2006 NJCC_05 binnenwerk 01.indd

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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adv 21

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

is all about:

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

561

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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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4

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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ß(1,3)-D-glucan

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 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

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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 ( 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.

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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



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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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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 (35 mmol/L, sCr >600 µmol/L dose late Elahi [15] Retrospective [64] ARF after cardiac Early: oliguria (30 mmol/L, sCr >250 µmol/L, reported Demirkilic [14] Retrospective [61] ARF after cardiac Early: oliguria ( 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)