Netherlands Journal. In this issue. Structured abstracts 77. Volume 10, No. 2 April J.P.J. Wester and H.M. Oudemans-van Straaten. L.D

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. 2 April 2006

In this issue

q u e s t i o n s and answers

How do I diagnose HIT in the critically ill?

61

J.P.J. Wester and H.M. Oudemans-van Straaten c l i n i c a l i mage

Touch the ICU patient with care!

65

L.D. Maatman c a s e r e p o rt

Unexpected pharmacokinetics of midazolam in a patient with severe head injury in a surgical intensive care unit

66

A.S. Winters, J. van Bastelaar, J.C. Paling en M.G.G. Rodgers o r i g i n a l paper

Early postoperative fever is not a determinant of cognitive decline following coronary artery bypass grafting

70

D. van Dijk, S. Dieleman, C.J. Kalkman c a s e r e p o rt

Citrate, calcium, parathyroid hormone and anion gap in a patient with citrate intoxication during citrate based CVVH

74

S.M.J. ter Veldhuis, A. Wolthuis, A.J. Bakker, P.H.J. van der Voort

Structured abstracts

77

NVICatern

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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. 2, April 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

Information for authors

59

Questions and Answers How do I diagnose HIT in the critically ill? J.P.J. Wester and H.M. Oudemans-van Straaten

•

61

Clinical image Touch the ICU patient with care! L.D. Maatman

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Scientific manuscripts, reviews, reports, opinions and guidelines Unexpected pharmacokinetics of midazolam in a patient with severe head injury in a surgical intensive care unit A.S. Winters, J. van Bastelaar, J.C. Paling en M.G.G. Rodgers

•

66

• Early postoperative fever is not a determinant of cognitive

70

decline following coronary artery bypass grafting D. van Dijk, S. Dieleman, C.J. Kalkman

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 Neth J Crit Care: www.nethjcritcare.com

• Citrate, calcium, parathyroid hormone and anion gap in a patient with

74

citrate intoxication during citrate based CVVH S.M.J. ter Veldhuis, A. Wolthuis, A.J. Bakker, P.H.J. van der Voort

Structured abstracts

77

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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.

n eth j crit care • volume 10 • no 2 • apri l 2006

NJCC_02 binnenwerk 02.indd 57

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n e th e rlan ds jou rnal of critical care

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 Dept. of Intensive Care Medicine VU University Medical Center PO box 7057 1007 MB Amsterdam

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

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

Johan Damen, Section Editor Anesthesiologie Dept. of Cardiothoracic Anesthesiology and Intensive Care Medicine “Isala Klinieken”, location “Weezenlanden” Groot Weezenland 20/28 8011 GM Zwolle

Jan Hazelzet, Section Editor Kinder IC Pediatric Intensive Care Unit; Sophia Children’s Hospital; Erasmus Medical Center Rotterdam PO Box 2060 3000 CB Rotterdam

Paul van den Berg Dept. of Intensive Care Medicine Leids University Medical Center PO Box 9600 2300 RC Leiden

Anton van Kaam Dept. of Neonatal Intensive Care Emma Children’s Hospital Academic Medical Centre University of Amsterdam, Meibergdreef 9 1105 AZ Amsterdam

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

58 NJCC_02 binnenwerk 02.indd 58

Hans van der Hoeven, Section Editor Beademing Dept. of Intensive Care Medicine UMC St. Radboud PO Box 9101 6500 HB Nijmegen

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 Scores/Kwaliteit 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 Nefrologie Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box 95500 1090 HM Amsterdam

Peter Pickkers, Section Editor Sepsis/ontsteking Dept. of Intensive Care Medicine UMC St. Radboud PO Box 9101 6500 HB Nijmegen Dick Tibboel, Section Editor Kinder IC 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

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


14-04-2006 10:54:09


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

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

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

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

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

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

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

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

General information. Manuscripts should be submitted by e-mail (as attachments) to: jolien. [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



59 14-04-2006 10:54:12

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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


14-04-2006 10:54:20

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

q u e s t i o n s

Received December 2005; accepted in revised form February 2006

a n d

a n s w e r s

How do I diagnose HIT in the critically ill? JPJ Wester and HM Oudemans-van Straaten Department of Intensive Care,Onze Lieve Vrouwe Gasthuis, Amsterdam

Dear Dr. Crick, Many of our patients receiving heparin develop a drop of platelet count. Because several conditions may explain thrombocytopenia in critically ill patients, we always have a discussion whether heparininduced thrombocytopenia is the cause or not. Can you explain us how HIT develops and how the diagnosis is confirmed?

How does HIT develop? During the use of unfractionated heparin (UFH), low molecular weight heparins (LMWH) or heparinoids (danaparoid) thrombocytopenia may develop. Two types of thrombocytopenia are recognized. Heparin-induced thrombocytopenia (HIT) type I is non-immunogenic and associated with an early, limited and self-recovering fall in platelet count. HIT II (or simply HIT) is a severe clinicopathologic syndrome associated with the development of immunoglobulin G antibodies, reacting with an antigenic complex consisting of heparin and platelet factor-4 (PF4), leading to a more severe drop in platelets, risk of bleeding, and additional paradoxical hypercoagulability [1]. The development of antibodies is probably related to a configurational change of PF4 induced by heparin. For the antibodies to become active and induce thrombocytopenia, they have to bind to PF4. Heparin binds to PF4 in relation to the chain length and degree of sulphation, explaining why low molecular weight heparins (LMWH) and danaparoid are less likely to cause HIT than UFH. ‘HIT antibodies’ have even been even detected during treatment with the pentasaccharide fondaparinux, but chain length of fondaparinux is too short to allow binding and subsequent effects on platelets [2]. In a recent meta-analysis, the risk of HIT with LMWH was 0.2% and with UFH 2.6% [3]. The incidence of HIT seems higher in critically ill patients, especially cardiac surgery patients. Prospective epidemiological studies are, however, not available in the critically ill.

How do we confirm the diagnosis HIT in the critically ill? In critically patients with multiple conditions contributing to thrombocytopenia, HIT is difficult to diagnose. A simple diagnostic criterion does not exist. Even a positive laboratory test is no definite proof, because HIT antibodies may be present without clinical signs of thrombocytopenia [2]. Diagnosis is based on the combination of initial clinical criteria (‘pretest criteria’), course of the platelet count after discontinuation of heparin and laboratory results. The diagno-

Correspondence H.M. Oudemans-van Straaten E-mail: [email protected]

sis HIT is expressed as the ‘probability of HIT’, which is a dynamic diagnosis, because probability may change in time. Support for the diagnosis HIT can be gained from laboratory testing. Two types of tests are available. The direct antibody assay (ELISA) detects the presence of antibodies against the heparin-PF4 complex, while a functional assay detects platelet aggregation in the presence of heparin, LMWH or danaparoid. There are two classification systems for HIT (table 1) [for last modifications see 4,5], which are unfortunately not unified yet. Both have drawbacks due to imprecise criteria or lack of combination of clinical and laboratory criteria. We therefore propose a new diagnostic classification system for critically ill patients integrating the features of the scoring systems of Chong and Warkentin and adding bleeding complications, for which critically ill patients with HIT seem to be at higher risk [6] (Table 2).

Table 1 Two existing classification systems for HIT Classification of HIT according to Chong [4] Clinical criteria points 1. start of thrombocytopenia 5-10 days after the start of heparin 3 2. start of thrombocytopenia after 1-4 days, or 11 or more days 1 3. exclusion of other causes of thrombocytopenia 2 4. resolution of thrombocytopenia after cessation of heparin 1 5. re-occurrence of thrombocytopenia after re-challenge with heparin 1 6. thrombosis or disseminated intravascular coagulation [7] 1 Laboratory criteria: 1. immuno-assay positive 2 2. functional assays: • two-point system (i.e measurement of aggregation in the presence of two heparin concentrations), positive 3 • non-two-point system positive 2 Probability of HIT

Classification of HIT as proposed by Warkentin [5]* Clinical criteria 1. Thrombocytopenia 2. Timing of onset of thrombocytopenia 3. Thrombosis (or other sequelae of HIT) 4. Other causes for thrombocytopenia Pre-test probabilitity of HIT high moderate low * on behalf of the Subcommittee on Platelet Immunology of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis



unlikely possible probable definite

0-2 3-4 5-6 ≥7 points 0-2 0-2 0-2 0-2 6-8 4-5 0-3

61 14-04-2006 10:54:22

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14-04-2006 10:54:28


q u e s t i o n s

a n d

a n s w e r s

After the proposal of three classification systems, we are totally confused. Could you please give us a practical advice? For clinical practice, the following steps are to be taken: 1. If platelet count drops, determine whether the patient has been treated with heparin, LMWH or danaparoid during the last three months. 2. Make a ‘HIT graph’ by plotting platelet counts, the use of any heparin(oid), thrombo-embolic events and bleeding complications against time. If necessary retrieve information from previous hospital admissions. 3. Determine the ‘pre-test probability of HIT’ from the clinical criteria in Table 2. 4. Stop all types of heparins if probability of HIT is moderate or high. 5. Start fondaparinux, danaparoid, lepuridin or bivaluridin. The pros and cons of the different drugs and recommended doses in the critically ill will be discussed in a following issue of the journal. 6. Have a HIT test performed. 7. Be aware that • Diagnosing HIT is a dynamic process. Recovery of platelet count after discontinuation of heparins increases the probability of HIT. • A HIT-antibody test can initially be negative. If clinical symptoms suggest HIT, a repeat test may become positive. • The HIT antibody assay may be negative, while the platelet aggregation test, which is labour intensive, is positive. If clinical criteria strongly suggest HIT, have a platelet aggregation test performed. • A re-challenge of patients with heparins is not recommended for the diagnosis of HIT, unless HIT is ‘unlikely’.

Table 2. Proposal for classification of HIT in the critically ill integrating the systems of Chong and Warkentin (OLVG 2005) Clinical criteria points 1. Thrombocytopenia • nadir 20-100 109/l with fall of > 30%, or any fall of > 50% 2 • nadir 10-19 109/l, or any 30-50% fall, or >50% fall after 1 cardiac surgery • nadir < 10 109/l, or any <30% fall in platelet count 0 2. Timing of onset of thrombocytopenia • clear onset 5-10 days after start heparin, or ≤ 1 day with heparin exposure within 30 days 2 • consistent with day 5-10, but not clear due to missing platelet counts, or ≤ 1 day with heparin exposure within 31-100 days, or after day 10 1 • ≤ 4 days without exposure to heparin within 3 months 0 3. Other causes for thrombocytopenia • no other explanation 2 • possible other cause (deep intravascular catheters, IABP, CRRT, CPB) 1 • definite other cause (sepsis, DIC, massive hemorrhage, hematological disease, chemotherapy) 0 4. Resolution of thrombocytopenia after withdrawal of heparin • ≤ 10 days 2 • > 10 days 1 • no resolution, or resolution under heparin or LMWH 0 5. Thrombosis or other sequelae of HIT • new thrombosis, skin necrosis, acute systemic reaction after heparin iv 2 • progressive or recurrent thrombosis, erythematous skin lesions, suspected thrombosis, asymptomatic upper deep venous thrombosis 1 • no thrombosis 0 6. Hemorrhage • unexplained major bleeding 2 • unexplained minor bleeding, or any bleeding with known cause 1 • no bleeding 0

Conclusion

Laboratory criteria (the highest score counts) • positive immuno-assay • positive functional assay (two-point system)

Dear Dr Crick, we have learned that the HIT is difficult to diagnose. The diagnosis is expressed in a score describing the probability of HIT, based on clinical criteria (including platelet count, course of thrombocytopenia, the existence of other causes of thrombocytopenia and complications of thrombosis or hemorrhage) and laboratory criteria (measuring anti-bodies or platelet aggregation). You proposed us an adjusted classification of HIT to be used in the critically ill.

Pre-test probability of HIT high moderate low Post-test Classification of HIT definite probable possible unlikely

2 3 9-12 6-8 0-5 11-15 8-10 5-7 0-4

IABP: intra-arterial balloon pump, CRRT: continuous renal replacement therapy, CPB: cardiopulmonary bypass, DIC: disseminated intravascular coagulation according to the ISTH criteria for overt DIC [7]. LMWH: low molecular weight heparin References 1.

Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE (2001) Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119(1 Suppl):64S-94S 2. Savi P, Chong BH, Greinacher A, Gruel Y, Kelton JG, Warkentin TE, Eichler P, Meuleman D, Petitou M, Herault J-P, Cariou R, Herbert J-M (2005) Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 105:139-144


3. Martel N, Lee J, Wells PS.. Risk of heparin induced thrombocytopenia with unfractionated and low molecular weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;15;106:2710-5 4. Chong BH, Chong JJH (2004) Heparin-induced thrombocytopenia. Expert Rev Cardiovasc Ther 2:547-559 5. Warkentin TE (2004) Heparin-induced thrombocytopenia. Diagnosis and management. Circulation 110:e454e458 6. Wester JPJ, Haas FJ, Biesma DH, Leusink JA, Veth G (2004) Thrombosis and hemorrhage in heparin-induced thrombocytopenia in seriously ill patients. Intensive Care Med 30:1927-1934

7.

Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327-30.


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NJCC_02 binnenwerk 02.indd 64 .*##?BINNENWERKINDD

14-04-2006 10:54:42


Received February 2006; accepted in revised form March 2006

c l i n i c a l

i m a g e

Touch the ICU patient with care! L.D. Maatman Chirurgical Intensive Care Unit, University Medical Centre Groningen A 64- year old male had surgery for a ruptured abdominal aortic aneurysm. During surgery, the patient needed many transfusions because of poor hemostasis and the abdomen was packed with gauzes. Post-operatively, he became septic and developed acute renal failure, acute lung injury and abdominal hypertension. Eight days after surgery, he was transferred to our intensive care unit for further treatment. At admission, his extremities were cold, poorly perfused and edematous. There were no bruises present on the extremities. Soon after admission the patient deteriorated, became jaundiced and developed hepatic failure and an ischemic left colon was resected. On day 8 after admission, we discovered some bruises on both upper extremities of the patient (figure 1, 2). While discussing the possible causes, we discovered that a thumb covered exactly the bruises on both arms (figure 3, 4).

In some patients even a simple movement by the medical or nursing staff may result in damage to the skin. Just lifting extremities can create friction and shearing forces that may injure the skin. Traumatic bruises easily lead to skin laceration. Such a skin tear is defined as a separation of the epidermis from the dermis [1]. As a result of an almost 20% loss in dermal thickness, the skin of the elderly is often fragile. Aging and fragile skin are only a few of the risk factors associated with skin tears. Other factors include drugs (e.g. steroids), compromised nutrition, use of devices, previous skin tears, and cognitive or sensory impairment. Patients dependent on total care are at an elevated risk [2]. The report underscores that we have to educate staff on the importance of carefully handling patients in our ICU’s. Proper turning, lifting, and transferring techniques may prevent unnecessary damage to the skin.

Picture 1 Bruise on the right arm

Picture 2 Bruise on the left arm

Picture 3 Lifting the right arm

Picture 4 Lifting the left arm

Correspondence:

References

L.D. Maatman E-mail: [email protected]

1.

Malone ML, Rozario N, Gavinski M, Goodwin J. The epidemiology of skin tears in the institutionalized elderly. J Am Geriatr Soc. 1991;39:591-5. 2. Milne CT, Corbett LQ. A new option in the treatment of skin tears for the institutionalized resident: formulated 2-octylcyanoacrylate topical bandage. Geriatr Nurs. 2005;26(5):321-5.



65 14-04-2006 10:55:29


Received May 2005; accepted in January 2006

Unexpected pharmacokinetics of midazolam in a patient with severe head injury in a surgical intensive care unit A.S. Winters, J. van Bastelaar, J.C. Paling en M.G.G. Rodgers Surgical Intensive Care Unit, University Medical Centre Groningen, The Netherlands

Abstract. Benzodiazepines, such as midazolam, are routinely used as sedatives in intensive care patients due to their anxiolytic and anticonvulsive properties. Moreover, benzodiazepines induce amnesia and function as muscle relaxants. However, there are plenty of factors that play an influential role in the pharmacokinetics of midazolam. Experience with midazolam reveals great individual variability in pharmacokinetic and pharmacodynamic responses in ICU patients. We discuss a patient that was admitted to our intensive care unit with severe head injury. Deep sedation was initiated to prevent secondary brain injury, but five days after the midazolam infusion had been stopped, our patient remained in a comatosed condition. Flumazenil, the benzodiazepine-antagonist, eventually awoke him. This case report emphasises the broad spectrum of individual pharmacological responses to midazolam in Intensive Care patients. The genetic expression of CYP3A4, the most important enzyme in the hydroxylation of midazolam, seems to be an important cause. Even in young patients, without kidney and/or liver failure, a prolonged sedation time can occur, especially if midazolam is administered simultaneously with propofol or other opiates. It must be stressed, however, in suspected cases of midazolam overdose, it is important to administer enough flumazenil before neurological diagnoses and prognoses are made.

Introduction In the Intensive Care Unit, the combined use of sedatives and analgesics serves the purpose of providing adequate ventilatory support, reduction of stress and providing optimal care of the Intensive Care patient. Moreover, for patients suffering from severe head injury, there are other reasons for administering these substances. The primary goal is prevention of secondary brain injury by maintaining a cerebral perfusion pressure (CPP) of at least 60 mmHg. This is achieved by maintaining the intracranial pressure (ICP) and mean arterial pressure (MAP = 2 x diastolic blood pressure + systolic blood pressure ÷ 3) at optimal values (CPP = MAP – ICP). Analgesics and sedatives prevent an increase in ICP and reduce cerebral metabolic needs [1]. Benzodiazepines, such as midazolam, are routinely used as sedatives in intensive care patients due to their anxiolytic and anticonvulsive properties. Moreover, benzodiazepines induce amnesia and function as muscle relaxants. Frequent neurological evaluation is essential for patients with head injury in order to monitor timely deterioration in neurological status. Neurological evaluation consists of clinical and instrumental tools such as the Glasgow Coma Scale (evaluation of Eye opening, Motor response and Verbal reaction), comprehensive neurological physical examination and computed tomography. A large percentage of patients with head injury cannot be adequately assessed due to facial injury for example, endotracheal intubation, or due to administration of sedatives and analgesics, which cause an altered level of consciousness [2]. We discuss a young male who was admitted to our Intensive Care Unit with severe head injury. Upon arrival at our emergency department, initial assessment revealed an abnormal response on the Glas-

Correspondence: M.G.G. Rodgers E-mail: [email protected]


cow Coma Scale (GCS). Computed tomography of his brain revealed severe head injury. Five days after midazolam infusion had been discontinued, our patient remained in a comatosed condition. Flumazenil (Anexate®) eventually awoke him.

Patient history A 26-year-old male was admitted to our Emergency Department after a motorcycle accident. He was travelling at a speed of 180 km/h on a racing circuit when he lost control of his motorcycle and fell. The trauma team assessed him at the scene of the accident; he had a GCS score of 7 (E1, M5, V1), his pupils were unequal in size and he had a diminished oxygen saturation, as determined by pulse oximetry. He was intubated and transported in the trauma helicopter to the Emergency Department of our Level 1 Trauma Centre. A comprehensive trauma assessment was completed, which lead to the following diagnoses: occipital condyle fracture, unilateral left tibia fracture and a cerebral contusion. Computed tomography revealed bruising near the internal capsule on the right side, diffuse cerebral oedema, however, without herniation of the brain stem. The tibia fracture was stabilised by means of intramedullary rod fixation using an Unreamed Tibia Nail (UTN) and the patient was given a soft cervical collar. Due to the abnormalities on the CT scan, our patient was given an intracranial pressure monitor (ICP-monitor) by the neurosurgeon. Shortly hereafter, our patient was admitted to our Surgical Intensive Care department; he was on mechanical ventilatory support and was initially sedated with midazoloam 6mg/hour, fentanyl 400 μg/hour and propofol 400 mg/hour. The following morning, a four-compartment fasciotomy procedure was performed due to a compartment syndrome of his left lower leg. In order to maintain adequate cerebral perfusion pressures (minimum 60mm mmHg), intracranial pressures of 40mmHg were treated with hypertonic saline and mannitol. Follow-up computed tomography revealed haemorrhaging and slight progressive cerebral oedema.


14-04-2006 10:55:32


Figure 2: Probability curves for discrete sedation scores (SS = 1,2,3,4,5 and 6) Permission obtained from Barr J, Zomorodi K, Bertaccini EJ, Shafer SL, Geller E. A Double-Blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model. Anesthesiology. 2001 Aug; 95(2): 286-98

Discussion

Pharmacokinetics of midazolam Figure 1: Predicted time required for (A) a 43% decrease and (B) a 75% decrease in plasma benzodiazepine concentration as a function of the duration of the benzodiazepine infusion. This corresponds to the benzodiazepine concentration change required to emerge from light and deep sedation. Permission obtained from Barr J, Zomorodi K, Bertaccini EJ, Shafer SL, Geller E. A Double-Blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model. Anesthesiology. 2001 Aug; 95: 286-98

On the fourth day of admission to our ICU, intracranial pressures remained below 20 mmHg and all sedation was discontinued in order perform further neurological assessment. Two days after all sedation had been stopped, our patient remained in a comatosed condition with a GCS score of E1, M1, V*. Medical causes and diffuse axonal injury (DAI) were considered. Patient was given 0.5 mg flumazenil intravenously to counteract the possible effect of midazolam. Subsequently, his condition remained unchanged, still without response to painful stimuli. An EEG was performed and demonstrated increased slow activity, with very little reactivity and no frontal intermittent rhythmic delta activity (FIRDA) (in young people FIRDA is indicative of increased intracranial pressure). These findings seemed consistent with DAI. To confirm this diagnosis, a MRI scan was performed. The MRI revealed bruising, as seen previously, and still no signs of herniation; there were no findings to corroborate the diagnosis of DIA. Our patient remained in an unexplained comatosed condition. On the fourth day after all sedation had been discontinued, a midazolam serum level was determined; this proved to be 290μg/L (therapeutic upper range 250μg/L). Once again flumazenil was administered; a total of 1 mg was administered. This had the desired effect and finally awoke our patient from his comatose condition. On the thirteenth day of admission we were able to extubate our patient and on day fourteen he had a GCS score of 11 (E4, M5, V2), equal and reactive pupils and symmetrical reflexes. He was subsequently transferred to the neurology medium-care department and has since made a full recovery.

Midazolam, a water-soluble benzodiazipine, is characterised by rapid uptake in the central nervous system after intravenous infusion, causing anxiolysis, sedation and amnesia within one to four minutes. Midazolam binds to specific receptors located on the post-synaptic GABA neuron at various locations in the brain, including the reticular formation. An increase in neuronal membrane permeability leads to an inward shift in chloride ions, which in turn causes hyperpolarisation of the cell membrane. Lowered consciousness, respiratory depression and apnoea are consequently induced [3]. After bolus administration of midazolam, it is rapidly eliminated from the bloodstream by transformation into three metabolites: 1hydroxymidazolam (constitutes 63% of the active metabolites, 4hydroxymidazolam (inactive) en 1-hydroxymidazolam glucuronide (constitutes 6% of the active metabolites of midazolam). The first step in the metabolism of midazolam is hydroxylation by hepatic cytochrome P4503A4 (CYP3A4), followed by glucuronidation in the liver and then elimination from the kidneys [4]. CYP3A4 belongs to the cytochrome P450 family. This host of enzymes consists of 28 known haemoproteins that collectively metabolise approximately 250.000 different substrates. The average half-life of midazolam after bolus administration is between 1.5 and 3.5 hours. The kidneys eliminate 50 – 70% within 24 hours after transformation into the active metabolite 1-hydroxymidazolam glucuronide. Prolonged infusion of midazolam in order to achieve deep sedation in ICU patients, results in delayed emergence from sedation. The literature claims that, on average, 15 hours is needed to emerge from deep sedation, after cessation of prolonged (longer than 12 hours) midazolam infusion [Figure 1] [4].

Factors that influence pharmacokinetics of midazolam

Several factors influence the metabolism and clearance of midazolam. It has been proven that the pharmacokinetics of midazolam vary greatly between healthy volunteers and ICU patients. Elimination half life and volume of distribution both increase in ICU patients [5]. Positive pressure mechanical ventilation leads to a decrease in cardiac output, which in turn reduces hepatic and renal blood flow.



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Table 1: Modified Ramsay Sedation Score. SS = Sedation score. SS Clinical Response 0 Residual neuromuscular blockade present; unable to assess level of sedation 1 Fully awake 2 Drowsy, but awakens spontaneously 3 Asleep, but arouses and responds appropriately to simple verbal commands 4 Asleep, unresponsive to commands, but arouses to shoulder tap or loud verbal stimulus 5 Asleep and only responds to firm facial tap and loud verbal stimulus 6 Aspleep and unresponsive to both firm facial tap and loud verbal stimulus

This could influence the clearance of pharmaceutical substances [6]. There is great interindividual variability in pharmacokinetic and pharmacodynamic responses amongst ICU patients. Moreover, there is a broad therapeutic range at adequate sedation levels and midazolam plasma concentrations are extremely variable at emergence from sedation [7]. Using the Modified Ramsay Sedation Score, it has been determined that a fixed midazolam plasma concentration can lead to varying levels of sedation [Figure 2 and Table 1] [8]. There is a substantial variation in plasma half life (4 – 12 hours) after cessation of prolonged midazolam infusion (80 – 360 hours) in critically ill ICU patients [9]. Age, weight and sex are all factors that can influence the pharmacokinetics of midazolam. Women have been known to have a prolonged elimination half life, an increased volume of distribution and decreased clearance compared to men [10]. Obesity furthermore increases the volume of distribution of midazolam, leading to a prolonged elimination half life (8.4 hours after bolus administration compared to 2.7 hours in non-obese individuals). Older, healthy men often demonstrate a prolonged elimination half life and reduced clearance when compared to younger, healthy men. This difference in pharmacokinetics is not seen in healthy women of varying age [11]. Sepsis also displays a stark contrast when compared to the healthy setting; midazolam appears to be metabolised at a slower rate in periods of sepsis [12]. Owing to the fact that midazolam is primarily metabolised in the liver, patients with disturbed liver function will exhibit a prolonged elimination half life. The active metabolite 1-hydroxymidazolam glucuronide is accumulated in patients with kidney function disturbances, which can lead to prolonged sedation times; the midazolam plasma concentration is not necessarily elevated in this instance [2]. The various pharmaceutical interactions are mainly due to substrate competition of the hepatic cytochrome CYP3A4. These substances include macrolide antibiotics, fluconazole, diclofenac, propofol, verapamil and quinidine. Grapefruit juice in large volumes produces the same effect. Other sedatives and analgesics that depress the central nervous system can work in a stimulatory fashion when administered with midazolam, for example narcotics, ethanol and barbiturates. CYP3A4 is involved in the metabolism of 50% of all drugs used in humans. Interindividual differences in CYP3A4 expression may account for the observed interindividual differences in pharmacokinetics of drugs metabolised by this enzyme. Variations in CYP3A4 expression may be caused by factors inhibiting or stimulating transcription and/or translation (for example, concomitant drug administration) and by genetic polymorphism (hereditary difference between plasma concentration and metabolic activity) [13].


Research has been focussed on allelic differences in the CYP3A4 and CYP3A5 genes and the possible consequences this has for gene expression (genotype-phenotype association). To date, no significant correlation has been found [14, 15,16]. Based on the differences in metabolism of CYP2D6 substrates and active alleles, extensive metabolisers (EM), intermediate metabolisers (IM) and poor metabolisers (PM) have been identified for the CYP2D6 enzyme [17].

Benzodiazepine antagonist In cases of unwanted levels of sedation, midazolam can be antagonised by flumazenil (Anexate®). Flumazenil counteracts the effects of sedation, amnesia and muscle relaxation by inhibiting the GABA-benzodiazipine-receptor complex. Benzodiazepines are the only sedatives of which, pharmacologically speaking, the action can be counteracted. In cases of suspected benzodiazepine overdose, 0.2 mg flumazenil should initially be administered intravenously in 30 seconds. If there is no direct effect, repeated doses can be administered (0.5 mg in 30 seconds with 1 minute intervals). The maximum dose is 3 mg. In patients that demonstrate a partial response to flumazenil, additional boluses up to 5 mg can be administered. If there is no visible effect five minutes after administering 5 mg of flumazenil, a benzodiazepine overdose is highly unlikely. The sedative effect of flumazenil lasts for approximately one hour, depending on the administered dose and plasma concentration. Repetitive doses at a maximum of 3 mg per hour or a continuous infusion of 0.1 – 0.4 mg per hour are necessary to preserve the antagonistic effect of flumazenil in patients with high plasma concentrations of midazolam. Flumazenil can also be administered via an endotracheal route (1 mg in 10 cc NaCl 0.9%), reaching peak plasma concentrations within one minute [18]. Hypersensitivity to benzodiazepines, patients using benzodiazepines to prevent potentially life threatening situations (raised intracranial pressure or status epilepticus) or patients with an overdose of cyclic antidepressants, all form contraindications for flumazenil administration.

Discussion It is important to administer adequate sedation in the ICU, in order to ensure comfort and an acceptable level of consciousness. To assess the level of sedation, several sedation scales can be used, for example the Richmond Agitation-Sedation Scale (RASS) or Ramsay Sedation Scale (RS). A deeper level of sedation will be necessary in patients admitted to the ICU with head injury who have an abnormal cerebral CT scan and lowered GCS scores; this is done in order to prevent and treat raised intracranial pressure. A prolonged elimination half life can be expected in the elderly patient with kidney and/or liver failure due to accumulation of midazolam metabolites. Drug reactions should always be considered in those using multiple drugs. Sampling the midazolam plasma concentration will have no added benefit in patients with suspected benzodiazepine intoxication that remain in a comatose condition. This is due to the large individual discrepancy between midazolam serum concentrations and the level of sedation. Counteracting the action of midazolam with flumazenil is both diagnostic and therapeutic. It is important to administer sufficient flumazenil in suspected cases of overdose, before neurological diagnoses and prognoses are made.


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In our opinion this case report illustrates that prolonged sedation times with midazolam can occur even in young patients without kidney and/or liver failure, especially when administered simultaneously with opiates and propofol. Of notable importance, is the fact that prolonged propofol infusion (longer than 24 hours) can lead to delayed emergence (24 to 72 hours) from deep sedation [15]. Inhibition of the CYP3A4 enzyme influences the midazolam metabolism and thus leads to prolonged sedation times, as is visible in our patient. Research has not been able to elucidate the question of interindividual differences of CYP3A4 expression. If extensive and poor metabolisers could be identified in the future, then adjusted individual drug doses could lead to improved treatment with CYP3A4 substrates.

List of abbreviations CPP = Cerebral Perfusion Pressure DAI = Diffuse Axonal Injury EEG = Electro encephalogram FIRDA = Frontal Intermittent Rhythmic Delta Activity GCS = Glascow Coma Score ICP = IntraCranial Pressure MAP = Mean Arterial Pressure MRI = Magetic Resonance Imaging UTN = Unreamed Tibia Nail

References 1. Gremmelt A, Braun U. Analgesia and sedation in patients with head-brain trauma. Anaesthesist. 1995 Dec;44 Suppl 3:S559-65 2. Stocchetti N, Canavesi K, Longhi L, Magnoni S, Protti A, Pagan F, Colombo A. How to quantify the severity of brain injury during intensive care after adult head trauma. Minerva Anestesiol. 2003 Apr;69(4):232-6. 3. Fragen RJ. Pharmacokinetics and pharmacodynamics of midazolam given via continuous intravenous infusion in intensive care units. Clin Ther. 1997 MayJun;19(3):405-19; discussion 367-8. 4. Hirata K, Matsumoto Y, Kurokawa A, Onda M, Shimizu M, Fukuoka M, et al. Possibility of Midazolam Sedation on the Diagnosis of Brain Death: Concentration of Active Metabolites after Cessation of Midazolam. Yakugaku Zassh . 2003 Sep;123(9):811-5 5. Malacrida R, Fritz ME, Suter PM, et al. Pharmacokinetics of midazolam administered by continuous intravenous infusion in intensive care patients. Crit Care Med. 1992 Aug;20(8):1123-6 6. Perkins MW, Dasta JF, DeHaven B. Physiologic implications of mechanical ventilation on pharmacokinetics. DICP. 1989 Apr;23(4):316-23. 7. Bolon M, Boulieu R, Flamens C, Paulus S, Bastien O. Sedation induced by midazolam in intensive care: pharmacologic and pharmacokinetic aspects. Ann Fr Anesth Reanim. 2002 Jun;21(6):478-92

8. Barr J, Zomorodi K, Bertaccini EJ, Shafer SL, Geller E. A Double-Blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model. Anesthesiology. 2001 Aug; 95(2): 286-98 9. Dirksen MS, Vree TB, Driessen JJ. Clinical pharmacokinetics of long-term infusion of midazolam in critically ill patients--preliminary results. Anaesth Intensive Care. 1987 Nov;15(4):440-4. 10. Driessen JJ, Dirksen MS, Rutten JM, Santman F, van Egmond J, Vree TB. Continuous infusion of midazolam during anaeshesia and postoperative sedation after maxillofacial surgery. Acta Anaesthesiol. Scand. 1989;33:116-121 11. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984 Jul;61(1):27-35 12. Shelley MP, Park GR, Mendel L. Failure of critically ill patients to metabolise midazolam. Anaesthesia. 1987;42:619-26 13. van Schaik RHN, de Wildt SN, van Iperen NM, Uitterlinden AG, van den Anker JN, Lindemans J. CYP3A4-V Polymorphism Detection by PCR-Retriction Fragment Length Polymorphism Analysis and Its Allelic Frequency among 199 Dutch Caucasians. Clinical Chemistry. 2000;46(11):1834-1836

14. Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 2004 April;5(3):243-72 15. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A4-mediated metabolism. Adv Drug Deliv Rev. 2002 Nov 18;54(10): 1271-94 16. Floyd MD, Gervasini G, Masica AL, Mayo G, George AL Jr, Bhat K, Kim RB, Wilkinson GR. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics. 2003 Oct;13(10):595-606 17. Mulder AB, van Lijf HJ, Bon MA, van den Bergh FA, Touw DJ, Neef C, Vermes I. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clin Pharmacol Ther. 2001 Dec;70(6):546-51. 18. Palmer RB, Mautz DS, Cox K, Kharasch ED. Endotracheal flumazenil: a new route of administration for benzodiazepine antagonism. Am J Emerg Med. 1998 Mar;16(2):170-2



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Received October 2005; accepted in revised form March 2006

Early postoperative fever is not a determinant of cognitive decline following coronary artery bypass grafting D. van Dijk, S. Dieleman, C.J. Kalkman University Medical Center Utrecht, Department of Anaesthesiology, Utrecht, The Netherlands

Abstract. Coronary artery bypass grafting (CABG) is associated with a 20 to 30 percent risk of postoperative cognitive decline, which cannot be explained entirely by the use of cardiopulmonary bypass. We hypothesized that postoperative fever is an additional determinant of cognitive decline in patients undergoing off-pump and on-pump CABG. The study population consisted of a subsample of 198 consecutive CABG patients who participated in the Netherlands based Octopus Study and who were randomized to off-pump or on-pump CABG. The on-pump patients, but not the off-pump patients, received an intraoperative bolus of dexamethasone 1 mg/kg to suppress the inflammatory response associated with cardiopulmonary bypass. Postoperative fever was defined as any period in the intensive care with a body temperature higher than 38 °C. Psychologists administered 10 neuropsychological tests one day before and 3 and 12 months after surgery to determine the presence of cognitive decline. Fourteen percent of the on-pump patients and 56% of the off-pump patients had postoperative fever (p=<0.001). Of the patients with postoperative fever, 24% had cognitive decline 3 months after surgery, versus 26% of the patients without fever (p=0.77). At 12 months, 22% of the patients with postoperative fever had cognitive decline versus 32% of the patients without fever (p=0.16). After correction for use of dexamethasone and cardiopulmonary bypass, no association could be established between postoperative fever and cognitive decline. In the present sample of 198 CABG patients, fever during the intensive care stay was not a determinant of cognitive outcome.

Introduction Coronary artery bypass surgery (CABG) with the use of cardiopulmonary bypass (CPB) is associated with significant cerebral morbidity, usually manifested as cognitive decline or stroke [1]. The incidence of cognitive decline ranges from 20 to 30 percent, depending on the type of patient, definition of decline and timing of neuropsychologic assessment. These figures should be interpreted cautiously, since in most patients the cognitive decline does not affect the patient in functional terms. However, a small proportion of patients with cognitive decline becomes sufficiently disabled to prevent return to employment [1]. Cerebral morbidity after CABG has largely been attributed to the use of CPB [1]. CPB increases the permeability of the blood brain barrier and generates microemboli, which may affect cognitive function [2-4]. It also requires cannulation and cross-clamping of the ascending aorta, which may induce atheromatous macroemboli causing stroke [5]. The assumption, however, that CPB is the main cause of cerebral morbidity after CABG, could not be confirmed in the Octopus Study, a recent randomized trial that directly compared cognitive outcome after off-pump and on-pump CABG in 281 patients [6]. In the on-pump group, the incidence of cognitive decline was 29%, three months after surgery. After off-pump surgery, however, the incidence was still 22%. This suggests that other factors than CPB may contribute to the occurrence of cognitive decline after CABG. There is literature indicating that cerebral outcome after a primary brain injury is influenced by body temperature [7-12]. The primary injury can be traumatic brain injury [7], cerebral bleeding [8-9], hypoxic injury after cardiopulmonary resuscitation [10-11], and maybe also major (heart-) surgery [12]. Correspondence:

We hypothesized that postoperative fever is an additional determinant of cognitive decline in patients undergoing off-pump and onpump CABG.

Materials and methods Patients

The study population consisted of a subsample of 100 off-pump patients and 98 on-pump patients who participated in the Netherlands based Octopus Study. These patients were operated upon in the University Medical Center Utrecht and their postoperative temperature was logged automatically in the intensive care patient data management system. The design and main outcomes of this randomized trial comparing off-pump and on-pump CABG have been reported elsewhere [6,13]. Only the patients undergoing an on-pump procedure received an intraoperative bolus of dexamethasone 1 mg/kg to suppress the inflammatory response associated with CPB. The onand off-pump patients did not receive anti-inflammatory medication after their arrival in the ICU. Temperature management and measurement

In the off-pump group, patients were operated upon under normothermic conditions. In the on-pump group, elective hypothermia was applied, with a minimal nasopharyngeal temperature of 32°C during CPB. By using a forced-air convective warmer, on-pump and offpump patients were actively warmed if they arrived in the intensive care unit (ICU) with a temperature lower than 35 °C. Warming and sedation were discontinued when a temperature of 36 °C was achieved. In the 198 consecutive patients included in the present analysis, postoperative body temperature was logged automatically during their ICU stay. In 48% of these patients, a pulmonary artery catheter was

D. van Dijk E-mail: [email protected]



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Table 1: Cognitive domains and neuropsychologic tests Domain Test Verbal memory, learning Rey Auditory Verbal Learning Verbal memory, retrieval Rey Auditory Verbal Learning Motor capacity Grooved Pegboard Divided attention Trail Making Test Part A and B Working memory speed Sternberg Memory Comparison Visuospatial capacity Line Orientation Test Selective attention Stroop Color Word Test Sustained attention Continuous Performance Task Working memory Self Ordering Tasks Visual working memory Visuospatial Working Memory Information processing Symbol Digit Modalities Test Table 2: Patients characteristics at baseline Characteristics, % Age, mean (SD), y Education, mean (SD), y Sex, male Coronary artery disease 1-vessel disease 2-vessel disease 3-vessel disease Diabetes History of stroke Hypertension

Off-pump (n=100) 61.8 (9.5) 9.4 (2.4) 69

On-pump (n=98) 61.2 (9.0) 9.6 (2.7) 74

26 49 25 9 4 60

15 50 34 14 3 57

used to measure blood temperature. In the other 52%, rectal temperature was logged. Postoperative fever was defined as any period within the ICU (up to the first 24 hours after surgery), with a rectal or blood temperature higher than 38 °C. Median ICU stay was 22 hours. The patients and the investigators performing the preoperative and postoperative neuropsychological assessments were blinded to the postoperative temperature profiles. Cognitive assessment

Psychologists administered 10 neuropsychological tests including 11 main variables, one day before and 3 and 12 months after surgery to determine the presence of cognitive decline (Table 1). In accordance with the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery [14], the testbattery included tests for motor skills, verbal memory capacity and attention. In addition, tests were included to assess speed and capacity of working memory, visuospatial capacity, selective and sustained attention and information processing. Administration of the tests lasted approximately 100 minutes. Cognitive decline was defined as a decrease in an individual’s performance of at least 20% from baseline, in at least 20% (i.e. three) of the main variables [15]. Data analysis

All analyses were performed using SPSS version 10.0 software. Primary objective of the present study was to compare the incidence of cognitive decline at 3 months after surgery, between patients with and without postoperative fever, using Fisher’s Exact test and expressed as an odd’s ratio (OR) with 95% confidence interval (CI). Multivariate logistic regression analysis was used to correct for use of dexamethasone and CPB, site of temperature measurement (blood versus rectal) and other risk factors of cognitive injury. As an additional analysis, the highest postoperative temperature of patients with and without cognitive decline was compared using a student’s t-test.

Main variable total score trial 1-5 delayed recall score time dominant hand, s time trail B, s time 4 character chart, s total score time C – time B, s mean reaction time, ms sum score average distance, cm total score

Table 3. Reasons for missing neuropsychologic assessment 3 months Patient appeared to be unsuitable for 1 neuropsychologic testing Withdrawal immediately after randomization 1 Withdrawal after baseline assessment, 1 but before surgery (Noncerebral) mortality at time of cognitive 1 follow-up Readmission to hospital or too ill for 5 postoperative assessment Unable to come for follow-up 5 (holiday or care for ill partners) Not motivated for follow-up/withdrawal 1 Total number of patients with failed neuropsychologic assessment

1 1 2 2 0 2 9

Results Mean age of the participating patients was 61 years and 72 percent was male (Table 2). One hundred patients underwent an off-pump procedure without dexamethasone, and 98 patients underwent an on-pump procedure with dexamethasone. Cognitive outcome could be determined in 183 patients (92%) at three month follow-up, and in 189 patients (95%) at twelve month follow-up. Reasons for missing neuropsychological data are summarized in Table 3. In the first 24 hours after surgery, 37% of the patients had fever. This proportion was higher in patients operated without CBP and without dexamethasone than in patients operated with CPB and dexamethasone (56% versus 14%, p=<0.001). The overall incidence of cognitive decline was 25% at three months and 29% at twelve month follow-up. Of the patients with postoperative fever, 24% had cognitive decline at 3 months, compared to 26% of the patients without fever (OR 0.90; 95% CI 0.45 – 1.81; p=0.77). At 12 months, 22% of the patients with postoperative fever had cognitive decline versus 32% of the patients without fever (OR 0.61; 95% CI 0.31 – 1.22; p=0.16). Table 4 shows three month cognitive outcome in a multivariate model. After correction for use of dexamethasone and CPB, and age and sex, again no association could be established between postoperative fever and cognitive decline. Similar results were found with 12 month cognitive outcome. (data not presented). In a multivariate model adjusting for the site of temperature measurement (rectal probe versus blood temperature measurement), again no association was found between postoperative fever and cognitive decline (data not presented). Separate analysis of on-pump patients and off-pump



15

12 months 1

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Table 4: Three-month cognitive outcome, logistic regression Predictor

All patients (n=183)

Fever, % Off-pump treatment, % Age > 70 y, % Female sex, %

37 51 19 27

Decline absent Decline pres(n=137) ent (n=46) 37 35 53 48 17 26 26 30

univariable analysis Odds ratio p-value

Multivariable analysis Odds ratio p-value

0.90 0.83 1.75 1.23

0.98 0.82 1.74 1.19

0.77 0.58 0.17 0.58

0.97 0.60 0.18 0.65

The 183 patients in this table are the patients in whom 3-month cognitive outcome was known. An odds ratio > 1.0 predicts cognitive decline at three months (< 1.0 absence). Off-pump treatment indicates patients operated without cardiopulmonary bypass and without dexamethasone administration.

patients, and separate analysis of patients with a rectal probe and a pulmonary artery catheter, again revealed no association between postoperative fever and cognitive outcome (data not presented). Finally, we compared the highest observed body temperature between patients with and without cognitive decline at three month follow-up. In both groups, the highest body temperature was on average 37.7 °C (SD 0.6 °C; p = 0.99).

Dicussion Several studies have assessed the effects of intra-operative temperature management on cerebral outcome after CABG [16-18]. We hypothesized that postoperative fever is an additional determinant of cognitive outcome in CABG patients. However, we found no association between postoperative fever and cognitive decline in either offpump or on-pump patients. One study by Grocott et al. has previously addressed the issue of postoperative hyperthermia and cognitive decline [19]. In contrast with our own results, this study showed a borderline significant relationship between maximum postoperative temperature and a greater amount of cognitive dysfunction 6 weeks after surgery. This study was conducted in a larger sample of 300 patients and only on-pump patients were included. These patients did not receive intraoperative steroids. This study may therefore represent a more homogeneous patient sample. Another difference is that the patients in Grocott’s study were assessed at 6 weeks after their surgery instead of 3 and 12 months. It is conceivable that some patients in the Octopus Study were suffering from cognitive decline at 6 weeks, but that they had recovered by the time that they underwent their 3-month assessment. Our inability to repeat the results of Grocott could therefore be caused by a lack of statistical power. However, none of our analyses demonstrated a trend towards a higher risk of cognitive decline after postoperative fever. Some analyses even showed a trend towards a protective effect of fever from cognitive decline at 5 days after surgery (data not presented) and at 12 months. Our findings are in contrast with literature indicating that hyperthermia may adversely affect the brain [7-12,19-22]. In experiments


in the rat, it was demonstrated that as little as 1.5°C of hyperthermia during a period of focal ischemia increases the size of cerebral infarction [20]. Hyperthermia in stroke patients has also been associated with increased infarct size and increased mortality [21-22]. In the Octopus Trial, the on-pump patients, but not the off-pump patients, received an intraoperative bolus of dexamethasone 1 mg/kg to suppress the inflammatory response associated with CPB. The question whether patients who do not receive dexamethasone have a greater risk of postoperative cognitive decline cannot be answered by the present study. This requires a randomized study directly comparing CABG with and without dexamethasone administration. There is excellent literature suggesting that the inflammatory response after CABG may be responsible for cognitive decline, even when this is not through the mechanism of hyperthermic injury [23]. The present study has one major limitation: two different methods were used to measure body temperature. In the analyses, both measurement techniques were considered equivalent in their ability to determine the highest body temperature of a patient during his or her ICU stay. Because none of the patients had both their blood temperature and their rectal temperature measured during their ICU stay, it was not possible to apply a correction factor. Although rectal temperature measurement is probably less reliable than blood temperature measurement, we have no indication that the ability to detect a period of fever during the entire ICU stay was influenced by the measuring device. The highest body temperature that was observed in patients with a rectal probe and patients with a pulmonary artery catheter was similar (mean 37.7 °C in both groups). Separate analysis of patients with a rectal probe and of patients with a pulmonary artery probe yielded no different outcomes. Inclusion of the temperature measurement site in multivariate models also did not influence the results.

Conclusion In the present sample of 198 CABG patients, fever during the intensive care stay was not a determinant of cognitive outcome.


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References 1. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, et al, for the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996;335:1857-1863. 2. Diegeler A, Hirsch R, Schneider F, Schilling LO, Falk V, Rauch T, et al. Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation. Ann Thorac Surg 2000;69:1162-1166. 3. Lloyd CT, Ascione R, Underwood MJ, Gardner F, Black A, Angelini GD. Serum S-100 protein release and neuropsychologic outcome during coronary revascularization on the beating heart: a prospective randomized study. J Thorac Cardiovasc Surg 2000;119:148-154. 4. Harris DN, Bailey SM, Smith PL, Taylor KM, Oatridge A, Bydder GM. Brain swelling in first hour after coronary artery bypass surgery. Lancet 1993;342:586-587. 5. Hartman GS, Yao FS, Bruefach M, Barbut D, Peterson JC, Purcell MH, et al. Severity of aortic atheromatous disease diagnosed by transesophageal echocardiography predicts stroke and other outcomes associated with coronary artery surgery: a prospective study. Anesth Analg 1996;83:701-708. 6. Van Dijk D, Jansen EWL, Hijman R, Nierich AP, Diephuis JC, Moons KGM, et al. Cognitive outcome after offpump and on-pump coronary bypass surgery: results from a randomized study. JAMA 2002;287:1405-1412. 7. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of Traumatic Brain Injury with Moderate Hypothermia. N Engl J Med 1997; 336:540-546.

8. Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS, Chang Y, Ogilvy CS, et al. Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology 2001;56:1299-1304. 9. Yoshimoto Y, Tanaka Y, Hoya K. Acute systemic inflammatory response syndrome in subarachnoid hemorrhage. Stroke 2001;32:1989-1993. 10. Hypothermia after Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med 2002; 346:549-556. 11. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med 2002; 346:557-563. 12. Grigore AM, Grocott HP, Mathew JP, Phillips-Bute B, Stanley TO, Butler A, et al. The rewarming rate and increased peak temperature alter neurocognitive outcome after cardiac surgery. Anesth Analg 2002;94:4-10. 13. Van Dijk D, Nierich AP, Eefting FD, Buskens E, Nathoe HM, Jansen EWL, et al. The Octopus Study: rationale and design of two randomized trials on medical effectiveness, safety and cost-effectiveness of bypass surgery on the beating heart. Control Clin Trials 2000;21:595-609. 14. Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995;59:1289-1295. 15. Stump DA. Selection and clinical significance of neuropsychologic tests. Ann Thorac Surg 1995;59:1340-1344. 16. Warm Heart Investigators. Randomized trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994;343:559–563.

17. Martin T, Craver J, Gott J, Weintraub W, Ramsay J, Mora C, et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994;57:298–302. 18. Grigore A, Mathew J, Grocott H, Reves J, Blumenthal J, White W, et al. A prospective randomized trial of normothermic versus hypothermic cardiopulmonary bypass on cerebral outcome after coronary artery bypass graft surgery. Anesthesiology 2001;95:1110–1119. 19. Grocott HP, Mackensen GB, Grigore AM, Mathew J, Reves JG, Phillips-Bute B, et al. Postoperative hyperthermia is associated with cognitive dysfunction after coronary artery bypass graft surgery. Stroke 2002;33:537-541 20. Busto R, Dietrich W, Globus M-T, Ginsberg M. The importance of brain temperature in cerebral ischemic injury. Stroke 1989;20:1113–1114. 21. Castillo J, Davalos A, Marrugat J, Noya M. Timing for fever-related brain damage in acute ischemic stroke. Stroke 1998;29:2455–2460. 22. Reith J, Jorgensen H, Pedersen P, Nakayama H, Raaschou H, Jeppesen L, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996;347:422–425. 23. Harris DN, Bailey SM, Smith PL, Taylor KM, Oatridge A, Bydder GM. Brain swelling in first hour after coronary artery bypass surgery. Lancet 1993;342:586-587.



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Received January 2006; accepted in revised form March 2006

Citrate, calcium, parathyroid hormone and anion gap in a patient with citrate intoxication during citrate based CVVH S.M.J. ter Veldhuis1, A. Wolthuis2, A.J. Bakker2, P.H.J. van der Voort1 1Dept. of Intensive Care, Medical Centre Leeuwarden, The Netherlands 2Dept. of Clinical Chemistry, Medical Centre Leeuwarden, The Netherlands

Abstract. Continuous veno-venous hemofiltration has evolved to a routine intensive care treatment. Citrate as an anticoagulant for the extracorporeal system is increasingly used. Metabolic complications may occur. We present a case with citrate intoxication. The unique feature is the direct measurement of citrate concentration and parathyroid hormone. With these data we determined the usefulness of the Dutch guideline. Ionised calcium is a sensitive but not specific marker of citrate intoxication. When ionised calcium is low, total-over-ionised calcium ratio is strongly related to citrate level. Both the classical anion gap and the strong ion gap are not specific for diagnosing citrate intoxication.

Introduction Continuous veno-venous hemofiltration (CVVH) is increasingly employed for the management of acute renal failure in critically ill patients with hemodynamic instability [1]. However, one of the main disadvantages of CVVH is the requirement for anticoagulation to prevent clotting of the extracorporal circuit [2]. The use of heparin as anticoagulant may be associated with a high complication rate of bleeding [3]. To reduce the risk of bleeding complications, citrate anticoagulation has been proposed as an alternative [4-7]. Citrate chelates calcium, consequently leading to a low ionised calcium level (iCa) and thereby inhibiting coagulation in the system. However, citrate anticoagulation has some potential adverse effects such as hypocalcaemia, metabolic acidosis, and occasionally alkalosis and hypernatriemia. The metabolic alkalosis may occur by the metabolization of citrate in liver and muscle cells; the acidosis occurs when citrate accumulates for instance by liver failure. Clinicians need to be aware of these effects to correctly interpret changes in acid-base and metabolic status from patients on citrate based hemofiltration. During citrate CVVH clinicians should actively search for metabolic derangement indicative of citrate intoxication. The diagnosis of citrate intoxication is made on the measurement of calcium (total and ionised) and anion gap [8]. The direct measurement of citrate is not available in most hospitals. Here, we report a case of a patient with citrate intoxication. We measured citrate levels and tested the clinical decision pathway according to the Dutch guideline.

Casus report A seventy-year-old man was admitted to the emergency department due to cardiogenic shock with bradycardia during combination therapy with verapamil and sotalol chloride for recurrent supraventricular arrhythmias. He had a medical history of Parkinson’s disease, psychiatric disorders, and a pre-existing kidney function disorder because of glomerulosclerosis (plasma creatinine 140 µmol/l). In 1999

Correspondence: PHJ van der Voort E-mail: [email protected]


he had been admitted to the hospital because of atrial fibrillation. A cardiac ultrasonography performed in 2004, showed moderate right and left ventricular function. On physical examination in the emergency department, he had a Glascow Coma score of E1M4V1, his pulse was 25 beats/minute, and his blood pressure was 95/60 mm Hg. Because of respiratory failure, the patient was sedated and intubated. Routine laboratory findings revealed in plasma a creatinine of 250 umol/l, urea of 15.1 mmol/l and potassium of 8.5 mmol/l. The ASAT, ALAT and LDH concentrations were respectively 50, 54 and 509 U/l. Arterial blood gas analysis showed a pH of 7.15, pCO2 5.4 kPa, pO2 14 kPa, bicarbonate 13.8 mmol/l and SaO2 86% (Table 1). Fluid resuscitation, atropine, dopamine and isoprenaline were given to treat bradycardia and shock. Calcium and sodiumbicarbonate were given to counteract the hyperkalaemia. After resuscitation the patient was admitted to the intensive care unit. Because of renal failure continuous venovenous hemofiltration (CVVH) was initiated in a postdilution mode. Substitution fluid was given at 3 l/hour and blood flow 200ml/hour. Citrate was infused prefilter at 35 mmol/hour by protocol. Repeated laboratory tests showed progressive hepatic failure and hypocalcemia (table 1). A cardiac ultrasonography showed moderate left and right ventricle function. Because of hypocalcemia, calcium was supplemented with increasing additional doses up to 10 mmol/hour. The blood ionised calcium level did not increase under this supplementation (Figure 1). The anion gap, calculated by the formula [sodium + potassium – (chloride + bicarbonate)], was marginally increased. The total-over-ionised calcium ratio was high (4.09). The diagnosis of citrate intoxication was then made. After reducing the citrate flow to 17.5 mmol/l, the total-over-ionised calcium ratio decreased. Cardiac index and mixed venous saturations remained low and several days afterwards the patient died because of persistent irreversible cardiogenic shock.

Discussion Anticoagulation with citrate is advised in critically ill patients with active bleeding, increased risk of bleeding, or with heparin-induced thrombocytopenia (HIT) [8]. Anticoagulation with citrate has complex metabolic consequences [9]. Thus, most citrate protocols use


14-04-2006 10:56:54


Table 1: Overview of laboratory results. 2 hours Before CVVH Na (mmol/l) 137 K (mmol/l) 8.5 Chloride (mmol/l) Bicarbonate (mmol/l) ICa (mmol/l) TotCa (mmol/l) Lactate (mmol/l) PTH (pmol/l) pH pCO2 (kPa) TotCa/iCa ratio Anion gap Ca gap Albumin (g/dl) Magnesium (mmol/l) Inorganic Phosphorus (mmol/l) ASAT U/l 50 ALAT U/l 54 Citrate (mmol/l) SIDeff SIDapp SIG

T=2 hours

T=6 hours

T=8 hours

T=17 hours

T=30 hours

T=54 hours

Normal values

137 6.1 113 14 0.83

140 3.5 110 18 0.56 1.86

148 3.0 107 20 0.59

146 4.0 107 24 0.78 2.80 5.0

135 5.4 107 18 1.04

134 4.3 102 24 1.26

3.4 29.3 7.35 4.3

3.3 7.41 5.2

15.4

12.3

136-145 3.8-5.0 96-106 21-28 1.10-1.35 2.1-2.6 0.6-2.2 1-8 7.38-7.44 4.7-5.3 <2.3

4.7 7.26 4.1 16 10 0.97 2.42 1270 1710 19.6 38.0 18.4

18.2 7.46 3.4 3.32 15.5 1.34 9 0.94 0.17 5410 5820 2.83 20.1 31.0 10.9

4.3 7.50 3.4 24

7.51 4.2 4.09 19 2.02 15 0.78 n.a. (1.0) 4.06 28.5 40.3 11.8

1.27 1.83 6480 5810 1.65

17 n.a. (1.0) 1.90

43-53 0.65-1.05 0.74-1.52 <35 <45

30.1 35.3 4.2

Legend table 1: PTH = parathyroid hormone SID effective = Bicarbonate + 0.2*Albumin + 1.5*Inorganic Phosphorus SID apparent = Na+K+Ca+Mg-Cl-lactate SIG = SID apparent - SID effective Anion gap = Na+K-Cl-Bicarbonate n.a. = not available (estimated value) Electrolytes were measured in Li-heparinplasma (Roche Diagnostics GmbH, Mannheim, Germany). Citrate was measured in Li-heparinplasma by citrate lyase method (Instruchemie, Delfzijl, Netherlands) with adaptation of the sample volume. The between run coefficient of variation was 1.6% at a level of 1.07 mmol/l (n=14).

specially designed substitution fluids to compensate for most of these metabolic disorders [10]. Because citrate is metabolised to bicarbonate in the liver, kidneys and skeletal muscles, citrate should be used cautiously in patients with liver failure. These potential problems imply that, in our view, citrate based CVVH should only be used in ICU’s where the medical and nursing staff is extensively trained and where CVVH treatment is routine. In our ICU around 800 CVVH days are performed per year. Citrate based CVVH is the standard way of CVVH since 2 years now in our ICU. Despite the extensive experience with citrate based CVVH, citrate intoxication occurred in the presented patient and remained undetected for several hours. The measurement of citrate was available in our clinic, which allowed us to, retrospectively, compare our observations to the Dutch guideline. In our patient, a few hours after the start of CVVH iCa was low but not alarming. The metabolic acidosis that was present (anion gap 16) was regarded as lactate acidosis. However, 4 hours later, iCa had decreased to 0.56 mmol/l, without a significant change of the anion gap. This combination was interpreted as calcium depletion and was substituted by calcium infusion. At that point, the total-over-ionised calcium ratio was retrospectively measured and appeared to be 3.32. The citrate concentration that was measured retrospectively indeed appeared to be high (2.83 mmol/l). Figure 1 shows that changes in the total-over-ionised calcium ratio parallel changes in citrate concentration. While citrate binds to calcium, blood iCa concentration falls, whereas the bound fraction of calcium rises. Total calcium (totCa) remains constant or rises, depending on the amount of calcium infused in an attempt to correct for the hypocalcemia. If calcium in-

fusion is increased to correct iCa, most of the calcium is bound to citrate. A disproportional rise in totCa occurs, while iCa remains low. The total-over-ionised calcium ratio increases. Analysing the presented data, we conclude that the anion gap is not a very sensitive indicator for citrate intoxication. In contrast, iCa is an early indicator that citrate intoxication might be present but a low iCa also might be caused by simple calcium depletion. Therefore, the total-over-ionised Ca ratio is decisive as it appears closely related to citrate concentration and is a specific diagnostic tool for citrate intoxication [9]. Therapy according to the guideline, developed by the Nederlandse Vereniging voor Intensive Care (NVIC), includes discontinuation or reduction of the infusion of citrate and replacement with normal sodium, bicarbonate-buffered substitution fluids when the total-over-ionised Ca ratio increases above 2.3 [8]. CVVH can generally be continued without anticoagulation and bicarbonate-buffered replacement, since the patients with liver failure generally have coagulopathy. Hypocalcemia, caused by accumulation of citrate, can not be treated by supplementation of calcium unless citrate infusion is reduced to a level that the body can metabolise. The citrate concentration in plasma depends on the rate of infusion, the loss by filtration and its metabolic degradation. Citrate circulates in plasma mainly bound to calcium and to other cations. Citrate may accumulate if liver and muscle fail to metabolise citric acid, as may occur in liver failure or severe shock. In these cases acid accumulates or, the strong anions increase and metabolic acidosis ensues. During the course of CVVH it is expected that if the patient’s condition improves, anion gap and strong ion gap (SIG) decrease



75 14-04-2006 10:56:57


3TART#66( )NORGPHOSPHORUS 4OTAL#ALCIUM 04(

#ITRATE

2ATIO#A#A #A

04(PMOLL

#ATOT0/MMOLL

#ITRATEMMOLL

#AMMOLL

4IMERELATIVETOSTARTOF#66(HOURS Figure 1: Plasma Inorganic Phosphorus (PO4), total calcium and Parathyroid hormone (PTH) levels after start CVVH

because unmeasured anions are removed. However, if the liver fails, both the classical anion gap and SIG will rise because of accumulating anions of liver failure. Even an absence of decrease in anion gap during the course of CVVH should already be a warning sign that the patient is deteriorating. Therefore, since other anions contribute to a rising SIG in liver failure, SIG is not a sensitive marker for citrate accumulation. This is what the presented case also shows.

In the case presented, liver failure developed as a consequence of cardiogenic shock. The patient showed a persisting metabolic acidosis with high lactate. At the start of the CVVH the liver enzymes in the blood were moderately increased. Therefore, the clinicians were not aware of the developing liver failure. The anion gap and the SIG were slightly increased. The blood iCa level remained very low, despite supplementation with high doses of calcium. At that time, because citrate intoxication was suspected, the total-over-ionised Ca was calculated, and turned out to be 4.09, which is very high compared to a maximal normal level of 2.3 [8]. Therapy was started according to the guidelines developed by the NVIC, first by reduction and later complete discontinuation of the citrate infusion, and adjustment with sodium bicarbonate buffered substitution fluids. The ratio declined after reducing the citrate flow as illustrated in Figure 1. Retrospectively, we also determined parathyroid hormone (PTH) level. PTH regulates the level of ionised calcium in the body fluids, primarily through calcium release from the bones (fast effect), and secondarily by vitamin D production, which increases absorption from the intestines (slow effect). Figure 1 shows the rapid increase of the parathyroid hormone after decrease of iCa. The increase in PTH with the decrease in ionized calcium is an interesting observation, but it does not have any further clinical consequences for this case. This case report shows that citrate intoxication can occur despite routine use of citrate for CVVH. Apparently, clinicians should always be very alert for citrate intoxication and a well-designed protocol should be used. In addition, the Dutch guideline appears to be useful. Both the classical anion gap and the SIG are not specific for diagnosing citrate intoxication. As a first line detector of citrate intoxication, iCa seems to be sufficient, followed by measurement of the total-over-ionised Ca ratio in case of low iCa. Anticoagulation with citrate during CVVH mandates determination of the total-overionised calcium ratio in case of low iCa since an increase is strongly related to high citrate levels.

References 1

2

3

Mehta RL, Letteri JM. Current status of renal replacement therapy for acute renal failure. A Survey of US nephrologists. The National Kidney Foundation Council on Dialysis. Am J Nephrol 1999;19:377-82. Van der Voort PHJ, Gerritsen RT, Kuiper MA, Egbers PHM, Kingma WP, Boerma EC. Filter Run Time in CVVH: pre- versus post-dilution and Nadroparin versus Heparin-Protamine anticoagulation. Blood Purification 2005;23:175-80. Van de Wetering J, Westendorp RG, van der Hoeven JG, Stolk B, Feuth JD, Chang PC. Heparin use in continuous renal replacement procedures: the struggle between filter clotting and patient hemorrhage. J Am oc Nephrol 1996;7:145-50.


4

5

6

Kutsogiannis DJ, Gibney RTN, Stollery D, Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 2005;67:2361-7. Monchi M, Berghmans D, Ledoux D, Canivet JL, Dubois B, Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med 2004;30:260-5. Palsson R, Niles JL. Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kidney Int 1999;55:1991-7.

7

8 9

Van der Voort PHJ, Postma SR, Kingma WP, Boerma EC, van Roon EN. Safety of citrate based hemofiltration in critically ill patients at high risk for bleeding: a comparison with nadroparin. Int J Artif Organs 2006;in press Oudemans-van Straaten HM. Review and guidelines for regional anticoagulation with citrate in continuous hemofiltration. Neth J Crit Care 2004;8:146-156. Meier-Krieske HU, Gitomer J, Finkel K, DuBose T. Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit Care Med 2001; 29:748-752.


14-04-2006 10:57:00


s t r u c t u r e d

a b s t r a c t s

Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely ill Patients Crit Care Med 2006;34:589-597

Introduction

Discussion

The optimal adrenergic support for patients in shock is still unknown. Dopamine reduces the release of a number of hormones from the anterior pituitary gland and through this has important effects on the immune system. The current observational study tried to determine if dopamine administration in patients with shock and septic shock was associated with a poor outcome.

This is an interesting observational study that needs careful interpretation. The dopamine and non-dopamine patients appear to be similar in several important ways (mean and maximum SOFA score, ICU-acquired infection, need for hemofiltration or hemodialysis). The assessment of the outcomes was naturally objective (death). The follow-up of the study patients was complete and long enough although the logistic regression analysis was only performed for ICU mortality and not for hospital mortality. An important issue in an observational study are the available arguments for causation. In this study the exposure preceded the onset of the outcome but there was no dose-response gradient or positive evidence from a dechallenge/rechallenge. The association of the use of dopamine with increased mortality is not consistent from study to study and the assosciation does not make clear biological sense. On the other hand the magnitude of the suggested increase in mortality is clearly important with an OR of 2.05 (1.25 – 3.37). The included patients in this study appear to be similar to those in general clinical practice and satisfying alternative treatments (noradrenalin or a combination with dobutamine) are available. The authors conclude correctly that a randomized controlled trial is now indicated. Until then, there is no reason to abandon the use of dopamine in the ICU although the use of alternative agents should be considered.

Study This observational study is a substudy from the SOAP database. The Sepsis Occurrence in Acutely ill Patients (SOAP) study included all patients > 15 yrs admitted to the ICU excluding postoperative patients who stayed in the ICU < 24 hours and patients with burns. Only patients with shock were included in the current study. Multivariable, forward stepwise, logistic regression analysis was performed to determine the independent risk factors for ICU mortality. A total of 1058 patients with shock were included out of 3147 (33.6%) in the original SOAP database. A total of 462 (14.7%) patients had septic shock. Dopamine was administered in 375 patients and 683 did not receive dopamine. Patients receiving dopamine had a significantly higher ICU mortality (42.9 versus 35.7%), mortality at 30 days (44.5 versus 36.9%) and hospital mortality (49.9 versus 44.6%). Dopamine administration was an independent predictor for an increase in ICU mortality in both the group with shock due to any cause (N = 1058, OR 1.67 (1.19 – 2.35)) and septic shock (N = 462, OR 2.05 (1.25 – 3.37)). Other independent risk factors were mean SOFA score, mean fluid balance, medical admission, age and the presence of cancer. Dopamine did not increase mortality in patients with non-septic shock.

J.G. van der Hoeven, internist-intensivist Nijmegen

Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis Lancet 2006; 367:413-18

Introduction

Study

Statins are potent lipid-lowering agents used to reduce the risk of cardiovascular events. Recent findings have shown that statins have a variety of properties that are independent of their lipid lowering ability. These so-called pleiotropic effects include anti-inflammatory, immunomodulatory, antioxidant, antithrombotic and endotheliumstabilizing properties. Also some experimental evidence is available for the therapeutic potential of statins in sepsis treatment.1

Hackman et al postulated that statins reduce the incidence of sepsis in a high-risk population with atherosclerosis. They established a retrospective population-based cohort analysis by linking administrative databases over 5 years, including patients older than 65 years with cardiovascular disease. Propensity-based matching yielded a cohort of 69.168 patients of whom half received a statin and half did not. The investigators adjusted the data for possible confounders. They concluded that statin therapy is associated with a decreased



77 14-04-2006 10:57:03


s t r u c t u r e d

Copyright ©2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved.

incidence of sepsis, severe sepsis and fatal sepsis. In statin users, sepsis was found in 71,2/10.000 patient years, while this incidence was 88,0/10.000 patient years (P=0,0003) in patients who had not used statins. Adjustment for demographic factors, sepsis risk factors, other comorbidities and measures of healthcare use gave similar results. This protective association persisted for high and low doses of statins and for important subpopulations, such as patients with diabetes and heart failure.

Discussion These results suggest that statins should be considered, or at least continued, for patients in particular circumstances, like high risk for sepsis, high risk elective surgery or major infections. Future randomized prospective trials are needed to analyze this interesting hypothesis. Prospective trials are needed to investigate the therapeutic potential of statins after the onset of sepsis. JJW Peeters PE Spronk

Referenceæ 1

a b stracts

Merx MW, Liehn EA, Graft J, et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation 2005; 112: 117-24

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NJCC_02 binnenwerk 02.indd 79 IKAZIA6002 210x277.indd 1

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Commissies & Afgevaardigden Voedingscommissie Drs. R. Tepaske, AMC, Amsterdam (voorzitter) P. Bruynzeel, AMC, Amsterdam Voedingscommissie Drs. R. Tepaske, AMC, Amsterdam (voorzitter) P. Bruynzeel, AMC, Amsterdam Drs. F.M.P. van Haren, VieCuri MC, Venlo Prof. Dr. E.M.H. Mathus-Vliegen, AMC, Amsterdam Dr. H.M. Oudemans-van Straaten, OLVG, Amsterdam Prof. Dr. D. Tibboel, Erasmus Medisch Centrum Sophia, Rotterdam Commissie IC transport Drs. E.J. van Lieshout, AMC, Amsterdam (voorzitter) Prof. Dr. J.J.L.M. Bierens, VUMC, Amsterdam Drs. R.J.R. Eijk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. J.H.J. Meeder, Medisch Centrum Rijnmond Zuid, Rotterdam Drs. G.D. Vos, Academisch Ziekenhuis, Maastricht Drs. J. van de Wetering, Isala Klinieken, Zwolle Commissie Producttypering IC Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede (voorzitter) Dr. A.N. Roos, Catharina Ziekenhuis, Eindhoven Drs. A.M.G.A. de Smet, UMCU, Utrecht Drs. J.I. van der Spoel, OLVG, Amsterdam (secretaris) Dr. P.E. Spronk, Gelre Ziekenhuizen, Apeldoorn Drs. L.F. te Velde, Albert Schweitzer Ziekenhuis, Dordrecht Commissie Richtlijnontwikkeling Dr. J. Damen, Isala Klinieken, Zwolle (voorzitter) Drs. E.C. Boerma, Medisch Centrum, Leeuwarden Drs. E.A.C. Bouman, Academisch Ziekenhuis, Maastricht Dr. A.W.W.M. Koopman-van Gemert, Albert Schweitzer Ziekenhuis, Dordrecht Dr. H.J. van Leeuwen, UMCU, Utrecht (secretaris) Dr. K.H. Polderman, VUMC, Amsterdam Drs. A.M.T.J. Raben, Groene Hart Ziekenhuis, Gouda Dr. J.J. Spijkstra, VUMC, Amsterdam Drs. R. Tepaske, AMC, Amsterdam Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem Wetenschapscommissie Prof. Dr. D. Tibboel, Erasmus Medisch Centrum Sophia, Rotterdam (voorzitter) Prof. Dr. L.P.H.J. Aarts, Universitair Medisch Centrum, Groningen Dr. D. Bergmans, Academisch Ziekenhuis, Maastricht Prof. Dr. Ir. C. Ince, AMC, Amsterdam Dr. J. Kesecioglu, UMCU, Utrecht Dr. R.P. Pickkers, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Dr. M.J. Schultz, AMC, Amsterdam Dr. P.E. Spronk, Gelre Ziekenhuizen, Apeldoorn Dr. J.E. Tulleken, Universitair Medisch Centrum, Groningen Dr. P.H.J. van der Voort, Medisch Centrum, Leeuwarden Commissie Internet Drs. C.P.C. de Jager, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch (voorzitter) Drs. F. Nooteboom, Viecuri Medisch Centrum, Venlo Dr. J. de Koning, Maxima Medisch Centrum, Veldhoven Drs. S. Kurban, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Dr. K.H.Polderman, VUMC, Amsterdam Drs. R.A.L. de Waal, Kennemer Gasthuis, Haarlem Vertegenwoordiging in de Gemeenschappelijk Intensive Care Commissie Prof. Dr. J.G. van der Hoeven, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. B.M. van der Kolk, Radboud Universiteit Nijmegen Medisch Centrum, Nijmegen Drs. A.M.G.A. de Smet, UMCU, Utrecht Commissie Kwaliteit Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede (voorzitter)


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

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

Intensivisten A.J.C. Slooter, Universitair Medisch Centrum Utrecht Mw J.J. Maas, Leids Universitair Medisch Centrum Mw J.W.C. Taal, Leids Universitair Medisch Centrum Mw W.J. Thijsse, Erasmus MC R’dam Dr. J. van der Naalt, Utrecht Medisch Centrum Groningen Dr. D. Hasan, VieCuri Venlo Dr. C. Hoedemaekers, Utrecht Medisch Centrum Nijmegen Drs J. Horn, Academisch Medisch Centrum Amsterdam K.H. Polderman, VUMC Amsterdam S.J.A. Aerdts, Isala locatie Sophia Zwolle Neurochirurgen Dr. B. Verweij, Universitair Medisch Centrum Utrecht Dr. S.M. Peerdeman, VU Medisch Centrum Amsterdam Dr. A.I.R. Maas, Erasmus MC

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


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Verenigingsnieuws Commissie Internet In de Commissie Internet heeft Drs EE de Bel aangegeven met zijn werkzaamheden voor de Internetcommissie te gaan stoppen. Het NVIC bestuur dankt hem voor zijn inzet voor de commissie en de vereniging. CPC de Jager, voorzitter commissie Internet

Medium Care Commissie NVIC Op 2 maart jl. werd met toestemming van het bestuur van de NVIC de commissie Medium Care van de NVIC opgericht. Doelstellingen van de commissie zijn het ontwikkelen van evidence-based richtlijnen voor medium care-opname en ontslagcriteria voor Nederland. Dit omdat er een trend is naar toenemende zorgzwaarte in de ziekenhuizen met grotere behoefte aan medium care faciliteiten. Voor IC-afdelingen zijn reeds opname- en ontslagcriteria beschikbaar, voor Medium Care zijn deze niet eenduidig. Tevens zal tegelijkertijd ook een inventarisatie plaats vinden van de huidige Medium Care voorzieningen in de Nederlandse ziekenhuizen middels een enquête die verstuurd zal worden naar alle ziekenhuizen in Nederland. Op basis van deze enquête hopen we inzicht te krijgen in de huidige organisatie van Medium Care’s, de zorgzwaarte en de capaciteit. De resultaten van de enquête zullen te zijner tijd bekend worden gemaakt in het Neth J Crit Care. Wij nodigen U uit om deze enquête in te vullen en te retourneren. De volgende leden zijn toegetreden tot de Commissie Medium Care : - Prof. Dr. J. Bakker, Erasmus Medisch Centrum, Rotterdam - Dr. M.A. Boermeester, Academisch Medisch Centrum, Amsterdam - Drs. L.E.M. Haas, Ziekenhuis Gelderse Vallei, Ede - Dr. J.J. van Lieshout, Academisch Medisch Centrum, Amsterdam - Drs. E.F. Salm, Reinier de Graaf Gasthuis, Delft - Dr. J.J. Spijkstra, VU Medisch Centrum, Amsterdam - Drs. M.S. van der Steen, Kennemer Gasthuis, Haarlem,

- Drs. D.H.T. Tjan, Ziekenhuis Gelderse Vallei, Ede - Drs. A.R.H. van Zanten, Ziekenhuis Gelderse Vallei, Ede Voor nadere informatie kunt u terecht bij het secretariaat NVIC of via E-mail: [email protected]. DHT Tjan, voorzitter Medium Care Commissie

Programmacommissie In de Programmacommissie heeft Dr JE Tulleken aangegeven met zijn werkzaamheden voor de Programmacommissie te gaan stoppen. Het NVIC bestuur dankt hem voor zijn inzet voor de commissie en de vereniging. JG van der Hoeven, voorzitter programmacommissie

Afvaardiging richtlijnontwikkeling Sedatie en/of analgesie door niet-anesthesiologen Voor de richtlijnontwikkeling Sedatie en/of analgesie door niet-anesthesiologen is JJ Spijkstra benaderd. Hij heeft aangegeven afgevaardigde voor deze richtlijn te willen zijn. JHJ Meeder, secretaris NVIC-bestuur

Werven visiteurs kwaliteitsvisitaties IC Voor Intensive Care afdelingen is het essentieel dat zij kwalitatief goede zorg verlenen. Het multidisciplinair werken op deze afdelingen staat centraal. Voor een goede kwaliteit van zorg is het van belang dat de medewerkers op deze afdeling zich openstellen voor evaluatie door beroepsgenoten. Dit zorgt ervoor dat zij kritisch blijven ten opzichte van de eigen zorgverlening en bereid zijn te leren van anderen. Daartoe zijn de NVIC en de Nederlandse Vereniging voor Intensive Care voor Verpleegkundigen (NVICV) onder begeleiding van het Kwaliteitsinstituut voor de Gezondheidszorg CBO gestart met een traject van multidisciplinaire visitatie op Intensive Care afdelingen.

• 8th Scientific Congress of the European Resuscitation Council: May 10th-13th, Stavanger, Norway • Venticare: May 11th-12th, Jaarbeurs Utrecht, the Netherlands • NVA/NVvH congres: May 18th-19th • ATS: May 19th-24th, San Diego, USA • NVIC Neurologische problematiek op de Intensive Care 2006: June 8th-9th, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www.nvic.nl • 19th European Society of Intensive Care Medicine Congress: September 24th-27th, Barcelona, Spain. Information: www.esicm.org • ICAAC: September 27th-30th, San Francisco, USA. Information: www.icaac.org • Europaediatrics 2006 Conference: October 7th-10th, Barcelona, Spain. Information: www.kenes.com/ europaediatrics/call.asp • Nationale Pijndagen 2006: October 11th-12th, Apeldoorn, the Netherlands. Information: www.nationalepijndagen.nl • CHEST 2006: 72nd Annual International Scientific Assembly of the American College of Chest Physicians: October 21th-26th, Salt Lake City, USA. Information: www.chestnet.org • NVIC Mechanische Beademingsdagen: November 30th and December 1st, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www.nvic.nl • NVIC Nederlandse Intensivistendagen 2007: January 31st- February 2nd, Hotel en Congrescentrum De Reehorst, Ede, the Netherlands. Information: www. nvic.nl • 3rd World Congress Abdominal Compartment Syndrome (WCACS 2007): March 22-24, 2007 Antwerp, Belgium. Information: www.wcacs.org • 5th World Congress of Pediatric Critical Care Societies: June 26-30 th 2007, Geneva Switzerland. Information: www.pcc2007.com

Uitgangspunt daarbij vormde toetsing aan de Richtlijn Organisatie en Werkwijze voor Nederlandse IC afdelingen ontwikkeld in samenwerking met het CBO. Dit document vormt tot nu toe nog het toetsingskader. Er is echter een nieuw toetsingskader in ontwikkeling. Graag nodigen wij uw Intensive Care afdeling uit om voor de visitaties aan IC afdelingen in Nederland twee artsen en twee verpleegkundigen als visiteur op te geven. De NVIC zal zorgen voor de



Agenda

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training die daarvoor vereist is. (Voorwaarde is wel dat zij nog werkzaam zijn op een intensive care afdeling). Deze trainingsochtend zal plaatsvinden op 14 april as. Het doel van de visitaties is het formuleren van afdelingsgebonden adviezen ter verbetering van de patiëntenzorg op de IC. Visitatie heeft daarnaast ook een externe doelstelling. Voor de continuïteit van de intensieve zorgverlening is het van belang dat er een breed gedragen vertrouwen is in de kwaliteit van deze afdelingen.

Visitaties zijn een middel om inhoud te geven aan de verplichting dit vertrouwen waar te maken. De resultaten van de visitaties kunnen eveneens leiden tot het geven van (geanonimiseerde) informatie of advies aan beleidsbepalende instanties. Zo hebben geaggregeerde gegevens uit de eerste 44 visitaties bijgedragen aan beleidsvoornemens in het Platform Intensive Care op het gebied van IC capaciteit, transport, opleiding voor Intensivisten en ICverpleegkundigen, regionalisering en separate DBC financiering voor IC.

De gezamenlijke verenigingen zien uw opgave van visiteurs graag tegemoet. Na het verenigingsnieuws treft u een antwoordformulier aan. Graag ontvangen we het antwoordformulier voor 15 maart as retour. ARJ Girbes, voorzitter Nationale Commissie Visitatie IC 547 intensivisten en fellows 2 rustende leden 989 overige leden 20 overige abonnees Totaal 1 februari 2006: 1520 Totaal 1 april 2006: 1558 Totaal lezersbereik: 3601

Congresverslag 26e International Symposium on Intensive Care and Emergency Medicine Brussel 21-24 maart 2006 Michaël Kuiper, Rik Gerritsen, Christiaan Boerma, Peter Spronk* Medisch Centrum Leeuwarden; Gelre Ziekenhuis Apeldoorn* Correspondentieadres Michaël A. Kuiper Intensivist Medisch Centrum Leeuwarden Postbus 888 8901 BR Leeuwarden tel +31 58 2866737 fax +31 58 2866715 e-mail [email protected]

Het 26e International Symposium on Intensive Care and Emergency Medicine (ISICEM) in Brussel werd dit jaar door Jean Louis Vincent geopend met een oproep het medisch beleid niet alleen te laten bepalen door hard medisch bewijs. Immers, er is maar weinig echt bewezen voor de Intensive Care geneeskunde door middel van ‘randomized controlled clinical trials’. Voor ons overig beleid blijven we vooralsnog aangewezen op het best beschikbare bewijs, wat vaak ook nog ‘expert opinion’ is. De Round Table over sepsis en orgaanfalen, voorafgaand aan het congres, leverde geen nieuwe concrete aanbevelingen op. De rol van het endotheel bij het ontstaan van sepsis wordt steeds duidelijker. Met name de rol van de glycocalyx wordt een groeiend focus van onderzoek. Zo zou de beïnvloeding van deze glycocalyx door scherpe glucose regulatie wel eens mede verantwoordelijk kunnen zijn voor de gunstige effecten die van deze behandeling


zijn gerapporteerd. Van den Berghe toonde de meest recente Leuvense data betreffende glucose regulatie bij de IC patiënt, en hierbij wordt duidelijk dat het gaat om de glucose-regulatie zelf, en niet om de hoeveelheid insuline die wordt toegediend. Naast dergelijke interventies die behulpzaam kunnen zijn bij verbetering van de zorg voor acuut zieke patiënten zijn er nieuwe ontwikkelingen die mogelijk het beloop van ziekte bij individuele patiënten beter kunnen voorspellen. Zo zal genetisch onderzoek ons in staat stellen om voorafgaand aan een operatieve ingreep patiënten te herkennen die op hypoxie zullen reageren door een ontstekingsrespons te ontwikkelen. Tevens begint bedside moleculaire detectie van infectie een reële mogelijkheid te worden.

Longsparende beademing Er was veel aandacht voor de potentieel nadelige effecten van beademing en de relatie met inflammatie. De cellulaire respons op deformerende stress leidt tot ‘ventilator induced lung injury’ (VILI). Gattinoni betoogde dat de lagere mortaliteit bij beademde patiënten het gevolg is van minder VILI. De slecht recruteerbare long is gevoeliger voor nadelige effecten van PEEP dan de long die goed recruteerbaar is. Maar het is de vraag of alleen PEEP hiervoor verantwoordelijk is. Amato betoogde dat de plateaudruk de belangrijkste oorzaak van inflammatie is, en dat het teugvolume irrelevant is. Verhogen van de gemiddelde luchtwegdruk leidt tot een toename van de permeabiliteit van de long. Post hoc analyse van de ruwe data van onder meer de ARDSnet studies laat zien dat een plateaudruk van 30 cm water of meer een onafhankelijke

voorspeller van mortaliteit is. Marini liet daarentegen zien dat de nadelige effecten van een hoge plateaudruk weer deels kunnen worden tenietgedaan door een hoger PEEP niveau. Hij vroeg meer aandacht voor de flow-karakteristieken waarmee wordt beademd. In zijn optiek leidt verkorting van de inspiratoire flow tot minder cellulaire longschade. Het is de vraag of de conclusie gerechtvaardigd is dat de plateaudruk en de teugvolumes scherp begrensd dienen te worden omdat dit potentieel leidt tot “permissive hypercapnia”. Hubmayer liet namelijk zien dat hypercapnie geassocieerd is met minder cellulair herstel en meer necrose in de long. Ook weten we dat atelectase leidt tot een verhoogde infectiekans en dus de ontwikkeling van pneumonie. Aan de andere kant zijn longcellen gevoeliger voor infectie nadat ze zijn overrekt, terwijl supernatant van overrekte longcellen bacteriegroei bevordert. Pugin en Gajic betoogden dat beschermende beademingsstrategieën geassocieerd zijn met een betere immuunfunctie. Gajic benadrukte tevens het belang van de transmurale druk en het gebruik van voorspeld lichaamsgewicht in plaats van actueel lichaamsgewicht bij het bepalen van de teugvolumes. Immers, met name patiënten met overgewicht worden vaak met zeer grote teugen beademd. De vraag dringt zich op of een anti-inflammatoire strategie de long zou kunnen beschermen tegen de nadelige effecten van beademing. Ranieri liet zien dat necrose door VILI wordt veroorzaakt door een fosforylatie mechanisme via de P13-kinaseγ route Als deze cascade wordt geblokkeerd treedt minder VILI op. Dit effect was niet afhankelijk van de inflammatoire res-


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pons op zich. Anti-inflammatoire therapie, zoals bijvoorbeeld met corticosteroïden, zou deels VILI kunnen voorkomen, maar kan ook potentieel gunstige effecten blokkeren. De meeste aanbevelingen over hoe te beademen worden gesteund door wetenschappelijke literatuur. Wie zich verdiept in de materie ontdekt echter al spoedig dat vrijwel alle bevindingen worden tegengesproken door andere onderzoekingen. In ieder geval lijkt het waarschijnlijk dat meer non-invasieve beademing zal worden toegepast op de ICU en dat nog beter zal moeten worden bewaakt welke effecten precies optreden tijdens beademing, bijvoorbeeld door middel van elektrische impedantie tomografie.

Recruitment strategie In de sessie over recruitment werden alle mogelijkheden en technieken om de long goed te openen en dit te bewaken, besproken. Optimaliseren van de CO2 afgifte en de compliantie worden het meest gebruikt om de optimale PEEP te vinden. De strategieën waarmee gerekruteerd wordt zijn verschillend; volume of drukgestuurd, langzaam of snelle inductie van recruitment. De nadelige effecten op de hemodynamica zijn het grootst bij de meest agressieve methoden van recruteren, waarbij het hartminuutvolume meer daalt dan

de bloeddruk. De vraag of dit betekent dat de patiënt dan ondervuld is, en dus vloeistofinfusiezou moeten krijgen, of dat de patiënt met ALI/ARDS juist krap gehouden moeten worden met vloeistof blijft vooralsnog onbeantwoord. Meer PEEP verbetert de ventilatie/perfusie verhouding bij de patiënten met ARDS (en in mindere mate ook bij patiënten met ALI). Zoals bekend: hoe vroeger in het ziekteproces wordt gerecruteerd, hoe groter de kans op succes. Toch werd door anderen weer gewaarschuwd voor de effecten van PEEP. Immers, dit leidt potentieel tot overdistensie van de anterieure longdelen en niet tot openen van de atelectatische posterieure delen. Buikligging lijkt dan ook veel effectiever, en zou vaker moeten worden toegepast (Vieillard-Baron). Dit heeft ook niet de nadelige effecten op de hemodynamica. Hoewel ‘High Frequency Oscillation’ een veelbelovend alternatief blijft kleven er ook veel potentiële nadelen aan deze methode. Er werd opvallend vaak barotrauma en pneumothorax gerapporteerd.

Hemodynamica en microcirculatie Het debat over de volgorde ABC of CAB bij reanimaties werd door Ewy nieuw leven ingeblazen: bij reanimaties draait alles alleen om

coronaire perfusie. Als 5 seconden wordt gestopt met massage duurt het 25 seconden tot dezelfde druk in de aorta weer bereikt is. Beademen is wellicht een zinloze complicerende handeling tijdens ‘basic life support’ bij een circulatiestilstand. Theoretisch zou het zelfs schadelijk kunnen zijn, want de aangebrachte positieve intrathoracale druk vermindert de coronairperfusie. De sessies over de pathofysiologie van sepsis en multi-orgaan falen leverde de gebruikelijke stortvloed van nieuwe afkortingen op. Duidelijk is wel dat er geen ‘magic-bullet’ bij de behandeling van sepsis bestaat. Herkennen van stadia van sepsis en aanpassen van therapie daarop hoort wel tot de mogelijkheden. In de sessies over vloeistoftherapie was de gebruikelijke discussie over colloïden vs kristalloïden naar de achtergrond verdwenen ter faveure van de discussie over fysiologisch zout vs Ringer’s lactaat. De nadelige effecten van door infusie met fysiologisch zout ontstane hyperchloremsiche acidose op de glomerulaire filtratie werden benadrukt. Het onderzoek naar de microcirculatie levert als nieuwe bevinding dat er bij shock verschillende patronen kunnen worden waargenomen: I stagnerende stroom, II stagnerende stroom + uitval van capillairen, III hyperdynamische

NVIC Bestuur Prof. Dr. J.G. van der Hoeven Internist-intensivist Universitair Medisch Centrum St. Radboud, Nijmegen Voorzitter E-mail: [email protected]

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

Drs. B.M. van der Kolk Chirurg-intensivist Universitair Medisch Centrum St. Radboud, Nijmegen Penningmeester E-mail: [email protected]

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

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

Dr. K.H. Polderman Internist-intensivist VU Medisch Centrum, Amsterdam Bestuurslid E-mail: [email protected]

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

Drs. J.H.J. Meeder Anesthesioloog-intensivist Medisch Centrum Rijnmond-Zuid, Rotterdam Secretaris E-mail: [email protected]

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

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

NVVC 13 pnt

NVA 13 uur

NVK 14 uur

NVZA 14 uur

NIV 14 uur

NVvH NVVM 16 pnt 14 pnt

NVN 0 pnt

NVALT 14 pnt

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NVIC -

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83 14-04-2006 10:57:18

Canc

circulatie. Het classificeren van deze patronen en het bewaken van de veranderingen hierin zouden op termijn wellicht kunnen leiden tot diversificatie van hemodynamische behandelingen. Hierbij zou de mogelijkheid om mitochondriale PO2 te meten van groot belang kunnen worden.

NAVA De belangrijkste technologische vernieuwing die in Brussel werd gepresenteerd was NAVA™ (“neurally adjusted ventilatory assist”) door de firma Maquet®. Er wordt hard gewerkt om

deze volstrekt nieuwe benadering van beademing te integreren in de dagelijkse praktijk van beademen op de IC. Sinderby uit Toronto presenteerde deze neurologisch gestuurde beademingsvorm. Doordat elektrische veranderingen van het diafragma en niet stroom- of drukveranderingen in het beademingssysteem zelf de ventilator aansturen, werkt dit veel sneller en meer synchroon met de patiënt. Naast een betere synchronisatie, leidend tot meer comfort voor de patiënt, en dus mogelijk tot minder sedatiebehoefte, lijken andere voordelen te zijn: betere

proportionele ondersteuning, geen problemen door intrinsieke PEEP en een betere aansturing van niet-invasieve beademing. Ook kan met NAVA een patiënt met een grote broncho-pleurale fistel, zelfs wanneer er geen lucht terugkomt in de ventilator, worden beademd.

hu


Samenvattend hebben we een kort overzicht gegeven van de ons inziens belangrijkste ontwikkelingen gepresenteerd op het Brussels IC congres.

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activiteiten nvic • NVIC Neurologische problematiek op de IC 8 en 9 juni 2006

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• FCCS

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• NVIC Nederlandse Intensivistendagen 2007


31 januari, 1 en 2 februari 2007 0205 CAN04NL86J 0204


14-04-2006 10:57:39

Cancidas Adv 210x277cpdf

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Fungal Cell Wall

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Precursors to ß(1,3)-D-glucan

Precursors to ß(1,3)-D-glucan

Normal Cell-Wall Synthesis

Synthesis Inhibited by CANCIDAS

CANDIDA ALBICANS

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• Bewezen effectiviteit • Gunstig veiligheidsprofiel 1

1 Duarte P.N.: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 347: 2020-9, 2002 2 David W. Denning: Echinocandin antifungal drugs. The Lancet 362: 1142-51, 2003

2

0205 CAN04NL86J 0204

Raadpleeg alvorens het product voor te schrijven de volledige productinformatie. CANCIDAS® is een geregistreerd handelsmerk van Merck & Co., Inc., Whitehouse Station, NJ, USA

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Postbus 581, 2003 PC Haarlem, Telefoon 023 - 5153153, www.msd.nl


18-04-2006 08:58:01

CARDIO-RESPIRATOIRE OPTIMALISATIE, DIAGNOSTIEK & BEWAKING SNEL, PRAKTISCH en BETROUWBAAR

1 NICO*

De EEN V O U D I G S T E

Non invasieve continue Cardiac Output meting Betrouwbare ademmechanica parameters* * Beademings apparatuur met interne ﬂowmeting kan bij teugvolumes tot 250 mL afwijkingen tot +67% & -30% vertonen. CCM 2002,30:2566-2574 R.Castle & J. Stocks

2 CardioQ De SNE L S T E Minimaal invasieve Slokdarm doppler aorta ﬂow meter en vullings-statusmonitor beat to beat • Hartfunctie en nasaal toepasbaar met en zonder beademing • Oraal • Betrouwbare pre- & afterload & contractiliteit monitoring ber 2004 g 23 septem es, donderda Uit: The Tim

& NIEUW 3 Innocor De SPO N TA N E Non invasieve Cardiac Output meting tijdens spontane ademhaling en belasting en poliklinisch, bij ergometrie of spoedopname bruikbaar •• PreTotal rebreathing Fick in 15 seconden

Informatie over onze methodieken, trainingsmateriaal of literatuur sturen wij u graag toe

MTT Medical Technology Transfer B.V. Telefoon: 0318 417 179; Fax: 0318 416 288 E-mail: [email protected]

MTT maakt het mogelijk NJCC_02 binnenwerk 02.indd 86

14-04-2006 10:57:45

87

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

Ben lid van de nvic Schrijf mij in als lid van de nvic

Wil geen lid worden van de nvic Wil post ontvangen op

< < (lidmaatschap 2006, inclusief netherlands journal of critical care) < < privé-adres < werk-adres Man < Vrouw

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Voorletters Titulatuur Adres Postcode/Woonplaats Telefoon privé Fax E-mail-adres Geboortedatum Bankrekeningnummer

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Ziekenhuis/Instelling Afdeling Adres Postcode/Woonplaats Telefoon Sein Fax E-mail-adres

Ben voor % (percentage) werkzaam op de Intensive Care afdeling


Z.O.Z.

14-04-2006 10:57:48

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

le de n

Fundamental Critical Care Support Course (FCCS) Congreshotel 'De Werelt', Lunteren < € 495 dinsdag en woensdag 16 en 17 mei 2006 < € 495 dinsdag en woensdag 12 en 13 september 2006 < € 495 dinsdag en woensdag 3 en 4 oktober 2006 < € 495 dinsdag en woensdag 10 en 11 oktober 2006 < € 495 dinsdag en woensdag 7 en 8 november 2006 < € 495 donderdag en vrijdag 14 en 15 december 2006 < Ik wil instructeur worden bij de FCCS-cursussen en zal de eerste keer als hybride meedoen, neem contact met mij op. NVIC Neurologische Problematiek op de IC 2006 Hotel en Congrescentrum De Reehorst, Ede Donderdag 8 en vrijdag 9 juni 2006 - Toeslag logies en ontbijt (éénpersoonskamer) - Treinkaartje dagretour 2e klas Reehorst Ede* - Treinkaartje dagretour 1e klas Reehorst Ede* - Treinkaartje meerdaags retour 2e klas Reehorst Ede* - Treinkaartje meerdaags retour 1e klas Reehorst Ede* * Prijswijzigingen voorbehouden

< € 240,-

NVIC Mechanische Beademingsdagen 2006 Hotel en Congrescentrum De Reehorst, Ede Donderdag 30 november en vrijdag 1 december 2006 - Toeslag logies en ontbijt (éénpersoonskamer) - Treinkaartje dagretour 2e klas Reehorst Ede* - Treinkaartje dagretour 1e klas Reehorst Ede* - Treinkaartje meerdaags retour 2e klas Reehorst Ede* - Treinkaartje meerdaags retour 1e klas Reehorst Ede*

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

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

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

ISBN-nummer

Prijs

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

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

€ € € € € € € € €

Aantal

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

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

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(bij machtiging dient u dus tweemaal uw handtekening te plaatsen. Buitenlandse incasso is niet mogelijk.) d it r e g i st r at i e f o rmu li e r i n e e n e nve lop gratis te rugstu re n naar: nvic, antwoordnumme r 2459, 6710 wb e de (gld)


14-04-2006 10:57:52


16-05-2006 10:16:12

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16-05-2006 10:16:01

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