summarise the current knowledge of these mechanisms and the possible clinical implications of volatile anaesthetic-induced cardioprotection.

Introduction

Excitation-Contraction coupling in the heart

Anaesthetics are used to induce and maintain anaesthesia in order to perform surgical procedures or to sedate patients in the intensive care unit (ICU). In addition to their effects on consciousness, most anaesthetics reduce cardiac function due to negative inotropic properties and with swings in the haemodynamic profile as a possible result. The contractile force of the heart is determined by myocardial Ca2+ handling, Ca2+ sensivity of the contractile elements and the cellular length just before contraction (preload). Volatile anaesthetics have profound inhibitory effects on cardiac Ca2+ homeostasis which leads to depression of cardiac function. These effects can be detrimental for patients with reduced myocardial function due to cardiovascular pathology. Interestingly, recent evidence shows that volatile anaesthetics exert cardioprotective properties and may protect cardiomyocytes against and reperfusion I/R-injury [1]. In particular, the myocardium contains intrinsic protective signalling pathways, which can be triggered by a variety of stimuli, including volatile anaesthetics. This cardioprotective effect is mediated intracellularly by means of interaction between reactive oxygen species (ROS), protein kinase C (PKC) and adenosine triphosphate-sensitive mitochondrial K+ (mitoK+ATP) channels [2,3]. However, the sequence of events in the signalling cascade is complex and the potential end-effector proteins of this cardioprotective strategy largely remain to be elucidated. Nevertheless, volatile anaesthetics may become an important therapeutic tool in the induction of protection against I/R-injury and may provide pointers to the development of clinical cardioprotective strategies. The purpose of this review is to discuss the effects of volatile anaesthetics on myocardial contractile function in relation to ischaemia and reperfusion (I/R)-injury and anaesthetic-induced cardioprotection (APC). Correspondence:

The heart ensures adequate circulatory blood flow and closely matches cardiac output to the metabolic demands of the organs. Cardiac output is modulated by cardiac contractile function, which is determined by force development of individual cardiomyocyte. The contractile machinery of cardiomyocytes consists of the contractile proteins arranged in myofibrils containing thick (myosin) and thin (actin) filaments. During contraction, the contractile filaments slide over one other due to formation of crossbridges between myosin heads and myosin-binding sites on the actin filament, followed by force-generating conformational changes (powerstroke). The process of cross-bridge cycling is dependent on adenosine triphosphate (ATP) and has been extensively reviewed [4]. Actomyosin interaction is closely regulated by the regulatory proteins tropomyosin and troponin (Tn). During cardiac rest (diastole) tropomyosin blocks crossbridge interaction by interfering with myosin-binding sites on actin. Due to Ca2+ binding to the TnC subunit, the inhibitory TnI subunit is released, allowing tropomyosin to move over the actin filament. Consequently, myosin-binding sites on actin are exposed and crossbridge cycling is initiated. In addition to activation of the contractile apparatus, Ca2+ is a major player in the regulation of cardiac electrical activity. This makes Ca2+ an important second-messenger in the coupling of cardiomyocyte excitation to contraction. The amplitude of developed force is dependent on the Ca2+ availability for activation of the contractile system. As a consequence, Ca2+ handling is tightly regulated and contractile dysfunction due to pathophysiological conditions is mostly due to alterations in Ca2+ homeostasis. When an action potential is generated, Ca2+ enters the cardiomyocyte via the voltage-gated L-type Ca2+ channels during the plateau phase of the action potential. This relatively small Ca2+ influx triggers massive Ca2+ release from the sarcoplasmic reticulum (SR) by activating the ryanodine-sensitive Ca2+ release channels (ryanodine-receptors, RyRs). This amplification of Ca2+ influx is known as Ca2+ induced Ca2+ release (CICR) and provides the necessary Ca2+

R. Arthur Bouwman, E-mail: [email protected] / [email protected]

for activation of the contraction. In order to allow for diastolic filling of the heart, cardiomyocyte relaxation is initiated by termination

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of Ca2+ release from the SR and subsequent reduction of intracellular [Ca2+] ([Ca2+]i). During relaxation, Ca2+ is removed from the cytosol by Ca2+ reuptake into the SR via the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) and extrusion from the cardiomyocyte in exchange for Na+ entry via the Na+/Ca2+-exchanger (NCX) (see Figure 1 ). The amplitude of force developed by the myocardium can be changed by 1) altering the amplitude or duration of the Ca2+ transient, or 2) altering the sensitivity of the myofilaments to Ca2+. Changes in the Ca2+ transient can be due to alterations in the amount of Ca2+ released into the cytosol, which is dependent on the amount of cellular Ca2+ influx as well as Ca2+ uptake and re-uptake by, and Ca2+ release from, the SR. Ca2+ sensitivity is influenced by various factors like myofilament length, temperature, pH and the phosphorylation status of the myofilaments (contractile proteins).

Effect of anaesthetics on excitation-contraction coupling The molecular structures of modern inhalational anaesthetic agents are based on ether (desflurane, enflurane, isoflurane and sevoflurane) or chloroform (halothane), which were used as the first general anaesthetics. The mechanism of their anaesthetic effects is yet to be elucidated, but using the lipid-solubility of these agents as a basis, alterations in membrane properties are expected to be involved. Volatile anaesthetics reduce myocardial contraction by both reducing the amount of Ca2+ available for contraction (a reduction in the Ca2+ transient) and reducing the myofilament sensivity to activating Ca2+. In an extensive review, Hanley et al. (2004) describes the current knowledge of the mechanisms of the negative inotropic effects of volatile anaesthetics [5]. Several electrophysiological studies show that volatile anaesthetics reduce the whole-cell Ca2+ inward current by the inhibition of the voltage dependent L-type Ca2+ channels. Cardiac contractility will diminish because less Ca2+ is available for Ca2+-induced Ca2+-release (CICR). As a consequence, diminished Ca2+ influx through the L-type Ca2+ channels will shorten the plateau phase of the cardiac action potential. Additional opening of the ATP sensitive sarcolemmal K+ channels (sarcK+ATP) also contributes to action potential shortening. The anaesthetic effects on the SR Ca2+ content seem to be differ according to the type of anaesthetic agent. Halothane decreases SR-Ca2+ content, as determined by caffeine-induced contractions. Halothane seems to facilitate opening of the SR Ca2+ release channel (RyR) causing Ca2+ to leak into the cytosol [6]. As a consequence, halothane exposure transiently increases the cardiac contractility due to Ca2+ filling of the cytosol. In contrast, during sevoflurane-exposure SR Ca2+ content is increased, suggesting that negative inotropy is due to a reduction of CICR in combination with a reduced cellular Ca2+ efflux [6]. Hannon and Cody (2002) suggest that sevoflurane reduced Ca2+ efflux via inhibition of the sarcolemmal Ca2+ ATPase [6]. Others show inhibitory effects of volatile anaesthetics on sarcolemmal Ca2+ transport via the NCX [7]. In contrast, we recently demonstrated in isolated rat trabeculae, that sevoflurane facilitates NCX-dependent Ca2+ influx (reverse mode of the NCX) providing another potential mechanism of sevoflurane-induced increase in SRload [8]. In addition to a reduction in the Ca2+ transient, volatile anaesthetics affect the sensitivity of the contractile system for Ca2+. This is supported by data showing that restoration of the Ca2+ transient by applying additional extracellular Ca2+ during anaesthetic exposure

does not completely restore force development [9]. However, conflicting results have been reported, since Davies et al. (2000) showed that sevoflurane exerts only minimal inhibitory effects on Ca2+ sensitivity [10]. Recently, Graham et al. (2005) provided a possible explanation for these contradictory results and reported that effects of volatile anaesthetics on the contractile myofilaments are dependent on the duration of exposure [11].

Cardioprotection against ischaemia/ reperfusion injury Ischaemia/reperfusion injury

Ischaemia is a condition in which the delivery of O2 and metabolic nutrients is inadequate due to a reduction or cessation of myocardial blood flow. If blood flow is not restored, irreversible injury of cardiomyocytes will occur. However, restoration of blood flow is followed by additional harmful events and, paradoxically, cellular injury is increased. This phenomenon is also known as reperfusion injury. Thus, the direct effects of ischaemia as well as its indirect effects through reperfusion, contribute to cellular damage due to ischaemia and reperfusion (I/R)-injury. After a brief reduction in blood flow (<20 minutes), myocardial viability is usually preserved, although contractile function will not be fully restored during reperfusion. Over time, the myocardial contractility recovers to baseline levels and this gradual restoration is known as stunning [12]. Prolonged ischaemic periods are characterised by irreversible tissue damage due to necrotic and apoptotic cell death. Cellular Ca2+ overload and the production of reactive oxygen species (ROS) are both recognized as critical mediators in the development of the adverse sequelae of I/R-injury. Under normal conditions, the metabolic demand and supply of the heart are closely matched and reduced metabolic supply is quickly followed by physiological and metabolic changes in cardiomyocytes. Within seconds after coronary blood flow reduction, the energy metabolism in cardiomyocytes shifts from aerobic to anaerobic glycolysis. Consequently, cardiomyocytes become energy depleted as the ATP production becomes less effective, and depletion of cellular energy reserves (high-energy phosphates) starts within seconds after complete cessation of blood flow [13]. These metabolic changes are accompanied by a reduction in cardiac contraction, which ultimately ceases completely. In addition to inadequate O2-delivery and nutrient supply, metabolic products are not washed out due to decreased blood flow. This causes lactate and protons to accumulate and within minutes after the onset of ischaemia , intracellular acidosis is detectable. In addition, intracellular Na+ concentration will rise due to an increased Na+-influx via the Na+/H+-exchanger (NHE) and reduced activity of the Na+/K+-ATPase. Furthermore, ischaemic Na+-overload alters the electrochemical driving force in favour of NCX-dependent Ca2+ influx (reverse mode of the NCX) leading to cytosolic accumulation of Ca2+ [14]. In addition to these changes in intracellular ion-homeostasis, recent evidence indicates that ROS are also produced during ischaemia itself and not only on reperfusion. These ROS originate from the mitochondrial electron transport chain (ETC) despite low O2 levels and contribute to ischaemic cell death as well as ATP-depletion and Ca2+ overload [15]. Upon reperfusion of the myocardium, rapid increases in ROS production as well as Ca2+ loading during the initial minutes of reperfusion have been demonstrated [16]. During reperfusion, due to restoration of energy production SERCA is quickly reactivated. However, the amount of cytosolic Ca2+ exceeds the capacity of the



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SR, and, as cellular Na+-levels remain elevated due to increased Na+influx via the NHE, cytosolic Ca2+ will continue to rise via the NCX in the reverse mode. In addition, energy is present for activation of the myofibrillar elements, but in the presence of high Ca2+ levels, myofibrillar activation leads to sustained force development causing hypercontraction [17]. According to Piper et al. (2004), the development of hypercontraction in combination with ischaemia -induced cytoskeletal and sarcolemmal fragility results in cellular disruption followed by necrotic cell death. In addition, elevation of intracellular Ca2+ is also associated with activation of a variety of protein kinases, phosphatases and proteases contributing to I/R-injury. Furthermore, mitochondrial function can be negatively affected as mitochondrial Ca2+ overload induces release of cytochrome C and pro-apoptotic factors into the cytosol [18]. Analogous with myocardial Ca2+ handling, ROS play an important role as signalling molecules in cell physiology and pathophysiology. However, during I/R-injury, uncontrolled ROS production leads to sarcolemmal damage by lipid peroxidation, modification of

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protein structure and mitochondrial dysfunction [19]. In particular the application of exogenous ROS to cardiomyocytes induces similar metabolic and physiological alterations including energy depletion, contracture development, reduced contractile function and Ca2+ overload [20]. Therefore, ROS are strongly implicated in the pathogenesis of I/R-injury. However, in animal studies, ROS-scavenging during I/R-injury has reported negative results and to date the clinical use of antioxidant therapy during I/R-injury has failed to show any beneficial effects. Furthermore, as Ca2+ overload can increase ROS production [21] and ROS production promotes Ca2+ overload [20], the exact relationship and contribution of ROS and Ca2+ overload to I/R-injury remains to be established. Ischaemic preconditioning (classical preconditioning)

Many experimental and clinical studies are focused on the development of cardioprotective strategies in order to protect the heart against the adverse sequelae of myocardial ischaemia and subsequent reperfusion. Interestingly, the heart can resist brief ischaemic


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periods remarkably well and Verdouw et al. (1979) show that repeated brief ischaemic periods favourably alter myocardial energy metabolism [22], whereas Basuk et al. (1986) suggest the possible cardioprotective effect of repeated brief ischaemic periods [23]. The phenomenon of ischaemic preconditioning (IPC) was introduced by Murry et al. (1986) who showed that four five-minute cycles of ischaemia reduced the infarct size after prolonged I/R-injury [24]. The cardioprotective effect of the preconditioning stimulus lasted for about 2 to 4 hours but thereafter protection was reduced [25]. Interestingly, 24 hours after the initial preconditioning stimulus the heart again developed an increased resistance to I/R-injury [26]. The delayed preconditioning response lasts for about 72 hours and this phenomenon is referred to as the ‘second window of protection’. These observations clearly suggest that the myocardium possesses endogenous protective mechanisms, which have been demonstrated in a variety of experimental studies. Due to the potential benefit of an effective clinical cardioprotective strategy, the underlying cellular mechanisms of cardioprotection have been extensively studied and the subject of many reviews [27,28]. Inhibitory G-protein coupled receptor agonists, like adenosine, bradykinin, norepinephrin, opioids, angiotensin and endothelin, can trigger preconditioning of the myocardium. In addition, ROS, NO and Ca2+ are also able to trigger cardioprotection. Several protein kinases are recognised as important mediators of the protective response: these include protein kinase C (PKC), tyrosine kinases (TK), mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase). The contribution of the mitoK+ATP channels to preconditioning is complex, as opening of the mitoK+ATP channels is involved as a trigger and mediator in the cardioprotective signalling cascade. In addition, of the possible endeffectors, it has been suggested that the mitoK+ATP channels might be involved in the preservation of mitochondrial function [29]. However, the interaction of the various intracellular signalling pathways during cardioprotection is complex and the exact mechanism and definition of end-effector proteins remain to be elucidated

Anaesthetic-induced preconditioning As long ago as 1976, Bland and Lowenstein described the beneficial effects of halothane on the severity of the ischaemic injury [30]. Subsequently, Davis et al. (1983) reported that halothane pretreatment reduced infarct size after I/R-injury [31]. Following the introduction of the concept of ischaemic preconditioning by Murry et al. in1986, [24], further extensive research on the mechanism of anaesthetic-induced protective signalling was carried out and has been summarised in several recent reviews [1,32,33]. In a number of experimental studies halothane, enflurane, isoflurane and sevoflurane were shown to reduce infarct size after I/R [34,35,36]. In addition to a reduction of cardiomyocyte cell death, several studies show that volatile anaesthetics also improve postischaemic contractile function [2,37]. Like ischaemic preconditioning, volatile anaesthetics also induce a second window of cardioprotection [38]. Finally, in several experimental studies, the application of volatile anaesthetics solely during reperfusion was also shown to reduce infarct size [39]. Only two minutes of sevoflurane exposure during reperfusion maximally protected the myocardium [40], and therefore mimics the recently reported phenomenon of postconditioning by brief ischaemic periods during reperfusion [41]. The exact mechanism of cardioprotection afforded by volatile anaesthetics remains unresolved, however the protective effect seems

to rely on the same intracellular signalling pathways involved in ischaemic preconditioning, including protein kinase C (PKC), ROS and mitoK+ATP channels. Figure 2 shows the cardioprotective signalling pathways involved in anaesthetic-induced cardioprotection. In addition to ROS, PKC and mitoK+ATP channels, volatile anaesthetic-induced cardioprotective signalling seems to rely on a variety of other signalling molecules. These include G-protein-coupled receptors (adenosine receptor [42], opioids receptor [43] and α- and β-adrenoreceptors [44]), G-proteins [45] in addition to other kinasedependent pathways like the phosphatidylinositol-3-kinase (PI3kinase)/protein kinase B (PKB) signalling pathway [46], nitric oxide (NO) synthase/NO/cyclic guanine monophosphate (cGMP)/protein kinase G (PKG)-pathway [45] and protein tyrosine kinase signalling pathway [47]. Currently, the exact interaction between the different protective signalling pathways remains unclear. Mechanisms of protection: end-effector proteins

The end-effector mechanisms that indeed result in cardioprotective activity induced by volatile anaesthetics remain unknown and the subject of speculation. However, reduction of cellular Ca2+ overload, ROS production and preservation of mitochondrial function have been associated with improved contractility, improved metabolic function and a reduction of infarct size, and may form the main endeffector targets for cardioprotective signalling pathways. Reduced cellular Ca2+ loading due to volatile anaesthetics has been attributed to the depressant effects on the various elements of the myocardial Ca2+ homeostasis (see: “effect of anaesthetics on excitation-contraction coupling”). In contrast to elevation of ROS during anaesthetic preconditioning, ROS production during and after I/R has been demonstrated to be reduced in preconditioned hearts and may contribute to anaesthetic-induced cardioprotection [48]. During ischaemia and reperfusion the mitochondria were demonstrated to be the major source of ROS [49], and therefore preservation of mitochondrial bioenergetics is the suggested underlying mechanism for reduced production of ROS in preconditioned hearts. Finally, several other mechanisms which may provide cardioprotection have been proposed. These include reduced membrane damage, reduced cytoskeletal fragility, reduced Ca2+ sensitivity (thereby preventing hypercontracture), preservation of cardiac (SR) Ca2+ handling and a reduced activation of pro-apoptotic signalling pathways [27,50,51,52].

Clinical implications Despite the interesting progress on the mechanism of cardioprotective signalling in experimental animal studies, the most important question is whether the phenomenon of preconditioning can be used in the development of clinical cardioprotective strategies. The phenomenon of ischaemic preconditioning in patients was reported soon after its introduction in animal studies, however, the choice of anaesthetic agent during surgery was generally believed not to influence the occurrence of ischaemic episodes [53]. Nevertheless, in vitro experiments in isolated human atrial trabeculae showed enhanced contractile recovery due to pretreatment with volatile anaesthetics [54]. Interestingly, the cardioprotective signalling cascade seems to rely on similar signal transduction elements as does ischaemic preconditioning such as PKC, ROS as well as mitoK+ATP channels [55,56]. Several clinical studies that focus on the cardioprotective effect of volatile anaesthetics were performed on patients scheduled for coronary artery surgery. As part of their



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and PKC-ε have been considered most important. However, in isolated trabeculae PKC-α activation also seemed to be involved in the preconditioning cascade (unpublished observations). After activation PKC translocate towards several subcellular structures, like the mitochondra, sarcolemma, intercalated disks and the cytoskeleton and modifying protein function due to phosphorylation. Although down-stream signalling targets remain to be elucidated, ATP-sensitive mitochondrial K+ (mitoK+ATP) channels, ATP-sensitive sarcolemmal K+ (sarcK+ATP) channels, sarcoplasmic reticulum and heat shock proteins are considered to be potential candidates. The opening of mitoK+ATP channels is considered a possible end-effector via preservation of mitochondrial bioenergetics. However,

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treatment during surgery, these patients are subjected to +myocardial Na K+ ischaemia induced by aortic cross-clamping. Ramsay et al. (1994) ATP reported that a volatile anaesthetic-based anaesthesia during cardiopulmonary bypass graft surgery (CABG) reduced the incidence + Na of peri-operative infarction [57]. The first clinical studies evaluating a classical preconditioning stimulus using volatile anaesthetics showed a slight reduction in the plasma markers of necrosis (troponin I and creatinine kinase MB), but failed to reach significance [58,59,60]. However, in the study of Penta de Peppo et al. (1999)2+ the Ca group of patients anesthetised with enflurane showed evidence of SR improved contractility of the left ventricle as demonstrated by pressure-area relations [60]. De Hert et al. (2002) were the first to demonstrate that patients receiving sevoflurane during coronary artery surgery had a better post-surgical cardiac function and reduced plasma levels of TnI compared to patients subjected to an intravenous anaesthetic regimen [61]. In subsequent studies, they showed that these beneficial effects could also be detected in high risk patients with SL reduced cardiac function [62] and they found that anaesthesia with sevoflurane reduced the length of stay in the ICU and in hospital on comparison with propofol anaesthesia [63]. It was advocated that the volatile anaesthetic should be given throughout the entire duration of

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• Less apoptosis • Improved contractile recovery

additional ROS production in response to channel opening is considered to participate as possible feed forward mechanism in further amplification of the cardioprotective signalling cascade. Other possible end-effects are shortening of the action potential due to sarcK+ATP-opening, heat shock protein-induced stabilisation of the cytoskeleton and preserved sarcoplasmic reticular function. AdR = adenosine receptor, PLC = phospholipase C, DAG = diacylglycerol, IP3 = inositol triphosphate, ROS = reactive oxygen species, ETC = electron transport chain, PKC = protein kinase C, mitoK+ATP = ATP-sensitive mitochondrial K+ channels, sarcK+ATP = ATP-sensitive sarcolemmal K+ channels, MAPK = mitogen activated protein kinase, HSP = heat shock protein, NCX = Na+/Ca2+-exchanger.

the procedure, since sevoflurane pretreatment or its institution durNa + ing reperfusion only, did not provide similar protection [64]. HowNCX ATP(2003) ever, Julier et al. included 72 patients in a multi-centre study and showed that sevoflurane pretreatment improved LV function, as Ca 2+ brain natriuretic peptide (BNP) plasma levels suggested by reduced [65]. In addition, it was elegantly shown in atrial appendages that after preconditioning, PKC-δ translocated to the sarcolemma and PKC-ε to the intercalated disks. However, the patients given sevoflurane werePLBalso given significantly more phenylephrine to maintain blood pressure. As α-adrenergic stimulation is cardioprotective due SERCA to the activation of PKC, these observations might be biased [66]. Therefore, the recent study of Fraβdorf et al. (2005) is the first study Ca 2+ pretreatment can reduce postoperative TnI to show that sevoflurane plasma levels significantly, indicating a reduction of myocardial necrosis [67]. The phenomenon of cardioprotection by volatile anaesthetics may be relevant to clinical practice, as at present patients are anaesthetised with this group of anaesthetics as part of daily practice. Interestingly, other commonly used anaesthetic agents such as propofol and opioids have also been reported to exert cytoprotective effects [68], but the clinical cardioprotective effect of propofol - when comr ia

Figure 2 Cardioprotective signalling pathways involved in volatile anaesthetic-induced preconditioning. Central to the volatile anaesthetic-induced cardioprotective signalling cascade is activation of PKC. PKC activation relies on the production of ROS most likely due to direct inhibitory effects of volatile anaesthetics on the mitochondrial respiratory chain. Other activation pathways are also considered to be involved including activation of G-protein coupled receptors, phospholipase C and diacylglycerol. Interestingly, we recently demonstrated that the reverse mode of the Na+/Ca2+-exchanger precedes PKC activation, presumably via facilitation of Ca2+ influx. [8] The exact sequence of events with respect to the NCX and ROS production remains to be elucidated. Among other isoforms, PKC-δ

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• reduced Ca2+ - overload


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pared to volatile anaesthetics - seems to be limited [61]. Interestingly, in experimental studies morphine was shown to enhance the efficacy of the cardioprotective response induced by volatile anaesthetics thus providing important clinical therapeutic options [43]. These observations may significantly contribute to the development of balanced anaesthesia techniques. Furthermore, it may be interesting to speculate how the anaesthesia technique may even exceed the purpose of cardioprotection and be extended to modulate the general response to surgical stress, thereby protecting several organ systems. It is interesting to realise that the choice of anaesthetic regimen can modify the cytokine production in response to surgery [69], and therefore the protection afforded may extend beyond the operating room. Interestingly, the observation that sevoflurane favourably alters the haemodynamic profile in septic rats (unpublished observations) may suggest that the choice of anaesthetics could influence the management of septic patients not only in the operating room but also in the intensive care unit. However, taking existing controversies upon the clinical induction of protection by anaesthetics into consideration, the need for large well-designed multi-centre trials in order to develop effective clinical cardioprotective strategies has been stressed by various investigators [70,71].

Future directions The clinical relevance of preconditioning may be questioned for several reasons. Preconditioning-induced cardioprotection is elicited by applying a preconditioning stimulus before ischaemia and reperfusion will occur. In clinical practice, the occurrence of ischaemic episodes may often not be predicted. This is the reason that many investigators now focus on postconditioning, thereby applying the protective stimulus during the reperfusion phase. Recently, it was shown that brief ischaemic periods during the initial minutes of reperfusion afford the same amount of protection compared to preconditioning. Zhao et al. (2003) defined this phenomenon as ‘postconditioning’,

although the beneficial effects of volatile anaesthetics during reperfusion have already been described in earlier studies [72,73]. Postconditioning seems to depend on similar signalling pathways to preconditioning, and was recently demonstrated to be cardioprotective in a clinical study performed by Staat et al. (2005) [74]. This study may be an important step in the development of clinical cardioprotective strategies that can be applied after the ischaemic phase. Preconditioning has been called a phenomenon of the healthy heart, as several studies have shown that the diseased heart is not effectively protected by preconditioning [75]. This is disappointing as diseased myocardium would benefit most from cardioprotective measures. Several studies aim to address this issue, however, our understanding remains limited. Therefore, studies with specific focus on the mechanism of cardioprotection in the diseased heart would greatly enhance the clinical potential. Finally, to date the use of volatile anaesthetics has mostly been limited to the operating theatre as most ICU ventilators do not meet the technical requirements for the safe application of these agents. Environmental pollution and the risk of occupational exposure have prevented the routine use of volatile anaesthetics in the ICU. Therefore, suitable ventilator systems that limit the risk of occupational exposure have to be developed in order to benefit from the protection of volatile anaesthetics in the ICU. Recent progress on volatile anaesthetic delivery systems for the ICU, such as the volatile anaesthetic reflection filter (AnaConDa®), are promising developments [76]. In summary, the past two decades of cardiac research have greatly improved our understanding on the interaction of volatile anaesthetics and the ischaemic heart. This group of anaesthetics has been shown to trigger distinct cardioprotective signalling cascades, which provide the heart with an increased resistance to ischaemic episodes. Despite the increased understanding of the mechanisms responsible, our knowledge has to be extended in order to implement in the clinical situation. However, the results remain promising, and suggest a possible new therapeutic action for volatile anaesthetics.

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60. Penta,dP, Polisca,P, Tomai,F, De Paulis,R, Turani,F, Zupancich,E, et al. Recovery of LV contractility in man is enhanced by preischaemic administration of enflurane. Ann Thorac Surg 1999;68:112-118. 61. De Hert,SG, ten Broecke,PW, Mertens,E, van Sommeren,EW, de Blier,IG, Stockman,BA, et al. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology 2002;97:4249. 62. De Hert,SG, Cromheecke,S, ten Broecke,PW, Mertens,E, de Blier,IG, Stockman,BA, et al. Effects of propofol, desflurane, and sevoflurane on recovery of myocardial function after coronary surgery in elderly high-risk patients. Anesthesiology 2003;99:314-323. 63. De Hert,SG, Van der Linden,PJ, Cromheecke,S, Meeus,R, ten Broecke,PW, de Blier,IG, et al. Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 2004;101:9-20. 64. De Hert,SG, Van der Linden,PJ, Cromheecke,S, Meeus,R, Nelis,A, Van,R, V, et al. Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 2004;101:299-310. 65. Julier,K, da Silva,R, Garcia,C, Bestman,L, Frascarolo,P, Zollinger,A, et al. Preconditioning by Sevoflurane Decreases Biochemical Markers for Myocardial and Renal Dysfunction in Coronary Artery Bypass Graft surgery: A Double-Blinded, Placebo-Controlled, Multicenter Study. Anesthesiology 2003;98:1315-1327. 66. Musters,RJ, van der Meulen,ET, van der Laarse,WJ, van Hardeveld,C. Norepinephrine pretreatment attenuates Ca2+ overloading in rat trabeculae during subsequent metabolic inhibition: improved contractile recovery via an alpha 1-adrenergic, PKC-dependent signalling mechanism. J Mol Cell Cardiol 1997;29:1341-1354. 67. Frassdorf,J, Weber,NC, Feindt,P, Borowski,A, Schlack,W. Sevoflurane- Induced Preconditioning: Evaluation of Two Different Protocols in Humans Undergoing Coronary Artery Bypass Grafting. Anesthesiology 2005;104: A338. 68. Kevin,LG, Novalija,E, Stowe,DF. Reactive oxygen species as mediators of cardiac injury and protection: the relevance to anaesthesia practice. Anesth Analg 2005;101:1275-1287. 69. El Azab,SR, Rosseel,PM, De Lange,JJ, Groeneveld,AB, van Strik,R, van Wijk,EM, et al. Effect of sevoflurane on the ex vivo secretion of TNF-alpha during and after coronary artery bypass surgery. Eur J Anaesthesiol 2003;20:380-384. 70. De Hert,SG. The concept of anaesthetic-induced cardioprotection: clinical relevance. Best Pract Res Clin Anaesthesiol 2005;19:445-459. 71. Bolli,R, Becker,L, Gross,G, Mentzer,R, Jr., Balshaw,D, Lathrop,DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 2004;95:125-134. 72. Zhao,ZQ, Corvera,JS, Halkos,ME, Kerendi,F, Wang,NP, Guyton,RA, et al. Inhibition of myocardial injury by ischaemic postconditioning during reperfusion: comparison with ischaemic preconditioning. Am J Physiol Heart Circ Physiol 2003;285:H579. 73. Schlack,W, Preckel,B, Stunneck,D, Thamer,V. Effects of halothane, enflurane, isoflurane, sevoflurane and desflurane on myocardial reperfusion injury in the isolated rat heart. Br J Anaesth 1998;81:913-919. 74. Staat,P, Rioufol,G, Piot,C, Cottin,Y, Cung,TT, L’Huillier,I, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148. 75. Ghosh,S, Standen,NB, Galinianes,M. Failure to precondition pathological human myocardium. J Am Coll Cardiol 2001;37:711-718. 76. Meiser A, Laubenthal H. Inhalational anaesthetics in the ICU: theory and practice of inhalational sedation in the ICU, economics, risk-benefit. Best Pract Res Clin Anaesth 2005;19(3):523-538.


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Recieved September 2006; accepted October 2006

g u i d e l i n e s

Guidelines for timing, dose, and mode of continuous renal replacement therapy for acute renal failure in the critically ill C.S.C. Bouman1, H.M. Oudemans-van Straaten2 On behalf of the committee of nephrology and intensive care of the NVIC and the committee of quality of the NFN (See appendix)

1Department of Intensive Care, Academic Medical Center, Amsterdam 2Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam

Abstract. Objective: To provide evidence-based recommendations for clinical practice on timing, dose, and mode of CRRT in critically ill patients with ARF admitted to the ICU. Methods Literature search was done in Pubmed database for human studies. Studies were rated at five levels to create recommendations grades from A to E, grade A being the highest. Conclusions: In critically ill patients with ARF it is recommended: • to define ARF according to the RIFLE classification system into ARFrisk, ARFinjury and ARFfailure • to base the decision when to start RRT not only on the severity of ARF, but also on the severity of other organ failure (grade E). Initiation of RRT is to be considered in oliguric patients (RIFLErisk-oliguria or RIFLEinjury-oliguria ), despite adequate fluid resuscitation, and/or a persisting steep rise in serum creatinine, in addition to persisting shock (grade E). RRT may be postponed when the underlying disease is improving, other organ failure recovering and the slope in the serum creatinine rise declines, in order to see if renal function is also recovering (grade E). • to continue RRT as long as the criteria defining severe oliguric ARF (RIFLEfailure-oliguria) are present (grade E). If the clinical condition improves, it may be considered to wait before connecting a new circuit to see whether renal function recovers. RRT should be restarted in case of clinical or metabolic deterioration. • to achieve a delivered (not prescribed) ultrafiltrate (dialysate) flow during CVVH(D) of 35 mL/kg/h in postdilution (grade A). A higher dose applied for a short period may be considered in sepsis/SIRS (grade E). The dose needs to be adjusted for predilution using the dilution factor, and for filter down time. • In non-shock patients, continuous and intermittent treatments are equivalent regarding survival (level I). However, CRRT is recommended over IHD for patients with ARF who have, or are at risk for, cerebral oedema (grade C). CRRT is preferred in the management of patients with ARF and shock (grade E). • CRRT should be applied in the venovenous mode (grade B) HF in patients with sepsis or SIRS without ARF is not supported by enough evidence to be recommended in daily clinical practice.

Introduction Up to now, there are no standard guidelines for the application of CRRT in critically ill patients with ARF. Practice patterns vary widely between individual centers [1,2]. CRRT for the critically ill patient with ARF was introduced in 1977 by Kramer et al. [3]. Since then, many studies have reported on CRRT in the critically ill, but for several reasons comparison among studies is difficult: Various treatment modalities have been applied in heterogeneous populations that differ not only in co-morbidities, but also in the clinical setting and underlying molecular biological mechanisms that initiate and maintain ARF. Furthermore, there are more than 35 definitions of ARF [4]. Recently a process of international consensus and evidence-based statements in the definition and management of ARF was proposed by the ADQI [5,6]. Aim of the present contribution is to provide evidence based recommendations for clinical practice on the timing, treatment dose, and mode of CRRT in critically ill patients admitted to the

Correspondence: Catherine S.C. Bouman, internist-intensivist E-mail: [email protected]

ICU. Anticoagulation strategies, substitution fluids, membranes and non-renal indications are beyond the scope of the present paper.

Consensus definition of acute renal failure Figure 1 summarizes the ADQI consensus criteria for ARF [6]. ARF is classified into three levels: ARFrisk, ARFinjury, and ARFfailure, based on glomerular filtration rate or urine output criteria, whichever is more severe.

Methods Studies were identified using the MeSH terms acute kidney failure OR acute renal failure OR shock combined with the words hemofiltration OR haemofiltration OR hemodialysis OR haemodialysis in PubMed, from 1984 until March 2006, and by scanning the lists of publications found by database searches and on the ADQI workgroup findings at www.ADQI.net. Searches were limited to adult human studies and English language. The identified studies were eligible if they fulfilled the following criteria: (a) critically ill patients with ARF or SIRS, and (b) renal replacement therapy (RRT) with specified treatment characteristics including at least mode, dose and/or timing. We excluded studies on CAVH, molecular adsorbent techniques, and plasmapher-



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Table 1. The guidelines of Evidence-Based medicine’s rating system for strength of recommendation and quality of evidence [7]. Rating system for references Level I Large randomized trials with clear-cut results; low false positive (α) or false negative (β) error. Meta-analysis with low false positive (α) or false negative (β) error. Level II Small, randomized trials with uncertain results; high false positive (α) or negative (β) error. Meta-analysis with high false positive (α) or false negative (β) error. Level III Nonrandomized, contemporaneous control. Level IV Nonrandomized, historical controls. Level V Case series, uncontrolled studies and expert opinion. Rating system for recommendations Grade A Supported by at least two ‘level I’ investigations. Grade B Supported by only one ‘level I’ investigation. Grade C Supported by ‘level II’ investigations only. Grade D Supported by at least one ‘level III’ investigation. Grade E Supported by ‘level IV’ or ‘level V’ investigations only.

esis. We also excluded studies applying haemofiltration during cardiac surgery and in patients with cardiac failure, because these studies specifically focus on the beneficial effects of fluid removal. We classified evidence and formulated recommendations according to evidence based medicine methodology (Table 1) [7]. Criteria for the qualification ‘level I’ and ‘level II’ with respect to the size of the RCT are not well settled. In the present review, we defined ‘level I’ studies to be those including at least 50 patients per randomized group.

Timing There is significant variation in the timing of initiation of RRT, with up to two-fold differences in the reported values of BUN, creatinine, or urine output at RRT initiation [8-11]. There are two RCTs [12,13], four non-randomized studies [14-17] and one observational study [18], investigating the effect of timing of RRT on mortality, and/or recovery of renal function in critically ill patients with documented ARF or in patients with sepsis/SIRS and imminent ARF (Table 2). Acute renal failure

1. In a two-center RCT (n=106), in critically ill patients with oliguric ARF (diuresis of <180 mL in 6 hours, despite fluid resuscitation, inotropic support and high-dose diuretics), 28-day survival and recovery of renal function were not increased when CVVH was started early (within 12 hours after the onset of oliguria) as compared to late (urea of >40 mmol/L, and/or severe pulmonary oedema with PO2/FiO2 of <150 mm Hg and 10 PEEP cm H2O) (level II) [12]. Of note, in this study, late was not as late as in earlier studies. Because of pulmonary reasons, nearly half of the patients in the late group started CVVH before serum urea reached 40 mmol/L. Median delay between the start of treatment and the development of oliguria was 42 hours. 2. A single-center, retrospective, non-randomized cohort study (n=100) in trauma patients, used BUN as a surrogate of ‘timing of intervention’ [16]. Survival was 39% in the early group (RRT started at a mean BUN of 42.6 mg/dl (15 mmol/L) compared with 20% in the late group (RRT started at a mean BUN of 94.5 mg/dl (34 mmol/L) (level III). However, this approach is likely to be seriously flawed, because BUN may reflect many factors other than time of initiation. 3. In a single-center retrospective cohort study in cardiac surgery

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patients, hospital mortality was higher in the late CVVH group (n=28) compared with the early CVVH group (n=36) (43% vs 22%, p < .05) (level IV) [15]. In the late group, CVVH was started on conventional reasons (urea of ≥30 mmol/L, creatinine of ≥250 µmol/L, or potassium of ≥6.0 mmol/L despite glucose-insulin infusion), regardless of urine output. In the early group, CVVH was started when urine output was <100 mL within 8 hours, despite furosemide infusion. 4. In a single-center retrospective study in patients with ARF following cardiac surgery hospital mortality decreased after the introduction of early CVVHDF compared with a historical control group (23.5% vs 55%, p=0.02) [14]. In the early group (n=34), CVVHDF was started for oliguria (urine output of <100 mL within 8 hours), and in the late group (n=27), CVVHDF was started for conventional criteria (creatinine of >444 µmol/L) (level IV). Sepsis or SIRS

5. In a small RCT (n=37), in patients with severe pancreatitis without documented ARF, early CVVH (within 48 h after onset of abdominal pain) improved hemodynamics and short-term survival, compared with late CVVH (96 h after onset abdominal pain) (level II) [13]. 6. In a single-center retrospective study (n=80) in patients with septic shock and oliguric ARF, the application of early CVVH improved hemodynamics, gas exchange, successful weaning, and 28-day survival compared with a historical control group receiving conventional therapy (level IV) [17]. However, only 75% of the patients in the conventional group received CVVH, despite overt renal failure, and the applied dose was lower (20 mL/kg/h) than in the early treatment group (mean daily dose 30-35 mL/kg/h). 7. In the cohort study by Honoré et al., in patients with refractory septic shock, post hoc analysis showed an association between increased survival and earlier start of hemofiltration (level V) [18]. Discontinuation RRT

There are no clinical data on stopping criteria for RRT in critically ill patients with (recovering) ARF. Discussion

In the above-mentioned studies there is a clear trend toward a better outcome with earlier timing of RRT. However, one small RCT did not confirm this trend. In the absence of large RCTs comparing early to late initiation of RRT, no firm overall recommendations for timing of RRT can be made. When initiation of RRT is considered, it is important to realize that the consequences of ureamic toxicity, metabolic acidosis and/or fluid overload are likely to be more severe in the critically ill patient. Moreover, renal function is unlikely to recover within a short period during persistent and severe failure of other organs. Furthermore, various inflammatory mediators are cleared by the kidney.

Treatment dose The importance of ‘adequacy of dialysis’ is widely recognized in patients with ESRD; however, much less attention has been paid to the concept of ‘adequacy of dialysis’ in critically ill patients with ARF [19]. In IHD, dose is generally expressed as Kt/V [20], where K = clearance, t = treatment duration and V = the volume of distribution. In ESRD a minimum Kt/V of 1.2 thrice weekly should be delivered, a lower dose is associated with higher mortality [19]. However, higher


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Table 2. Clinical studies evaluating the timing of initiation of CRRT in critically ill patients Study design Clinical setting Definition of timing [no.patients]

Confounding Survival CRRT factors advantage early group Bouman [12] RCT [105] oliguric ARF and Early: < 12 h after onset oliguria (<180 mL in 6 h) no no MOF Late: urea > 40 mmol/L or severe pulmonary edemaa) Jiang [13] RCT [37] Severe pancreatitis Early: < 48 h after onset abdominal pain. no yes Late: > 96 h after onset abdominal pain Gettings [16] Retrospective [100] Post trauma Early: urea of <60 mg/dlb) Dose not yes Late: urea of ≥60 mg/dl reported Piccini [17] Retrospective [80] Sepsis with oliguric Early: < 12 h after ICU admission. Dose early >> yes ARF and ALI Late: urea >35 mmol/L, sCr >600 µmol/L dose late Elahi [15] Retrospective [64] ARF after cardiac Early: oliguria (<100 mL in 8 h) Dose not yes surgery Late: urea >30 mmol/L, sCr >250 µmol/L, reported Demirkilic [14] Retrospective [61] ARF after cardiac Early: oliguria (<100 mL in 8 h) Dose not yes surgery Late: SCr > 5 mg/dLc) reported Honore [18] Cohort [20] Severe septic shock Early: refractory septic shock HF, 35 L in 4 h yes CRRT continuous renal replacement therapy; ARF, Acute renal failure; ALI, acute lung injury; sCr, serum creatinine; HF haemofiltration; a) pO2/FiO2 < 150 mm Hg and 10 PEEP cm H2O; b) 21 mmol/L; c) 420 µmol/L.

doses may be beneficial in critically ill patients with ARF. In CRRT, treatment dose is generally expressed as filtrate volume/kg per time, for pure convective transport with postfilter replacement, and as Kt/V for other modalities. To calculate the treatment dose for predilution HF, the recommended ultrafiltrate rate should be multiplied by the dilution [21]. It is to be emphasized that dose quantification in acute RRT is not thoroughly validated and associated with numerous problems [21;22]. Recenly, single pool Kt/V appeared to be a useful way to prescribe dose for different modalities of CRRT [23]. Moreover, dose estimates do not take into account differences between the pore size of membranes and mode. The middle molecular clearance is better when high cut off membranes are compared with low cut off membranes, and when haemofiltration is compared with hemodialysis. Furthermore, the removal of middle molecules declines when membranes are used for longer periods. There are at present six RCTs (one applying IHD) [12,24-27], and one retrospective study [28], on the effect of renal replacement dose on mortality and recovery of renal function and/or physiologic endpoints, in critically ill patients with ARF (Table 3). After the first observations of Gotloib et al. [29] on the beneficial effects of haemofiltration in the septic acute respiratory distress syndrome, four RCTs [13,30-32] and four observational cohort studies [18,33-36] evaluated the effects of dose of RRT in patients with SIRS without documented ARF. Acute renal failure

1. In a RCT in 146 critically ill patients with ARF, survival (14 days after the last IHD session) was significantly higher in the patients treated with daily IHD compared with alternate day IHD [27] (level I). Patients with hepatorenal syndrome or cardiogenic shock were excluded from the study and treated with CRRT. Patient characteristics were comparable between groups. Daily IHD resulted in a better control of uraemia, fewer IHD related hypotension, and faster resolution of ARF, compared with alternate day IHD. In a multiple regression analysis, less frequent IHD was an independent risk factor for death. Unfortunately, although the prescribed dose of dialysis was 3.6 Kt/V per week in the alternate day group, the delivered dose was far less (about 3.0). All the surviving patients, except the two with Goodpasture’s disease, had full recovery of renal function.

II II III IV IV IV IV

2. A positive association between survival time and ultrafiltrate dose was also described in a large (n=425) RCT in patients with multiple organ failure, and ARF, treated with CVVH [26] (level 1). Small, but significant differences were present for age, APACHE II score, and BUN levels at baseline. Survival, 15 days after discontinuation of CVVH, was significantly lower in the group receiving 20 mL/kg/h (41%), compared with the higher volume groups receiving 35 mL/kg/h (57%) and 45 mL/kg/h (58%). The difference in the duration of CVVH, and the rate of renal recovery were not significantly different among the survivors of the three groups. 3. In a RCT in 206 critically ill patients with ARF, 28-day survival was significantly increased in the group receiving a higher replacement dose by adding a dialysis dose to CVVH [32]. Renal recovery rate among survivors was comparable between the high dose CVVHDF group and the low dose CVVH group. 4. An association between survival time and ultrafiltrate dose was not found in a smaller RCT (n=106) in critically ill, ventilated patients with shock and oliguric ARF (level II) [12]. The patients were randomized into three groups: early high-volume hemofiltration (EHV, 72-96 L/24h), early low-volume hemofiltration (ELV, 24-36 L/24h), and late low-volume hemofiltration (LLV, 2436 L/24h). Early treatment started within 12 hours after the onset of oliguria, and late when the patient fulfilled the conventional criteria for RRT (as in paragraph on timing). The 28-day survival was 74.3% in EHV, 68.8% in ELV and 75% in LLV (p=0.80). All hospital survivors had recovery of renal function. 5. In a RCT in 70 patients with ARF secondary to severe malaria or sepsis, the risk of death was higher in the group receiving peritoneal dialysis (70 L/day) compared with the group receiving CVVH (25 L/day) [25] (level II). The estimated Kt/V per week of 5.5 in the CVVH group was comparable to the low intensity groups in the studies of Ronco et al. [26] and Bouman et al. [12]. Unfortunately, the authors did not report the measurements necessary to calculate effective Kt/V in the peritoneal dialysis, but we can speculate that it was lower than in the CVVH group because the peritoneal dialysis group had a lower rate of resolution of acidosis and a slower rate of decline in plasma creatinine levels. 6. In a crossover study that compared high-volume (6 L/h) with low-volume CVVH (1 L/h) in 11 septic shock patients with ARF, the dose of norepinephrine required for the maintenance of tar-



Level of evidence

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Table 3. Comparison of randomized controlled trials on the effect of renal replacement dose on mortality and recovery of renal function Study [Ref]

Randomization (number of patients)

Mean Delivered dose mL/kg/h Kt/V per week

Survival (%)

p

ARF in days (mean)

p

Evidence Level

Day 14 after end IHD 46 0.01 16 .001 I 28 9 Day 15 after end CVVH Ronco [26] CVVH 20 mL/kg/h (146) 19 5.3 41 0.008 11 N.S. I CVVH 35 mL/kg/h (139) 34 9.5 57 13 CVVH 45 mL/kg/h (140) 42 11.8 58 12 Day 28 after inclusion Saudan [32] CVVH 25 mL/kg/h (102) 22 6.2 39 0.03 Not reported I CVVHDF 42 mL/kg/h (104) 34 9.4 59 Day 28 after inclusion Bouman [12] ELV 1,5 L/h (35) 20 5.6 69 0,8 8,6 .55 II LLV 1,5 L/h (35) 19 5.3 75 11,6 EHV 4 L/h (36) 48 13.4 74 8,6 ICU survival Phu [25] PD (36) << 5,5 53 0.005 Not reported II CVVH 25 L/day (34) 5,5 85 Day 14 after start CVVH Jiang [13] ELV 1 L/h (9) Not reported HV 68 <0.01 Not reported II LLV 1 L/h (10) LV 89 EHV 4 L/h (9) E 84 <0.05 LHV 4 L/h (9) L 74 IHD, intermittent haemodialysis; CVVH, continuous venovenous haemofiltration; CVVHDF, continuous venovenous hemodiafiltration; ELV, early low-volume haemofiltration, LLV, late low-volume haemofiltration; EHV, early high volume haemofiltration; LHV, late high-volume haemofiltration; Kt/V, clearance times duration of treatment divided by volume of distribution; ARF acute renal failure; HV, high volume; LV, low volume; E. early; L, late. Schiffl [27]

Alternate day IHD (72) Daily IHD (74)

3.0 5.8

get MAP decreased more during high-volume CVVH than during low-volume CVVH (p=0.02) (level II) [24]. 7. In a non-randomized prospective interventional pilot study (n=56), Brause et al. [28] compared very low-volume CVVH (1 L/h), with low-volume CVVH (1.5 L/h), and assessed the effect on the daily Kt/V. As expected the 1.5 L/h group achieved a higher Kt/ V (0.80 per day versus 0.53 per day) and better control of ureamia and acid base (level III). Mortality was high in both groups (73% and 69%, p=NS), but the study was not powered for survival as an endpoint. Sepsis or SIRS

1. In a small (n=24) RCT in patients with early septic shock or organ dysfunction, CVVH at 2 L/h did not affect clinical outcome compared with no CVVH (level II) [30]. The study was not powered for survival as an endpoint. 2. In a small RCT in 37 patients with severe pancreatitis, heamodynamics and short term survival rate improved more during high-volume CVVH (4 L/h) compared to low-volume CVVH (1 L/h) (Level II) [13]. The study was not powered for survival as an endpoint. 3. In a RCT in 61 patients after cardiac arrest, very high-volume HF (100 L in 8 hours) with, or without hypothermia significantly increased 6-months survival compared with standard care (level II) [31]. 4. In a large observational study (n=306) in critically ill patients receiving CVVH (100 L/day) mortality was significantly lower (33%) than predicted by APACHE II (76%) and SAPS II (71%) illness severity scores [34]. Improved heamodynamics and increased survival were also reported in four smaller cohort studies (level IV) in:

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5. Patients with intractable septic shock (n=20) treated with shortterm very high- volume HF (35 L in 4 hours) [18]. 6. Patients with septic shock (n=24) treated with high-volume CVVH (40-60 mL/kg/h) [33]. 7. Patients with severe sepsis treated with pulse very high-volume HF (85 mL/kg/h for 6-8 hours) [35]. 8. Patients with severe septic shock treated with short-term very high-volume HF (100 mL/kg/h for 12 h) [36]. Discussion

In some of the above-mentioned studies, Kt/V in the low-volume groups was extremely low, even lower than the Kt/V currently recommended for chronic dialysis [25,27,28] and nearly as low as the dose in earlier CAVH studies yielding a mortality rate of 80%. From the foregoing, it can be concluded that delivered RRT dose should not be too low. The highest evidence indicates a recommended dose of at least 35-45 mL/kg/h for CVVH(D) [26,32] and daily sessions for IHD [27]. The 35 ml/kg/h dose corresponds to a single pool Kt/V of 1.4 per day [23]. In contrast, a smaller RCT, suggests that 1.5 L/h (20 mL/kg/h) is as good as 4 L/h (48 mL/kg/h) [12]. The differences in outcome of the randomized studies may result from differences in case mix, ICU format, membrane, substitution fluid or concomitant treatment [37]. There are three multicenter RCTs underway looking at dose of RRT in ARF: The Acute Renal Failure Trial Network (ATN) Study in the US run by Palevsky [38], The Renal Study in Australia and New Zealand run by Bellomo [39], and the IVOIRE study in Europe run by Joannes-Boyau [40]. It is to be emphasized that in daily clinical practice the prescribed ultrafiltrate flow should be adjusted, in order to achieve the intended delivered ultrafiltrate flow. Evidence for a beneficial effect of (short-term) high, or very-high volume in patients with SIRS/sepsis and imminent or no ARF is still low. The studies are not randomized or underpowered for survival


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Table 4. Modes of CRRT

Slow continuous ultrafiltration Continuous arteriovenous or venovenous haemofiltration (CAVH or CVVH) Continuous arteriovenous or venovenous haemodialysis (CAVHD or CVVHD) Continuous arteriovenous hemodiafiltration or venovenous hemodiafiltration (CAVHDF or CVVHDF) Continuous arteriovenous or venovenous high flux dialysis (HDF)

[13,31]. Low-volume (2 L/h) CVVH [30] seems to have no positive effects in patients with sepsis/SIRS and imminent ARF (level II).

Modes of acute renal replacement therapy In the ICU, renal replacement therapies are primarily limited to conventional IHD and CRRT. During IHD, intensive dialysis is performed for 3-4 hours at variable intervals, whereas during CRRT, continuous and gradual removal of fluid and toxins is provided at lower blood flow. More recently several hybrid therapies [41] have been described, with a treatment duration between CRRT and conventional IHD, (ie extended dialysis [42], sustained low-efficiency dialysis [43], shortterm HF [18] or pulse HF [35]. The nomenclature and definitions of the various CRRT techniques are based on their operational characteristics [44] (Table 4). Haemodialysis and haemofiltration are the two main principles of solute transport of CRRT. During haemodialysis, removal of solutes is driven by diffusion (solute transport across a semi-permeable membrane generated by a concentration gradient). During haemofiltration, removal of solutes is based on convection (water and solute transport across a semipermeable membrane generated by a pressure gradient). There are no data showing any given modality as superior with regard to clinical outcomes. Haemofiltration resembles most the principle of glomerular filtration and increases the middle molecule clearances [45]; however, whether this is beneficial in ARF is unknown. Factors that may affect current practice include local availability of equipment, fluids and costs. CRRT is applied either in the arteriovenous (driving force is patient’s blood pressure and flow) or venovenous mode (driving force is external pump). Advantages of the arteriovenous therapies include ease of set-up and operation and low extracorporeal blood volumes. Disadvantages of arteriovenous therapies include the prolonged arterial cannulation, the requirement of a MAP of >60 mm Hg to maintain circuit blood flow, and the low blood flows that can be achieved. Advantages of the venovenous therapies are the decreased risk of vascular damage as compared to the arteriovenous therapies, the ability to maintain blood flow independent of MAP, the ability to achieve higher blood flow rates and clearances (level III) [46,47]. The higher clearances associated with better survival [26] cannot be achieved without the introduction of a blood pump. The use of blood pumps has increased the complexity of CRRT systems, but in clinical practice this disadvantage does not counterbalance the advantages, and there is general consensus that venovenous systems are the modality of choice [46-49]. CRRT vs conventional IHD

One of the most pressing clinical questions regarding the use of CRRT

Solute transport

Blood flow (mL/min)

Ultrafiltrate flow (mL/min) 1-2 8 - 66 2-3

Dialysate flow (mL/min) No No 10 - 20

Clearance (L/24h)

No Convection Diffusion

50 – 100 50 -200 50 -200

Convection and diffusion 50 -200

8 - 12

10 - 20

20 - 40

Convection and diffusion 50 -200

2-8

50 - 200

40 - 60

is whether CRRT offers an important advantage over IHD, regarding survival and/or recovery of renal function. The effects of IHD versus CRRT on survival and/or recovery of renal function were reported in five prospective RCTs [50-54] and two meta-analyses [55,56]. 1. In a large multicenter RCT (n=160) CVVHDF showed no survival (ICU and hospital) advantage compared with alternate day IHD after adjustment for severity of illness (level I) [52]. However, CRRT was associated with a significantly higher rate of complete renal recovery in surviving patients who received an adequate trial of therapy, without crossover to IHD (CRRT 92.3% vs IHD 59.4%, p < .01). Of notice, in this study patients were excluded when MAP was <70 mm Hg in the 8 hours preceding randomization. Furthermore, significant baseline differences in severity of illness existed between groups and the delivered dialysis dose per group was not reported, making comparison difficult. 2. In a large multicenter RCT (n=224) septic patients were randomized to receive either IHD or CVVHDF with the same polyacrilonitrile membrane and bicarbonate buffer [54]. The 60-day survival was 23,5% in the CVVHDF group and 28,6% in the IHD group (p=0.23) (level I) 3. In a single-center RCT (n=125) patients were randomized into CVVHDF or daily IHD treatment [53]. IHD was started gently with a low blood flow and small hemofilter and removing small amounts of fluid, to avoid haemodynamic instability. The treatment doses were comparable between groups. Hospital mortality was 47% in the CVVHDF group and 51% in the IHD group (p = 0.72). Unfortunately, the study was underpowered due to the preterminal end and the smaller than expected number of patients included (level II). 4. A single-center RCT (n=80) that compared CVVHD with alternate day IHD showed no survival or renal recovery advantages between groups, despite a significant decrease in MAP for patients on IHD therapy not seen in those on CVVHD therapy (level II) [50]. However, the study was not sufficiently powered for survival as an endpoint. 5. A single-center RCT (n=104) showed no differences in survival or MAP between patients receiving CVVH and patients treated with daily IHD (level II) [51]. Again, this study was not adequately powered to detect small differences between modalities. Furthermore, the majority of patients (n=33) in the CVVH group were treated with low-volume CVVH (18 mL/kg/h) and this may also have adversely affected the outcome in the CVVH group. 6. Kellum et al. [55] performed a metaanalysis, including 13 studies (n=1400) comparing CRRT with IHD, and did not find a statistically significant impact of dialysis modality on survival and renal recovery in haemodynamic stable patients (level I). 7. Tonelli et al. [56] included six studies in their metaanalysis



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Final recommendations Because of the quality of the studies recommendation grades are low. Comparison among the studies is complicated by the use of various definitions of ARF. Furthermore, strategies of timing, dose and RRT mode are likely to interact. However, most of the studies only investigate one of these items and do not report on the others, making it difficult to draw firm conclusions.

Figure 1. The RIFLE Classification for acute renal failure [6]. (With approval of the ADQI) Screat, serum creatinine (4 mg/dL = 354 mmol/L, 0.5 mg/dL = 44 mmol/L); GFR, glomerular filtration rate; UO, urine output; ARF, acute renal failure; ESKD, end stage kidney disease;

(n=624) and concluded that in unselected critically ill patients with ARF, CRRT does not improve survival or renal recovery (level I). 8. In a large (n=839) prospective, multicenter cohort study mortality was comparable between the patients undergoing IHD and the patients undergoing CRRT, however patients undergoing IHD had lower Logistic Organ Dysfunction Scores (level III) [57]. 9. Likewise, in another large (n=587) observational prospective multicenter study RRT was not found to have any prognostic value [58]; however, patients selected for CRRT had a higher number of organ dysfunction at admission and at the time of ARF (level III). 10. Two smaller observational studies [59,60] reported improved survival with CRRT, even though CRRT patients were sicker at baseline (level III). 11. Two retrospective studies [61,62] in critically ill patients with ARF showed comparable mortality between the IHD group and the CRRT group, but patients with severe illness were preferentially selected for CRRT (level IV).

HF in patients with sepsis or SIRS without ARF is not supported by enough evidence to be recommended in daily clinical practice.

Discussion

None of the level I or level II studies showed a survival advantage for CRRT as compared with conventional IHD [50-56]. However, the largest RCT [52] suggest that CRRT is associated with increased complete renal recovery (level I). Although most of the studies did not report on the delivered treatment dose per group, none of the studies seem to have achieved the higher dose associated with a better survival in the CRRT studies [26,32]. The study of Mehta et al. [52], suggests that there is a physician’s bias for CRRT being the treatment of choice for patients in shock and this was also suggested in numerous prospective observational and retrospective studies [57-62]. Indeed, beneficial effects on cardiovascular stability, cerebral oedema and intestinal acidosis have been reported during CRRT therapy in comparison with conventional IHD [50;63-67] (level II). On the other hand, the study of Uehlinger et al. [53], suggests that haemodynamic instability during IHD can be avoided even in unstable patients, as long as gentle IHD is applied (daily sessions using low blood flow, small surface filter and discrete fluid removal).

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The below recommendations concern critically ill patients with ARF • It is recommended to define ARF according to the RIFLE classification system into ARFrisk, ARFinjury and ARFfailure. • It is recommended to base the decision when to start RRT not only on the severity of ARF, but also on the severity of other organ failure (Grade E). Initiation of RRT is to be considered in oliguric patients (RIFLErisk-oliguria or RIFLEinjury-oliguria), despite adequate fluid resuscitation, and/or a persisting steep rise in serum creatinine, in addition to persisting shock (Grade E). RRT may be postponed when the underlying disease is improving, other organ failure recovering and the slope in the serum creatinine rise declines, in order to see if renal function is also recovering (Grade E). • It is recommended to continue RRT as long as the criteria defining severe oliguric ARF (RIFLEfailure-oliguria) are present (grade E). If the clinical condition improves, it may be considered to wait before connecting a new circuit to see whether renal function recovers. RRT should be restarted in case of clinical or metabolic deterioration. • The recommended delivered (not prescribed) ultrafiltrate (dialysate) flow during CVVH(D) is 35 mL/kg/h in postdilution (Grade A). A higher dose applied for a short period may be considered in sepsis/SIRS (grade E). The dose needs to be adjusted for predilution using the dilution factor, and for filter down time. • In non-shock patients, continuous and intermittent treatments are equivalent regarding survival (level I). However, CRRT is recommended over IHD for patients with ARF who have, or are at risk for, cerebral oedema (Grade C). CRRT is preferred in the management of patients with ARF and shock (Grade E). • CRRT should be applied in the venovenous mode (Grade B)

Samenvatting aanbevelingen De aanbevelingen hebben betrekking op de ernstig zieke IC patiënt met acute nierinsufficiëntie. • Het advies is om acute nierinsufficientie volgens het RIFLE classificatie system te definiëren in de categorieen ARFrisk, ARFinjury and ARFfailure • Het advies is om de beslissing om met nierfunctie vervangende therapie (NVT) te beginnen niet alleen te laten afhangen van de ernst van het acute nierfalen maar ook van de ernst van het overig orgaanfalen (niveau E). Starten van RRT kan worden overwogen bij oligure patiënten (RIFLErisk-oliguria of RIFLEinjury- oliguria), en/ of bij patiënten met een aanhoudende snelle stijging in het kreatinine gehalte in combinatie met aanhoudende shock (niveau E). Uitstel van NVT kan worden overwogen indien de onderliggende ziekte aan het verbeteren is, overig orgaan falen herstellende en het kreatinine gehalte aan het aftoppen is, om te zien of de nierfunctie ook herstellende is (niveau E).


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• Het advies is om de NVT voort te zetten zolang er voldaan wordt aan de ernstige oligurie criteria (RIFLEfailure-oliguria) (niveau E). Men kan overwegen het aansluiten van een nieuw circuit uit te stellen indien de klinische conditie aan het verbeteren is om te beoordelen of de nierfunctie ook aan het herstellen is. • Het advies is om tijdens CVVH(D) in postdilutie daadwerkelijk een ultrafiltraat (dialysaat) flow van 35 mL/kg/h te geven (niveau A). Bij sepsis/SIRS kan men overwegen gedurende korte tijd te behandelen met een hogere ultrafiltraat flow (Niveau E). De dosis moet worden gecorrigeerd voor predilutie met de verdunnings factor en voor de uren dat de filtratie (dialyse) niet loopt. • Bij patiënten zonder shock is geen verschil in overleving aangetoond tussen continue en intermitterende behandeling (level I). Echter, bij patiënten met hersenoedeem of een verhoogd risico hierop wordt CRRT aanbevolen (niveau C). Continue behandelingen verdienen de voorkeur bij patiënten met shock (niveau E). • Voor continue behandelingen moeten venoveneuze technieken worden toegepast (niveau B) Er bestaat onvoldoende bewijs om HF te adviseren bij patiënten met sepsis of SIRS zonder acute nierinsufficientie.

List of abbreviations. ADQI: acute dialysis quality initiative APACHE: acute physiology and chronic health evaluation ARF: acute renal failure BUN: blood urea nitrogen CAVH: continuous arteriovenous haemofiltration CRRT: continuous renal replacement therapy CVVH: continuous venovenous haemofiltration CVVHD: continuous venovenous haemodialysis CVVHDF: continuous venovenous haemodiafiltration ESRD: end stage renal disease ICU: intensive care unit IHD: intermittent haemodialysis Kt/V: fractional clearance (K=clearance, t=time, V=volume) MAP: mean arterial pressure RCT: randomized controlled trial RIFLE: Risk Injury Failure Loss End stage kidney disease RRT: renal replacement therapy SAPS: simplified acute physiology score SIRS: systemic inflammatory response syndrome

Appendix - Committee of nephrology and intensive care of the Dutch Society of Intensive Care (NVIC): Heleen M. Oudemans-van Straaten, Catherine C.S. Bouman, Anne-Cornelie J.M. de Pont, A.B. Johan Groeneveld, Miet Schetz, Arend Jan Woittiez. - Committee of quality of the Dutch Federation of Nephrology (NFN): Robert Zietse, Jeroen Kooman, Coen A. Stegeman. References 1. Oudemans-van Straaten H, Wester J. Resultaten van de enquete naar de praktijk van nierfunctievervangende behandeling op de intensive care in Nederland. Neth J Crit Care 2002;6:18-19. 2. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-818. 3. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. Arteriovenous haemofiltration: a new and simple method for treatment of over-hydrated patients resistant to diuretics. Klin Wochenschr 1977;55:1121-1122. 4. Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care 2002;8:509-514. 5. Ronco C, Kellum JA, Mehta R. Acute dialysis quality initiative (ADQI). Nephrol Dial Transplant 2001;16:15551558. 6. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-R212. 7. Damen J, van Diejen D, Bakker J, van Zanten A. NVICstandpunten, NVIC-richtlijnen en de juridische implicaties. Neth J Crit Care 2002;6:18-21. 8. Ricci Z, Ronco C, D’Amico G, De Felice R, Rossi S, Bolgan I, et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant 2006;21:690-696. 9. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ. Acute renal failure in intensive care units--causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996;24:192-198.

10. Cole L, Bellomo R, Silvester W, Reeves JH. A prospective, multicenter study of the epidemiology, management, and outcome of severe acute renal failure in a “closed” ICU system. Am J Respir Crit Care Med 2000;162:191196. 11. Himmelfarb J, Tolkoff RN, Chandran P, Parker RA, Wingard RL, Hakim R. A multicenter comparison of dialysis membranes in the treatment of acute renal failure requiring dialysis. J Am Soc Nephrol 1998;9:257-266. 12. Bouman CS, Oudemans-van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial. Crit Care Med 2002;30:2205-2211. 13. Jiang HL, Xue WJ, Li DQ, Yin AP, Xin X, Li CM. Influence of continuous veno-venous hemofiltration on the course of acute pancreatitis. World J Gastroenterol 2005;11:4815-4821. 14. Demirkilic U, Kuralay E, Yenicesu M, Caglar K, Oz BS, Cingoz F, et al. Timing of replacement therapy for acute renal failure after cardiac surgery. J Card Surg 2004;19:17-20. 15. Elahi MM, Lim MY, Joseph RN, Dhannapuneni RR, Spyt TJ. Early hemofiltration improves survival in post-cardiotomy patients with acute renal failure. Eur J Cardiothorac Surg 2004;26:1027-1031. 16. Gettings LG, Reynolds HN, Scalea T. Outcome in posttraumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 1999;25:805-813. 17. Piccinni P, Dan M, Barbacini S, Carraro R, Lieta EMSZN, Brendolan A, et al. Early isovolaemic haemofiltration in oliguric patients with septic shock. Intensive Care Med 2006;32:80-86.

18. Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, Pirenne B, et al. Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000;28:3581-3587. 19. NKF-DOQI clinical practice guidelines for hemodialysis adequacy. National Kidney Foundation. Am J Kidney Dis 1997;30:S15-S66. 20. Gotch FA, Sargent JA, Keen ML. Whither goest Kt/V? Kidney Int Suppl 2000;76:S3-18. 21. Marshall MR. Current status of dosing and quantification of acute renal replacement therapy. Part 2: dosing paradigms and clinical implementation. Nephrology (Carlton ) 2006;11:181-191. 22. Marshall MR. Current status of dosing and quantification of acute renal replacement therapy. Part 1: mechanisms and consequences of therapy under-delivery. Nephrology (Carlton ) 2006;11:171-180. 23. Ricci Z, Salvatori G, Bonello M, Pisitkun T, Bolgan I, D’Amico G, et al. In vivo validation of the adequacy calculator for continuous renal replacement therapies. Crit Care 2005;9:R266-R273. 24. Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978-986. 25. Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, et al. Hemofiltration and peritoneal dialysis in infectionassociated acute renal failure in Vietnam. N Engl J Med 2002;347:895-902. 26. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Piccinni P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;356:26-30. 27. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305-310.



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28. Brause M, Neumann A, Schumacher T, Grabensee B, Heering P. Effect of filtration volume of continuous venovenous hemofiltration in the treatment of patients with acute renal failure in intensive care units. Crit Care Med 2003;31:841-846. 29. Gotloib L, Barzilay E, Shustak A, Wais Z, Jaichenko J, Lev A. Hemofiltration in septic ARDS. The artificial kidney as an artificial endocrine lung. Resuscitation 1986;13:123-132. 30. Cole L, Bellomo R, Hart G, Journois D, Davenport P, Tipping P, et al. A phase II randomized, controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002;30:100-106. 31. Laurent I, Adrie C, Vinsonneau C, Cariou A, Chiche JD, Ohanessian A, et al. High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. J Am Coll Cardiol 2005;46:432-437. 32. Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, et al. Martin PY: Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 2006;70:1312-1317 33. Joannes-Boyau O, Rapaport S, Bazin R, Fleureau C, Janvier G. Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock. ASAIO J 2004;50:102-109. 34. Oudemans-van Straaten HM, Bosman RJ, van der Spoel JI, Zandstra DF. Outcome of critically ill patients treated with intermittent high-volume haemofiltration: a prospective cohort analysis. Intensive Care Med 1999;25:814-821. 35. Ratanarat R, Brendolan A, Piccinni P, Dan M, Salvatori G, Ricci Z, et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Crit Care 2005;9:R294-R302. 36. Cornejo R, Downey P, Castro R, Romero C, Regueira T, Vega J, et al. High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med 2006;32:713-722. 37. Oudemans-vanStraaten HM, Bouman CS, Zandstra DF. Survival in acute renal failure. Intensive Care Med 2005;31:889-890. 38. Palevsky P. the Renal Failure Trial Network (ATN) study. http://www ATNStudy org. Accessed on August 2006. 39. Bellomo R. Augmented versus normal renal replacement therapy in severe acute renal failure. http:// www clinicaltrials gov/ct/show/NCT00221013?order=3. Accessed on August 2006. 40. Joannes-Boyau O: the IVOIRE study. www clinicaltrials gov/ct/show/NCT00241228?order=1. Accessed on August 2006. 41. Marshall MR, Golper TA, Shaver MJ, Chatoth DK. Hybrid renal replacement modalities for the critically ill. Contrib Nephrol 2001;252-257. 42. Kumar VA, Yeun JY, Depner TA, Don BR. Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: a two-year single center report. Int J Artif Organs 2004;27:371-379.

43. Marshall MR, Golper TA, Shaver MJ, Alam MG, Chatoth DK. Sustained low-efficiency dialysis for critically ill patients requiring renal replacement therapy. Kidney Int 2001;60:777-785. 44. Ronco C, Bellomo R. Basic mechanisms and definitions for continuous renal replacement therapies. Int J Artif Organs 1996;19:95-99. 45. Ricci Z, Ronco C, Bachetoni A, D’Amico G, Rossi S, Alessandri E, et al. Solute removal during continuous renal replacement therapy in critically ill patients: convection versus diffusion. Crit Care 2006;10:R67. 46. Canaud B, Garred LJ, Christol JP, Aubas S, Beraud JJ, Mion C. Pump assisted continuous venovenous hemofiltration for treating acute uremia. Kidney Int Suppl 1988;24:S154-S156. 47. Tam PY, Huraib S, Mahan B, LeBlanc D, Lunski CA, Holtzer C, et al. Slow continuous hemodialysis for the management of complicated acute renal failure in an intensive care unit. Clin Nephrol 1988;30:79-85. 48. Macias WL, Mueller BA, Scarim SK, Robinson M, Rudy DW. Continuous venovenous hemofiltration: an alternative to continuous arteriovenous hemofiltration and hemodiafiltration in acute renal failure. Am J Kidney Dis 1991;18:451-458. 49. Storck M, Hartl WH, Zimmerer E, Inthorn D. Comparison of pump-driven and spontaneous continuous haemofiltration in postoperative acute renal failure. Lancet 1991;337:452-455. 50. Augustine JJ, Sandy D, Seifert TH, Paganini EP. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004;44:1000-1007. 51. Gasparovic V, Filipovic-Grcic I, Merkler M, Pisl Z. Continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)--what is the procedure of choice in critically ill patients? Ren Fail 2003;25:855-862. 52. Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154-1163. 53. Uehlinger DE, Jakob SM, Ferrari P, Eichelberger M, Huynh-Do U, Marti HP, et al. Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 2005;20:16301637. 54. Vinsonneau C, Camus C, Combes A, Costa de Beauregard MA, Klouche K, Boulain T, et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet 2006;368:379-385. 55. Kellum JA, Angus DC, Johnson JP, Leblanc M, Griffin M, Ramakrishnan N, et al. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med 2002;28:29-37.

56. Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002;40:875-885. 57. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30:2051-2058. 58. Guerin C, Girard R, Selli JM, Ayzac L. Intermittent versus continuous renal replacement therapy for acute renal failure in intensive care units: results from a multicenter prospective epidemiological survey. Intensive Care Med 2002;28:1411-1418. 59. Bellomo R, Farmer M, Parkin G, Wright C, Boyce N. Severe acute renal failure: a comparison of acute continuous hemodiafiltration and conventional dialytic therapy. Nephron 1995;71:59-64. 60. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR. A comparison of continuous arteriovenous hemofiltration and intermittent hemodialysis in acute renal failure patients in the intensive care unit. ASAIO J 1993;39: M778-M781. 61. Gangji AS, Rabbat CG, Margetts PJ. Benefit of continuous renal replacement therapy in subgroups of acutely ill patients: a retrospective analysis. Clin Nephrol 2005;63:267-275. 62. van Bommel E, Bouvy ND, So KL, Zietse R, Vincent HH, Bruining HA, et al. Acute dialytic support for the critically ill: intermittent hemodialysis versus continuous arteriovenous hemodiafiltration. Am J Nephrol 1995;15:192-200. 63. Davenport A, Will EJ, Davison AM, Swindells S, Cohen AT, Miloszewski KJ, et al. Changes in intracranial pressure during machine and continuous haemofiltration. Int J Artif Organs 1989;12:439-444. 64. Davenport A, Will EJ, Davison AM, Swindells S, Cohen AT, Miloszewski KJ, et al. Changes in intracranial pressure during haemofiltration in oliguric patients with grade IV hepatic encephalopathy. Nephron 1989;53:142146. 65. Ronco C, Bellomo R, Brendolan A, Pinna V, La Greca G. Brain density changes during renal replacement in critically ill patients with acute renal failure. Continuous hemofiltration versus intermittent hemodialysis. J Nephrol 1999;12:173-178. 66. Van der SG, Diltoer M, Laureys M, Huyghens L. Intermittent hemodialysis in critically ill patients with multiple organ dysfunction syndrome is associated with intestinal intramucosal acidosis. Intensive Care Med 1996;22:747-751. 67. John S, Griesbach D, Baumgartel M, Weihprecht H, Schmieder RE, Geiger H. Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: a prospective, randomized clinical trial. Nephrol Dial Transplant 2001;16:320-327.

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Commissies & Afgevaardigden Voedingscommissie Drs. R. Tepaske, AMC, Amsterdam (voorzitter) P. Bruynzeel, AMC, Amsterdam Drs. F.M.P. van Haren, VieCuri MC, Venlo Prof. Dr. E.M.H. Mathus-Vliegen, AMC, Amsterdam Dr. H.M. Oudemans-van Straaten, OLVG, Amsterdam Prof. Dr. D. Tibboel, Erasmus Medisch Centrum Sophia, Rotterdam Commissie IC transport Drs. E.J. van Lieshout, AMC, Amsterdam (voorzitter) Prof. Dr. J.J.L.M. Bierens, VUMC, Amsterdam Drs. R.J.R. Eijk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. J.H.J. Meeder, Medisch Centrum Rijnmond Zuid, Rotterdam Drs. G.D. Vos, Academisch Ziekenhuis, Maastricht Drs. J. van de Wetering, Isala Klinieken, Zwolle Commissie Producttypering IC Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede (voorzitter) Dr. A.N. Roos, Catharina Ziekenhuis, Eindhoven Drs. A.M.G.A. de Smet, UMCU, Utrecht Drs. J.I. van der Spoel, OLVG, Amsterdam (secretaris) Dr. P.E. Spronk, Gelre Ziekenhuizen, Apeldoorn Drs. L.F. te Velde, Albert Schweitzer Ziekenhuis, Dordrecht Commissie Richtlijnontwikkeling Dr. J. Damen, Isala Klinieken, Zwolle (voorzitter) Drs. E.C. Boerma, Medisch Centrum, Leeuwarden Drs. E.A.C. Bouman, Academisch Ziekenhuis, Maastricht Dr. A.W.W.M. Koopman-van Gemert, Albert Schweitzer Ziekenhuis, Dordrecht Dr. H.J. van Leeuwen, Ziekenhuis Gelderse Vallei, Ede (secretaris) Dr. K.H. Polderman, Universitair Medisch Centrum Utrecht Drs. A.M.T.J. Raben, Groene Hart Ziekenhuis, Gouda Dr. J.J. Spijkstra, VUMC, Amsterdam Drs. R. Tepaske, AMC, Amsterdam Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem Wetenschapscommissie Prof. Dr. D. Tibboel, Erasmus Medisch Centrum Sophia, Rotterdam (voorzitter) Prof. Dr. L.P.H.J. Aarts, Universitair Medisch Centrum, Groningen Dr. D. Bergmans, Academisch Ziekenhuis, Maastricht Prof. Dr. Ir. C. Ince, AMC, Amsterdam Prof. Dr. J. Kesecioglu, UMCU, Utrecht Dr. P. Pickkers, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Dr. P.E. Spronk, Gelre Ziekenhuizen, Apeldoorn Dr. J.E. Tulleken, Universitair Medisch Centrum, Groningen Commissie Internet Drs. C.P.C. de Jager, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch (voorzitter) Dr. J. de Koning, Maxima Medisch Centrum, Veldhoven Drs. S. Kurban, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. F. Nooteboom, Viecuri Medisch Centrum, Venlo Dr. K.H. Polderman, Universiteit Medisch Centrum Utrecht Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem Vertegenwoordiging in de Gemeenschappelijk Intensive Care Commissie Drs. B.M. van der Kolk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Dr. K.H. Polderman, Universiteit Medisch Centrum Utrecht Drs. A.M.G.A. de Smet, UMCU, Utrecht Commissie Kwaliteit Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede (voorzitter) Dr. M.S. Arbous, Leids Universitair Medisch Centrum, Leiden Dr. J. Damen, Isala Klinieken, Zwolle Prof. Dr. A.R.J. Girbes, VUMC, Amsterdam

Drs. F.M. Versteegen, adviseur Dr. P.H.J. van der Voort, Medisch Centrum, Leeuwarden Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem Dr. A.J. Woittiez, Twenteborg Ziekenhuis, Almelo Commissie Fellows Drs. I. Stijn, Onze Lieve Vrouwe Gasthuis, Amsterdam (voorzitter) Drs. N. van Bussink-van Dijk, Academisch Ziekenhuis Maastricht Dr. H. Buter, Universitair Medisch Centrum, Groningen Drs. J.A.R. van Dijk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. M.I. Fokkema, Universitair Medisch Centrum, Groningen Drs. M.G.E.C. Hilkens, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. B. Kors, VU Medisch Centrum, Amsterdam Drs. C. Kleppe, VU Medisch Centrum, Amsterdam Dr. H.G. Kreeftenberg, UMCU, Utrecht Drs. D.J. Mehagnoul, Academisch Ziekenhuis Maastricht Drs. A.J. Paling, Leids Universitair Medisch Centrum, Leiden Drs. M. van Spreuwel-Verheijen, OLVG, Amsterdam Commissie Kwaliteitsindicatoren IC Dr. P.H.J. van der Voort, Onze Lieve Vrouwe Gasthuis, Amsterdam (voorzitter) Drs. D.H.C. Burger, St. Elisabeth Ziekenhuis, Tilburg Drs. A.A. Corsten, Canissius-Wilhelmina Ziekenhuis, Nijmegen Drs. F.E. van Dijk, Antonius Ziekenhuis, Nieuwegein (NVICV) Mw. M. Fuijkschot, Ziekenhuis Rivierenland Tiel Dr. E. de Jonge, AMC, Amsterdam Dr. W.C. Graafmans, RIVM, Utrecht Drs. M. de Vos, RIVM, Utrecht Mevr. J. Vreman, Radboud Universiteit Nijmegen Medisch Centrum , Nijmegen Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Commissie Nefrologie Dr. H.M. Oudemans-van Straaten, OLVG, Amsterdam (voorzitter) Drs. C.S.C. Bouman, AMC, Amsterdam Prof. Dr. A.B.J. Groeneveld, VUMC, Amsterdam Dr. A.C.J.M. de Pont, AMC, Amsterdam Prof. Dr. M.R.C. Schetz, Universiteitsziekenhuis, Leuven Dr. A.J. Woittiez, Twenteborg Ziekenhuis, Almelo Commissie Complicatieregistratie Dr. M.S. Arbous, Leids Universitair Medisch Centrum, Leiden (voorzitter) Dr. A. Balzereit, Leids Universitair Medisch Centrum, Leiden Dr. B. Beishuizen, VU Medisch Centrum, Amsterdam Drs. L. Dawson, Reinier de Graafgasthuis, Delft Drs. S. Dijkstra, Groene Hart Ziekenhuis, Gouda Prof. Dr. J.G. van der Hoeven, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. A. Manten, Meander Medisch Centrum, Amersfoort Commissie Ethiek Dr. R.Th. Gerritsen, Medisch Centrum, Leeuwarden (voorzitter) Dr. R.G. Hoff, UMCU, Utrecht Dr. B.S. Hylkema, Medisch Spectrum Twente, Enschede Dr. E.J.O. Kompanje, Erasmus Medisch Centrum, Rotterdam Mr. E.W.M. Meulemans, advocaat, Zwolle Dr. B.W. Mooi, Isala Klinieken, Zwolle Prof. Dr.J. Kesecioglu, Universitair Medisch Centrum Utrecht Nationale Visitatiecommissie IC Prof. Dr. A.R.J. Girbes, VUMC, Amsterdam (voorzitter) Drs. S.J. van Leeuwen, St. Jans-Gasthuis, Weert C. Tielemans, Amphia Ziekenhuis, Breda (NVICV) Drs. F.M. Versteegen, adviseur Commissie Zorgvernieuwingsprojecten Dr. A.J.J. Woittiez, Twenteborg Ziekenhuis, Almelo (voorzitter)

Drs. M. van Berkel, Beatrix Ziekenhuis, Gorinchem Dhr P. Bocxe, AMC, Amsterdam Mw. H. van Dijk, Reinier de Graaf Gasthuis, Delft Mw. A. Klijnstra, Ziekenhuis Tjongerschans, Heerenveen Mw. Drs. L.M.T. Schouten, Senior adviseur kwaliteitsinstituut voor de gezondheidszorg CBO Drs. F. van Tilborg, Reinier de Graaf Gasthuis, Delft Dhr. H. Verhey, Twenteborg Ziekenhuis, Almelo (secretaris) Commissie Accreditatie Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem (voorzitter) Prof. Dr. A.R.J. Girbes, VUMC, Amsterdam Drs. A. Manten, Meander Medisch Centrum, Amersfoort Drs. I.A. Meynaar, Reinier de Graaf Gasthuis, Delft Drs. H.H. Ponssen, Albert Schweitzer Ziekenhuis, Dordrecht Drs. D.H.T. Tjan. Ziekenhuis Gelderse Vallei, Ede Dr. D.F. Zandstra, OLVG, Amsterdam Programmacommissie 2007 Prof. Dr. J.G. van der Hoeven, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen (voorzitter) Dr. S.J.A. Aerdts, Isala Klinieken, Zwolle Prof. Dr. A.R.J. Girbes, VUMC, Amsterdam Prof. Dr. G.J. Scheffer, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Prof. Dr. D. Tibboel, Erasmus Medisch Centrum Sophia, Rotterdam Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Bestuurscommissie FCCS Nederland Drs. F. Nooteboom, VieCuri MC, Venlo (voorzitter) Drs. B.M. van der Kolk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. L.M. Lambalk, Westfries Gasthuis, Hoorn Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede FCCS Course Directors Drs. F. Nooteboom, VieCuri MC, Venlo (National Course Director) Drs. D.H.C. Burger, St. Elisabeth Ziekenhuis, Tilburg Dr. N.A. Foudraine, VieCuri MC, Venlo Drs. H.P.M.M. Gelissen, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Prof. Dr. J.G. van der Hoeven, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. E.F. Salm, Reinier de Graaf Gasthuis, Delft Drs. J.M.M. Verwiel, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Prof. Dr. J.H. Zwaveling, Academisch Ziekenhuis, Maastricht Commissie NVIC Medium Care Drs. D.H.T. Tjan, Ziekenhuis Gelderse Vallei, Ede (voorzitter) Drs. L.E.M. Haas, Ziekenhuis Gelderse Vallei, Ede Drs. M.S. van der Steen, Kennemer Gasthuis, Haarlem Dr. J.J. Spijkstra, VU Medisch Centrum, Amsterdam Dr. M.A. Boermeester, Academisch Medisch Centrum, Amsterdam Drs. E.F. Salm, Reinier de Graaf Gasthuis, Delft Dr. J.J. van Lieshout, Academisch Medisch Centrum, Amsterdam Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Prof. Dr. J. Bakker, Erasmus MC locatie Dijkzigt Werkgroep Neuro-Intensive Care Neurologen Dr. G.W. van Dijk, Canisius Wilhelmina Ziekenhuis Dr. M. van der Jagt, Erasmus MC R’dam Dr. R.W.M. Keunen, Hagaziekenhuis Den Haag Dr. R.A. van der Kruijk, Slingeland Doetinchem Dr. P.E. Vos, UMCN Nijmegen Intensivisten Dr. M.A. Kuiper, Medisch Centrum Leeuwarden (voorzitter) Dr. S.J.A. Aerdts, Isala klinieken locatie Sophia Zwolle Dr. D. Hasan, VieCuri Venlo Dr. C. Hoedemaekers, Universitair Medisch Centrum St Radboud Dr. J. Horn, Academisch Medisch Centrum Amsterdam Drs. J.J. Maas, Leids Universitair Medisch Centrum



Dr. J. van der Naalt, Utrecht Medisch Centrum Groningen Dr. K.H. Polderman, VUMC Amsterdam Dr. A.J.C. Slooter, Universitair Medisch Centrum Utrecht Drs. J.C.W. Taal, Leids Universitair Medisch Centrum Drs. W.J. Thijsse, Erasmus MC R’dam Neurochirurgen Dr. A.I.R. Maas, Erasmus MC Dr. S.M. Peerdeman, VU Medisch Centrum Amsterdam Dr. B. Verweij, Universitair Medisch Centrum Utrecht

Afgevaardigden Stuurgroep IC Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Nederlandse Reanimatieraad Drs. M.J. Gardien, Medisch Centrum Rijnmond Zuid, Rotterdam Hemovigilantie Project TRIP Dr. A.W.M.M. Koopman-van Gemert, Albert Schweitzer Ziekenhuis, Dordrecht SWAB Richtlijn Gist- en Schimmelinfecties Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede CBO Richtlijn perioperatieve Voeding Drs. R. Tepaske, AMC, Amsterdam Liaison officer NIV richtlijn commissie Drs. E.J. van Lieshout, AMC, Amsterdam CBO Richtlijn cystic fibrosis Drs. P.M.S. Schröder, Ziekenhuis, Blaricum. EBRO richtlijn AAA Drs. J.C. Pompe, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen ESICM Cobatrice Prof. Dr. A.R.J. Girbes, VUMC, Amsterdam Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Werkgroep Infectie Preventie (herzien richtlijn Intravasale Therapie) Drs. C.V. Elzo Kraemer, Leids Universitair Medisch Centrum, Leiden Werkgroep Preventie van perioperatieve cardiale complicaties bij niet-cardiale chirurgie Dr. H.J. van Leeuwen, Ziekenhuis Gelderse Vallei, Ede Externe Klankbordgroep Cardiochirurgische Zorgketen Dr. P.H.J. van der Voort, Medisch Centrum Leeuwarden locatie MCL zuid, Leeuwarden Genosept, ESICM DR. J.A. Hazelzet, Erasmus Medisch Centrum, Rotterdam Werkgroep Richtlijnontwikkeling Sedatie en/of analgesie door niet-anesthesiologen Dr. J.J. Spijkstra, VU Medisch Centrum, Amsterdam Werkgroep Richtlijnontwikkeling Perioperatieve behandeling van de pulmonaal belaste patiënt Drs. J.M. van der Klooster, St Franciscus Gasthuis, Rotterdam

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Verenigingsnieuws CBO richtlijn Perioperatieve behandeling van de pulmonaal belaste patiënt

derland twee artsen en twee verpleegkundigen als visiteur op te geven. De NVIC zal zorgen voor de training die daarvoor vereist is. (Voorwaarde is wel dat zij nog werkzaam zijn op een intensive care afdeling). Deze trainingsochtend zal plaatsvinden op 14 april as. Het doel van de visitaties is het formuleren van afdelingsgebonden adviezen ter verbetering van de patiëntenzorg op de IC. Visitatie heeft daarnaast ook een externe doelstelling. Voor de continuïteit van de intensieve zorgverlening is het van belang dat er een breed gedragen vertrouwen is in de kwaliteit van deze afdelingen. Visitaties zijn een middel om inhoud te geven aan de verplichting dit vertrouwen waar te maken. De resultaten van de visitaties kunnen eveneens leiden tot het geven van (geanonimiseerde) informatie of advies aan beleidsbepalende instanties. Zo hebben geaggregeerde gegevens uit de eerste 44 visitaties bijgedragen aan beleidsvoornemens in het Platform Intensive Care op het gebied van IC capaciteit, transport, opleiding voor Intensivisten en IC-verpleegkundigen, regionalisering en separate DBC financiering voor IC. De gezamenlijke verenigingen zien uw opgave van visiteurs graag tegemoet. Na het verenigingsnieuws treft u een antwoordformulier aan. Graag ontvangen we het antwoordformulier voor 15 maart as retour. ARJ Girbes, voorzitter Nationale Commissie Visitatie IC

In het kader van de richtlijnontwikkeling wordt een multidisciplinaire werkgroep Perioperatieve behandeling van de pulmonaal belaste patiënt samengesteld. Als vertegenwoordiger namens de NVIC is Drs JM van der Klooster afgevaardigd. JHJ Meeder, secretaris

Werven visiteurs kwaliteitsvisitaties IC Voor Intensive Care afdelingen is het essentieel dat zij kwalitatief goede zorg verlenen. Het multidisciplinair werken op deze afdelingen staat centraal. Voor een goede kwaliteit van zorg is het van belang dat de medewerkers op deze afdeling zich openstellen voor evaluatie door beroepsgenoten. Dit zorgt ervoor dat zij kritisch blijven ten opzichte van de eigen zorgverlening en bereid zijn te leren van anderen. Daartoe zijn de NVIC en de Nederlandse Vereniging voor Intensive Care voor Verpleegkundigen (NVICV) onder begeleiding van het Kwaliteitsinstituut voor de Gezondheidszorg CBO gestart met een traject van multidisciplinaire visitatie op Intensive Care afdelingen. Uitgangspunt daarbij vormde toetsing aan de Richtlijn Organisatie en Werkwijze voor Nederlandse IC afdelingen ontwikkeld in samenwerking met het CBO. Dit document vormt tot nu toe nog het toetsingskader. Er is echter een nieuw toetsingskader in ontwikkeling. Graag nodigen wij uw Intensive Care afdeling uit om voor de visitaties aan IC afdelingen in Ne-

Donderdag 21 september 2006 Restaurant Het Oude Politiebureau, Ede

• Nationale Pijndagen 2006: October 11th-12th, Apeldoorn, the Netherlands. Information: www.nationalepijndagen.nl • CHEST 2006: 72nd Annual International Scientific Assembly of the American College of Chest Physicians: October 21th-26th, Salt Lake City, USA. Information: www.chestnet.org • Recent advances in medical gas therapy: October 28th, Amsterdam, The netherlands. Information: www.medical-gases.eu • Topics in IC: Multidisciplinair IC congres. November 1st, Lunteren, the Netherlands. Information: [email protected] • Najaarscongres NVA-NVT-NVIC: November 17th, Nieuwegein, the Netherlands. Information: www.nvic.nl • PAOG-cursus Urgentiegeneeskunde: November 24th, Amsterdam, the Netherlands. Information: www.cursusurgentiegeneeskunde.nl • NVIC Mechanische Beademingsdagen: November 30th and December 1st, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www.nvic.nl • NVIC Nederlandse Intensivistendagen 2007: January 31st- February 2nd, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www.nvic.nl • 3rd World Congress Abdominal Compartment Syndrome (WCACS 2007), March 22-24, 2007, Antwerp, Belgium. Information: www.wcacs.org

• NVIC Traumacongres 2007, June 14th – 15th, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www.nvic.nl

4. Bestuursmededelingen

• 5th World Congress of Pediatric Critical Care Societies: June 26-30 th 2007, Geneva Switzerland. Information: - Drs BM van der Kolk treedt af per 21 septemwww.pcc2007.com

1. Opening

De waarnemend voorzitter, KH Polderman, opent de vergadering om 20.05 uur. 2. Notulen vorige vergadering

De leden van de NVIC gaan akkoord met de notulen van de Algemene Ledenvergadering van 8 juni 2006.

Er zijn geen aanvullende agendapunten.

• Europaediatrics 2006 Conference: October 7th-10th , Barcelona, Spain. Information: www.kenes.com/europaediatrics/call.asp

• 12th International Symposium on Infections in the Critically ill Patient, June 8th-9th, 2007, Amsterdam, The Netherlands

Algemene Ledenvergadering NVIC

3. R ondvraag leden voor aanvullende agendapunten

Agenda

ber 2006. - Het bestuur draagt Drs JI van der Spoel voor • NVIC Circulatiedagen 2007: September 6th – 7th, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. als kandidaat-voorzitter. Tegenkandidaten Information: www.nvic.nl worden opgeroepen zich te melden. De kandidaten voor de overige vacante bestuursposi- • NVIC Infectiecongres 2007: November 8th – 9th, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. ties zijn nog niet bekend. Tijdens de AlgemeInformation: www.nvic.nl ne ledenvergadering van november worden de kandidaat-bestuursleden gekozen. - De NVIC wil graag een samenwerkingsverband aangaan met de NICE in het kader van de kwaliteitsregistratie en kwaliteitsverbetering. In de toekomst zal er een uitwisseling van bestuursleden plaatsvinden tussen de NVIC en de NICE. In het NJCC van oktober en op de website zal een voorstel tot samenwer-


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king gepubliceerd worden. Tijdens de ALV van november zal hierover een besluit genomen worden. 5. Concept richtlijn CRRT

De richtlijn Continuous Renal Replacement Therapy is ter stemming aan de leden voorgelegd en wordt aangenomen. 6. G ewijzigd voorstel verhoging contributie

De penningmeester doet een voorstel voor verhoging van de contributie per 1 januari 2007: - Intensivisten en fellows die ingeschreven zijn in het specialistenregister € 300 - Overige leden € 130 Dit voorstel wordt aangenomen.

7. Herregistratiereglement Er wordt opgemerkt dat andere verenigingen bepalen wie zich intensivist mogen noemen en dat de kwalificaties niet duidelijk benoemd zijn. De GIC heeft het initiatief genomen voor het opstellen van het herregistratiereglement. In artikel 6.2 staat dat de GIC een bindend advies geeft en dus een adviserende rol vervult naar de moederspecialismen. Ook part-timers moeten

activiteiten nvic • NVIC Mechanische Beademingsdagen

30 november en 1 december 2006

• NVIC Nederlandse Intensivistendagen 2007

31 januari, 1 en 2 februari 2007

• NVIC Traumacongres

14 en 15 juni 2007

• NVIC Circulatiedagen

6 en 7 september 2007

• NVIC Infectiecongres

de kans krijgen om zich te registreren en dit is mogelijk met de eisen die beschreven staan in het herregistratiereglement. Het document sluit ook aan bij de CBO-richtlijn. De algemene indruk is dat er geen tegenstemmers zijn. Dit zal door de NVIC-vertegenwoordigers gecommuniceerd worden naar de GIC.

geldt. Dit bezwaar was al bekend bij het bestuur en is in behandeling. Er wordt opgemerkt dat er veel vraag is naar FCCS-cursussen maar dat er veel te weinig instructeurs zijn. Geïnteresseerden kunnen zich melden op het NVIC-secretariaat. 9. Sluiting

De waarnemend voorzitter sluit de vergadering om 21.00 uur.

Accreditatie

De moederverenigingen beoordelen de accreditatie vakinhoudelijk. De NVIC is, omdat ze geen wetenschappelijke vereniging is, niet opgenomen in het GAIA-project en kan dus per 1 januari 2007 geen accreditatie meer verlenen. Het bestuur gaat dit opnemen met GAIA. 8. Rondvraag

In de zaal wordt gevraagd of de NVIC een belastingprobleem heeft. Dit wordt bij de penningmeester nagevraagd en hier wordt de volgende ledenvergadering op terug gekomen. Er wordt bezwaar gemaakt tegen de verhoging van de FCCS-kosten en de combinatie van het lidmaatschap voor nieuwe leden. Het bestuur geeft aan dat dit een korting is voor NVICleden die net als bij alle andere congressen

554 intensivisten en fellows 2 rustende leden 1028 overige leden 39 overige abonnees Totaal 1 juni 2006: 1626 Totaal 1 augustus 2006: 1623 Totaal lezersbereik: 3751

NVIC Bestuur Dr. K.H. Polderman Internist-intensivist University Medical Center, Utrecht Voorzitter a.i. E-mail: [email protected] Drs. B.M. van der Kolk Chirurg-intensivist Universitair Medisch Centrum St. Radboud, Nijmegen Penningmeester E-mail: [email protected] Drs. J.H.J. Meeder Anesthesioloog-intensivist Medisch Centrum Rijnmond-Zuid, Rotterdam Secretaris E-mail: [email protected]

Drs. I. van Stijn Internist-intensivist i.o. Onze Lieve Vrouwe Gasthuis, Amsterdam Bestuurslid E-mail: [email protected]

Prof. Dr. D. Tibboel Kinderarts-intensivist Erasmus MC Sophia Kinder ziekenhuis, Rotterdam Bestuurslid E-mail: [email protected]

Drs. C.P.C. de Jager Internist-intensivist Jeroen Bosch Ziekenhuis, Den Bosch Bestuurslid E-mail: [email protected]

Secretariaat NVIC: Stationsweg 73 C, 6711 PL Ede. Telefoon: 0318-693337, Fax: 0318-693338, E-mail: [email protected]

Drs. A.M.G.A. de Smet Anesthesioloog-intensivist Universitair Medisch Centrum, Utrecht E-mail: [email protected]

8 en 9 november 2007

Verenigingen die accreditatie verlenen aan NVIC activiteiten in 2006 NVIC Nederlandse Intensivistendagen 2007 Woensdag 1, donderdag 2 en vrijdag 3 februari 2006 Hotel en Congrescentrum De Reehorst, Ede NVIC Congres: Neurologische Problematiek op De Intensive Care Donderdag 8 en vrijdag 9 juni 2006 Hotel en Congrescentrum De Reehorst, Ede NVIC Mechanische Beademingsdagen 2006 Donderdag 30 november en vrijdag 1 december

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Concept uitgangspunten samenwerking NVIC NICE De NVIC is voornemens voor langere tijd een samenwerking met de stichting NICE aan te gaan voor de kwaliteitsindicatoren. De hieronder beschreven uitgangspunten zijn ter bespreking op de ledenvergadering van november 2006. 1

2

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ren commissie rapporteert half jaarlijks aan hierover. Analyses dienen niet in strijd te zijn zowel het NVIC bestuur als het NICE bestuur. met de doelstellingen van de stichting NICE. Verder onderhoudt de indicatorencommissie Het bestuur beslist of een verzoek om analyse contacten met andere organisaties voor zover past bij de doelstellingen van NICE. Analyses het indicatoren betreft. Ook houdt de indicatoworden in beginsel onder wetenschappelijke ren commissie zich bezig met de ontwikkeling verantwoordelijkheid van de KIK uitgevoerd. van indicatoren in de tijd, in nauw overleg met 11 Publicatie: Voorafgaande aan publicatie worDe samenwerking betreft de ontwikkeling, verwerking, terugkoppeling, analyse, publicatie de besturen van stichting NICE en de NVIC. den manuscripten ter beoordeling aan het en andere aspecten betreffende de set kwalit- 9 De privacy commissie zoals die nu binnen de bestuur van NICE en de indicatoren commissie eitsindicatoren voor intensive care afdelingen. NICE functioneert, zal ook voor de indicatoren voorgelegd. Het bestuur van stichting NICE en de indicatoren commissie is gerechtigd pubVoor andere data en projecten dienen aanvulset functioneren.10 Wetenschappe lende samenwerkingsovereenkomsten gelijke bewerking vindt plaats door de KIK. licatie te verbieden op grond van één van volmaakt te worden. Deelnemers en NVIC hebben voorzover een en gende redenen: ander niet in strijd is met de doelstellingen van Deze samenwerkingsovereenkomst geldt voor - vertrouwelijke informatie van de stichting, 3 jaar, te beginnen 1-1-2007 en kan eventueel NICE het recht om analyses op de database te de NVIC of een deelnemer dreigt te worden tussentijds aangepast worden als beide partijen laten uitvoeren over de periode vanaf start vergeopenbaard. Op verzoek van het stichtingsdaar overeenstemming over bereiken. Medio zameling indicatoren. Deelnemers hebben het bestuur zal de bewerker alle vertrouwelijke 2009 wordt een afspraak over vervolg of beëinrecht analyses te laten uitvoeren over de periode informatie uit de publicatie verwijderen. diging van de samenwerking gemaakt. dat zij deelnemer van NICE waren. Het bestuur - De publicatie bevat niet beschermde octroovan NICE is gerechtigd analyses die niet aan ieerbare informatie van de stichting NICE of Het eigendom van de data ligt bij het deelnemend centrum, mede met het oog op mogelideze voorwaarden voldoen toch toe te staan de NVIC. In deze situatie kan uitstel van pubjke bedreigingen door de Wet Openbaarheid maar informeert de indicatoren commissie licatie van max. 90 dagen worden geëist. Advertentie WCACS 04-10-2006 16:11 Pagina 1 Bestuur. Dit kan altijd als argument gebruikt (advertenties) worden om gegevens niet aan overheid te overhandigen omdat noch de vereniging, noch de stichting NICE eigenaar zijn. Houder van registratie is Stichting NICE. Het NVIC bestuur heeft het recht één bestuurslid van NICE te benoemen. Het bestuur van NICE heeft het recht één positie in het NVIC bestuur te bemannen. De stichting NICE zal hiertoe een persoon voordragen, de NVIC leden Antwerp, Belgium moeten deze benoeming goedkeuren. Doel van de indicatoren registratie: verzameling, verwerking en terugkoppeling van gegevens op gebied van IC geneeskunde met het oog op de organisatie en kostenbeheersing van Endorsed by • WSACS - www.wsacs.org Endorsed by • ESICM - www.esicm.org de gezondheidszorg, alsmede met het oog op Endorsed by • IPACCMS - www.ipaccms.org de bewaking en de verhoging van de kwalitEndorsed by • SCCM - www.sccm.org Endorsed by • RBSS - www.belsurg.org eit van de gezondheidszorg en ten behoeve van Endorsed by • SIZ - www.siz.be wetenschappelijk onderzoek (dit is ook de tekst Accreditation confirmed by the Nederlandse in de NICE statuten voor de huidige registratVereniging voor Heelkunde ies). DIAMOND Sponsors De indicatorencommissie bestaat uit 2 door het NVIC bestuur voor te dragen leden en twee door NICE-bestuur voor te dragen leden. Andere leden worden door de indicatoren commissie voorgedragen aan zowel bestuur van NVIC GOLD Sponsors als NICE die ieder hierover een veto mogen uitspreken. Taak van de indicatoren commissie is onder meer het bewaken dat de handelingen SILVER Sponsors door stichting NICE overeenkomstig de statuten worden uitgevoerd gericht op kwaliteitsverbetering in de Intensive Care geneeskunde For further information: www.wcacs.org and [email protected] en wetenschappelijk onderzoek. De indicato-



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Surviving Sepsis Campaign Netherlands SSC Symposium 2006

Update in sepsis management 15 december 2006 Cinemec Ede, Nederland Speciale workshops en interactieve sessies voor verpleegkundigen en artsen Met medewerking van (inter)nationale topsprekers


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Update in sepsis management 15 december 2006, Cinemec Ede, Nederland

Speciale workshops en interactieve sessies es vo 09.00 uur

Registratie

09.30 uur

Opening

Plenaire Sessie I Voorzitters:

Dave Tjan & Harald Faber

09.35 uur

Update: Ontstekingsmechanismen bij sepsis Prof. dr. Johan Groeneveld, VU Medisch Centrum Amsterdam

10.00 uur

Update: Interventies in het stollingsysteem bij sepsis Prof. dr. Marcel Levi, AMC, Amsterdam

10.25 uur

Update: Early resuscitation of sepsis patients Dr. Richard Beale, Guy’s & St. Thomas’ NHS Foundation Trust, London, UK

10.50 uur

Update: Optimale antimicrobiële therapie bij sepsis Prof. dr. Marc Bonten, UMC, Utrecht

11.15 uur

Pauze

Voorzitters:

Arthur van Zanten & Hazra Biemond-Moeniralam

11.45 uur

Update: Corticosteroids in sepsis Prof. dr. Djillali Annane, Raymond Poincaré University Hospital, Garches, France

12.10 uur

Update: Strikte glucose regulatie bij sepsis patiënten Prof. dr. Greet van den Berghe, Universitair Ziekenhuis Gasthuisberg, Leuven, België

12.35 uur

Update: Long-protectieve beademing bij ernstig respiratoire insufficiëntie Prof. dr. Hans van der Hoeven, internist-intensivist, UMC St. Radboud, Nijmegen

13.00 uur

Lunch en Posters

Medische Workshops (selecteer 2 workshops die u graag wil bezoeken) 14.00 uur

A B C D E

Early-goal directed therapy in clinical practice Clinical use of corticosteroids Hoe bereik ik strikte glucose regulatie? Longsparende beademing: Hoe ik het doe? How to start the surviving sepsis campaign?

Richard Beale Djillali Annane Greet van den Berghe Hans van der Hoeven Mitchell Levy

14.40 uur

A B C D E

early-goal directed therapy in clinical practice clinical use of corticosteroids Hoe bereik ik strikte glucose regulatie? Longsparende beademing: Hoe ik het doe? How to start the surviving sepsis campaign?

Richard Beale Djillali Annane Greet van den Berghe Hans van der Hoeven Mitchell Levy

15.20 uur

Pauze


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es voor vo verpleegkundigen en artsen Interactieve voordrachten voor verpleegkundigen Voorzitters:

Hendrik-Jan Stienstra & Meta van der Woude

14.00 uur

Hoe implementeer ik glucoseprotocollen? Hazra Biemond-Moeniralam, St. Antonius Ziekenhuis, Nieuwegein

14.20 uur

Welke rol speelt de IC-verpleegkundige in de SSC? Hendrik-Jan Stienstra, Ziekenhuis Gelderse Vallei, Ede

14.40 uur

Vroege herkenning van sepsis door verpleegkundigen Harald Faber, Wilhelmina Ziekenhuis, Assen

15.00 uur

De behandeling van sepsis in de eerste 24 uur Meta van der Woude, Atrium Medisch Centrum, Heerlen

15.20 uur

Pauze

Plenaire Sessie II Voorzitters:

Dave Tjan & Arthur van Zanten

15.50 uur

Verandermanagement en het bouwen van een professioneel team Arthur van Zanten, Ziekenhuis Gelderse Vallei, Ede

16.10 uur

Sepsisincidentie en behandelstrategieën in Nederland Dr. Evert de Jonge, AMC, Amsterdam

16.30 uur

New information on the International Surviving Sepsis Campaign & Guidelines Prof.dr. Mitchell Levy, Rhode Island Hospital, Providence, USA

16.55 uur

Voortgang van de Surviving Sepsis Campaign Netherlands Dave Tjan, Ziekenhuis Gelderse Vallei, Ede

17.10 uur

Afsluiting en uitreiking van de Poster Awards SSC 2006


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Surviving Sepsis Campaign Netherlands SSC symposium 2006: Update in sepsis management 15 december 2006, Cinemec Ede, Nederland Sprekers en voorzitters • Prof. dr. Djillali Annane, Raymond Poincaré University Hospital, Garches, France • Dr. Richard Beale, Guy’s & St. Thomas’ NHS Foundation Trust, London, United Kingdom • Prof. dr. Greet van den Berghe, Universitair Ziekenhuis Gasthuisberg, Leuven, België • Dr. Hazra Biemond-Moeniralam, St. Antonius Ziekenhuis, Nieuwegein • Prof. dr. Marc Bonten, UMC, Utrecht • Drs. Harald Faber, Wilhelmina Ziekenhuis, Assen • Prof. dr. Hans van der Hoeven, UMC St. Radboud, Nijmegen • Dr. Evert de Jonge, AMC, Amsterdam • Prof. dr. Marcel Levi, Academisch Medisch Centrum, Amsterdam • Prof. dr. Mitchell Levy, Rhode Island Hospital, Providence, USA • Prof. dr. Johan Groeneveld, VU Medisch Centrum Amsterdam • Dhr. Hendrik-Jan Stienstra, Ziekenhuis Gelderse Vallei, Ede • Drs. Dave Tjan, Ziekenhuis Gelderse Vallei, Ede • Drs. Meta van der Woude, Atrium Medisch Centrum, Heerlen • Drs. Arthur van Zanten, Ziekenhuis Gelderse Vallei, Ede Doelgroepen • Anesthesiologen • Arts-assistenten Intensive Care • Arts-assistenten van betrokken specialismen • Arts-microbiologen • Chirurgen • Fellows Intensive Care • IC-verpleegkundigen • Intensivisten • Internisten • Laboratoriumartsen • Longartsen • SEH-artsen • SEH-verpleegkundigen • Ziekenhuisapothekers

Taal Alle voordrachten zijn in het Nederlands behoudens die van de buitenlandse sprekers, die in het Engels worden gehouden. Opdrachtgever Stichting Surviving Sepsis Campaign Netherlands Posters U dient uw posterabstract aan te melden voor 15 november 2006 per e-mail. Stuur uw abstract naar [email protected] onder vermelding van SSC 2006. Alle abstracts moeten Engelstalig worden ingestuurd. De lengte van de abstracts is maximaal 500 woorden. Indien het abstract tabellen bevat dient het abstract met 50 woorden per tabel te worden verminderd. Relevante inzendingen zullen als poster worden geaccepteerd. Het formaat van de posters is maximaal 120 cm (horizontaal) x 90 cm (verticaal). Tijdens de lunchpauze bestaat de mogelijkheid de poster te presenteren aan de jury. U ontvangt hiervan een bevestiging. Posterprijzen Er zijn drie posterprijzen van respectievelijk € 500,– € 300,– en € 200,–. De jury wordt samengesteld uit de sprekers en voorzitters en staat onder leiding van Dave Tjan & Mitchell Levy. Deelnameprijzen € 95,– : IC-verpleegkundigen, SEHverpleegkundigen, Verpleegkundigen € 135,– : Arts-assistenten Intensive Care, Arts-assistenten van betrokken specialismen, SEH-artsen, Fellows Intensive Care € 175,– : Anesthesiologen, Arts-microbiologen, Chirurgen, Intensivisten, Internisten, Laboratoriumartsen, Longartsen, Ziekenhuisapothekers

Locatie Congrescentrum Cinemec Laan der Verenigde Naties 150 6716 JE Ede Telefoon: 0900 - 321 0 321 www.cinemec.nl Inschrijfformulieren Downloaden: www.interactie.org

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Accreditatie is verleend door: • Nederlandse Vereniging voor Intensive Care • Nederlandse Vereniging voor Medische Microbiologie • Nederlandse Vereniging voor Ziekenhuisapothekers Accreditatie is aangevraagd bij: • Nederlandsche Internisten Vereeniging • Nederlandse Vereniging voor Anesthesiologie • Nederlandse Vereniging voor Artsen voor Longziekten en Tuberculose • Nederlandse Vereniging voor Heelkunde Sponsors • Altana Pharma • Becton Dickinson Benelux • Brahms • Dirinco • Eli Lilly Nederland • Lamepro • Medical Technology Transfer • Merck Sharp & Dohme • Pulsion Benelux • Stichting ADRA Nederland • Tyco Healthcare • Viasys Healthcare • Wyeth Pharmaceuticals

Organisatie Organisatie- en Congresbureau InterActie BV Stationsweg 73C, 6711 PL Ede Telefoon 0318-693 501, Fax 0318-693 365, E-mail: [email protected] www.interactie.org


12-10-2006 09:12:57

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me c h a n i s c h e bea d e mi n g s dag e n 200 6 donderdag 30 november 2006 vrijdag 1 december 2006 hotel en congrescentrum de reehorst, ede


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m e c h a n i s c h e b eademi ngsdagen 2006

2 0 0 6

Hotel en Congrescentrum De Reehorst, Ede

programma

dag 1 d o n derdag 30 november 2006 08.30 uur

Ontvangst en inschrijving

13.45 uur

Workshop

14.15 uur

Workshop

Voorzitters:

JG van der Hoeven ARH van Zanten

Voorzitters:

B van den Berg A Manten

9.30 uur

Mechanische beademing: gevolgen van mechanische beademing JG van der Hoeven

14.45 uur

Luchtwegmanagement: bezint eer ge begint DHT Tjan

9.55 uur

Klassieke beademingsmodaliteiten: voor- en nadelen ARH van Zanten

15.10 uur

Pauze

15.40 uur

De percutane tracheotomie H Delwig

16.05 uur

Non-invasieve beademing JMM Verwiel

16.30 uur

Casusbespreking: Een patiënt met een ernstige status astmaticus JG van der Hoeven

10.20 uur

Nieuwe beademingsvormen: algemene aspecten JG van der Hoeven

10.45 uur

Geassisteerde beademing en longmechanica B van den Berg

11.10 uur

Pauze

11.45 uur

Workshop

17.15 uur

Borrel

12.15 uur

Workshop

18.00 uur

Diner

12.45 uur

Lunch

20.00 uur Algemene Ledenvergadering

w o r ksh o p 1

workshop 3

w o r ksh o p 2

workshop 4

Servo I DHT Tjan / ARH van Zanten Tijdens deze workshop worden enkele algemene aspecten van mechanische beademing uitgelegd. Volume- en druk, constante beademing en de consequenties hiervan zullen op het scherm inzichtelijk gemaakt worden. Veel aandacht wordt besteed aan het vaststellen en meten van PEEPi. Evita XL A Manten Deze workshop zal met name gericht zijn op de 2 bijzondere beademingsvormen die op deze machine mogelijk zijn: APRV en PPS.


Gallileo DA Dongelmans Deze workshop richt zich volledig op het inzichtelijk maken van adaptive support ventilation (ASV).

Percutane Tracheotomie H Delwig Tijdens deze workshop oefent u zelf het uitvoeren van de verschillende technieken.

12-10-2006 09:13:28


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m e c h a n i s c h e beademi ngsdagen 2006 Hotel en Congrescentrum De Reehorst, Ede

programma

dag 2 vrijdag 1 d e c e m b e r 2006 9.00 uur

Workshop

14.00 uur

Workshop

9.30 uur

Workshop

14.30 uur

Workshop

Voorzitters:

MJM Bonten JE Tulleken

Voorzitters:

JG van der Hoeven ARH van Zanten

10.00 uur

Pathofysiologie van ARDS: consequenties voor de behandeling ABJ Groeneveld

15.00 uur

Algemene beoordeling van de thoraxfoto op de Intensive Care RFE Wolf

10.25 uur

Mechanische beademing bij ARDS: recente inzichten bij mechanische beademing ARH van Zanten

15.25 uur

Pauze

15.55 uur

Beademing geassocieerde pneumonie: preventie en diagnostiek JE Tulleken

16.20 uur

Beademing geassocieerde pneumonie: therapie MJM Bonten

16.45 uur

Einde programma

10.50 uur

Ontwennen van mechanische beademing B van den Berg

11.15 uur

Pauze

11.45 uur

Kinetische therapie en buikligging ARH van Zanten

12.10 uur

Recruitment manoeuvres: hoe en wanneer? JG van der Hoeven

12.35 uur

Hoog frequente beademing: klinische resultaten AJ van Vught

13.00 uur

Lunch

w o r ksh o p 5

workshop 7

w o r ksh o p 6

workshop 8

Non-invasieve beademing JMM Verwiel Met behulp van een specifiek hiervoor ontworpen beademingsapparaat oefent u het instellen en vergelijkt u dit met een standaard beademingsmachine.

Capnografie B van den Berg Tijdens deze workshop leert u de praktische aspecten van capnografie. Aandacht zal vooral gericht zijn op het detecteren van acute noodsituaties.


Buikligging / Kinetische therapie HJA Hensing Tijdens deze workshop krijgt u meerdere mogelijkheden van buikligging gedemonstreerd. Hierbij wordt veel aandacht geschonken aan verschillen in beschikbare matrassen en bedden.

Bronchoscopie PMS Schröder / LMA Heunks Tijdens deze workshop kunt u met de bronchoscoop oefenen op een model van de luchtwegen. Aandacht zal worden geschonken aan het opheffen van atelectase en het verrichten van een BAL.

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Dr B van den Berg Internist-intensivist Erasmus MC Dijkzigt, Rotterdam

Prof Dr ABJ Groeneveld Internist-intensivist VU Medisch Centrum, Amsterdam

Drs A Manten Internist-intensivist Meander Medisch Centrum, Amersfoort

Drs JMM Verwiel Internist-intensivist Radboud Universiteit Nijmegen Medisch Centrum

Dr MJM Bonten Internist-infectioloog Universitair Medisch Centrum, Utrecht

Drs HJA Hensing Beademingsverpleegkundige Leids Universitair Medisch Centrum, Leiden

Drs PMS Schröder Longarts-intensivist Ziekenhuis Gooi-Noord, Blaricum

Prof Dr AJ van Vught Kinderarts-intensivist Wilhelmina Kinderziekenhuis, Utrecht

Drs H Delwig Internist-intensivist Universitair Medisch Centrum, Groningen

Dr LMA Heunks Longarts i.o. Radboud Universiteit Nijmegen Medisch Centrum

Drs DHT Tjan Anesthesioloog-intensivist Ziekenhuis Gelderse Vallei, Ede

Dr RFE Wolf Radioloog Universitair Medisch Centrum, Groningen

Drs DA Dongelmans Anesthesioloog-intensivist Academisch Medisch Centrum, Amsterdam

Prof Dr JG van der Hoeven Internist-intensivist Radboud Universiteit Nijmegen Medisch Centrum

Dr JE Tulleken Internist-intensivist Universitair Medisch Centrum, Groningen

Drs ARH van Zanten Internist-intensivist Ziekenhuis Gelderse Vallei, Ede

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6,80 g 0,30 g 0,20 g 0,37 g 3,27 g 0,67 g

De elektrolytenconcentratie bedraagt in mmol/l: Natrium 140,0 Kalium 4,0 Calcium 2,5 Magnesium 1,0 Chloride 127,0 Acetaat 24,0 Malaat 5,0 Therapeutische indicaties Aanvulling na extracellulair vochtverlies in het geval van isotone dehydratie bij bestaande of dreigende acidose.

Dosering De dosering is afhankelijk van leeftijd, gewicht, klinische en biologische toestand van de patiënt de toegepaste therapie. De aanbevolen dosering is voor volwassenen, ouderen en adolescenten 500-3000ml. per 24 uur. Voor baby’s en kinderen 20 tot 100ml/kg/24uur. Bijwerkingen Verschijnselen van overdosering kunnen optreden. Overgevoeligheidsreacties gekenmerkt door urticaria zijn af en toe beschreven na de intraveneuze toediening van magnesiumzouten. Hoewel orale magnesiumzouten de peristaltiek bevorderen is in zeldzame gevallen paralytische ileus waargenomen na intraveneuze infusie van magnesiumsulfaat. Bijwerkingen kunnen ook het gevolg zijn van de techniek bij toediening, bijv. koortsreactie, infectie op de plaats van toediening, lokaal pijn of een plaatselijke reactie, irritatie van de vene, veneuze trombose of flebitis welke zich verspreid vanaf de plaats van injectie en extravasatie. Bijwerkingen kunnen ook het gevolg zijn van medicatie welke aan de oplossing is toegevoegd; afhankelijk van de aard van de toevoeging kunnen andere bijwerkingen optreden. RVG nummer 27041 Op aanvraag is de volledige 1B tekst beschikbaar.

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12-10-2006 09:13:31

Balanced Solutions


12-10-2006 09:13:32

O R G A N I S A T I E -

Organisatie- en Congresbureau InterActie BV

Stationsweg 73 c 6711 PL Ede

Telefoon: 0318-693501 Fax: 0318-693365

E-mail: [email protected]

Website: www.interactie.org

E N

C O N G R E S B U R E A U

Sinds augustus 2006 is Interactie officieel erkend door de Vereniging van Nederlandse Congres- en Vergaderbelangen (VNC). De erkenningsregeling van de VNC is een keurmerk dat borg staat voor kwalitatieve dienstverlening en bekwaamheid van personeel. InterActie behoort daarmee tot één van de elf erkende congresorganisatiebureaus in Nederland. Al meer dan 10 jaar heeft congres- en organisatiebureau InterActie ervaring in het organiseren van evenementen. Van 10 tot 3200 deelnemers. InterActie verzorgt met 7 werknemers de volledige administratieve dienstverlening als het vaste congresbureau van de Nederlandse Vereniging voor Intensive Care. Naast NVIC wordt ook aan andere verenigingen en organisaties uit de medische- en ICT sector ondersteuning geboden. Meer informatie over InterActie: www.interactie.org

De NVIC feliciteert Congres- en Organisatiebureau

InterActie met het behalen van de status van Erkend Congresbureau


12-10-2006 12:03:44


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ta b l e

New perspectives in the treatment of severe yeast- and fungal infections in critically ill patients: the role of Mycograb® K.H. Polderman1 , A.R.H. van Zanten2 1University Medical Center Utrecht, 2Gelderse Vallei Hospital, Ede, The Netherlands

Summary. On May 17TH 2006, a round table conference was held in Ede, the Netherlands, to discuss a novel and potentially important accessory treatment for yeast and fungal infections. This novel drug, called Mycograb®, is a human recombinant monoclonal antibody that binds specifically to so-called heat shock protein 90 (HSP90), an immunodominant fungal antigen that appears to play a key role in fungal infections. This mechanism of action is different from all the other currently available “traditional” drug treatments, such as amphotericin-B, fluconazole, voriconazole and caspofungin. Mycograb® is intended to be used as an additive (combination) treatment with one or more of the “traditional” anti-fungal drugs. It could be combined with any of these “traditional” drugs, and preliminary evidence indicates that it could significantly enhance the performance of these drugs and thus improve outcome, reduce mortality and decrease the time required before a clinical therapeutic response is observed. A panel of eight medical specialists (two chairmen and six invited medical experts with different backgrounds (intensivists, infectiologists, microbiologists and clinical pharmacologists) was invited to discuss this potentially important new development and review the currently available evidence. The meeting was chaired by the authors of this paper, doctors van Zanten and doctor Polderman, and was sponsored by the manufacturer of Mycograb®, Neutec Pharma plc. NeuTec Pharma was recently acquired by Novartis AG, which thus will be handling the distribution and marketing of Mycograb in the future.

Participants P. Donnelly, MD, PhD, medical microbiologist University Medical Center St Radboud, Nijmegen Professor A.R.J. Girbes, internist-intensivist, clinical pharmacologist VU University Medical Center, Amsterdam Professor J. Kesecioglu, MD, PHD, anesthesiologist-intensivist University Medical Center Utrecht P.E. Spronk, MD, PhD, internist-intensivist Gelre hospital, Apeldoorn Dr. E.L. Swart, Pharm MD, Clinical Pharmacologist VU University Medical Center, Amsterdam Professor A.B.J. Groeneveld, MD, PhD, internist-intensivist VU University Medical Center, Amsterdam Chairmen: Kees H. Polderman, MD, PhD, internist-intensivist University Medical Center Utrecht Arthur R.H. van Zanten, MD, internist-intensivist Gelderse Vallei Hospital, Ede Present on behalf of Neutec Pharma, manufacturer of Mycograb Mr. G. Heron Business Development Manager, Neutec Pharma Mr. S. Tague Business Development Manager, Neutec Pharma

Correspondence: Kees H. Polderman, MD, Ph.D. E-mail: [email protected]

Introduction Infections with various Candida species and, to a lesser extent, Aspergillus infections (Table 1) present a growing problem in intensive care units (ICU’s) throughout the western world. Nosocomial Candida infections can particularly affect patients with prolonged length of stay in the ICU, especially those who have suffered one or more bacterial infections requiring prolonged antibiotic treatment. Other categories at risk include patients undergoing major surgical interventions, especially complicated abdominal surgery. The development of systemic Candida infections, especially Candidaemia or “Candida sepsis” is associated with significant attributable morbidity and mortality, ranging from 5%-15% [1-6]. Yeast infections occur frequently in immune-compromised patients, especially those with haematological malignancies and neutropaenia. However, it would be wrong to assume that the problem is (mainly) limited to this category of patients, or that the Candida infections rarely develop in immune-competent patients. Indeed, critically ill patients in the ICU frequently develop a form of immune suppression known as immunoparalysis [7-10]. Data from the United States National Nosocomial Infection Surveillance (NNIS) system for the years 1990-2002 show that between 5% and 10% of all bloodstream infections in critically ill patients were caused by Candida species [11-14], with similar or even higher rates in the paediatric population [15-16]. In theory this number could be somewhat lower in Europe, because the use of systemic antibiotics is lower compared to the United States. However, data from various European countries suggest that the incidence of Candida infections is comparable. Vincent et al. reported that fungi were responsible for 17.1% of ICU-acquired infections in the European Prevalence of Infection in Intensive Care (EPIC) Study [17]. Geffers and associates studied data from the German Nosocomial Infections Surveillance



587

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System and reported that Candida albicans was one of the most frequently isolated pathogens in patients with device-associated nosocomial infections, with a rate of 11.2 per 100 [18]. Regarding the specific situation in the Netherlands, no detailed information is currently available. A national surveillance program on nosocomial infections in 16 hospitals was published in the Dutch medical journal (NTVG) in 2001, but this paper did not report the incidence of specific causative pathogens such as Candida [19]. However, the results of the Europe-wise EPIC study strongly suggested that the incidence of yeast infections was high in all participating countries, though the overall infection rates were higher in Southern Europe than Northern Europe. Thus the available evidence strongly suggests that yeast and fungal infections present a significant clinical problem in critically ill ICU patients. Moreover, the number of yeast infections seems to be slowly but steadily increasing over the past few years [1-3]. Candidaemia is frequently associated with a sepsis syndrome, and often involves presence of disease outside of the bloodstream [2021]. Mortality of the disease is high even when the initial treatment is adequate [1-5,20,21]; this problem is compounded by the fact that antifungal therapy may not be adequate in many cases. For example, Morgan et al. reported in a surveillance study that of the patients in whom Candidaemia was found 30%–39% received inadequate treatment (usually the problem was too short duration of treatment, i.e. less than 7 days), and that 10% of patients received no therapy at all [22]. This problem is further compounded by the fact that Candida species are relatively difficult to culture, and thus diagnostic testing for susceptibility to antifungal drugs may take long; in addition diagnostic testing for Candida can be unreliable, and thus the incidence of Candida infections may be underestimated [23]. Aspergillus infections occur far less frequently. However, they are by no means rare; up to 7% of patients dying in European teaching hospitals have invasive Aspergillosis, often but not always in the context of some form of immune suppression [24-26]. Currently, four classes of antifungal drugs are available for treatment of systemic yeast and fungal infections (Table 1, references 1-5, 2735). These are the polyenes (amphotericin-B), the azoles (ketoconazole, itraconazole, fluconazole, and voriconazole), flucytosine, and echinocandin antifungal drugs such as caspofungin. Amphotericin-B, the first drug to treat systemic fungal infections (available since the end of the 1950’s) is still a highly effective broadspectrum antifungal agent; it remains the gold standard to which other treatments are compared. The main problems associated with its use are its potentially severe side effects, which include nephrotoxicity as well as acute toxic reactions and other infusion related side effects. Lipid-based and liposomal forms of amphotericin B (Abelcet® and Ambisome®) were developed in the 1990’s has may have fewer side effects than “normal” amphotericin B, though this remains a matter for debate and the relatively high costs of these drugs has somewhat limited their use. Agents from the azole category have been available since the 1980’s, and have gained popularity because their toxicity and risk of side effects is far lower than is the case for amphotericin B. A potential disadvantages of azole regimens is that many azoles are not effective against Aspergillus species; in addition, many drugs from the azole group inhibit fungal growth in susceptible organisms (fungistatic effect) but may not eliminate fungi as effectively as am-

588


Fungal

Human

HSP90 IL6

CRP

NO Vasodila- Platelet tation Malfunction

Bradykinin Hypotension

Pyrexia Figure 1. Role of HSP 90 in vasodilation and septic shock.

photericin B (fungicide effect). However, recent studies suggest that regimens including voriconazole, the latest agent from the azole category to reach the market, may be equally effective as regimens including amphotericin B (30). Another important addition to the therapeutic arsenal of antifungal drugs is the category of echinocandins, which include drugs such as caspofungin, micofungin and anidulafungin (27,34-35). Echinocandins specifically inhibit the synthesis of beta (1-3)glucan, a protein that is specific to the cell walls of yeasts and fungi and is not found in mammalian cell walls. Echinocandins have a fungicide effect in Candida species and a fungistatic effect in Aspergillus species. Because the mechanism of action is different from that of other antifungal drugs, combination treatments with drugs from other categories would be feasible. In spite of all the recent improvements and additions to the therapeutic arsenal, invasive fungal infections in critically ill patients still present a formidable problem. For example, even in recent studies in patients with invasive Candida infections who were receiving adequate treatment (comparing novel treatments with echinocandins or voriconazole to “conventional” amphotericin B), Candida-attributable mortality still ranged from 4.4-8.7%; in untreated patients or those receiving inadequate treatment mortality ranges of 15%-49% have been reported in matched case-control studies. As described above, various studies have shown that initial antifungal therapy is often inadequate (22), with an associated high mortality. Cure rates could be improved by combining different treatment regimens but this strategy could be hampered by side effects, particularly those associated with use of amphotericin B. In addition, drug resistance is becoming an increasing problem (1-5). This includes both an increase in fungal drug resistance and a shift from infections caused by Candida albicans, which is usually highly susceptible to antifungal treatment, to non-albicans infections that are less easy to treat such as Candida glabrata and Candida kruzei (1,3). In recent years, a protein called heat shock protein 90 (HSP90) has emerged as a completely novel target for antifungal treatments. HSP90 is a molecular chaperone with various complex cellular func-


12-10-2006 09:13:33


tions. Briefly, it allows cells and organisms to cope with protein folding defects that arise from insults including mutations and environmental stress. In humans the release of HSP90 from injured cells or micro-organisms and lead to NO-mediated vasodilation and shock (Figure 1). HSP90 has raised significant interest as a potential target of anti-cancer treatments (36-40). However, this paper will not deal with this issue, focussing instead on the role of HSP90 in fungal infections and as a potential target of anti-fungal therapy. Recent studies have shown that HSP90 is crucial for the survival of a fungal cell, and that it also plays a key role in the development of drug resistance (41-42). Conversely, inhibition of HSP90 significantly increases fungal susceptibility to various drug treatments. For example, addition of HSP90 can allow fungistatic drugs from the azole group such as fluconazole to become fungicidal, i.e. fully lethal to yeasts and fungi (42). The key role of HSP90 in the development of fungal infections and drug resistance make it an ideal target for antifungal drugs. This applies particularly because in humans HSP90 should not be present outside the cell or on the cell wall; this means that, in theory, inhibition of HSP90 should not cause significant side effects. Inhibition of HSP90 would have a three-pronged approach, simultaneously hampering fungal replication, increasing efficacy of antifungal treatment and decreasing the risk of developing resistance to antifungal drugs. An anti-HSP90 drug, more specifically a human genetically recombinant antibody to HSP90, has recently been developed and tested in various small and medium-sized clinical trials (43-51). The potential clinical applications of this novel drug, called Mycograb®, include all invasive mycoses. It is intended for use in combination treatments, i.e. it should always be combined with one of the traditional or novel antifungal drugs listed above. Pre-clinical studies have demonstrated that Mycograb® binds to and inactivates HSP90 present in the fungal cell wall and in extra cellular material, particularly around foci of infection. The latter effect may provide additional benefits in the clinical setting in infected patients, by reversing HSP90-mediated vasodilatation and inflammation. The aim of the round table meeting was to assess the currently available evidence for the use of Mycograb® and to discuss the potential place of Mycograb® in the treatment of severe yeast-and fungal infections in the general ward and especially the intensive care setting.

Round Table meeting The meeting started at 18.30 with a brief introduction by the chairmen, Kees Polderman, internist-intensivist from the VU medical center in Amsterdam and Arthur van Zanten, internist-intensivist from the Gelderse Vallei hospital in Ede. After the participants had briefly introduced themselves the meeting began with opening statements from three representatives of Neutec Company, the sponsor of the meeting. The first speaker, George Heron, provided some background information about Neutec Pharma Company. NeuTec Pharma is a small company founded in 1998 that is situated in the United Kingdom. It is in the process of developing three drugs,

all recombinant antibodies: Mycograb® for the treatment of severe fungal Infections, Aurograb® for the treatment of severe staphylococcal infections (currently being tested in a phase III trial in Europe) and Enterograb® for the treatment of symptomatic Clostridium difficile infections. The latter drug is still in the stage of preclinical development. A few weeks after the organisation of this round table meeting, NeuTec pharma was acquired by Novartis AG, which will thus be handling the further development and marketing of Mycograb® and other Neutec products. Mycograb® was first tested clinically in 2003. A phase IIb confirmatory study was completed in 2004. Recently, a confirmatory study was published in clinical and infectious diseases (50). A summary of this study was provided by one of the subsequent speakers, Dr. Spronk from Apeldoorn, The Netherlands, who participated in this study. The first lecture was concluded with a summary of Mycograbs’ potential applications and advantages. The target group should be patients with invasive fungal infections at high risk for mortality; it should be used in a combination regimen and not as a single drug therapy; potential advantages include improved outcome, lower morbidity, low risk of side effects and prevention of resistance to current and new drugs. In addition, it might allow use of lower doses of existing drugs without decreasing the therapeutic efficacy. Mycograb® was given Orphan Drug status in both Europe and the United States. Submission for marketing in Europe was submitted to the European Medicine Evaluation Agency (EMEA) in 2005; at the time of the round table meeting approval was still pending, a decision is expected shortly. The next speaker was doctor Polderman, who provided background information on the problem of Candida infections in the ICU and on the currently available anti-fungal drugs. The information provided in this lecture is summarised in the introduction section of this paper. The third and final speaker was Dr. Spronk from the Gelre hospital in Apeldoorn. As stated above dr. Spronk was one of the coauthors of the latest study with Mycograb® (50). Dr. Spronk summarized the results of this study as an introduction to the round table discussion. The study objective of this double-blind placebo-controlled randomised study was to determine the efficacy and safety of Mycograb® combined with liposomal amphotericin B versus liposomal amphotericin and placebo. Patients with culture-confirmed invasive Candidiasis (sub-divided into patients with Candida albicans or nonalbicans) were included in the study. Each patient received Abelcet® (5 mg/kg daily for at least 10 days) or Ambisome® (3 mg/kg daily for a minimum of 10 days). Patients also received either Mycograb® (1mg/kg body weight twice daily for 5 days) or placebo. Efficacy was assessed using both clinical criteria and mycological responses (using cultures taken every day from day 2 after beginning of treatment or until all signs of infection had disappeared and cultures were repeatedly negative). Assessment of clinical response was made by the local investigator and considered complete if all signs and symptoms thought to be due to the Candida infection had resolved completely. Adverse events were also monitored by an independent expert and safety monitoring committee. The results showed a significant improvement in clinical response rate associated with Mycograb®, with a 86% favourable response in patients treated with a combination of amphotericin B and Mycograb



589

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Table 1. Role of different hospital functionaries in the decision to acquire and start using an expensive novel treatment such as Mycograb, and the influence of these functionaries as estimated by the participants expressed on a scale of 0-10. Columns 1-6 show the scores of the individual participants, the last two columns show the average scores with standard deviations. Functionary Spontaneously mentioned by Individual scores 1 2 3 4 5 6 7 8 Avg Sd Antibiotics-committee 7 7 8 5 0 8 8 8 7 6,4 2,8 Intensivist 7 0 3 8 2 10 8 8 9 6,0 3,7 Infectious disease-specialist 2 0 3 6 2 3 8 7 8 4,6 3,0 Pharmacist 2 0 3 1 6 5 6 9 7 4,6 3,1 Chairman/ ICU management 2 5 0 8 8 10 10 9 9 7,4 3,4 Hospital management 3 0 0 1 9 5 4 0 2 2,6 3,2 Patient 1 0 0 0 0 5 7 0 0 1,5 2,8 Micro-biologist 3 0 3 5 2 7 8 8 5 4,8 2,9 Hematologist 1 0 3 8 0 7 6 4 1 3,6 3,2 Table 2: Strengths and Weaknesses of Mycograb as indicated by the participants. Strengths Spontaneously menWeaknesses: tioned by: No resistance issue 5 Probably expensive New concept/ mechanism of action 3 Unknown pharmacokinetic/PD profile Relatively low side-effects in heterogeneous 6 Lack of clinical data patient-groups Promising in vitro data 4 No proven superiority over standard drugs Consistent in vitro/in vivo data 1 Unknown optimal duration Works in fungi and yeast 1 Unknown optimal dose Synergism with antifungal drugs 3 Unknown additional effects of HSP90 Makes sense 1 Few data on combinations with other anti-fungal drugs Promising initial clinical data 1 Unclear effect on mortality

vs. 52% in controls, i.e., patients treated with amphotericin B alone (p<0.001). Similar results were seen in the mycological response rate (89% vs. 54%, p<0.001). Candida-attributable mortality was 4% in patients treated with Mycograb® vs. 18% in those treated with amphotericin B alone (p<0.05). The rate of serious adverse events (SAEs) was 10.3% in the Mycograb® group vs. 7.3% patients in the placebo group (P=NS). The most frequent side effect was the development of hypertension in patients receiving inotropic support, requiring tapering of vasoactive drugs. The authors concluded that Mycograb enhances the efficacy of lipid amphotericin-B treatment of invasive Candidiasis and decreases mortality (50). In addition, the speed of mycological response was significantly faster in patients treated with Mycograb. The authors recommend the use of Mycograb as an additive treatment in patients with invasive candidiasis as soon as the diagnosis of Candidaemia is culture-confirmed. They further recommended that the efficacy of Mycograb® in combinations with other antifungal drugs such as caspofungin and voriconazol should be assessed in future studies. This also applies to a potential role for Mycograb® in other diseases such as invasive Aspergillosis. The results of this study, which have recently been published in Clinical Infectious Diseases (50), were described as heralding “the third age of antimicrobial therapy” in an accompanying editorial in CID (51). After these introductions the meeting was continued with a discussion about the presentations, and on the potential role of Mycograb in the treatment of various fungal infections. Many of the participants had not heard of this novel drug and approach to antifungal therapy before being invited to participate in this round table discussion and receiving the literature for review. All participants stated that they were impressed with the potential of this new treatment, although

590


Spontaneously mentioned by: 5 5 5 1 3 2 4 1 1

some stressed that the available evidence should still be regarded as preliminary. A discussion then ensued on the phrase “Candida-attributable mortality” in the abovementioned study. Although Candida-attributable mortality was significantly lower in patients receiving Mycograb® (18% vs. 4%), although overall mortality was initially also lower in patients treated with Mycograb® this difference disappeared over time (overall mortality on day 12: 15% vs. 29%; overall mortality on day 33: 39% vs. 43%; and on day 90: 48% vs. 48% for Mycograb patients vs. controls, respectively. One of the participants asked what the commercial price of the new drug would be. The representatives of Neutec answered that this had not yet been finally determined, but that the drug would be relatively expensive, “in the range of activated protein C (Xigris®) and recombinant factor VIIa (Novo Seven®)”. The discussion than briefly turned to issues of cost-effectiveness, and how to assess cost effectiveness. Some participants held that treatment with Mycograb would almost certainly be cost-effective if the mortality of invasive candidiasis could indeed be reduced by around two-thirds, as is suggested by the results of the study by Pachl et al. (50). This study reported an absolute reduction in candida-attributable mortality of 14% (4% vs. 18% in patients treated with Mycograb® or placebo, respectively), which indicates a relative reduction of 67%. However, this view was challenged because the total number of patients with candida-attributable mortality was relatively low and, more importantly, the overall mortality in the two groups at 3 months was similar although initially there was a decreased mortality in the Mycograb group (see above). Other participants questioned the choice of amphotericin-B rather than voriconazole or caspofungin as the drug of choice in the study by Pachl et al.; voriconazol and caspofungin can be expected to have fewer side effects than amphotericin-B. However, at the time that this study was designed these drugs were not available for use in


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Table 3: Assessment/scoring of the strengths listed in Table 2. 0=unimportant, 10=of great importance. Strengths Promising initial clinical data New concept/ mechanism of action Relatively low side-effects in heterogeneous patient-groups Consistent in vitro/in vivo data Works in fungi and yeast No resistance issue Promising in vitro data Makes sense Synergism with antifungal drugs

1 6 6 9 8 8 8 7 5 4

2 7 8 8 5 5 8 5 0 5

3 9 8 9 8 8 8 8 8 0

4 9 5 7 7 7 4 5 7 5

5 10 10 10 10 10 10 10 10 10

6 8 9 5 6 5 2 5 7 2

7 9 9 7 9 7 8 9 8 7

8 9 9 8 9 9 9 8 8 9

Avg 8,4 8,0 7,9 7,8 7,4 7,1 7,1 6,6 5,3

Sd 1,3 1,7 1,6 1,7 1,8 2,7 2,0 3,0 3,4

Order 1 2 3 4 5 6 7 8 9

Table 4: Scoring of the weaknesses listed in Table 2. Weaknesses Probably expensive Unclear effect on long-term mortality in recent study by Pachl et al. [ref. 50] Unknown optimal dose Lack of clinical data No proven superiority over standard drugs

1 8 8

2 10 9

3 10 8

4 10 8

5 9 9

6 9 9

7 9 7

8 9 8

Avg 9,3 8,3

Sd 0,7 0,7

8 8 8

8 8 7

8 8 7

10 4 8

6 10 8

9 10 9

7 7 8

7 7 7

7,9 7,8 7,8

1,3 1,9 0,7

Unknown pharmacokinetic/PD profile Unknown optimal duration

8 8

7 8

8 8

10 10

9 6

8 9

7 7

4 5

7,6 7,6

1,8 1,6

Unknown additional effects of HSP90 Few data on combinations with other anti-fungal drugs

8 8

6 7

4 8

10 6

8 8

10 7

7 8

7 6

7,5 7,3

2,0 0,9

the treatment of invasive fungal infections, and (lipid formulations of )amphotericin-B represented the main therapeutic option. Indeed amphotericin-B remains the gold standard for antifungal treatment even at this time. The participants were then asked which functionaries in their hospital would be involved in the decision to introduce a new and potentially expensive drug such as Mycograb® in their hospital. The functionaries mentioned by the participants are listed in table 1. Subsequently, the participants were asked to score the importance of these functionaries on a scale of 0-10, with 0 indicating (almost) no influence and 10 indicating great influence over the decision. The results are also listed in Table 1. Table 1. Role of different hospital functionaries in the decision to acquire and start using an expensive novel treatment such as Mycograb, and the influence of these functionaries as estimated by the participants expressed on a scale of 0-10. Columns 1-6 show the scores of the individual participants, the last two columns show the average scores with standard deviations. The ICU chairman/ICU management were thought to have the most influence on n this type of decision, closely followed by the hospital antibiotics committee (in which intensivists, microbiologists, infectious disease specialists and pharmacists are most frequently represented). One of the participants remarked that actually none of the parties had decisive influence, but that many had the power of veto, i.e. would be able to block the use of a new drugs. The introduction of this type of new drug into a hospital would thus require a certain degree of consensus among various functionaries. In many hospitals there is a form of structured discussion between intensivists, microbiologists and infectiologists regarding the use of novel antibiotics

2 3 4 5 6 7 8 9

and antifungal therapy. Other participants disagreed; they indicated that in their hospital they had a certain budget for drugs in the ICU, which they could spend more or less as they wished. Certainly if the numbers as reported in the study by Pachl et al. hold up, the use of Mycograb® would be efficacious and cost-effective, and thus would be likely to find its way to the patient without too much difficulty. Most of the participants agreed but reserved judgement because the results were still preliminary (the study had not yet been published at the time of the round table meeting), and no confirmatory studies were yet available. After the introduction and initial discussion the participants in the round table meeting were asked to perform a so-called SWOT (strengths, weaknesses, opportunities and threats) analysis for the use of Mycograb. In this regard strengths of Mycograb® would be properties inherent to the drug that would increase the likelihood of its use; conversely, potential weaknesses are properties inherent to the drug that would hamper its use. Opportunities and threats are external factors, not directly linked to the drug itself, which could nevertheless influence its use. For example, the target mechanism of Mycograb (blocking HSP90) is inherent to the drug, and could be regarded as a strength; the side effects associated with currently available treatments are not inherent to Mycograb, but could still help its usage and thus represent an opportunity. After the procedure had been explained the participants were asked to name strengths and weaknesses of Mycograb, followed by opportunities and threats. When these factors had been named the participants were asked to score the arguments for relevancy and importance, again (as explained above) on a scale of 0-10, with 0 indicating total disagreement and 10 indicating total agreement. The results are shown in Tables 2, 3 and 4.



Order 1

591

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Table 5: Opportunities and threats as indicated by the participants. Opportunities Spontaneously mentioned by: Increasing Candida-infections 2 Increasing drug-resistance

2

Many complex clinical situations for use Toxicity of other anti-fungals Current therapy imperfect More immune compromised patients (HIV, Cancer, transplant) Rapid cure (cost-reduction, HLOS) Aspergillosis Non-infectious indications Patients request more therapies Better survival

2 1 1 5 1 1 1 1 1

Threats Highly effective other treatments at low side effects Uncertainty surrounding issue of Candida-infections New, other, expensive drugs Late toxicity Budget issues Development of resistance Not cost effective Scepticism Insufficient clinical data Negative effects on bacterial infections Difficult clinical studies Jumping the gun

Table 6: Scoring of the opportunities listed in Table 5 (0=unimportant, 10=of great importance). Opportunities 1 2 3 4 5 More immune compromised patients (HIV, Cancer, trans8 9 9 8 10 plant) Increasing Candida-infections 10 8 8 6 10 Better survival 8 8 9 9 8 Rapid cure (cost-reduction, HLOS) 6 9 9 8 10 Increasing drug-resistance 10 8 4 6 10 Current therapy imperfect 8 8 8 8 4 Many complex clinical situations for use 10 9 9 7 5 Aspergillosis 8 8 5 6 10 Toxicity of other anti-fungals 6 7 4 7 8 Patients request more therapies 0 7 9 5 0 Non-infectious indications 0 7 4 7 2

The overall average of the strengths was 7,3 points, with a median of 8,0. The promising initial clinical data (in spite of the fact that the full results of the study discussed at the meeting had not yet been published) was regarded as the most important strength, with an average of 8,4 points. The novel mechanism of action and the favourable safety profile of Mycograb were also viewed as important strengths, with 8 and 7,9 points, respectively. The synergism with other antifungal drugs received only 5,3 points, with judgments ranging from 0 to 10 points. This was explained by the participants who gave low marks as an expression of “you need more than one drug, i.e. you are adding a very expensive drug that still can’t do the job alone”; whereas the participants who gave high marks for this issue regarded the fact that lower doses of potentially toxic drugs would perhaps be required, and the synergy between fungistatic/fungicide drugs and HSP90 inhibition as potentially very valuable. Finally, the novel mechanism of action (targeting HSP90) and the physiological concepts underlying this novel treatment and “line of attack” were viewed as significant strengths, at 7,7 points. The average score for the potential weaknesses of Mycograb was 7,9 (median 7,8) points. The expected high price was regarded as the most important potential weakness of Mycograb. When asked why these scores were so high in spite of the previous comments that any efficacious treatment would probably find its way to the clinic anyway, the participants remarked that because there is so far little absolute proof from large well-designed studies of Mycograbs’ efficacy, and the participants expect that the expected costs may therefore hamper the widespread usage of the new drug. The fact that initially significant differences in mortality associ-

592


Spontaneously mentioned by: 1 1 2 2 2 1 1 2 1 1 3 2

6 9

7 9

8 9

Avg 8,9

SD 0,6

Ranking 1

9 9 8 9 8 5 5 6 9 2

9 8 9 9 9 7 7 9 6 6

10 9 9 10 9 8 8 9 2 5

8,8 8,5 8,5 8,3 7,8 7,5 7,1 7,0 4,8 4,1

1,4 0,5 1,2 2,2 1,6 1,9 1,7 1,7 3,7 2,6

2 3 4 5 6 7 8 9 10 11

ated with Mycograb use had disappeared after three months in the study by Pachl et al. (50) was also regarded as an important weakness by the participants, with 8,3 points. The fact that total “Candida attributable mortality” was relatively low further complicates the interpretation of the results of this study. Overall, the novel mechanism of action, the absence of significant side effects combined with its efficacy was viewed as the most important strength of Mycograb by most participants. Almost all participants also regarded the broad spectrum as an important advantage. The most significant problem was the potentially high price and lack of large amounts of clinical evidence for ts efficacy. After this discussion the participants focussed their attention on external factors, by assessing and scoring opportunities and threats for the use Mycograb. The results are shown in tables 5, 6 and 7. The overall average of all the opportunities was 7,4 points (median 8,0 points); for the threats the average was 7,0 (median 7,0 points). The increasing number of immune-compromised patients admitted to the ICU (8,9 points) as well as the rising number of Candida infections in the ICU (8,8 points) were viewed as the most important opportunities for Mycograb. The reported increase in survival (in spite of the discussion outlined above) was also viewed as an important opportunity, as was the speeding up of cure rates in the study by Pachl et al. (50). The increase in drug resistance was also viewed as an important opportunity. Indeed only the items “non-infectious


12-10-2006 09:14:16


Table 7: Scoring of the threats listed in Table 5 Threats Budget issues Difficult clinical studies Insufficient clinical data Scepticism Not cost effective Highly effective other treatments with low risk of side effects Late toxicity Jumping the gun Negative effects on bacterial infections Uncertainty surrounding issue of Candida-infections New, other, expensive drugs Development of resistance

1 8 8 8 6 6 8 6 6 6 10 6 6

2 8 8 10 9 7 9 7 10 8 7 7 9

3 8 8 4 7 9 7 8 6 8 6 4 7

4 9 9 8 8 8 9 5 9 4 5 5 1

5 10 10 10 10 8 4 8 8 8 3 6 2

6 10 10 10 7 7 3 7 3 6 3 6 6

7 9 8 8 8 8 7 8 6 6 6 6 6

Table 8. Potential indications for the use of Mycograb as seen by the participants: Indication Spontaneously menIndividual scores (minimum 0, maximum 10) tioned by: Treatment failure of other drugs 2 8 5 5 10 10 10 10 Candidaemia 1 8 7 9 8 10 9 8 Invasive/systemic yeast infections 3 6 7 5 8 10 9 9 Candida endocarditis 1 8 7 9 2 8 9 9 Candida and severe sepsis (multi-site colo- 1 8 8 9 8 0 9 9 nisation) Candida endopthalmitis 1 8 6 5 3 10 9 8 Candida in immune-compromised patients 1 8 9 5 3 4 9 9 Invasive Aspergillosis 1 6 7 8 3 0 2 6

indications” and “patient request for more therapies for fungal infections” received low overall marks (4,1 points and 4,8 points, respectively). The average for the other opportunities, which are more directly related to the critical care setting, is 8,0 points. The most important threats perceived by the participants were, again, the perceived potential for high costs and the paucity of the evidence available so far, with associated difficulty in interpretation. The issue of ”insufficient clinical data” is closely related to this issue. Other issues that were mentioned but achieved lower “scores” were the availability of other expensive drugs “competing” for scare ICU funds and the potential for general sceptcism surrounding “magic” novel treatments. In view of all the arguments that had been exchanged and the information provided the participants then proceeded to draw up a list of potential indications for the use of Mycograb. These were first mentioned, and then scored in the same way as explained above with 0 indicating total disagreement by the participant that this is a good indication for caspofungin, and 10 that this was an excellent indication. Table 8 shows the results of this evaluation. Treatment failure of other “first line” drugs was viewed as the best current potential indication for the clinical use of Mycograb based on the currently available evidence. An average of 8,5 points was given for this indication. Opinions diverged somewhat, with two participants scoring just 5 points whereas others gave this indication full marks (i.e., 10 points). When asked the two physicians who scored just 5 points stated that the currently available evidence suggests that Mycograb should be used early rather than late, in combination with other drugs, and that it should not be used as a rescue therapy. Or, put another way, no studies have yet been performed where Mycograb was used as a rescue therapy, and although it might be suitable for

Avg 8,9 8,6 8,0 7,9 7,4 6,9 6,8 6,6 6,5 5,6 5,6 5,3

Sd 0,8 0,9 2,2 1,3 1,1 2,2 1,3 2,3 1,4 2,3 0,9 2,6

Avg

Order 1 2 3 4 5 6 7 8 9 10 11 12

10 8 9 8 10

8,5 8,4 7,9 7,5 7,6

SD 2,3 0,9 1,7 2,3 3,2

8 9 6

7,1 7,0 4,8

2,3 2,6 2,8

Rank 1 2 3 4 5 6 7 8

this purpose this needs to be tested in clinical studies first. Proven Candidaemia was also viewed as a very good potential indication, with an average of 8,4 points and with none of the participants scoring lower than 7 points here, indicating a high degree of consensus. At this point many participants expressed their opinion that they saw great potential in the new drug but that the lack of studies was a problem. The currently available evidence was tantalizing and in some respects convincing, but much remains to be determined. all participants expressed the hope that new studies would soon be forthcoming. The representatives of Neutec expressed sympathy for this viewpoint but, being a relatively small company, it would be very difficult to raise the money to perform (very) large studies.

Conclusions All participants agreed that the problem of Candida infections in critically ill patients is widely underestimated, and that it is a rising clinical problem. Mortality remains high in spite of the availability of various reasonably effective treatments. The risk of side effects associated with some of these treatments (in particular the use of amphotericin-B) remains a problem. Thus there certainly would be a place for a novel treatment strategy such as blocking HSP90, provided that this is shown to be effective. The potentially high price of Mycograb was viewed as a clear but not insurmountable hurdle in the introduction and usage of the drug. The best potential indication based on the currently available evidence is proven Candidaemia and fungal drug resistance/treatment failure. More indications may emerge if and when more evidence becomes available. The participants expressed a desire for more information in the form of additional studies.



8 9 8 6 8 6 8 5 5 6 5 5 5

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Invasive aspergillosis is also more common than generally appreciated, especially in immune-compromised patients, and in view of the even higher mortality assoiciated with this situation the need for better treatments may be even greater here. The potential place for HSP90 inhibition remains to be determined for this indication.

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35. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351:1391-402. 36. Neckers L, Neckers K. Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update. Expert Opin Emerg Drugs 2005;10:137-49. Review. 37. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE, Morgan G, Akiyama M, Shringarpure R, Munshi NC, Richardson PG, Hideshima T, Chauhan D, Gu X, Bailey C, Joseph M, Libermann TA, Rosen NS, Anderson KC. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107:1092-100. 38. Chiosis G, Rodina A, Moulick K. Emerging Hsp90 inhibitors: from discovery to clinic. Anticancer Agents Med Chem 2006;6:1-8 (review). 39. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005;5:761-72 (review). 40. Thomas X, Campos L, Le QH, Guyotat D. Heat shock proteins and acute leukemias. Hematology. 2005;10:225-35 (review). 41. Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 2005;309:2185-89 42. Heitman J. Cell biology. A fungal Achilles’ heel. Science 2005;309:2175-6. 43. Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, Illidge C, Burnie J. Preclinical assessment of the efficacy of Mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother 2003;47:2208-16. 44. Matthews RC, Burnie JP. Human recombinant antibody to HSP90: a natural partner in combination therapy. Curr Mol Med 2005;5:403-11. 45. Nooney L, Matthews RC, Burnie JP. Evaluation of Mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies. Diagn Microbiol Infect Dis 2005;51:19-29. 46. Matthews RC, Burnie JP. Recombinant antibodies: a natural partner in combinatorial antifungal therapy. Vaccine 2004;22:865-71. Review. 47. Burnie J, Matthews R. Genetically recombinant antibodies: new therapeutics against candidiasis. Expert Opin Biol Ther 2004;4:233-41. Review. 48. Burnie J, Matthews R. The role of antibodies against hsp90 in the treatment of fungal infections. Drug News Perspect 2003;16:205-10. Review. 49. Matthews R, Burnie J. Antifungal antibodies: a new approach to the treatment of systemic candidiasis. Curr Opin Investig Drugs 2001;2:472-6 (review). 50. Pachl J, Svoboda P, Jacobs F, Vandewoude K, van der Hoven B, Spronk P, Masterson G, Malbrain M, Aoun M, Garbino J, Takala J, Drgona L, Burnie J, Matthews R; Mycograb Invasive Candidiasis Study Group. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis 2006;42:1404-13. 51. Casadevall A. The third age of antimicrobial therapy. Clin Infect Dis 2006;42:1414-6.


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Interne indicatoren voor Intensive Care afdelingen: een continue nationale registratie ten behoeve van kwaliteitsverbetering De commissie kwaliteitsindicatoren van de NVIC1 1 Bestaande uit: Dr. P.H.J. van der Voort, Internist-intensivist, Medisch Centrum Leeuwarden (voorzitter) Drs. M.L.G de Vos, Onderzoeker, RIVM (secretaris) Drs. D.H.C. Burger, Chirurg-intensivist, St. Elisabeth Ziekenhuis Tilburg Drs. A.A. Corsten, Anesthesioloog-intensivist, Canisius Wilhelmina Ziekenhuis Nijmegen Drs. F.E. van Dijk, Beleidsmedewerker, Antonius Ziekenhuis Nieuwegein (NVICV) Dr. W.C. Graafmans Senior Onderzoeker, RIVM Dr. E. de Jonge, Internist-intensivist, Academisch Medisch Centrum Amsterdam Dr. M. Kallewaard, Orde Medisch Specialisten Drs. A.R.H. van Zanten, Internist-intensivist, Ziekenhuis Gelderse Vallei Ede Voorheen waren lid van de commissie: J.P. Gielen, Verpleegkundig afdelingshoofd, Universitair Medisch Centrum Maastricht (NVICV) Drs. W. de Graaf, Verpleegkundig afdelingshoofd, Academisch Medisch Centrum Amsterdam (NVICV) Drs. E. Keesman, Onderzoeker, RIVM Dr. K.H. Polderman, Internist-intensivist, Vrije Universiteit Medisch Centrum Amsterdam (namens bestuur NVIC) M. Fuijkschot, IC verpleegkundige, Ziekenhuis Rivierenland Tiel Recent zijn aan de commissie toegevoegd: Drs. J. Vreman, Kwaliteitsfunctionaris, Universitair Medisch Centrum Nijmegen

Achtergrond Verbetering van kwaliteit van patiëntenzorg wordt reeds vele jaren in de Nederlandse ziekenhuizen nagestreefd. In navolging van het bedrijfsleven wordt in de geneeskunde in toenemende mate gewerkt met specifieke kwaliteitsprojecten. Zo worden bijvoorbeeld (standaard) procedures uitgebreid beschreven, protocollen ingesteld, visitaties uitgevoerd en accreditatie volgens bepaalde kwaliteitsinstituties zoals het NIAZ nagestreefd. De mate waarin kwaliteit aandacht heeft, verschilt per ziekenhuis en per afdeling binnen elk ziekenhuis. Sprekende over kwaliteit, is het meten van kwaliteitsindicatoren op dit moment een hot-topic. Kwaliteitsindicatoren zijn bekend geraakt door de introductie van het prestatie-indicatoren project van de Inspectie voor de Gezondheidszorg (IGZ) in 2003 (referentie: www. prestatie-indicatoren.nl). Voor het eerst zijn alle Nederlandse ziekenhuizen verplicht gesteld om bepaalde ziekenhuisprestaties openbaar te maken en te rapporteren, waaronder twee IC-indicatoren. Zo dient elk ziekenhuis openbaar te maken hoeveel intensivisten in hun ziekenhuis werken en wat het totale aantal beademingsdagen in het ziekenhuis is. De verwachting is dat de Inspectie in de komende jaren meer geleverde prestaties (-indicatoren) door de ziekenhuizen aangeleverd wil gaan krijgen. Dit zal de Inspectie, maar ook het publiek, inzicht geven hoe ieder ziekenhuis en/of Intensive Care (IC) functioneert. De inspectie gebruikt deze indicatoren dan ook bij het prioriteren van haar toezicht. Deze indicatoren, die gebruikt worden voor verantwoording naar buiten, worden externe indicatoren genoemd.

Correspondence: Dr. P.H.J. van der Voort, MSc E-mail: [email protected]

Hier tegenover staan interne indicatoren die met nadruk NIET zijn bedoeld om openbaar te maken. Interne indicatoren worden bij voorkeur door de beroepsgroep zelf opgesteld, verzameld en beoordeeld. Deze interne indicatoren zijn vaak moeilijker te interpreteren en behoeven voor een juiste conclusie een gedegen kennis van inhoudelijke en locale factoren. Interne indicatoren worden ontwikkeld om een beroepsgroep zelf handvatten te geven om verbeterprojecten op hun eigen afdeling in te stellen. De Nederlandse Vereniging voor Intensive Care (NVIC) en de Nederlandse Vereniging voor Intensive Care Verpleegkundigen (NVICV) streven ook naar een goed kwaliteitssysteem op elke nederlandse IC-afdeling. Eind 2003 is daarom door het bestuur van de NVIC de ‘Commissie Kwaliteitsindicatoren’ ingesteld, waarin ook de NVICV vertegenwoordigd is. De doelstelling van deze commissie is het formuleren van een basisset kwaliteitsindicatoren die door intensivisten en IC-verpleegkundigen gebruikt kunnen worden om een indruk te krijgen van de kwaliteit van zorg en behandeling op de eigen IC-afdeling. Deze gegevens kunnen uiteindelijk aanleiding geven om bepaalde punten in de zorg te verbeteren, om de ontwikkelingen in de tijd te vergelijken, om een vergelijking met een nationaal gemiddelde te kunnen maken en om de effecten van verbeteracties te kunnen meten.

Indicatoren Een indicator is een meetbaar element van de behandeling dat een indruk geeft van de kwaliteit van die behandeling. Een indicator geeft slechts een signaal en is geen directe maat voor de geleverde kwaliteit. Deze gegevens zijn daarom niet altijd eenduidig en eenvoudig te interpreteren. Zo kan er een reden zijn dat de ene IC-afdeling veel minder decubitus ziet dan een andere IC-afdeling, b.v. door dat op de



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Tabel 1 Was de werkbelasting die de registratie met zich meebracht aanvaardbaar? N Percentage

Tabel 2 Hoeveel extra tijd heeft de registratie in het totaal voor de afdeling meegebracht? N Percentage

Oneens Eens Zeer eens Totaal

< 30 min p.d. > 30<60 min p.d. > 60 min p.d. Totaal

5 18 12 35

14,3 % 51,4 % 34,3 % 100 %

ene IC-afdeling veel meer kortliggende (postoperatieve) IC-patiënten liggen dan op een andere IC-afdeling. Snelle en niet ter zake deskundige interpretatie kan in verkeerde handen, bijvoorbeeld bij de media tot foutieve en schadelijke conclusies leiden, die dan ook nog eens publiekelijk worden gemaakt in de krant of op televisie. Het is van belang dat indicatoren aan een aantal criteria voldoen. Ze moeten relevant zijn voor medisch handelen, verband houden met de uitkomst van zorg, leiden tot acties ter verbetering, eenvoudig meetbaar zijn, snel beschikbaar en breed toepasbaar zijn. Daarnaast is ook de validiteit van groot belang. Dit wil zeggen dat gemeten wordt wat beoogd wordt gemeten te worden.

Indicatorgebruik: 3 niveau’s Indicatoren kunnen op verschillende niveaus gebruikt worden: A Binnen een afdeling. De gegevens worden verzameld en na verloop van tijd vergeleken: bijvoorbeeld hoe scoort de afdeling ten opzichte van vorig jaar? B Tussen verschillende afdelingen. De gegevens worden vergeleken tussen de afdelingen, ‘benchmarking’. Deze vergelijking behoeft een database, bijvoorbeeld op nationale schaal. C Afleggen van externe verantwoording. De gegevens worden naar buiten gebracht aan bijvoorbeeld de IGZ, of aan de patiënt. Dit worden ook wel “externe indicatoren” genoemd. Interne indicatoren dienen per definitie alleen gebruikt te worden op niveau A en B. Externe indicatoren kunnen ook op niveau C gebruikt worden. De door de commissie Kwaliteitsindicatoren beschreven indicatoren zijn alleen interne indicatoren en dus alleen voor intern gebruik.

Indeling indicatoren Er bestaan verschillende manieren om indicatoren in te delen. In dit project is gekozen voor de indeling in structuur, proces en uitkomsten van zorg volgens Donabedian. Onder structuur van zorg verstaat Donabedian de bronnen en middelen die nodig zijn om zorg te verlenen. Met proces wordt het zorgproces bedoeld dat plaatsvindt tussen zorgverlener en patiënt. Uitkomsten zijn de resultaten van de verleende zorg gemeten bij de patiënt. Het medisch inhoudelijk (be)handelen wordt voornamelijk in de proces- en uitkomstindicatoren beschreven. Doelstellingen

Het doel van het indicatorenproject is het ontwikkelen van een bruikbare, valide en betrouwbare set kwaliteitsindicatoren voor de Intensive Care in Nederland waarvan de registratie haalbaar is. Daarnaast is het van belang om de beroepsgroep aangrijpingspunten voor verbeteracties te bieden door middel van terugrapportage. Een duidelijke rapportage kan inzicht verschaffen in de kwaliteit van het eigen handelen (ten opzichte van zichzelf (in een eerdere periode)of ten opzichte van anderen) en geeft mogelijke verbeterpunten aan. De specifieke doelstellingen van het indicatorenproject waren:

596


16 13 6 35

45,7 % 37,1 % 17,1 % 100 %

1. Opstellen van een set indicatoren op basis van de wetenschappelijke literatuur en expert opinion; 2. Evaluatie van de haalbaarheid en wenselijkheid van het gebruik van de set interne indicatoren (procesevaluatie); 3. Ontwikkelen en toepassen van een methodiek om beleidsrelevante informatie over de indicatoren te kunnen terugkoppelen naar de beroepsgroep.

Werkwijze commissie kwaliteitsindicatoren Om bovenstaande doelstellingen te verwezenlijken, is gebruikt gemaakt van een literatuurstudie uitgevoerd door het RIVM, expert opinion van de commissieleden en de richtlijn ‘organisatie en werkwijze IC-afdelingen in Nederland’ die destijds in conceptvorm bestond. De commissie kwaliteitsindicatoren van de NVIC vergaderde vanaf februari 2004 maandelijks om een selectie van indicatoren te maken en deze verder uit te werken. Op grond van een systematische aanpak is de commissie gekomen tot een samenhangende set van 12 indicatoren die gezamenlijk een beeld zouden moeten geven van de kwaliteit van een IC-afdeling en de aldaar geleverde behandeling. (Referenties: “Kwaliteitsindicatoren voor intensive care en high care afdelingen.” Netherlands Journal of Critical Care. 2004;8(5):423-37 en “Een kwaliteitszeef voor de IC.” Medisch Contact 2006;61(21):871-3). De verschillende domeinen van kwaliteit, namelijk effectiviteit, efficiëntie, veiligheid, patiëntgerichtheid, toegankelijkheid en gelijkheid, komen in deze allemaal aan de orde. De voorgestelde set kwaliteitsindicatoren IC is in november 2004 door de ledenvergadering van de NVIC goedgekeurd voor verdere analyse in een pilotstudie. Pilot studie

Al in het begin van het proces tot IC-indicatorontwikkeling zijn ziekenhuizen door de commissie op de hoogte gebracht van een te starten pilot-studie naar interne kwaliteitsindicatoren. De NVIC heeft ziekenhuizen ook actief benaderd. Uiteindelijk hebben 33 ziekenhuizen aangegeven deel te willen nemen aan de pilot-studie. Deze ziekenhuizen zijn onderverdeeld in een viertal categorieën om uiteindelijk een representatieve groep van IC-afdelingen deel te laten nemen. Hierbij heeft de commissie op arbitraire gronden gekozen voor twee IC-afdelingen in opleidingsklinieken, acht grote IC-afdelingen in STZ ziekenhuizen, acht IC’s van ziekenhuizen in perifere niet-STZ klinieken en één categoraal ziekenhuis. Via loting zijn de volgende 19 ziekenhuizen geselecteerd: - Ziekenhuis met opleiding tot intensivist: Universitair Medisch Centrum Utrecht, Onze Lieve Vrouwe Gasthuis Amsterdam; - Samenwerkend Topklinisch opleidingsZiekenhuis (STZ): St. Antonius Ziekenhuis Nieuwegein, Catharina Ziekenhuis Eindhoven, Reinier de Graaf Gasthuis Delft, Haga Ziekenhuis Den Haag, Canisius-Wilhelmina Ziekenhuis Nijmegen, Martini Ziekenhuis Groningen, Medisch Centrum Leeuwarden, Alysis Zorggroep locatie Rijnstate Arnhem, St. Elisabeth Ziekenhuis Tilburg; - Perifeer geen STZ ziekenhuis: Lucas Andreas Ziekenhuis Amsterdam, BovenIJ Ziekenhuis Amsterdam, Ziekenhuis Nij Smellinghe


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Drachten, Dirksland Ziekenhuis, Rode Kruis Ziekenhuis Beverwijk, Diakonessenziekenhuis Utrecht, Gelre Ziekenhuis Apeldoorn; - Categoraal ziekenhuis: Antoni van Leeuwenhoek Ziekenhuis Amsterdam. De commissie realiseert zich dat deze ziekenhuizen een positieve selectie zijn vanwege de spontane aanmelding. Eén ziekenhuis haakte in de voorbereidingsperiode af omdat de logistiek voor de dataverzameling niet op tijd rond te maken was. De overgebleven 18 ziekenhuizen zijn op één na ook daadwerkelijk op deze datum gestart met het registreren van de indicatoren. Eén ziekenhuis is twee weken later gestart met registreren. Deze vertraagde start werd onder andere veroorzaakt door onduidelijkheid over de interne financiering van de pilot-studie. Van één IC-afdeling zijn door technische/ softwarematige redenen in de loop van de pilot data verloren gegaan. Nadat de deelnemende ziekenhuizen waren geselecteerd, is aandacht besteed aan het draagvlak van de pilot studie. Onder draagvlak wordt verstaan de ondersteuning (materieel, moreel en inhoudelijk) die er voor het onderzoek is bij de betrokken partijen. Om het draagvlak binnen deze pilot te vergroten is er door de commissie kwaliteitsindicatoren een scholingsdag georganiseerd. Het doel van deze dag was het uitwisselen van informatie en het beantwoorden van vragen met betrekking tot de pilot. Op deze dag zijn de volgende aspecten aan de orde gekomen: 1) achtergrond project, 2) doel en opzet pilot, 3) presentatie deelnemende ziekenhuizen, 4) bespreking indicatoren aan de hand van een uitgereikt handboek (=datadictionary), 5) methode dataverzameling, 6) plan van aanpak/tijdsplanning Tijdens de scholingsdag is er genoeg ruimte gelaten voor discussie en zijn op basis van opmerkingen van deelnemers een aantal definities van indicatoren aangepast om de eenduidigheid te vergroten. Datadictionary

Voordat de pilot van start is gegaan, is aan alle deelnemende ziekenhuizen een datadictionary uitgereikt. Deze datadictionary is door de leden van de commissie kwaliteitsindicatoren samengesteld en bestaat uit twee delen. Het eerste deel bevat vragen over basiskenmerken van de deelnemende IC (afdelingsgegevens). Het tweede deel geeft aan hoe de (proces en uitkomst) indicatoren gerapporteerd dienen te worden op grond van geformuleerde definities. Er zijn gegevens die dagelijks, maandelijks en tweemalig tijdens de pilot geregistreerd dienden te worden. De datadictionary bevordert een uniforme registratie van de indicatoren. Registratiesystemen

Tijdens de pilot studie werd door de IC-afdelingen gebruik gemaakt van verschillende registratiesystemen om de indicatoren te registreren. Speciale invoermodules (Mediscore en Marek IT) zijn voor deze studie ontwikkeld en door sommige deelnemende ziekenhuizen aangeschaft voor de registratie. Deze invoermodules konden gekoppeld worden aan de NICE-registratie. Andere deelnemende ziekenhuizen maakten gebruik van andere, zelf ontwikkelde, registratiesystemen. Deze laatste systemen waren vaak niet gekoppeld aan bestaande registraties en bleken over het algemeen niet gebruiksvriendelijk opgezet. Dit maakte de registratie van interne kwaliteitsindicatoren soms erg arbeidsintensief.

Voor verwerking van de data is gekozen voor samenwerking met de stichting NICE (Nationale Intensive Care Evaluatie). Argumenten hiervoor waren de grote ervaring op gebied van IC-uitkomstregistratie en vertrouwelijkheid, de mogelijkheid tot snelle uitvoering van het project, de redelijke financiële kosten en de overlap die er bestaat tussen de huidige NICE registratie (Minimale Data Set) en de door de commissie ontwikkelde set interne kwaliteitsindicatoren. Daarnaast valt de NICE niet onder de Wet Openbaarheid Bestuur, zodat de gegevens niet op te vragen zijn door derden. De NVIC is met de stichting NICE een overeenkomst voor de duur van de pilot-studie aangegaan. De stichting NICE en de NVIC zijn in gesprek over invulling van een langdurende samenwerking van onafhankelijke en vertrouwelijke gegevensverzameling.

Verloop dataverzameling Van 1 juni tot 1 december 2005 zijn de 12 geselecteerde interne kwaliteitsindicatoren uitgetest. De vragen over basiskenmerken van de deelnemende IC’s werden in het begin en op het einde van de pilot geregistreerd en verstuurd naar NICE. Alle overige gegevens werden dagelijks of maandelijks geregistreerd en driemaandelijks verstuurd naar NICE, waar verdere analyse plaatsvond.

Algemene analyse pilot studie indicatoren Is het haalbaar en wenselijk om de geselecteerde set kwaliteitsindicatoren te introduceren en te registreren op verschillende IC afdelingen in Nederland?

Deze hoofdvraag kan uitgewerkt worden in een aantal onderzoeksvragen: 1. Hoe wordt het registreren van de set door de betrokken deelnemers ervaren? 2. Welke indicatoren zijn volgens betrokken deelnemers betrouwbaar, valide en uiteindelijk aan te bevelen en welke niet? 3. Wat zijn succesbevorderende en –belemmerende factoren ten aanzien van de registratie?

Methode procesevaluatie Om de pilot te kunnen evalueren zijn twee methodes gebruikt om te achterhalen of het haalbaar is om een set kwaliteitsindicatoren te introduceren en te registreren op verschillende IC-afdelingen in Nederland. Er zijn vragenlijsten verstuurd en er hebben semi- gestructureerde interviews plaatsgevonden met één of meerdere afgevaardigden van de deelnemende ziekenhuizen. Schriftelijke vragenlijst

In deze vragenlijst zijn vragen opgenomen met betrekking tot draagvlak, werkbelasting en ervaring met het registreren. Daarnaast zijn vragen opgenomen met betrekking tot betrouwbaarheid en validiteit van de indicatoren. De vragenlijst bestond uit 22 vragen verdeeld over zeven onderwerpen. De onderwerpen zijn als volgt verdeeld: 1) achtergrond en doel, 2) betrokkenheid, verantwoordelijkheid, 3) werkbelasting, 4) gebruiksvriendelijkheid 5) presentatie invoermodule, 6) betrouwbaarheid indicator, 7) validiteit indicator. De vragenlijst bestond uit open en gesloten vragen. Open vragen geven de beoordelaar de volledige vrijheid het antwoord op eigen manier weer te geven. De gesloten vragen bestonden voor het grootste deel uit ja- en nee vragen. Daarnaast werd bij een aantal vragen gebruik gemaakt van een vierpunt- Likert schaal die loopt van 4 (zeer



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Tabel 3 Indicator Beschikbaarheid intensivist Verpleegkundige patiënt ratio Beleid medicatiefouten Registreren patiënt/ familietevredenheid IC verblijfsduur Beademingsduur Interklinisch transport 100% bezetting Glucoseregulatie Mortaliteit Decubitus Ongeplande extubatie

Betrouwbaar Ja Nee

Valide Zeer eens/ eens

94% 80% 74% 71% 94% 89% 80% 80% 86% 91% 83% 69%

97% 89% 97% 71% 43% 63% 80% 74% 94% 63% 100% 71%

11% 11% 14% 3% 11% 11% 11% 3% 9% 23%

Zeer oneens / oneens 9% 23% 51% 28% 17% 23% 6% 29% 29%

Algemeen oordeel Aan te bevelen Niet aan te bevelen 100% 100% 100% 74% 88% 89% 80% 83% 97% 97% 97% 80%

11% 17% 11% 3% 3% 11%

eens), via 3 (eens) en 2 (oneens) naar 1 (zeer oneens). Na alle vragen waren regels voor commentaar beschikbaar. Aan het einde van de vragenlijst is een algemeen oordeel gevraagd. Deze bevatte een reeks opties ‘sterk aan te bevelen’, ‘aan te bevelen’, ‘niet aan te bevelen’ en ‘onzeker’. Het algemene oordeel vereist dat de beoordelaar de desbetreffende indicator aanbeveelt voor toekomstige implementatie of juist niet. De vragenlijst is aan twee personen uit de pilot ziekenhuizen gestuurd; in principe een verpleegkundige en een intensivist die betrokken waren bij de registratie. Zij hebben onafhankelijk van elkaar de vragenlijst ingevuld. Dit vergrootte de betrouwbaarheid van de beoordeling.

Draagvlak, extra tijd en werkbelasting

Mondelinge interviews

In onderstaande tabel wordt per indicator het percentage respondenten weergegeven die de indicator wel of niet betrouwbaar of valide beoordelen. Het gaat hier om een subjectieve waarneming (dus een persoonlijk oordeel) van de validiteit en betrouwbaarheid. Een indicator is betrouwbaar als het tijdens een herhaalde meting dezelfde score geeft, ongeacht wie de indicator scoort. Onder validiteit wordt verstaan dat het meet wat het beoogt te meten. Oftewel: zegt de indicator echt iets over een beoogd kwaliteitsaspect van de behandeling en/of zorg? In de eerste kolom van tabel 3 staat de indicator vermeld. De tweede kolom geeft het percentage respondenten weer die de geregistreerde gegevens betrouwbaar vinden of juist niet. De derde kolom (“valide”) resulteert in het percentage respondenten dat vindt dat de desbetreffende indicator bijdraagt aan een betere zorg en uiteindelijk een betere gezondheid van de patiënt of juist niet. De vierde kolom (“algemeen oordeel”) geeft weer hoeveel procent van de respondenten de desbetreffende indicator aanbeveelt voor toekomstige implementatie. Uit de resultaten van de vragenlijsten is gebleken dat de indicator beschikbaarheid intensivisten en IC verblijfsduur door de respondenten als het betrouwbaarst worden beschouwd. Daarnaast wordt de betrouwbaarheid van de indicator ongeplande extubatie het meest in twijfel getrokken. Wanneer er gekeken wordt naar de validiteit van de indicatoren geeft alle respondenten aan dat de indicator decubitus het meest valide is en de indicator IC verblijfsduur het minst valide. Tenslotte bevelen alle respondenten de indicator beschikbaarheid intensivist, verpleegkundige patiënt ratio en een beleid ter voorkoming van medicatiefouten aan voor toekomstige implementatie. Meer dan 75% van de respondenten gaf aan de implementatie van de gehele set aan te bevelen.

Bij aanvang van de pilot zijn ziekenhuizen (n=15) bezocht om het draagvlak te vergroten en om eventuele vragen te beantwoorden. Na drie maanden zijn alle ziekenhuizen (n=18) bezocht. Bij dit laatste bezoek heeft de vragenlijst, voor zover geretourneerd, als leidraad gediend voor de interviews. Belangrijke en opvallende opmerkingen uit de vragenlijst zijn genoteerd en tijdens de interviews besproken. De interviews dienden als aanvullende informatie.De resultaten van de interviews hielpen om een beeld te krijgen van de ervaringen van de deelnemers met de haalbaarheid en werkwijze van de indicatorverzameling en de beoordeling van de validiteit, betrouwbaarheid en het nut van deze IC-kwaliteitsindicatoren.

Resultaten Vragenlijsten

In totaal zijn er 36 vragenlijsten verstuurd. In geval van non-respons werd de desbetreffende persoon verzocht de vragenlijst te retourneren. Uiteindelijk zijn van de 36 vragenlijsten, 35 vragenlijsten geretourneerd. Twee ziekenhuizen hebben één vragenlijst teruggestuurd en één ziekenhuis heeft drie vragenlijsten teruggestuurd. De vragenlijsten zijn ingevuld door 16 intensivisten, 15 verpleegkundigen en 4 personen met een andere functie, maar wel bij het project betrokken (bijvoorbeeld een ICTer, kwaliteitsmedewerker, etc). Interviews

Vooraf was het streven om twee personen uit ieder pilot ziekenhuis te interviewen die ook de vragenlijst hadden ingevuld. Bij voorkeur een verpleegkundige en een intensivist. Uiteindelijk zijn 37 personen geïnterviewd waarvan 17 intensivisten, 13 verpleegkundigen en 7 personen met een andere functie.

Van de respondenten vindt 86% dat de werkbelasting die de pilot met zich meebrengt aanvaardbaar is. Daarnaast kost de registratie bij 46% van de respondenten minder dan een half uur gemiddeld per dag, bij 37% meer dan een half uur maar minder dan een uur gemiddeld per dag en bij 17% van de respondenten meer dan een uur per dag. 71% van de respondenten vindt de invoermodule waarmee ze werkten gebruiksvriendelijk. Concluderend kan worden gesteld dat de werkdruk van het registreren van de set indicatoren over het algemeen aanvaardbaar is en als voldoende gebruiksvriendelijk wordt beoordeeld. Betrouwbaarheid, validiteit en algemeen oordeel

Succesbevorderende en –belemmerende factoren

Onderdelen die volgens de meerderheid van de deelnemende zieken-

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huizen de werkwijze van de pilot positief hebben beïnvloed zijn: - De mogelijkheid om aan te sluiten bij huidige NICE-registratie door middel van een speciaal daarvoor ontwikkelde invoermodule (Mediscore/Marek IT); - Organisatie van een scholingsdag en het brengen van bezoeken aan de deelnemende ziekenhuizen; - Uitgebreide datadictionary ter ondersteuning van de registratie; - Subsidie voor deelname aan de pilot. Onderdelen die volgens de meerderheid van de deelnemende ziekenhuizen de werkwijze van de pilot negatief hebben beïnvloed: - Het versturen van de databestanden was vaak moeilijk; - Het missen van feedback over de aangeleverde data; is alles ontvangen en is er goed geregistreerd?; - De pilot uitvoeren tijdens vakantieperiode; - Geen uitgebreide uitleg over de werkwijze van de registratiesystemen Mediscore/ Marek IT; - Het ontbreken van een PDMS of labkoppeling in het ziekenhuis; - Geen medewerking van het bestuur van het ziekenhuis of van de ICT-afdeling; - Slechte communicatie binnen afdeling of ziekenhuis waardoor niet iedereen betrokken werd bij de pilot. Belangrijkste succesbevorderende factoren waren: gebruik van de NICE registratie, voldoende technische ondersteuning en maatregelen voor voldoende draagvlak. Implementatie van continue registratie van kwaliteitsindicatoren vergt van iedere IC-afdeling een forse inspanning en kan niet zonder ICT ondersteuning. Overige bevindingen bij de dagelijkse registratie van data bij de deelnemende pilot ziekenhuizen

- De indicator “transport” blijkt in de pilot beperkt geregistreerd te zijn, vaak ten gevolge van logistieke problemen. Deze indicator is daarom ongeschikt om gebruikt te worden. Registratie van transporten zal in de toekomst op andere wijze geregistreerd gaan worden (regionale MICU en registratie DBC IC-transport). - Registratie van mortaliteitsgegevens en behandelduur (uitkomstindicatoren) verliep beter op IC-afdelingen die bij de NICE aangesloten zijn dan bij beginnende ziekenhuizen.. - Hantering van het begrip ‘operationeel bed’ behoeft uitvoerige toelichting en betere definiëring maar is wel mogelijk om te registreren en is een kernvariabele voor meerdere indicatoren. - Registratie van glucoseregulatie kan verbeterd worden door bijvoorbeeld oppervlakte berekeningen. Dit behoeft registratie van alle glucose bepalingen op patiënt niveau met tijdstip van afname. Dit is op korte termijn echter niet te realiseren voor alle IC afdelingen. Het streven is om dit zo spoedig mogelijk voor alle afdelingen te realiseren om de validiteit van deze procesindicator te verhogen. - Iedere indicator behoeft gedetailleerde definiëring, waarvoor een eenduidige datadictionary cruciaal is. - Extractie van indicatoren uit reeds aangeleverde andere gegevens uit de centrale database (afgeleide data) is in het algemeen te prefereren boven aparte registratie van extra data (bv 100% bezetting of verpleegkundige/bedratio). Echter de algoritmes (databeheer en analyse) die NICE hanteert moeten kritisch geëvalueerd en gevalideerd worden. - Duurzame structurele implementatie van de registratie en verwerking van kwaliteitsindicatoren op alle IC- afdelingen in Nederland lijkt mogelijk.

- Het blijkt dat registratie beter verloopt als er een duidelijke verantwoordelijkheid bij één persoon ligt en er inbedding in de afdelingsstructuur is. - De pilot heeft een groot aantal data opgeleverd van de indicatoren per IC afdeling. Al de indicatoren gaven voldoende variatie te zien om te kunnen leiden tot initiatieven van kwaliteitsverbetering. De deelnemende centra hebben hiervan een terugrapportage ontvangen met eigen data gespiegeld aan gemiddelden van alle andere deelnemende IC afdelingen. Concluderend kan worden gesteld dat de resultaten bemoedigend zijn. Alle 18 ziekenhuizen hebben gedurende een half jaar geregistreerd en zijn over het algemeen positief geweest over de pilot-studie.

Voorstel definitieve set kwaliteitsindicatoren Op grond van bovenstaande rapportage komt de commissie kwaliteitsindicatoren van de NVIC, in samenwerking met anderen, tot het voorstel om onderstaande set indicatoren landelijk uniform te gaan registreren en centraal te beheren en te analyseren ten behoeve van terugrapportage en ‘benchmarking’. Het directe doel is te komen tot kwaliteitsverhoging door effecten op verschillende niveau’s: 1. Iedere IC-afdeling in Nederland krijgt meer inzicht in eigen kwaliteit van behandeling en zorg die een aanzet kan zijn tot verdere kwaliteitsverbetering. 2. Op nationaal niveau kunnen trends en verschillen aanleiding zijn om beleid te maken. 3. Op den duur kan een grote database inzicht geven in de relatieve waarde voor kwaliteit van zorg van organisatorische, procesmatige en inhoudelijke factoren. Met de formulering van interne indicatoren wordt aan het kwaliteitshoofdstuk van de richtlijn ‘organisatie en werkwijze IC-afdelingen in Nederland’ invulling gegeven. Nogmaals wordt expliciet gesteld dat interne kwaliteitsindicatoren voor de IC vertrouwelijk zijn en dienen te blijven. Interne indicatoren dienen niet voor het afleggen van externe verantwoording. Naast de bovengenoemde indicatoren zullen de volgende structuur kenmerken jaarlijks worden geregistreerd ten behoeve van de interpretatie (en benchmarking) van de indicatorgegevens. • • • • • • • • • • • • • • • • •

Datum registratie Type ziekenhuis Ziekenhuis met intensivisten opleiding; STZ ziekenhuis; perifeer geen STZ ziekenhuis; categoraal ziekenhuis, nl… Eventueel naam afdeling Aantal IC-bedden (voor definities: zie deel 3 datadictionary) aantal bedden totaal aantal bedden intensive care niveau 1; niveau 2; niveau 3 aantal bedden coronary care op IC Hartchirurgie ja/nee Intra-craniele neuro-chirurgie ja/nee Supra-regionale traumatologie ja/nee Transplantatiegeneeskunde ja/nee Brandwondencentrum ja/nee Calamiteitenbed (= extra IC-bed met voorzieningen zoals monitoring en (beademings)apparatuur, maar zonder IC-verpleegkundigen, waarop in geval van nood een IC-patiënt (tijdelijk) kan worden opgevangen) ja/nee • Aparte stepdownafdeling • Onder eindverantwoordelijkheid van intensivist ja/nee



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Tabel 4. Voorgestelde definitieve set kwaliteitsindicatoren voor Intensive Care afdelingen Indicator (niveau: afdeling (A) of Definitie (D) en registratie frequentie (F) patiënt (P)) Structuur Aanwezigheid en beschikbaarheid intensivist (A)

Specificaties (T=teller / N=noemer) Bereik (B); Doel (D)

D: Aantal uren per dag dat intensivist aanwezig en beschikbaar is F: per 3 maanden

T: aantal uren per etmaal dat geregistreerd intensivist aanwezig of beschikbaar. N: 24 uur B: 0-100%; D: 30-100% afhankelijk van IC niveau Patiënt:verpleegkundigen ratio D: Aantal gediplomeerde IC verpleegkundigen ten opz- T: aantal aanwezige patiënten. (A) ichte van aantal aanwezige patiënten N: aantal gediplomeerde IC verpleegkundigen F: 3 maal daags B: 0-4; D: 1-2 Beleid ter voorkoming medicatiefouten D: Aanwezigheid van preventieve interventies ter T: aantal aanwezige interventies (A) voorkoming van medicatiefouten gemeten aan 10 N: 10 items B: 0-10; D:10 F: per maand Registratie patiënt / familie tevreden- D: Meten van patiënt- en familietevredenheid op enige T: wel of niet heid wijze N: 1 (A) F: per 3 maanden B: 0-1; D: 1 Proces IC verblijfsduur D: Behandelduur van op de IC afdeling behandelde T: totaal aantal verblijfsdagen op de IC in een bepaalde (P) patiënten periode F: Dagelijks N: totaal aantal op de IC ontslagen patiënten in dezelfde periode B: 0-oneindig; D: ongedefinieerd Beademingsduur D: Beademingsduur van op IC beademde patiënten T: aantal beademingsdagen op de IC in een bepaalde (P) F: Dagelijks periode N: aantal beademde patiënten op de IC in dezelfde periode B: 0-oneindig; D: ongedefinieerd Dagen 100% bezetting D: Aantal dagen dat er op enig moment 100% bezetT: aantal dagen in een bepaalde periode dat op enig (P) ting is van de operationele IC bedden moment alle operationele bedden bezet zijn F: Dagelijks N: totaal aantal dagen in die periode B: 0-100%; D: 0% Glucoseregulatie D: Percentage bloedglucose metingen boven 8,0 en T: aantal metingen boven 8,0 mmol/l of onder 2,2 (P) onder 2,2 mmol/l mmol/l F: Dagelijks N: totaal aantal metingen B: 0-100%; D: 0% Accidentele detubatie D: Niet intentionele verwijdering van endotracheale T: aantal accidentele detubaties per tijdseenheid (P) tube of tracheostoma N: totaal aantal beademingsdagen in diezelfde tijdseenF: Dagelijks heid B: 0-oneindig; D: ongedefinieerd Uitkomst Mortaliteit D: Sterfte op de IC alsmede, gecorrigeerd voor ernst van T: a.Totaal aantal op de IC overleden patiënten (P) ziekte, in het ziekenhuis b.Totaal aantal in het ziekenhuis overleden patiënten F: Dagelijks N: a.Totaal op de IC behandelde patiënten b.Verwachte aantal overleden patiënten op grond van gemiddelde voorspelde mortaliteit door ernst-vanziekte-score B: 0-1; D: 0 Decubitus D: Nieuw ontstane decubitus op de IC (incidentie), T: aantal patiënten met nieuw opgetreden decubitus (P) graad 3 of 4 graad 3 of 4 tijdens IC behandeling F: Dagelijks N: totaal aantal behandelde patiënten in diezelfde periode B: 0-100%; D: 0

• Aantal bedden stepdownafdeling onder eindverantwoording intensivist ….. • Niet onder eindverantwoordelijkheid van intensivist ja/nee • Aantal bedden stepdownafdeling niet onder eindverantwoording intensivist ….. • 24-uurs Post-Anesthesia Care Unit (PACU) met beademingsmogelijkheid; ja/nee • Aantal bedden PACU + beademing ….. • Aantal fte volledig erkende IC-verpleegkundigen (aan bed) ….. • Aantal fte leerling IC-verpleegkundigen …..

600


• • • •

Aantal fte intensivisten ….. Aantal fte IC-artsen (niet-intensivisten) ….. waarvan aantal fellow-IC ….. Opleiding intensivisten ja/ nee

Dankbetuiging: De NVIC is de Orde van Medisch Specialisten zeer erkentelijk voor de financiële en inhoudelijke bijdrage, het RIVM voor de inhoudelijke en praktische bijdrage aan het kwaliteitsindicatoren project IC en de NVICV voor de inhoudelijke bijdrage binnen de commissie.


12-10-2006 09:14:51

Zorg kent vele gezichten VieCuri, Medisch Centrum voor Noord-Limburg VieCuri is een algemeen opleidingsziekenhuis met twee locaties in Venlo en Venray met een verzorgings-gebied van ± 280.000 inwoners. Patiënten uit de regio Noord-Limburg kunnen er voor vrijwel alle specialismen terecht. Binnen VieCuri zetten 133 specialisten met gemiddeld 40 artsassistenten, ruim 2500 medewerkers en een groot aantal vrijwilligers zich in voor een kwalitatief goede behandeling, verzorging en begeleiding van de patiënten. In oktober 2006 heeft visitatie plaatsgevonden ivm aansluiting bij de Stichting Topklinische Ziekenhuizen. De ziekenhuisorganisatie beschikt over 569 bedden, waarvan 481 op de locatie Venlo en 88 op de locatie Venray. Zowel in de directe patiëntenzorg als de ondersteunende dienstverlening staat het patiëntgericht handelen voorop. Venlo, gelegen in de rustige en groene Maasregio tussen de Nationale Parken ‘De Maasduinen’ en ‘De Meinweg’, biedt uitstekende en betaalbare vestigingsmogelijkheden. De Intensive Care is een ambitieuze afdeling, gevestigd op de locatie Venlo. De huidige IC beschikt over 10 beademingsbedden. Naast de IC bestaat een aparte Medium Care (“open format”, 5 bedden), waarop niet -beademde patiënten worden opgenomen. Voor de MC coördineren de intensivisten vooralsnog alleen de beddentoewijzing. Het verpleegkundig IC team bestaat uit 41 fte verpleegkundigen, waaronder 4 ventilation practitioners, een research nurse en gespecialiseerde wondverpleegkundigen. We werken graag met vernieuwende technologie zoals een mobiele opstelling van alle IC-apparatuur en zullen binnenkort starten met NAVA-gestuurde beademing. De afdeling is door de beroepsgroep gevisiteerd als niveau II (door de Inspectie van Volksgezondheid als niveau III). Ten behoeve van de IC is er formatieve ruimte voor een volledige voorwacht door arts-assistenten (7), waarvan 3 in opleiding zijn tot specialist. Kernbegrippen voor onze IC zijn: topklinische zorg, onderwijs/ opleiding, transparantie, klinisch onderzoek, en samenwerking, zowel binnen Viecuri als in een grote regio. In 2007 zal een aanvang gemaakt worden met een ingrijpende verbouwing. Uiteindelijk zal de IC/MC geheel vernieuwd en uitgebreid worden tot 3 units met in totaal 24 bedden. Wegens vertrek van een van de intensivisten zijn we op zoek naar een fulltime

Intensivist (m/v) U bent hoofdbehandelaar op de IC en verzorgt met uw collega intensivisten de supervisie in alle diensten. Wij zoeken primair een enthousiaste, integere en ondernemende collega, die met ons mee wil groeien in de verdere uitbouw van onze IC. Kwalitatief uitstekende patiëntenzorg is voor u vanzelfsprekend, waarbij u bereid bent protocollair en toetsbaar te werken. U investeert in de nieuwe generatie artsen en verpleegkundigen. U bent bereid tot deelname aan management in het kader van verbetering van zorg en organisatie. U participeert in lopend klinisch onderzoek en bent bereid eventueel nieuw onderzoek mee op te starten. Een promotie is een pré. U heeft een consultatieve taak voor de reguliere afdelingen en participeert in de traumaopvang van patiënten. Tevens fungeren de intensivisten als te consulteren medische achterwacht ten behoeve van de RAV Limburg-Noord. Voor meer informatie over deze functie kunt U contact opnemen met een van uw aanstaande collegae: Dr. D Hasan, Mevr. Drs M de Bruin, Dr. N. Foudraine (vakgroepcoördinator) allen via tel. 077 – 3205392 dan wel met de voorzitter van de Raad van Bestuur, de heer Drs. P.J.H. van Dreumel (077-3206500). Schriftelijke sollicitaties kunnen binnen 3 weken na verschijnen van deze advertentie worden gericht aan de Raad van Bestuur van VieCuri, Medisch Centrum voor Noord-Limburg, Postbus 1926, 5912 BL Venlo.

www.viecuri.nl Deze instelling maakt gebruik van de diensten van Zorg aan Zet. Zorg aan Zet geeft uitvoering aan het gezamenlijke arbeidsmarktbeleid van de Limburgse zorg. Informatie over de zorg in Limburg en meer vacatures vindt u op www.zorgaanzet.org.


Telefoon 0475 - 577 557 [email protected]

12-10-2006 11:55:14

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Medische vragen over een Pfizer geneesmiddel? Bel gratis Pfizer bv 0800-medinfo (633 46 36).

Postbus 37 2900 AA Capelle aan den IJssel www.pfizer.nl


VFE-05-016

Verkorte productinformatie VFEND (augustus 2006). Samenstelling: VFEND 50 mg en 200 mg filmomhulde tabletten bevatten respectievelijk 50 mg en 200 mg voriconazol. VFEND I.V., poeder voor oplossing voor infusie, bevat 200 mg voriconazol per flacon, overeenkomend met een 10 mg/ml oplossing na reconstitutie. VFEND 40mg/ml poeder voor orale suspensie bevat per ml 40 mg voriconazol. Indicaties: Behandeling van invasieve aspergillose, candidemie bij niet-neutropenische patiënten, fluconazol-resistente ernstige invasieve Candida-infecties, ernstige schimmelinfecties, veroorzaakt door Scedosporium spp en Fusarium spp. VFEND dient in eerste instantie te worden toegediend aan patiënten met progressieve, mogelijk levensbedreigende infecties. Farmacotherapeutische groep: antimycotica voor systemisch gebruik; triazoolderivaten; ATC code: J02A C03. Contra-indicaties: Overgevoeligheid voor voriconazol of één van de hulpstoffen; gelijktijdige toediening van de CYP3A4-substraten terfenadine, astemizol, cisapride, pimozide, kinidine, en van rifampicine, carbamazepine, fenobarbital, efavirenz, ergotamine-alkaloïden (ergotamine, dihydro-ergotamine), ritonavir (in een dosering van tweemaal daags 400 mg en hoger) en sirolimus. Waarschuwingen en voorzorgen: Voorzichtigheid bij toediening aan patiënten met een overgevoeligheid voor andere azolen. Sommige azolen, met inbegrip van voriconazol, zijn geassocieerd met een verlenging van het QT-interval. Er deden zich zeldzame gevallen voor van torsade de pointes bij patiënten behandeld met voriconazol, die risicofactoren vertoonden en die gelijktijdig geneesmiddelen toegediend kregen die mogelijk aan deze voorvallen hadden bijgedragen. Voorzichtigheid is geboden bij de toediening van voriconazol aan patiënten met potentieel pro-aritmische factoren. Electrolytstoornissen dienen voor aanvang van de behandeling met VFEND te worden gecontroleerd en gecorrigeerd. Ernstige hepatische reacties, die meestal reversibel zijn na staken van de VFEND toediening, kunnen optreden. Controle van de leverfunctie dient zowel bij kinderen als bij volwassenen en zowel bij aanvang van de behandeling als bij patiënten met abnormale leverfunctiewaarden routinematig tijdens de behandeling te worden uitgevoerd. Acuut nierfalen kan voorkomen, daarom is een controle van de nierfunctie noodzakelijk. Patiënten ontwikkelden zelden exfoliatieve huidreacties tijdens VFEND behandeling. Bij uitbreiding van deze reacties dient VFEND toediening te worden gestopt. Patiënten dienen zonlicht te vermijden tijdens de behandeling tengevolge van het voorkomen van overgevoeligheid voor licht. Onder de leeftijd van twee jaar zijn de veiligheid en effectiviteit van VFEND niet aangetoond. Voriconazol is geïndiceerd voor pediatrische patiënten van twee jaar of ouder. De orale biologische beschikbaarheid kan beperkt zijn bij pediatrische patiënten van 2 tot <12 jaar met malabsorptie en een voor de leeftijd zeer laag lichaamsgewicht. In dat geval is de intraveneuze toediening van voriconazol aanbevolen. Bij gelijktijdig gebruik met fenytoïne of rifabutine wordt een zorgvuldige controle van de fenytoïnespiegels of volledige bloedceltelling (bij rifabutine) aanbevolen. Een frequente controle op methadongerelateerde ongewenste voorvallen en toxiciteit, waaronder QTc-verlenging, wordt aanbevolen bij gelijktijdige toediening van voriconazol. Een dosisvermindering van methadon kan noodzakelijk zijn. Gelijktijdige toediening van voriconazol en lage dosis ritonavir (tweemaal daags 100 mg) dient vermeden te worden, tenzij de risico/batenanalyse het rechtvaardigt. De tabletten bevatten lactose en mogen niet gebruikt worden bij Lapp-lactase deficiëntie of glucose-galactosemalabsorptie patiënten. De orale suspensie bevat saccharose en mag niet gebruikt worden bij patiënten met zeldzame, erfelijke problemen van fructose-intolerantie, sucrase-isomaltase-deficiëntie of glucose-galactose-malabsorptie. Bijwerkingen: De meest gerapporteerde, zeer vaak voorkomende bijwerkingen (≥1/10) zijn visuele stoornissen, koorts, huiduitslag, braken, misselijkheid, diarree, hoofdpijn, perifeer oedeem en abdominale pijn. Verder zijn vaak waargenomen (>1/100, ≤1/10): griepachtige symptomen, gastro-enteritis, trombocytopenie, anemie, beenmergdepressie, leukopenie, pancytopenie, purpura, sinusitis, hypoglykemie, hypokaliëmie, angst, depressie, hallucinatie, duizeligheid, verwardheid, tremor, agitatie, paresthesie, hypotensie, tromboflebitis, flebitis, ademnood, acute respiratory distress syndrome, longoedeem, thoraxpijn, geelzucht, cholestatische geelzucht, erytheem, cheilitis, aangezichtsoedeem, pruritus, maculo-papulaire huiduitslag, maculaire huiduitslag, papulaire huiduitslag, lichtovergevoeligheidsreactie, alopecia, exfoliatieve dermatitis, rugpijn, acuut nierfalen, hematurie, rillingen, asthenie, reactie/ontsteking op de injectieplaats, verhoogde leverfunctiewaarden (met inbegrip van ASAT, ALAT, alkalische fosfatase, gammaGT, LDH, bilirubine), verhoogde bloedcreatininespiegel. Soms (>1/1000, ≤ 1/100) zijn waargenomen: lymfadenopathie, eosinofilie, diffuse intravasculaire coagulatie, agranulocytose, overgevoeligheid, anafylactoïde reactie, bijnierschorsinsufficiëntie, ataxie, hersenoedeem, diplopie, vertigo, hypesthesie, blefaritis, oogzenuwstoornis, papiloedeem, scleritis, nystagmus, supraventriculaire aritmie, bradycardie, syncope, tachycardie, ventriculaire aritmie, ventrikelfibrillatie, supraventriculaire tachycardie, constipatie, duodenitis, dyspepsie, gingivitis, glossitis, pancreatitis, gezwollen tong, peritonitis, hepatomegalie, cholecystitis, cholelithiasis, hepatitis, leverfalen, allergische dermatitis, angioneurotisch oedeem, eczeem, psoriasis, syndroom van Stevens-Johnson, urticaria, geneesmiddelovergevoeligheid, artritis, nefritis, proteïnurie, verhoogde bloedureumspiegel, verhoogde bloedcholesterolspiegel, verlengd gecorrigeerd QT interval op het electrocardiogram. Zelden (≤1/1000) komen voor: pseudomembraneuze colitis, hyperthyreoïdie, hypothyreoïdie, slapeloosheid, syndroom van Guillain-Barré, extrapiramidale symptomen, encefalopathie, slaperigheid tijdens infusie, convulsie, retinale bloeding, corneatroebeling, optische atrofie, oogdraaien, hypoacusis, oorsuizen, volledig atrioventriculair blok, bundeltakblok, nodaal ritme, ventriculaire tachycardie, torsade de pointes, lymfangitis, dysgeusie, hepatisch coma, discoïde lupus erythematodes, erythema multiforme, toxische epidermale necrolyse, hypertonie, tubulaire necrose van de nier. Afleveringsstatus: UR. Verpakking en Registratienummer: VFEND, filmomhulde tabletten 50 mg: EU/1/02/212/006 (30 stuks), filmomhulde tabletten 200 mg: EU/1/02/212/018 (30 stuks) VFEND, poeder voor oplossing voor infusie 200 mg: EU/1/02/212/025 (1 injectieflacon) VFEND, poeder voor orale suspensie: EU/1/02/212/026 (1 flacon). Vergoeding en prijzen: VFEND, filmomhulde tabletten en poeder voor orale suspensie worden volledig vergoed binnen het GVS, VFEND I.V. is niet opgenomen in het GVS. Voor prijzen wordt verwezen naar de Z Index taxe. Voor medische informatie over dit product belt u met 0800-MEDINFO (6334636). De volledige productinformatie (SPC van 28 augustus 2006) is op aanvraag verkrijgbaar. Registratiehouder: Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, Verenigd Koninkrijk. Neem voor correspondentie en inlichtingen contact op met de lokale vertegenwoordiger: Pfizer bv, Postbus 37, 2900 AA Capelle a/d IJssel.

12-10-2006 09:14:55

603

r e g i s t r at i e f o r m u l i e r Lidmaatschap (altijd invullen !)

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12-10-2006 09:14:56

r e g i st r at i e f o r m u l i e r co n g r e s s e n , c u rsusse n e n symposia Alle congressen, cursussen en symposia zijn inclusief een gratis reader

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< € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575 < € 575

< € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650 < € 650

< € 240,-

< € 315,-

< € 350,-

< € 95,- < € 15,50 < € 25,- < € 19,50 < € 29,50

< € 95,- < € 15,50 < € 25,- < € 19,50 < € 29,50

< € 95,< € 15,50 < € 25,< € 19,50 < € 29,50

Fundamental Critical Care Support Course (FCCS) Congreshotel 'De Werelt', Lunteren < € 495 woensdag en donderdag 17 en 18 januari 2007 < € 495 dinsdag en woensdag 13 en 14 februari 2007 < € 495 dinsdag en woensdag 6 en 7 maart 2007 < € 495 donderdag en vrjidag 12 en 13 april 2007 < € 495 woensdag en donderdag 18 april en 19 april 2007 < € 495 donderdag en vrijdag 10 mei en 11 mei 2007 < € 495 donderdag en vrijdag 31 mei en 1 juni 2007 < € 495 donderdag en vrijdag 13 en 14 september 2007 < € 495 donderdag en vrijdag 27 en 28 september 2007 < € 495 dinsdag en woensdag 9 en 10 oktober 2007 < € 495 woensdag en donderdag 14 en 15 november 2007 < € 495 donderdag en vrijdag 13 en 14 december 2007 < Ik wil instructeur worden bij de FCCS-cursussen en zal de eerste keer als hybride meedoen, neem contact met mij op. NVIC Mechanische Beademingsdagen 2006 Hotel en Congrescentrum De Reehorst, Ede Donderdag 30 november en vrijdag 1 december 2006 - Toeslag logies en ontbijt (éénpersoonskamer) - Treinkaartje dagretour 2e klas Reehorst Ede* - Treinkaartje dagretour 1e klas Reehorst Ede* - Treinkaartje meerdaags retour 2e klas Reehorst Ede* - Treinkaartje meerdaags retour 1e klas Reehorst Ede*

kwa l it e itsvi s itati e < Graag ontvang ik een informatiepakket om een kwaliteitsvisitatie op mijn Intensive Care afdeling aan te vragen. De kosten van een visitatie bedragen € 3950 < Ik wil visiteur worden bij de Nationale Visitatiecommissie en ontvang hierover graag informatie. l i d ma ats c h a p Ik word alleen lid van NVIC en ik betaal: Intensivist-leden en fellows: Buitengewone leden: readers, symposiumboeken en cd-rom’s ik bestel de volgende artikelen: Plaats (bij deelname aan cursussen en symposia is het cursusmateriaal inbegrepen) < NVIC Nederlandse Intensivisten Dagen 2002 Arnhem < NVIC Circulatiecursus 2003 Arnhem < NVIC Nederlandse Intensivisten Dagen 2004 Arnhem < NVIC Mechanische Beademingsdagen 2004 Arnhem < NVIC Circulatiecursus 2004 Arnhem < NVIC Nederlandse Intensivistendagen 2005 Ede < NVIC NEMO-cursus Ede < NVIC Circulatiedagen 2005 Ede < NVIC Nederlandse Intensivistendagen 2006 Ede < NVIC Neuro-congres Ede < ik bestel geen readers De prijs is inclusief verzendkosten. Handtekening

< € 165 (contributie 2006) < € 110 (contributie 2006) Datum

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07/08-02-2002 20 /21-11-2003 10/11/12-03-2004 10/11-06-2004 16 /17-09-2004 23/24/25-02-2005 9/10-06-2005 10/11/2005 1/2/3-02-2006 8/9-06-2006

90-75523-33-5 90-75523-41-6 90-75523-45-9 90-75523-44-0 90-75523-46-7 90-75523-48-3 90-75523-50-5 90-75523-49-1 90-75523-69-6 90-75523-61-0

€ € € € € € € € € €

Aantal

22,50 15,00 22,50 15,00 15,00 22,50 15,00 15,00 22,50 15,00

Naam ondergetekende Datum Plaats

(niet ondertekende of onvolledig ingevulde registratieformulieren kunnen niet in behandeling genomen worden) machtiging Overeenkomstig de bekende algemene inschrijvings- en betalingsvoorwaarden van de nvic verklaar ik dat de nvic gemachtigd is om van eerdergenoemd bank- of girorekeningnummer de bedragen af te schrijven die samenhangen met: < deelname aan de aangegeven congressen, cursus(sen) en/of symposia < lidmaatschap van de nvic < bestelling van reader(s) en/of symposiumboeken Handtekening

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12-10-2006 09:14:56

adv 210x277

15-05-2006

13:58

Pagina 1

06.tyg.6.8 Productinformatie zie elders in dit blad.

Een nieuw antibioticum doet de ronde


Leading the way to a healthier world

12-10-2006 09:20:19

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12-10-2006 09:20:11

Netherlands Journal. E.J. Lust, W.K. Lagrand, M. van der Ent, A.P.W.M. Maat, M.L. Simoons

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