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1 Netherlands Journal Netherlands Journal o f cc r i t i c al l Cc ar re e Volume 10, No. 5 October 2006 bi-monthly official journal of the dutch society of intensive care ( nvic) In this issue clinical image Incomplete circle of Willis 530 H.R.H. de Geus, J. Bakker case reports Ventricular septal rupture as an early and fatal complication 531 of acute myocardial infarction: case-report 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 538 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 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 561 therapy for acute renal failure in the critically ill C.S.C. Bouman, H.M. Oudemans-van Straaten NVICatern Nederlandse Vereniging voor Intensive Care (NVIC) round table New perspectives in the treatment of severe yeast- and fungal 587 infections in critically ill patients: the role of Mycograb K.H. Polderman, A.R.H. van Zanten V O L U M E 1 0

2 TOTAL is all about: PERFORMANCE SPEED STRENGTH ENDURANCE Voor productinformatie zie elders in dit blad

3 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 Publisher Netherlands Journal of Critical Care issn: nvic Stationsweg 73C 6711 PL Ede (Gld) Telephone: Fax: KvK Utrecht V Production Interactie, Ede Design v i l l a y, The Hague Layout Unit-1, The Hague Printing Perfect DM Groep, Rotterdam Advertising-exploitation/ Business contacts Eldering Studio BV Thomas Eldering Communication and media-specialists Zijlweg BA Overveen Telephone: Fax: Internet address Dutch IC society: Bankaccount ABN AMRO Ede IBAN NL 55ABNA 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 or by fax at 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. Netherlands Journal o f c r i t i c a l c a r e Vol. 10, No. 5, October 2006 Information for authors 429 Clinical image Incomplete circle of Willis 530 H.R.H. de Geus, J. Bakker Case reports Ventricular septal rupture as an early and fatal complication 531 of acute myocardial infarction: case-report 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 538 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 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 Guidelines Guidelines for timing, dose, and mode of continuous renal replacement 561 therapy for acute renal failure in the critically ill C.S.C. Bouman, H.M. Oudemans-van Straaten NVICatern Commissies en Afgevaardigden 571 Verenigingsnieuws 573 Agenda 573 Round Table: New perspectives in the treatment of severe yeast- and fungal 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 een continue nationale registratie ten behoeve van kwaliteitsverbetering De commissie kwaliteitsindicatoren van de NVIC Inschrijvingsformulier

4 (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 (Augustus 2005) ALTANA Pharma bv, Postbus 31, 2130 AA Hoofddorp, WT bijsl 90x :46 Pagina 1 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 met uw CV sturen naar: Voor meer informatie kunt u bellen met een van onze medisch specialist/consultants of bezoek onze website 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, 06.tyg.6.8. Leading the way to a healthier world

5 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 MB Amsterdam Arthur van Zanten, Managing Editor Dept. of Intensive Care Medicine Gelderse Vallei Hospital PO box HN Ede Kees Polderman, Internet Editor/ Section Editor Neuro University Medical Center Utrecht PO Box GA Utrecht Peter van der Voort, Correspondence Editor Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box BR Leeuwarden Jan Bakker, Section Editor Hemodynamics Dept. of Intensive Care Medicine Erasmus Medical Center Rotterdam PO Box CA Rotterdam Johan Damen, Section Editor Anesthesiology Dept. of Cardiothoracic Anesthesiology and Intensive Care Medicine UMC St. Radboud, PO Box 9101, 6500 HB Nijmegen Armand Girbes, Section Editor General Dept. of Intensive Care Medicine VU University Medical Center PO box MB Amsterdam Jan Hazelzet, Section Editor Pediatrics Pediatric Intensive Care Unit; Sophia Children s Hospital; Erasmus Medical Center Rotterdam PO Box CB Rotterdam Hans van der Hoeven, Section Editor Mechanical Ventilation Dept. of Intensive Care Medicine UMC St. Radboud PO Box HB Nijmegen 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 AZ Amsterdam Heleen Oudemans-van Straaten, Section Editor Nephrology Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box HM Amsterdam Saskia Peerderman, Section Editor Neuro Dept. of Neurosurgery Intensive Care VU University Medical Center PO box MB Amsterdam Peter Pickkers, Section Editor Sepsis and inflammation Dept. of Intensive Care Medicine UMC St. Radboud PO Box HB Nijmegen Dick Tibboel, Section Editor Pediatrics Pediatric Intensive Care Unit; Sophia Children s Hospital; Erasmus Medical Center Rotterdam PO Box CB Rotterdam Paul van den Berg Dept. of Intensive Care Medicine Leids University Medical Center PO Box RC Leiden Alexander Bindels Dept. of Internal Medicine Catharina Hospital Michelangelolaan EJ Eindhoven Reinier Braams Dept. of Intensive Care Medicine University Medical Center Utrecht PO Box GA Utrecht Can Ince Dept. of Physiology Academic Medical Center, University of Amsterdam Meibergdreef AZ Amsterdam Anton van Kaam Dept. of Neonatal Intensive Care Emma Children s Hospital Academic Medical Centre University of Amsterdam, Meibergdreef 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 GA Utrecht Michael Kuiper Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box BR Leeuwarden Andrew Maas Dept. of Neurosurgery Erasmus Medical Center Rotterdam PO Box CB Rotterdam Manu Malbrain Dept. of Intensive Care Medicine Academic Hospital Stuivenberg Lange Beeldekenstraat 267 B-2060 Antwerpen, Belgium Gerrit-Jan Scheffer Dept. of Anaesthesiology UMC St. Radboud PO Box HB Nijmegen Marcus Schultz Dept. of Intensive Care Medicine Academic Medical Center, University of Amsterdam Mail stop G3-206 Meibergdreef AZ Amsterdam Peter Spronk Dept. of Intensive Care Medicine Gelre Hospital, location Lukas PO Box DS Apeldoorn Tjip van der Werf Intensive and Respiratory Care Unit Dept. of Internal Medicine Groningen University Hospital PO Box RB Groningen Durk Zandstra Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box HM Amsterdam 527

6 Laat de humane cel ongemoeid 4 Cell Membrane Fungal Cell Wall ß(1,3)-D-glucan Cell Membrane Fungal Cell Wall CANCIDAS Precursors to ß(1,3)-D-glucan Precursors to ß(1,3)-D-glucan Normal Cell-Wall Synthesis Synthesis Inhibited by CANCIDAS Invasieve candidiasis 1 Invasieve aspergillose 2 Empirische antifungale therapie 3 C. albicans C. rugosa C. glabrata C. parapsilosis C. tropicalis C. krusei C. guilliermondii C. lipolytica C. dubliniensis C. kefyr C. lusitaniae A. flavus A. fumigatus A. terreus A. niger A. nidulans CANDIDA ALBICANS CANDIDA NON-ALBICANS ASPERGILLUS Bewezen effectiviteit 1 Gunstig veiligheidsprofiel CAN06NL155J0306 Referenties: 1. Duarte P.N.: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Eng J Med 347;2020-9, Maertens J.: Effi cacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant for conventional antifungal therapy. CID 2004;39: 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: David W. Denning: Echinocandin antifungal drugs. The Lancet 362: , 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 , Evidence. Experience. Confidence.

7 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. Major Articles. Major articles report the results 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 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 (as attachments) to: The manuscript should be accompanied by a cover letter stating the following: the complete mailing address, address, telephone number and fax number of the corresponding author. Receipt of the manuscript will be acknowledged by 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 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 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: 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 Proofs. The corresponding author will receive proofs by 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. 529

8 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received August 2006; accepted in revised form September 2006 c l i n i c a l 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: H.R.H. de Geus References 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):

9 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received January 2006; accepted in revised form July 2006 c a s e r e p o r t Ventricular septal rupture as an early and fatal complication of acute myocardial infarction: case-report E.J. Lust 1 *, W.K. Lagrand 1, M. van der Ent 1, A.P.W.M. Maat 2, M.L. Simoons 1 1 Departments of Cardiology and 2 Cardiothoracic 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 S 3 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 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 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 531

10 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. 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 GUS- TO-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, although 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 532

11 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: 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): 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: 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: David ET, Dale L, Sun Z. Postinfarction ventricular septal rupture: repair by endocardial patch with infarct exclusion. J Thorac Cardiovasc Surg 1995;110: 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): Blanche C, Khan SS, Chaux A, Matloff JM. Postinfarction ventricular septal defect in the elderly: analysis and results. Ann Thorac Surg. 1994;57:

12 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received June 2006; accepted in revised form September 2006 c a s e r e p o r t Syphilis-associated Guillain- Barré Syndrome M. Hijmering 1, C. Hoedemaekers 1, A. Oude Lashof 2 and J. van der Hoeven 1 1 Department of Intensive Care, 2 Department 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 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 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. Correspondence: M. Hijmering Discussion 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 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 Mycoplasma pneumoniae H. influenzae Helicobacter pylori Herpes virusses HIV West-Nile virus Hepatitis A, B, C virusses M. neisseria Y. enterocolitica S. typhy Chl. pneumoniae Hanta virus Parvo virus B19 Para-infuenza virus 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 534

13 Figure 1. Spirochetes in a supraclavicular lymph node. (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 infectious 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): Weisenberg E, Baron BW. Syphilis-associated Guillain- Barre syndrome: response to plasmapheresis. J Clin Apher 1994; 9(3): Kouznetsov AV, Prinz JC. Molecular diagnosis of syphilis: the Schaudinn-Hoffmann lymph-node biopsy. Lancet 2002; 360(9330): Ciesielski CA. Sexually Transmitted Diseases in Men Who Have Sex with Men: An Epidemiologic Review. Curr Infect Dis Rep 2003; 5(2): Doherty L, Fenton KA, Jones J, Paine TC, Higgins SP, Williams D et al. Syphilis: old problem, new strategy. BMJ 2002; 325(7356): Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003; 290(11): Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis 2004; 4(7):

14 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received and accepted: oktober 2006 c a s e r e p o r t Fatal Invasive Aspergillosis in an Apparently Immunocompetent Host W.M. Dijkman 1, B.H. Postma 2 1 dept. intensive care medicine, Máxima Medisch Centrum. 2 Laboratory 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 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. 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 Discussion 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 536

15 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 Biopsy Microscopy: no hyphae Culture: A. fumigatus 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 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): Hartemink KJ, Paul MA, Spijkstra JJ, Girbes AR, Polderman KH: Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003, 29(11): Richardson MD WD: Fungal Infection. Diagnosis and treatment, 3 edn: Blackwell 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): 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): 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): 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): 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):R Richardson MD K, M: Aspergillus. Philadelphia: Churchill Livingstone; 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):

16 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received June 2006; accepted September 2006 c a s e r e p o r t Polychemotherapy with bleomycin for metastasized choriocarcinoma of the testis in a ventilated patient M. de Bruin 1, T. Müller, N. Foudraine 1, S. Wouda 3, P. ter Horst 2, F. Nooteboom 4 1 Department of Intensive Care, 2 Department of Clinical Pharmacy, 3 Department 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 (FiO 2 = 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 38 th 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 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 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 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 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 H 2 O and 14 cm H 2 O of PEEP and a FiO 2 of 60% resulted in a p a O kpa (p a O 2 /FiO 2 = 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*10 9 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 H 2 0 (including up to 8 cm H 2 O PEEP) and a FiO 2 538

17 Table 1 Respiratory parameters and laboratory results Respiratory parameters ICU d 5 ICU d -4 On Intake ICU ICU d 4 ICU d 12 ICU d 19 ICU d38 before bleomycin after 1st cycle day 0 after 2nd cycle after 3rd after 4th premortum cycle cycle Blood gas analysis ph (in kpa) paco pao HCO BE SaO2 98% 96% 89% 98% 97% 94% 76% Respiration parameters FiO2 NRBM NRBM NRBM Pressures in cm H2O Mode 60% Spontaneous 60% 60% PC PS PS PC Peak pressure NA above PEEP PEEP PaO2/FIO2 ratio Tumour markers AFP HCG LDH GFR 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 p a O 2 of 8.8 kpa (p a O 2 /FiO 2 = 8.8). The patient was placed in the prone position on day 34, unfortunately without appropriate improvement in oxygenation and an essentially unchanged p a O 2 /FiO 2 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, pco kpa, p a O 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 10 7 per year or only 1% of malignancies in male in the Netherlands[2,21]. Mortality rate is 0.3 per 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 539

18 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 Bleomycin- Fe 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. 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. 540

19 References 1. Sleijfer S, Bleomycin-induced Pneumonitis; Chest 2001; 120; Einhorn L.H., Curing metastatic testicular cancer; PNAS; 2002 April 2; vol 99; no 7; 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: 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: 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 ): Maher J., Daly P., Severe bleomycin lung toxicity: reversal with high dose corticosteroids; Thorax 1993; 48 : Joselson R., Warnock M., Pulmonary veno-occlusive disease after chemotherapy. Hum. Pathol> 1983; ( 14 ): 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): Holoye P., Luna M., Mackay B., Bleomycin hypersensitivity pneumonitus. Ann Intern. Med. 1978; 88: Bakowska J., Adamson I., Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury. J. Pathol. 1998; 185 ( 3 ): 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): 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: Cooper J, White D, Matthay R. Drug-induced pulmonary disease. Am Rev Respir Dis 1986; 133: Chandler D. Possible Mechanisms of Bleomycin-Induced Fibrosis. Clin Chest Med 1990; 11(1): 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): Cersosimo R, Matthews S, Hong W. Bleomycin pneumonitis potentiated by oxygen administration. Drug Intelligence and Clinical Pharmacy 1985; 19: 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): Krakoff I, Cvitkovic E, Currie V. Clinical pharmacologic and therapeutic studies of bleomycin given by continuous infusion. Cancer 1977;(40): 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): 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;

20 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. 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. Sherrington 1, A. Tillyard 1, A. Rhodes 2 and R.M. Grounds 2 1 Specialist Registrar in Intensive Care, St Georges Hospital, London, UK. 2 Consultant 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 Correspondence: Andrew Tillyard 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. Amplification This starts with vascular disruption and exposure of tissue factor bearing cells to platelets, Von Willebrand factor and Factor VIII. The 542

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