Krachtige HbA 1c -verlaging voor patiënten met type 2-diabetes die met metformine alleen onvoldoende onder controle zijn.

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1 <<opgekregen rugdikte 8 mm Krachtige HbA 1c -verlaging voor patiënten met type 2-diabetes die met metformine alleen onvoldoende onder controle zijn. 25 e Internistendagen Abstractboek april 2013 MECC Maastricht 25 e Internistendagen Abstractboek (Abstracts submitted to the Annual Meeting of the Netherlands Association of Internal Medicine, April 2013, Maastricht, the Netherlands) april 2013 MECC Maastricht Postbus 581, 2003 PC Haarlem Tel.: Voor meer productinformatie zie verkorte SPC elders in dit blad. Raadpleeg de volledige productinformatie alvorens JANUMET voor te schrijven. Een andere weg naar glucoseregulatie DIAB DIAB Adv 210x297.indd :04

2 Inhoud 25 e Internistendagen Abstractboek april 2013 MECC, MAASTRICHT Voorwoord 3 Presentations Schop de Heilige Huisjes omver! 4 I Oral Presentations Research 10 II Oral Presentations Case reports 24 III Endocrinology Research 37 IV Endocrinology Case reports 40 V Diabetes Mellitus Research 55 VI Diabetes Mellitus Case reports 57 VII Haematology Research 58 VIII Haematology Case reports 59 IX Oncology Research 77 X Oncology Case reports 79 XI Vascular Medicine Research 85 XII Vascular Medicine Case reports 91 XIII Gastro-Enterology Case reports 94 XIV Infectious Diseases Research 99 XV Infectious Diseases Case reports 102 XVI Nephrology Research 120 XVII Nephrology Case reports 124 XVIII Intensive Care Research 132 XIX Intensive Care Case reports 133 XX Rheumatology Research 140 XXI Rheumatology Case reports 141 XXII Immunology/Allergology Research 144 XXIII Immunology/Allergology Case reports 145 XXIV Other Research 151 XXV Other Case reports 153 XXVI General Internal Medicine Research 155 XXVII General Internal Medicine Case reports 157 Index 169 1

3 Voorbereidingscommissie Karin Kaasjager voorzitter Kim Bunthof (JNIV) Paul van Daele Kees Hovingh Eelco de Koning An Reyners Anita Rijneveld Hilde Royen Joost Wiersinga Deelnemende verenigingen Nederlandse Internisten Vereniging (NIV) Internistisch Vasculair Genootschap Juniorafdeling Nederlandse Internisten Vereniging Nederlandse Federatie voor Nefrologie Nederlandse Vereniging voor Allergologie Nederlandse Vereniging voor Endocrinologie Nederlandse Vereniging voor Gastro-Enterologie Nederlandse Vereniging voor Haematologie Nederlandse Vereniging voor Immunologie Nederlandse Vereniging voor Klinische Farmacologie en Biofarmacie Nederlandse Vereniging voor Medicale Oncologie Nederlandse Vereniging voor Medical Onderwijs NIV Sectie Acute Interne Geneeskunde NIV Sectie Intensive Care NIV Sectie Ouderengeneeskunde Vereniging voor Infectieziekten Organiserende vereniging Nederlandse Internisten Vereniging (Medicinae Internae B.V.) Postbus LB Utrecht Tel Fax Congressecretariaat Congress & Meeting Services Holland Postbus AZ EINDHOVEN Tel Fax Uitgever Van Zuiden Communications B.V. Postbus CC Alphen aan den Rijn Tel.: Fax: Internet: Overname van delen uit dit abstractboek kan alleen plaatsvinden na schriftelijke toestemming van de uitgever. ISBN:

4 VOORWOORD/INTRODUCTION Met genoegen presenteer ik u het Abstractboek van de 25 e Internistendagen, die worden gehouden van april 2013 in het MECC te Maastricht. De abstracts betreffen zowel wetenschappelijk onderzoek als case reports. Uit alle windrichtingen zijn de abstracts in grote getale ingestuurd. Er zijn 302 abstracts ingediend, die zijn opgenomen in dit Abstractboek. Uit deze abstracts werden 50 abstracts geselecteerd voor mondelinge presentatie. Deze worden eerst vermeld, gevolgd door de overige abstracts, geclassificeerd per vakgebied. De selectie is gebaseerd op wetenschappelijke inhoud, originaliteit en presentatie. De selectie gebeurt anoniem (auteurs en instituut worden geblindeerd) door drie leden van de commissie. De abstracts met de hoogste scores zijn geselecteerd voor mondelinge presentatie. Dit jaar is er voor gekozen om de abstracts zoveel mogelijk per thema te bundelen met een algemene inleiding door de voorzitters. Het grote aantal ingezonden abstracts onderschrijft dat dit een belangrijk onderdeel is van de Internistendagen. In de eerste plaats voor de arts-assistenten omdat de Internistendagen een uniek podium zijn om resultaten van onderzoek of bijzondere observaties te presenteren aan een enthousiast publiek. In de tweede plaats voor de toehoorders, die kunnen vernemen wat er gebeurt aan het front van de Interne Geneeskunde in Nederland en in de derde plaats om de diverse onderzoeksgebieden binnen de Interne Geneeskunde met elkaar in contact te brengen. Ook dit jaar zal per sessie een winnaar worden aangewezen die een prijs van 500 euro overhandigd zal krijgen! Ook zullen de zes uitgekozen Heilige Huisjes in dit Abstractboek worden vermeld. Tijdens de plenaire sessie op vrijdagochtend 26 april zullen de auteurs proberen hun Heilige Huisje omver geschopt te krijgen. Namens de hele Commissie Internistendagen wens ik u veel plezier toe met het lezen maar vooral aanhoren van de vaak gloednieuwe onderzoeksresultaten en het oplossen van de leerzame puzzels in de case reports uit alle klinieken van Nederland! Dr. H.A.H. Kaasjager Voorzitter Commissie Internistendagen This abstract book contains all abstracts that have been submitted to the Annual Meeting of the Netherlands Association of Internal Medicine, april 2013 in Maastricht, the Netherlands. Both research abstracts and case reports are included, representing all disciplines of Internal Medicine. 50 abstracts have been selected for oral presentation. These abstracts are printed first, in the order of presentation. The remainder of abstracts is categorized according to discipline. Dr. H.A.H Kaasjager Chairman Organizing Committee 3

5 PRESENTATIONS Schop de Heilige Huisjes omver! (Sessie vrijdag 26 april uur Auditorium 1) HH1 Digital rectal examination in patients with abdominal pain in the emergency department: is it really that necessary? B.P.A. Spaetgens, P.M. Stassen Maastricht University Medical Centre, Department of Internal Medicine, P. Debyelaan 25, 6229 HX MAASTRICHT, the Netherlands, Introduction: Digital rectal examination (DRE) is traditionally recommended to evaluate patients with abdominal pain. This recommendation is based on the theory that DRE irritates the inflamed peritoneum and thus helps to distinguish serious from non-serious causes of abdominal pain. Even some well-known and highly respected textbooks (recent versions included) proclaim that DRE is mandatory in every patient with abdominal pain. 1 Because DRE is (meant to be) part of the standard physical examination, we often forget that DRE is considered (very) inconvenient by many patients (and doctors), especially in the emergengy department, where an atmosphere needed for mutual trust cannot easily be built up. 2,3,4 There is reasonable doubt about the use of DRE and in this time of evidence based medicine (EBM) we already excluded DRE to be part of standard physical examination in children, because of discomfort and disappointing diagnostic value. 5 Why do we not apply EBM to adults? Because there is a continuing and lively debate on this topic, we wanted to end this discussion for once and for all at the 2013 Internistendagen. We investigated the diagnostic utility of DRE for abdominal pain and assessed its necessity. Clinical Question: Is DRE indicated in every patient with abdominal pain in the emergency department? This clinical question was critically appraised using the following PICO: - Patient: Patients in the emergency department presenting with abdominal pain. - Intervention: Performing DRE. - Control: Not performing DRE. - Outcome: 1) Diagnostic value of DRE in differentiating between causes of abdominal pain, 2) DRE leading to correct decisions in the diagnostic process. Search strategy: A literature search of PubMed was performed. Search terms were: Digital Rectal Examination AND Abdominal pain. There were 13 hits and after screening abstracts and titles, 6 articles seemed useful to answer the clinical questions. Results: Concerning the diagnostic value of DRE in the assessment of right lower quadrant abdominal pain, Bonello et al. retrospectively showed low predictive values (PPV = 0.43, NPV = 0.50) for DRE in diagnosing appendicitis. DRE was considered positive if there was generalized rectal tenderness when performing DRE. Appendicitis was diagnosed during surgery. They also showed that the positive predicitive value of DRE was only 0.48 when performed in patients with appendiceal perforation. 6 Likewise, Sedlak et al. found low predictive values (PPV = 0.45 (95% CI ), NP V= 0.54 (95% CI )) and odds ratio (OR = 0.95) for positive DRE in diagnosing appendicitis in a group of patients admitted to the emergency department with pain in the right-lowerquadrant of the abdomen. 7 Dixon et al. showed approximately the same odds ratios for positive DRE (OR = 1.03 when generalized rectal tenderness on DRE and OR = 1.34 when right-sided rectal tenderness on DRE) in a prospective study diagnosing appendicitis in adults. They included 1028 consecutive patients admitted to hospital with pain in the right lower quadrant of the abdomen. Patients were assessed by a surgeon. The odds ratios for the findings right-lowerquadrant pain (OR = 5.09), guarding (OR = 3.07), rebound tenderness (OR = 3.34) and abdominal rigidity (OR = 5.03) however, were much higher and thus of more diagnostic value than DRE. 8 Concerning the diagnostic value of DRE in undifferentiated abdominal pain Quaas et al. prospectively studied the use of DRE in the emergency department to determine its value in decision making. 9 In total, 528 DREs were performed of which 494 (92%) were classified as not being useful. The remaining 8% of all DREs were just as often classified as helpful (= indicating correct diagnosis) as harmful (= indicating incorrect diagnosis or rejecting correct diagnosis). Likewise, Manimaran et al. prospectively showed that DRE did not change the diagnostic process or initial management of acute abdominal pain in 100/100 consecutive patients referred to the emergency surgical unit. Additionally, DRE did not reveal any other (unrelated) pathology, colorectal cancer in particular. 4 The above-mentioned studies were elegantly reviewed in three studies, all of which came to the same conclusion as we: DRE in patients with acute abdominal pain does not add to or aid in diagnosing appendicitis and peritonitis. 3,10,11 Conclusion: DRE is of very little use in diagnosing appendicitis. Additionally, DRE does not play a role in differentiating between causes of undifferentiated abdominal pain. The above- summarized studies also show that DRE only rarely changes the diagnostic process, and if so, it seems to be as potentially helpful as harmful. Appraising these studies and weighing the certainly present discomfort for both patient and doctor caused by DRE, we plead against routine DRE in people with abdominal pain and thus DRE should not be used as a 4

6 diagnostic or decisive instrument in the assessment of abdominal pain at the emergency department. References 1. Kasper DL, et al. Harrison s principles of internal medicine (18th ed.). New York: McGraw-Hill Medical Publishing Division ISBN Macias DJ, et al. Male discomfort during the digital rectal examination: does examiner gender make a difference? Am J Emerg Med. 2000;18: Werner J, et al. Sinnhaftigkeit der digital-rektalen untersuchung bei akutem abdomen in der notfallaufnahme. Zentralbl Chir. 2011:5. 4. Manimaran N, et al. Significance of routine digital rectal examination in adults presenting with abdominal pain. Ann R Coll Surg Engl. 2004;86: Naheed N. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: digital rectal exams in children who present with constipation. Emerg med J. 2010;27: Bonello JC, et al. The significance of a positive rectal examination in acute appendicitis. Dis Colon Rectum. 1979;22: Sedlak M, et al. Is there still a role for rectal examination in suspected appendicitis in adults? Am J Emerg Med. 2008;26: Dixon JM, et al. Rectal examination in patients with pain in the right lower quadrant of the abdomen. BMJ. 1991;302: Quaas J, et al. Utility of the digital rectal examination in the evaluation of undifferentiated abdominal pain. Am J Emerg Med. 2009;27: Moll van Charante EP, et al. Physical examination of patients with acute abdominal pain. Ned Tijdschr Geneeskd. 2011;155:A Kessler C, et al. Utility of the digital rectal examination in the emergency department: A review. J Emerg Med. 2012:7. HH2 Perioperative corticosteroid supplementation: supported by evidence? A.G. Otto-Minasian, J.M.M. de Boer Rijnstate Hospital, Department of Internal Medicine, Wagnerlaan 55, 6815 AD ARNHEM, the Netherlands, Introduction: Long-term use of corticosteroids may result in suppression of the hypothalamic-pituitary-adrenal axis (corticosteroid induced adrenal insufficiency). During periods of physical stress, like surgery, the adrenal glands of patients on chronic corticosteroid therapy might produce insufficient amounts of cortisol. It is therefore generally believed that these patients require supplemental perioperative (stress) doses of corticosteroids to prevent adrenal insufficiency and subsequently cardiovascular collapse during the stressful period. Since the publication of two case reports in the early 1950s of postoperative cardiovascular collapse and death in two corticosteroid-dependent patients whose preoperative steroids were abruptly discontinued before surgery, stress doses of corticosteroids up to mg hydrocortisone per 24 h have become routine in the perioperative management of patients receiving long-term corticosteroid therapy. Subsequently, many corticosteroid supplementation strategies have been developed since then. Nowadays, however, it is questionable whether supraphysiological doses of corticosteroids are necessary to prevent perioperative adrenal insufficiency and hemodynamic instability. Moreover, high doses of corticosteroids may have potential detrimental effects that can influence surgical outcomes. These include reduced tissue repair, immunosuppression, increased susceptibility to infections, hyperglycaemia, hypertension, fluid retention, psychological symptoms, and disturbances of electrolytes. Clinical question: Is supplemental perioperative corticosteroid therapy required in adult patients receiving long-term corticosteroid therapy to prevent corticosteroid induced adrenal insufficiency and hemodynamic instability? Methods: A literature search was conducted using PubMed. The entered search terms were: - [ corticosteroid OR glucocorticosteroid OR steroid ] - [ perioperative OR surgery ] - [ adrenal insufficiency ] - Limitations: English language The titles and abstracts of 777 articles were screened and 5 articles (3 reviews and 2 recent retrospective studies) were selected to answer the clinical question. These articles were selected because they gave the best overall picture of the studies published on this subject in the last decades. Results and discussion: A Cochrane review of 2 randomized controlled trials (RCTs) (n = 37) was published in 2009 and updated in The studies compared the use of supplemental perioperative steroids to placebo in adult patients on maintenance doses of corticosteroids who required surgery. There was no difference in the hemodynamic profile between patients receiving supplemental perioperative steroids compared with patients receiving only their usual daily dose of corticosteroids. Both studies were graded as having a high risk of bias and the authors concluded that owing to the small number of patients the results might not be representative. Available evidence was insufficient to support or refute the use of supplemental perioperative corticosteroids for patients with adrenal insufficiency during surgery. However, the authors found it to be likely that in the majority of adrenally suppressed patients undergoing surgery, administration of the patient s daily maintenance dose of corticosteroid may be sufficient and that supplemental doses may not be required. 5

7 In their systematic review of the literature Marik and Varon discussed the 2 RCTs described above, as well as 7 cohort studies (6 prospective, 1 retrospective) that enrolled a total of 315 patients who underwent 389 surgical procedures. In the 5 cohort studies in which patients continued to receive their usual daily dose of corticosteroids without the addition of stress doses, no patient developed unexplained hypotension or adrenal crisis. One patient in each of the 2 cohort studies (5% and 1% respectively) in which the usual daily dose of corticosteroids was discontinued 48 and 36 hours before surgery did develop unexplained hypotension; both patients responded to hydrocortisone and fluid administration. The authors concluded that patients receiving therapeutic doses of corticosteroids (with exclusion of those with primary adrenal insufficiency) who undergo a surgical procedure do not routinely require stress doses of corticosteroids so long as they continue to receive their usual daily dose of corticosteroids. Similar conclusions were put forward in the review of de Lange and Kars who argued that the current and rather defensive strategy of perioperative supraphysiological corticosteroid supplementation is not supported by evidence. Recently, 2 retrospective studies have been published on this issue. Zaghiyan et al. performed a retrospective analysis of 74 corticosteroid-treated patients with inflammatory bowel disease (IBD) who underwent a total of 97 major colorectal surgery s (49% were on corticosteroids at the time of the surgery while 51% were off corticosteroids but had been previously treated with corticosteroids < 1 year before surgery). There were no significant differences in hemodynamic instability or surgical outcomes when treated with low-dose steroids (LDS, i.e. 30 mg bolus and 100 mg/24h hydrocortisone for patients on corticosteroids at the time of the surgery and no perioperative corticosteroids for patients off corticosteroids at the time of the surgery) versus high-dose steroids (HDS, i.e. 100 mg bolus and 300 mg/24h hydrocortisone). Hemodynamic instability, defined as heart rate > 100 or < 60 beats/min or systolic blood pressure < 90 mmhg, was more frequent in a subgroup of patients on corticosteroids at the time of the surgery receiving perioperative LDS versus HDS (100% vs. 72%, p = 0.02). However, these episodes of hemodynamic instability were clinically unimportant, because in all but 3 cases, hemodynamic instability resolved with simple measures. In the 3 patients who were treated with vasopressors, hemodynamic instability was due to other causes rather than adrenal insufficiency. No patient required rescue HDS because of adrenal insufficiency. This study was mainly limited by its retrospective nature and selection bias. Finally, another publication of this study group showed no clinically significant hemodynamic instability in corticosteroidtreated patients (n = 26) with IBD undergoing 32 surgical procedures who were treated with perioperative LDS. Conclusion: In conclusion, the current practice of perioperative supraphysiological corticosteroid supplementation in patients on chronic corticosteroid therapy is not supported by evidence. Small retrospective, prospective, and randomized controlled trials, though all methodologically flawed, have suggested that corticosteroid-treated patients undergoing surgery who are at risk of developing corticosteroid induced adrenal insufficiency may be safely treated with only their baseline corticosteroid doses in the perioperative period. Moreover, excessive doses of corticosteroids may be harmful due to the known adverse effects of these medications. Large RCTs of high quality in various surgical settings are warranted to further assess the requirement for supplemental perioperative corticosteroids and the dose required to prevent adrenal insufficiency in patients receiving long-term corticosteroid therapy. HH3 The value of routine follow-up chest radiography after community acquired pneumonia E.J. van Koppen Haga Hospital, Department of Internal medicine, Leyweg 275, 2545 CH DEN HAAG, the Netherlands, Background: Community acquired pneumonia is a common health problem and affects 5-10 individuals per 1000 persons per year in the Netherlands. After hospital admission due to a community acquired pneumonia a chest X-ray of the thorax is often part of routine follow-up procedures in the outpatient clinic to ensure that a pulmonary malignancy is not missed. However, there is little research evidence to support this practice. The purpose of this critical appraisal of literature is to search for evidence of benefit of a routine follow-up chest X-ray, taken into account the costs and radiation exposure. Methods: A structured search in PubMed was conducted using the following search terms: Pneumonia [Mesh] AND follow-up AND chest radiography. Limits were set to the English language, humans and adults. The search yielded 132 articles that were screened by title and abstract for relevance. This led to selection of 5 relevant articles that were critically appraised. Furthermore the guidelines of The Canadian Community- Acquired Pneumonia Working Group, the Infectious diseases society of America, the American Thoracic society, the Dutch Association of Physicians for Pulmonary Diseases and Tuberculosis and The Dutch Working Party on Antibiotic Policy were reviewed. Results: All articles targeted on the new diagnosis of a pulmonary malignancy as benefit of follow-up. Holmberg et al. conducted a retrospective study of 1011 hospitalized 6

8 patients with pneumonia where pulmonary carcinoma was found by convalescent chest radiography in 2/88 patients not feeling well and in 2/524 patients feeling well at follow-up. They suggested that if signs or symptoms of respiratory disease persisted, chest radiography should be performed but that it could be omitted if the patient has completely recovered 1 month after the acute onset of illness. Marrie et al. found in a prospective study in 1269 patients admitted with a pneumonia that 4 patients were newly diagnosed with a pulmonary malignancy due to a follow-up chest radiograph. Soyseth et al. compared the incidence of lung cancer among patients admitted for pneumonia with a general population and showed that patients admitted with a pneumonia had an increased incidence of lung cancer compared with the general population. This risk persisted for 6 years after the onset of the lung infection. Mortensen et al. showed that of 40,744 patients hospitalized with pneumonia, 3760 (9.2%) patients were diagnosed with pulmonary malignancy after their index pneumonia admission. Only 27% was diagnosed within 90 days of admission. They identified factors significantly associated with a new diagnosis of pulmonary malignancy like history of chronic pulmonary disease, any prior malignancy, white race, being married and tobacco use. Tang et al. conducted a population-based cohort study of 3398 patients with chest radiographyconfirmed pneumonia. The incidence of new lung cancer was approximately 1% within 90 days and 2% over 5 years. They suggested that only patients 50 years or older should be targeted for radiographic follow-up. The Canadian and American guidelines recommended a follow-up chest X-ray 4-8 weeks after discharge. In the Dutch guidelines it was not mentioned. Conclusion: There are no randomised studies regarding this topic. However, according to the existing literature, routine follow-up chest X-ray after admission with pneumonia seems to be obsolete and should only be performed when a pulmonary malignancy is suspected. There is some evidence that certain patient groups with risk factors still could benefit from routine follow-up, but more research is needed. HH4 Acetaminophen (paracetamol) against fever in infections: at best ineffective and may even contribute to mortality E.M.E. Verbeek, A.B. Arntzenius, G.H. Wattel-Louis Spaarne Hospital, Department of Internal Medicine, Spaarnepoort 1, 2134 TM HOOFDDORP, the Netherlands, Introduction: The symptomatic treatment of fever is nowadays a widespread practice. One of the most common methods is the administration of antipyretics. Many observational studies concern the prescription of acetaminophen. Although this practice is employed commonly in febrile patients because of the feared intrinsic harm of fever and patients discomfort, controversy over the value of fever remains. Preclinical studies suggested that active cooling confers benefit in acute brain trauma patients, but clinical trials have been inconclusive so far. In patients with other types of diagnosis, the actual support for the necessity of fever treatment is lacking. In fact, several clinical data suggest that fever has a beneficial effect on the outcome of many infectious diseases and mortality would be higher in hypothermic patients. Other studies show that antipyretics increase the duration of chickenpox illness in children as well as the inhibition of antibody responses in adults. Experimental evidence shows that fever is a natural host respons against infectious diseases which causes an increase of cytokines and heat shock proteins, T-cell proliferation and the synthesis of antibodies. These processes are essential to prevent organ damage by oxidative injury in situations of stress. Fever also plays a key role in the inhibition of microbial growth. So fever could be in advantage of the host, and suppression of this natural reaction has never been proven to be safe in general. The aim of the study is to be able to give answer to the question whether the standard use of paracetamol in infectious fever management is in the advantage of the patient or not. Methods: Two searches were conducted throughout PubMed and Cochrane (a PICO design): - critical care or critical illness or ICU or Emergency department AND paracetamol or acetaminophen and fever or pyrexia - paracetamol or acetaminophen AND fever or pyrexia AND treatment outcome (a mesh term covering efficacy and safety) Search results: The combined search resulted in the discovery of: 1 review, 1 retrospective study, 2 randomised prospective studies and 3 prospective observational studies. All studies excluded patients with neurological illness or liver diseases. The only conducted review with meta-analysis about antipyretics (including NSAIDs) and mortality, unfortunately could not draw a conclusion because of the heterogeneity of the studies. In a retrospective study about the efficacy of paracetamol on fever reduction two cohorts of fever episodes in SIRS patients were formed: a paracetamol group versus a group receiving no medication. The absolute temperature drop in patients who received paracetamol was quite unpredictable as well as variable but in the end significantly greater than in non treated patients (mean drop of 0.86 C vs C 7

9 for treated vs. untreated) and the cooling rate was slightly more rapid (a significant temperature reduction in time of 0.20 C/h vs C/h for treated vs. untreated). Although statistically significance was reached, the differences were minor and normalisation of body temperature did not occur more often in treated patients (mean 56% vs. 43.5% treated vs untreated p = 0.352). The only two randomised studies conducted, confirm the result of modest temperature reduction. The first study showed a significant temperature fall of 0.5 C in a small population (30 patients). The second randomised study (not double blinded, 82 patients) by Schulman showed that the daily mean temperature was 1.09 C (significant) lower in the aggressive (acetaminophen when temperature > 38.5 C, and a cooling blanket when temperature > 39.5 C) treatment group compared to the daily mean temperature in the permissive (acetaminophen and a cooling blanket when temperature > 40 C) group. But aggressive treatment did not have an influence on the average daily maximum temperature. Taking this into account and the fact that the mean of all temperatures in the permissive group was not high at all (mean of 37.8 C), one may question the potential benefit of prescribing paracetamol. A striking result in the aggressive group was that antibiotics were more frequently given (77.2 vs. 70.9%; aggressive versus permissive) and SIRS- score during the study was higher (while APACHE score at baseline was similar in each group). This study was stopped prematurely due to a trend noticed by interim analysis towards a higher mortality in the aggressive treatment group (p = 0.06, Fisher Exact Test). Definite conclusions may not be drawn but these findings raise the concern whether interrupting the natural actions of fever may be harmful to some patients. The most recent and largest study is a prospective, observational multicentre study which only adds to the concern mentioned above. 5 A significantly higher mortality rate was found in non-septic patients with a fever > 39.5 C, and in septic patients administration of NSAIDs and acetaminophen was independently associated with mortality (after multivariable adjustment, adjusted odds ratio: NSAIDs 2.61, p = 0.028; acetaminophen 2.05, p = 0.01). Finally two other smaller studies conducted focused on the safety of paracetamol administration in critically ill patients. Both observational studies concluded that paracetamol (or propacetamol: a bio precursor) caused a significant drop in systolic blood pressure, sometimes even requiring an intervention with noradrenaline. Conclusion: There is evidence that paracetamol lowers temperature but the degree to which is not quite convincing and is less than assumed. Because large randomised, double blinded studies are lacking it might be premature to make firm conclusions about the causality between symptomatic reduction of infectious fever and mortality. Conversely, we can conclude that adverse effects do occur, and that there is not enough evidence that fever management is safe in all patients. Currently underway is the HEAT trial (a New Zealand and Australian trial) in which 700 patients are being randomised between receiving 1 gr. of intravenous paracetamol or placebo, and safety and efficacy will be studied. While awaiting the results of the HEAT trial, we advise restraint in the symptomatic treatment of fever with acetaminophen in adult patients. HH5 No pictures please enough of plain abdominal radiographs S.C.M. Tops, C.G. ter Meulen Canisius Wilhelmina Hospital, Department of Internal Medicine, Weg door Jonkerbos 100, 6532 SZ NIJMEGEN, the Netherlands, Background: Acute abdominal pain accounts for 5-10% of the visits to the emergency department in the Netherlands. Medical decision making in patients with abdominal pain based on clinical and laboratory evaluation alone can result in unnecessary interventions or delayed treatment. Therefore additional diagnostics in this patient population are often required. In the 70 s nearly 43% of all patients with acute abdominal pain had plain abdominal radiography. Now, 40 years later, in 20% of these patients an abdominal X-ray is performed, while over the years more and more accurate diagnostic instruments such as ultrasonography and computed tomography (CT) have become available. Although plain X-ray is relatively cheap, quick available and has low exposure to radiation, the question is whether there is still an indication for this investigation in the evaluation of patients with acute abdominal pain. Research question: What is the diagnostic accuracy of plain abdominal radiography in patients with acute abdominal pain (compared to ultrasonography and CT)? Methods: A structured search on PubMed Central database was conducted using the following search terms: Abdominal Pain [Mesh] AND Radiography, Abdominal [Mesh] and Abdominal Pain [Mesh] AND Plain abdominal radiography. Limits were set to English language, full text available and article type (inclusion of randomized controlled trials, (controlled) clinical trials, (systematic) reviews and multicenter studies). Of each relevant publication found, the related citations in PubMed and the reference list of the article were screened for other relevant articles. Also a search on UptoDate was performed on indications often used for plain abdominal radiography. 8

10 Search terms were ileus, urolithiasis, bowel obstruction, foreign body, constipation and bowel perforation. Results: The search on PubMed Central database yielded 103 articles of which 5 articles were found relevant: 3 reviews and 1 multicenter study performed in the Netherlands (2 articles referred to this study). Screening of the related citations in PubMed and the reference list of each article resulted in another 11 relevant articles. The search in UptoDate resulted in 5 relevant items. Abnormal plain radiographs Plain abdominal radiographs are abnormal in only a minority of cases. Between 10-22% of all patients with acute abdominal pain have abnormal findings on plain X-ray as foreign bodies, signs of obstruction or urinary stones. In patients with diffuse, nonspecific abdominal pain or with complaints of nausea and vomiting abdominal X-ray is mostly (98%) normal. When an abnormality is noted on abdominal X-ray in only 1 on 10 patients initial clinical diagnosis is changed. However in the vast majority (78%) these changes are not accurate. Besides, in case of surgical treatment CT is needed in preoperative planning to provide information about size, cause and location of the problem. This is another shortcoming of plain abdominal investigation. The only exception is an ingested foreign body: there is no evidence available that CT has a higher sensitivity and specificity than plain abdominal radiography to establish this diagnosis. Though the advantage of CT remains the ability to provide information about the location of the foreign body, which is a prerequisite when surgical treatment is planned. Normal plain radiographs A normal abdominal X-ray can be misleading in the work-up of acute abdominal pain. Because of its low sensitivity a normal plain abdominal investigation can not rule out diseases. In a study in which all patients with acute abdominal pain whose abdominal X-ray results were normal had follow-up imaging (ultrasonography or CT) 72% of these showed abnormal findings. Beside a better diagnostic accuracy an important advantage of ultrasonography and CT compared to abdominal X-ray lies in the possibility of providing an alternative diagnosis. More arguments In a Dutch prospective multicentre study the added value of different diagnostic modalities was evaluated after clinical and laboratory evaluation. In approximately 1000 patients at the emergency department with abdominal pain more than 2 hours and less than five days duration, no improvement in diagnostic accuracy was seen with plain abdominal radiography compared to clinical assessment alone. CT after negative or inconclusive ultrasonography resulted in the highest overall accuracy. This shows once again that in the diagnostics of patients with acute abdominal pain abdominal X-ray should be replaced by ultrasonography or CT. Conclusion: There is abundant evidence that in the work-up of patients with acute abdominal pain, plain abdominal radiography is obsolete. HH6 To salt or not to salt in heart failure, that is the question! S.I. Lok, L.T. Dijkhorst-Oei Meander Medical Centre, Department of Internal Medicine, Utrechtsteweg 160, 3818 ES AMERSFOORT, the Netherlands, Introduction: Current guidelines and patient folders advise sodium restriction to < 2 gr/day in patients with moderate to severe chronic heart failure (HF). The relationship of salt intake to blood pressure (BP) is the basis for the belief that restriction in dietary sodium intake will prevent BP-related cardiovascular events. In chronic HF, reducing BP and extracellular volume through salt restriction is thought to prevent the detrimental rise in pre-and afterload. Pharmacological treatment is supported by a wealth of evidence. However, guidelines report little evidence for the aforementioned life-style intervention with large impact on quality of life. Clinical question: What is the evidence for a low-sodium diet with respect to better outcome in chronic HF patients? Literature search: A literature search was conducted using the PubMed database. The entered search terms were: low sodium diet, systolic heart failure patients AND mortality. Fifteen articles were found of which two were eligible. Results: A systematic review and meta-analysis written by DiNicolantonio et al. evaluated six randomized trials comparing low-sodium diet (1.8 gr/day; 80 mmol/day) with normal-sodium diet (2.8 gr/day; 120 mmol/day) in 2774 patients with HF with reduced ejection fraction (HFrEF). Compared with a normal diet, a low-sodium diet increased all cause mortality (RR 1.95; 95% CI ), sudden death (RR 1.72; 95% CI ), death due to HF (RR 2.23; 95% CI ) and HF readmissions (RR 2.10; 95% CI ). One prospective study by Arcand et al. evaluated 123 stable ambulatory patients with systolic HF during a median follow-up time of 3 years. Mean sodium intakes were 1.4 ± 0.3; 2.4 ± 0.3 and 3.8 ± 0.8 gr/day in the lower, middle and upper tertiles, respectively. The high-sodium tertile was associated with an adjusted hazard ratio of 1.39 (95% CI ) for all-cause hospitalization and 3.54 (95% CI ) for mortality. Interpretation of results: These data suggest that the dietary advice for sodium intake should not be below 2 gr/day, as suggested by the European Guidelines of Cardiology. Although, one randomized trial included in the metaanalysis by DiNicolantonio was referred in the latter 9

11 guideline, the common advice on sodium restriction was not adjusted. This may be because the idea of abandoning the decennia-lasting practice of sodium restriction conflicts with physiologists model of high pre- and afterload as causes of morbidity and mortality in chronic HF. However, other mechanisms such as hyponatraemie and neurohumoral activation may be more important in determining outcome in HF patients. Paterna et al. showed that, in contrast with a normal sodium diet, a low-sodium diet increased brain natriuretic peptide, plasma renin activity and aldosterone concentrations. Furthermore, serum sodium concentration significantly decreased despite fluid restriction of 1 l/day. Conclusion: In patients with chronic HF, available evidence should lead to a recommendation against strict sodium restriction of < 2 gr/day. Whether an upper-limit of sodium intake can be advised, remains to be investigated by randomized trials. I. ORAL PRESENTATIONS RESEARCH 1 Potentiating effects of sodium restriction and hydrochlorothiazide and their combination on RAAS-blockade efficacy in type II diabetes and nephropathy: a randomized controlled trial J. Kwakernaak 1, J.A. Krikken 1, F.W. Visser 1, M.H. Hemmelder 2, A.J. Woittiez 3, G.D. Laverman 3, G. Navis 1 1 University Medical Centre Groningen, Department of Internal Medicine/Nefrology, Hanzeplein 1, 9700 RB GRONINGEN, the Netherlands, 2 Medical Centre Leeuwarden, LEEUWARDEN, the Netherlands, 3 Zorggroep Twente, ALMELO, the Netherlands Introduction: Reduction in sodium intake has proven an efficient non-pharmacological intervention to optimize treatment response to RAAS-blockade in non-diabetic chronic kidney disease. Whether this holds true for diabetic kidney disease is however unknown. We therefore investigated the potentiating effects of dietary sodium restriction (SR) and hydrochlorothiazide (HCT) and their combination, in subjects with type II diabetes and nephropathy. Methods: Multicentre, randomized, double-blind, placebocontrolled, cross-over trial, with 6-week treatment periods in a rotation design, testing the separate and combined effects of SR and HCT (50 mg daily) in addition to standardized maximal ACE-inhibition (ACEi; lisinopril 40 mg daily) on proteinuria (Up) and blood pressure in 45 patients with type II diabetes and nephropathy (84% male, age 65 ± 9 yrs, BMI 32 ± 5 kg/m 2 ). Results: Urinary sodium excretion, as a measure of dietary sodium intake, decreased from 224 ± 76 mmol/d during regular sodium to 150 ± 66 mmol/day upon SR (p < 0.001). Median Up during baseline treatment (ACEi and regular sodium diet) was 1.1 ( ) gr/day; it decreased to 0.7 ( ) and 0.7 ( ) gr/day during SR and HCT, resp. (both < vs. baseline). The combination of HCT and SR further reduced up to 0.5 ( ) gr/day (p < vs. baseline). Mean arterial blood pressure (MAP) at baseline was 104 ± 11 mmhg; it was reduced to 100 ± 11 and 96 ± 9 mmhg in response to SR and HCT, respectively (both < 0.02). MAP was more reduced by HCT than by SR (p = 0.017). Creatinine clearance at baseline was 101 ± 47 ml/ min; it remained unaffected by SR (99 ± 48 ml/min, p = 0.5) and HCT (97 ± 48 ml/min, p = 0.4), however, was significantly reduced by their combination (86 ± 42 ml/ min, p < vs. baseline). Conclusion: In this population with very high regular sodium intake, both moderate SR and HCT, added to RAAS-blockade, reduced proteinuria and blood pressure, without affecting creatinine clearance. Combination of SR and HCT reduced proteinuria and blood pressure even further, however, at the expense of a decrease in creatinine clearance. Intervention in sodium status is an effective measure to increase efficacy of RAAS-blockade in type II diabetic subjects with nephropathy. 2 High cut-off hemodialysis for myeloma-associated nefropathy. A single centre cohort series M.R.K.L Lie, I.J.A.M. Verberk-Jonkers, A.A. van Houten, M.B.L. Leijs, P.J. Gundlach, M.A. van den Dorpel Maasstad Hospital, Department of Internal Medicine, Maasstadweg 21, 3079 DZ ROTTERDAM, the Netherlands, Introduction: Acute renal failure occurs frequently in multiple myeloma (MM) and significantly affects patient prognosis.most often acute renal failure in MM is caused by cast nefropathy, due to tubular light chain deposits. The use of high cut-off hemodialysis (HCO-HD) to rapidly remove circulating free light chains has been proposed as a novel adjunct treatment for cast nefropathy. Methods/Results: Since 2009, 12 patients with dialysisdependent renal failure secondary to MM were treated with HCO-HD in combination with chemotherapy (dexamethasone and bortezomib in 11 patients, dexamethasone and lenalidomide in 1 patient). Data from these 12 treatment episodes were analysed. Treatment response was defined as dialysis independence within 3 months of start of treatment. The population s mean age was 63 years, they were predominantly male (9/12), while the majority (8/12) of them had a new presentation of MM without a history of chronic kidney disease. Mean serum creatinine at presentation was 711 mmol/l, whereas mean free light chains 10

12 (FLC) were 5500 mg/l. Seven patients had adequate thrombocyte counts allowing for safe kidney biopsies, which showed cast nephropathy in 5. A total of 223 HCO-HD sessions were performed. 10 patients responded to treatment and were dialysis independent within 3 months (mean serum creatinine 213 mmol/l) after a mean number of 15 HCO-HD sessions (range 3-40). The 2 non-responders both died (at 3 and 17 months after treatment). Of the responders, 2 are without recurrence and 1 is in complete remission after stem cell transplantation. In the remaining 7 responders, mean time to progression was 10 months (range 3-17 months). Mean survival up until January 2013 was 13 months, with 6 of the responders still alive. Responders primarily had a newly diagnosed MM (7 out of 10), and all responders still alive had a newly diagnosed MM (6 out of 6). The main complications of HCO-HD were circuit coagulation (12/223 sessions in 7 patients) and catheterrelated bloodstream infections (3 events in 2 patients). Conclusion: The use of high cut-off hemodialysis in patients with myeloma-associated acute renal failure seems to facilitate the recovery of renal function, with a low risk of complications. Despite its high costs, high cut-off hemodialysis should be considered as an adjunctive treatment in patients with myeloma-associated nefropathy. Further data on treatment efficacy and follow-up are needed, for which we propose centralisation of HCO-HD treatment and a national registry. 3 Effect of bariatric surgery on asthma: 3 months follow-up A. van Huisstede 1, M. Castro Cabezas 1, H. Zengerink 1, R. Luitwieler 1, A. Rudolphus 1, C. Taube 2, P.S. Hiemstra 2, G.J. Braunstahl 1 1 St Franciscus Hospital, Department of Pulmonology, Kleiweg 500, 3045 PM ROTTERDAM, the Netherlands, 2 Leiden University Medical Centre, LEIDEN, the Netherlands Background: Asthma in obese subjects is poorly understood and the effect of weight loss on asthma control is not well described. Aim: To investigate the effects of bariatric surgery on asthma control, quality of life and lung function. Methods: We performed a prospective study in patients with a confirmed diagnosis of asthma (FEV 1 12% and/or PD20 < 1.76 mg (= bronchial hyperresponsiveness, BHR)) and non-asthmatic patients undergoing bariatric surgery (BMI > 35kg/m 2, age 18-50y). Lung function, medication and quality of life were assessed at baseline and 3 months after bariatric surgery. Obese asthmatics who did not undergo bariatric surgery served as an additional control group. Results: 35 asthma patients (BS+A) and 50 non-asthmatics (BS-A) underwent bariatric surgery, 17 asthma patients served as controls (NBS+A). Only BMI of NBS+A (41 kg/ m 2 ) was significantly lower compared to BS+A (46 kg/m 2 ) or BS-A (44 kg/m 2 ), while there were no other differences between the groups at baseline (e.g. comorbidity, lung function). Following bariatric surgery, BMI decreased to 38 kg/m 2 in BS+A and 36 kg/m 2 in BS-A, and remained stable in NBS+A group (41 kg/m 2 ). There were no differences in asthma control questionnaire (ACQ), asthma related quality of life questionnaire (AQLQ), FEV 1 or FeNO between the two asthma groups (BS+A and NBS+A) at baseline. Following surgery, ACQ and AQLQ significantly improved in BS+A group (1.4 to 0.7, p = 0.045; respectively 4.9 to 6.1, p = 0.002), whereas no change was detectable after 3 months in NBS+A (1.5 to 1.2, p = 0.275; respectively 5.3 to 5.2, p = 0.676). The group without asthma (BS-A) also showed a significant improvement in ACQ (0.6 to 0.1, p = 0.002) and AQLQ (5.0 to 6.7, p = 0.001) 3 months after bariatric surgery. There was no change in FeNO in any group. FEV 1 improved significantly only in BS+A (mean 86.2 to 92.4% predicted, p = 0.001). After surgery, a 50% reduction in BHR was observed in BS+A (88% to 46%). Conclusion: Bariatric surgery improves lung function, asthma control and quality of life in patients with asthma and morbid obesity already after 3 months. This suggests that weight loss can be an important component of the management of obese asthmatics. Non-asthmatic obese controls also have asthma-like symptoms, which underlines the importance of adequate diagnosis of asthma in the morbidly obese. 4 GLP-1 analogs in Clinical Practice E.F.S. van Velsen, J. Lamers, V. Blok, R.J.M. van Leendert, R.M. Kiewiet-Kemper Albert Schweitzer Hospital, Department of Internal Medicine, Albert Schweitzerplaats 25, 3318 AT DORDRECHT, the Netherlands, Introduction: Glucagon-like-peptide-1 (GLP-1) analogs are since 2009 approved in the Netherlands for the treatment of type 2 diabetes in patients with a BMI larger than 35kg/m 2 and inadequate glycaemic control with oral glucose-lowering medication. Literature shows a significant reduction in HbA 1c and body weight in comparison to placebo. Aim: To determine the effect of GLP-1 analogs on glycaemic control and body weight in clinical practice. Patients and Methods: From April 2010 until May 2012 we included all patients starting GLP-1 analogs (liraglutide/ exenatide) at the Department of Internal Medicine in our 11

13 hospital. At inclusion, all patients were diagnosed with type 2 diabetes. HbA 1c, body weight, medication (oral medication, insulin) and side effects were registered at baseline, after three and after six months. Results: During the study period we included 238 patients. Mean age was 57.0 years, and 109 (46%) subjects were women. At baseline, mean HbA 1c was 67.8 mmol/mol, while mean BMI and mean body weight were 40.1 kg/m 2 and kg respectively. Furthermore, 161 patients (68%) used any form of insulin therapy, 32% oral glucose-lowering medication only. 229 patients (96%) started liraglutide, while 9 (4%) started exenatide. HbA 1c decreased 6.3 mmol/mol (± 13.6 mmol/mol) and 6.0 mmol/mol (± 14.0 mmol/mol) after three and six months respectively (both p < compared to baseline). Furthermore, a weight reduction of 7.9 kg (± 6.1 kg) and 11.3 kg (± 8.5 kg) was observed after three and six months respectively (both p < compared to baseline). At six months, 47 of 161 patients (29%) had stopped using any form of insulin therapy, while 51 (32%) using four or two times insulin therapy a day at baseline decreased towards once daily. Additionally, those who could not stop or change the baseline insulin regimen were able to significantly reduce the total daily dose of insulin. During the study, 18 patients (8%) were discharged due to adequate glucose-regulation. 17 patients (7%) discontinued GLP-1 analogs due to lack of effect on glycaemic control, while 7 (3%) stopped due to intolerable side effects. No pancreatitis was observed during the study period. Conclusion: GLP-1 analogs in the treatment of type 2 diabetes induce a significant reduction in HbA 1c and body weight. Additionally, we have demonstrated that patients already on insulin therapy benefit from GLP-1 analogs as well: despite significant reduction or discontinuation of insulin dose, HbA 1c levels and body weight decreased. We suggest that the present indication for the use of GLP-1 analogs in the Netherlands should be reconsidered. 5 Frequency Rhythmic Electrical Modulation System (FREMS), a possible additional treatment for patients with therapy resistant diabetic neuropathy? M.E.W. Schepens, J.H. Heijster, B.P.M. Imholz Twee Steden Hospital, Department of Internal Medicine, Dr. Deelenlaan 5, 5042 AD TILBURG, the Netherlands, Introduction: Diabetic neuropathy (DN) is a complication of diabetes mellitus (DM) that will occur in a significant part of the patients. Twenty-one percent of the patients with DN will eventually develop painful neuropathy. There are multiple pharmacological therapies available for painful DN, but these are not always sufficient. One of the alternative treatments is Frequency Rhythmic Electrical Modulation System (FREMS), which stimulates vasomotor activity and the production of neovascular growth factors. The effect on pain management has been demonstrated by two randomised controlled trials. Aim of the study: A phase IV study to evaluate the effect of FREMS therapy on painful DN resistant to pharmacological treatments and to determine predictive factors for a response to FREMS therapy. Materials and Methods: Seventy patients who had been unsuccessfully treated for DN according to the DN guideline were included and received FREMS therapy during ten sessions of forty minutes in fourteen days.the patients were seen at least three days before (control) and one (M1) and three (M3) months after treatment. They were evaluated for pain (neuropathic pain symptom inventory (NPSI)), quality of life (EQ-5 score), vibration perception (biothesiometer), mobility (sensewear) and the presence of glycation end products (AGEs) (AGE reader). We examined the following possible predictive factors: absolute pain score in rest, duration of DM, the average vibration threshold measured at the hallux and the presence of AGEs. Results: Absolute pain scores were significantly improved after one and three months compared to control (p < 0,001). After one month the NPSI score was diminished with at least fifty percent in 23/70 patients and with at least thirtyfive percent in half of the patients. After three months the NPSI score was diminished with at least fifty percent in 19/66 patients and with at least thirty percent in half of the patients. The quality of life also improved significantly (M1 p = 0,001, M3 p = 0,01). There were no significant changes in vibration perception and mobility. There were no significant correlations found between the examined predictive factors and the response to FREMS therapy. Conclusion: For patients with painful DN who do not respond to traditional pharmacological treatments, FREMS therapy may prove to be a valid alternative for over one third of the patients. 6 Hospital admissions due to an adverse event: an economic burden? F.J.H. Magdelijns, E. Pijpers, P.M. Stassen Maastricht University Medical Centre, Department of Internal Medicine, P. Debyelaan 25, 6229 HX MAASTRICHT, the Netherlands, Background: Health care related adverse events are an important problem in medicine. Apart from medical consequences for the patient, the economic burden is substantial. The information available on costs caused by adverse events is limited to costs of adverse events occurring during hospitalisation. Information on costs of adverse events leading to hospitalization is however limited and focuses on adverse drug events. 12

14 Aim: The aim of our study is to provide insight in costs of hospital admissions due to (preventable) health care related adverse events. Methods: All patients who were admitted via the emergency department to an internal medicine department because of a health care related adverse event (during a 5 month period) were included. We retrospectively retrieved all information from the admission charts. The costs of the admissions were evaluated by adding up the costs of the visit to the emergency department, the inpatient days, the diagnostic tests and the provided treatment. All medical costs were based on hospital invoices. Results: In total, 324 admissions (in 284 patients) due to a health care related adverse event were included in this study (28.7% of all admissions in a 5 month period). Total costs were calculated to be v 1,396,718. Medication related adverse events were most common (43.5%) and contributed most to the costs (v 584,399; 41.8% of total costs). Inpatient days proved to be most expensive (v 1,076,385; 77.3% of total costs). The 90 adverse events that were judged preventable accounted for v 276,180 of total costs (19.8%). Conclusion: Our study demonstrates that hospitalization due to a health care related adverse event is not only common (28.7%) but also a serious economic burden (v 1,396,718 in 5 months). Preventable health care related adverse events accounted for 19.8% of these costs. In conclusion: (preventable) health care related adverse events add substantially to overall healthcare costs. Awareness of our medical actions with their possible adverse events is necessary to reduce our already high health care costs. 7 Ambulance patients with sepsis: a seriously ill population M. Groenewoudt, F.M.M. Leijten, P.M. Stassen Maastricht University Medical Centre, Department of Internal Medicine, P. Debyelaan 25, 6229 HX MAASTRICHT, the Netherlands, Introduction: Sepsis is a major problem with high mortality. The surviving sepsis campaign aims to reduce this mortality and provides treatment guidelines that emphasize the need of early start of treatment. However, treatment of sepsis patients before arriving at the hospital is not considered in these guidelines. Transportation by ambulance may offer an opportunity to start treatment early. Aim of the study: This study investigated how many patients with sepsis are transported by ambulance, whether sepsis is recognised by the ambulance staff and how these patients are assessed and treated in the ambulance. Further we compared patients who are transported by the ambulance with those who are not, regarding demographic data, hospitalisation and outcome. Materials and Methods: All patients with sepsis who were assessed by an internist at the emergency department of our secondary and tertiary hospital between March 2011 and March 2012 were prospectively included in our study. Data from patient charts were completed with data from the ambulance service. Results: In the one-year study period, 664 patients with sepsis were included. Almost half (47.6%) of the patients had been transported by ambulance. These patients were significantly older (71 vs. 56 years), had more severe grades of sepsis and were admitted more frequently to the hospital (96 vs. 86%) and to the intensive care unit (7.0 vs. 0.6%) than the other sepsis patients. Mortality within 28 days was 19.4% in the ambulance patients compared to 6.3% in the other patients. Sepsis or infection was recognized in the ambulance in 74.3% of the patients. Half of the ambulance rides were considered non urgent, even in 34.6% of the patients with septic shock. Assessments of vital signs were not routinely performed and treatment was started in only 43.7%. Conclusion: Almost half of the sepsis patients who are assessed by the internist at the emergency department are transported by ambulance. These patients are seriously ill with a mortality of 19.4%, but are often transported with non urgent rides and assessment of vital signs and early start of treatment are not routinely performed. The ambulance offers an opportunity for early start of treatment. However, recognition and acknowledgment of the seriousness of sepsis must be improved. 8 The effects of the 34C>T variant of the AMPD1 gene on immune function, multi-organ dysfunction and mortality in patients with sepsis B.P.C. Ramakers 1, E.J. Giamarellos-Bourboullis 2, M. Coenen 1, M. Kox 1, S. Vermeulen 1, J.G. van der Hoeven 1, C. Routsi 2, A. Savva 2, I. Perdios 2, F. Diamantea 2, D. Sinapidis 2, P. Smits 1, N.P. Riksen 1, P. Pickkers 1 1 UMC St Radboud, Department of Intensive Care, Geert Grooteplein 10, 6500 HB NIJMEGEN, the Netherlands, 2 University of Athens, Medical School, ATHENS, Greece Introduction: Adenosine exerts anti-inflammatory and tissue protective effects during systemic inflammation. While the anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance, the direct tissue protective effects might limit organ damage. Aim of the study: To investigate the effects of a common loss-of-function variant of the Adenosine Monophosphate Deaminase 1 gene (AMPD1), which is associated with increased adenosine formation, in patients with sepsis. Materials and Methods: In a prospective cohort, geneticassociation study, the effects of the presence of the AMPD1 13

15 gene on immune function, multi-organ dysfunction and mortality in septic patients was studied. Pneumosepsis patients (n = 402) and controls without infection (n = 101) were enrolled. Results: In pneumosepsis patients and controls, the prevalence of the 34C > T (rs ) mutation in the AMPD1 gene was similar. Univariate logistic regression analysis showed a tendency of increased mortality in patients with the CT genotype, compared to patients with the CC genotype (OR 1.53; 95% CI ). Moreover, carriers of the CT genotype tended to suffer more from multi-organ dysfunction, OR 1.4 ( ) and 3.0 ( ), for CT and TT, respectively (p = 0.07). In septic carriers of the CT genotype, the ex vivo production of TNF-a by LPS-stimulated monocytes was attenuated (p = 0.005), indicative for more pronounced immunoparalysis in these patients. Conclusion: The presence the 34C > T variant of the AMPD1 gene is not related to infection susceptibility, however it is associated with more pronounced immunoparalysis in patients with sepsis, and shows a tendency towards increased mortality. Mechanistically, the antiinflammatory effects of adenosine may account for this and apparently overrule its direct tissue protective effects. 9 Standard dosing of low molecular weight heparin (LMWH) based on weight leads to subtherapeutic anti-factor Xa levels in intensive care patients. An observational study S. Zwaveling, H.J.C. Vonken, D.H. van de Kerkhof, S. Houterman, A.J.G.H. Bindels, A.N. Roos Catharina Hospital, Department of Intensive Care Unit, Michelangelolaan 2, 5623 EJ EINDHOVEN, the Netherlands, Purpose: LMWH is the first-choice anticoagulant in intensive care (ICU) patients. Dosage is based on admission weight, according to current guidelines of the Dutch Society of Intensive Care Medicine (NVIC). Monitoring anti-factor Xa levels (afxa) is only advised in ICU patients with renal insufficiency. The target range for afxa levels in literature, albeit unproven, is IU/ml. The aim of this study was to observe if recommended afxa levels are being achieved in ICU patients. Materials and Methods: We conducted an observational, prospective study in a 25-bed general and surgical ICU and an 8-bed medium care unit (MCU) in the Catharina Hospital in Eindhoven. Patients were included between September 15th and December 15th, 2012 and received LMWH subcutaneous. Patients with an ICU stay less than 24 hours were excluded. Patients received 2500 IU dalteparin (sc.) if admission weight < 80 kg, and 5000 IU dalteparin (sc.) if admission weight 80 kg. The afxa levels were measured four hours after administration using the validated chromogenic method (STA liquid anti-xa assay). Results: We collected data from 246 patients of whom 127 < 80 kg and kg. The median afxa of the entire population was IU/ml (IQR ). The median afxa of patients < 80 kg was significantly lower compared to patients 80 kg (0.165 IU/ml (IQR ) vs IU/ml (IQR ) respectively; p = 0.001). In patients < 80 kg 17% (n = 22) did reach the lower limit of the target range (0.2 IU/ml) each day compared to 37% (n = 44) in patients 80 kg (p = 0.001). In patients < 80 kg 53% (n = 67) never reached the lower limit compared to 29% (n = 35) in patients 80 kg (p < 0.001). Conclusion: Dosing of dalteparin (LMWH) based on admission weight, according to current guidelines, leads only in a small minority to therapeutic afxa activity. Monitoring of the afxa levels should be considered in all ICU patients. 10 The Critically Appraised Topic appraised C.M.W. Teunissen, G.S. Mijnhout, P.H.P. Groeneveld Isala Clinics, Department of Internal Medicine, Dokter van Heesweg 2, 8025 AB ZWOLLE, the Netherlands, Introduction: A common tool to teach residents how to find evidence for questions about treatment or diagnosis arising in their daily practice, is the Critically Appraised Topic (CAT). The CAT is performed by formulating a structured question, using the Patient Intervention Control Outcome (PICO) format. To find the best available evidence, aggregated evidence is searched first using a top-downapproach. First, the National Guideline Clearinghouse and CBO guidelines are searched for evidence-based guidelines, followed by the TRIP database and Cochrane Library for systematic reviews. Only when no clear answer is found yet, PubMed is searched for primary studies as the final resort. Aim of the study: To assess the yield, benefit and influence on daily clinical practice of the CAT performed by internal medicine residents. Methods: From July to December 2012, both the presenting resident (a different one each week) and two staff members (the same two if present, or only one if the other was absent) completed a questionnaire consisting of standard list of previously defined questions about the yield, benefit and influence on daily clinical practice of each consecutive CAT and the resident was asked his/her opinion about the benefit of the CAT in general. Results: A total of 17 CATs were appraised. All residents found the CAT a useful part of their medical specialist training and an important competency for their future work 14

16 as a medical specialist. However, only 22% stated that they regularly use the CAT method outside the weekly CAT. In 55% of CATs, a clear answer was found. The staff members judged the PICO format was applied well in all CATs. The search strategy was adequate in 79%. However, in only 46% of CATs there was enough evidence available to properly answer the question. Aggregated evidence was available in only 53% of CATs. The answer to the CAT rarely influenced medical practice (11%) or our medical protocols (6%). Conclusion: The CAT seems to be a useful tool to search medical evidence and a valued part of the internal medicine specialist training, but questions frequently cannot be answered due to lack of (aggregated) evidence and the results rarely influence our daily practice. Has the time come to change our CAT education? 11 Randomized double blind placebo controlled PK/PD study on the effects on a single intravenous dose of the anti-hepcidin spiegelmer NOX_H94 on serum iron during experimental human endotoxemia L.T. van Eijk 1, D.W. Swinkels 1, A.S.E. John 1, F. Schwoebel 2, F. Fliegert 2, L. Summo 2, S. Vauleon 2, J.M.M. Laarakkers 1, K. Riecke 2, R.P. Pickkers 1 1 UMC St Radboud, Department of Intensive Care, Geert Grooteplein Zuid 10, 6500 HB NIJMEGEN, the Netherlands, 2 NOXXON Pharma A.G., BERLIN, Germany Introduction: Anemia of chronic disease (ACD) is generally attributed to increased hepcidin production. The first-inclass hepcidin antagonist NOX-H94, a PEGylated antihepcidin L-RNA oligonucleotide, is in development for targeted treatment of ACD. Aim of the study: To investigate whether NOX-H94 prevents the inflammation-induced serum iron decrease during experimental human endotoxemia. Effects on the innate immune response were studied as secondary endpoints. Materials and Methods: This randomized, double-blind, placebo-controlled trial was carried out in 24 healthy young men. At T = 0 hours (h), 2 ng/kg E. coli endotoxin (LPS) was administered intravenously (iv), followed by 1.2 mg/kg NOX-H94 or placebo iv at T = 0.5 h. Blood was drawn serially for 24 h and at day 3, 8 and 15 after endotoxin administration for measurements of inflammatory parameters, cytokines, NOX-H94 pharmacokinetics, total hepcidin-25 (free and NOX-H94-bound), and iron parameters. The difference of serum iron change from baseline at T = 9 h was defined as primary endpoint. Data are expressed as mean ± SD. Results: LPS administration led to flu-like symptoms and an increase in CRP, leucocytes and plasma levels of TNF-a, IL-6, IL-10, and IL-1RA that was similar for both treatment groups. NOX-H94 plasma concentrations peaked at 0.7 ± 0.4 h after the start of administration, after which they declined according to a two-compartment model, with a T1/2 of 22.5 ± 4.28 h. Total hepcidin-25 rose to a peak of 23.0 ± 5.2 nm at T = 5.5 ± 0.05 h post LPS in control subjects and normalized at about T = 24 h. In the NOX-H94 treated group, total hepcidin-25 concentrations, which include hepcidin-25 bound to NOX-H94, rose to 559 ± 112 nm at T = 9.5 ± 1.5 h post-lps and normalized slowly until day 15. In the placebo group, serum iron increased from 19.0 ± 7.6 mmol/l at baseline to a peak of 32.6 ± 6.71 mmol/l at T = 3 h, and decreased to its lowest point at T = 12 h, being 8.0 ± 2.95 mmol/l. In the NOX-H94 group, serum iron concentrations rose to 38.3 ± 8.09 mmol/l at T = 6 h and then slowly declined to 9.3 ± 5.83 at T = 24 h. From 6 to 12 h post LPS, the serum iron concentrations in NOX-H94 treated subjects were significantly higher than in placebo treated subjects (p < , ANCOVA). At T = 24 h and 48 h, serum iron tended to be lower in NOX-H94 treated subjects than in placebo controls. Conclusion: Treatment with NOX-H94 had no effect on innate immunity, but effectively prevented the inflammation-induced drop in serum iron concentrations during experimental human endotoxemia. These findings demonstrate the clinical potential of the anti-hepcidin drug NOX-H94 for further development to treat patients with ACD. 12 Increased circulating nucleosomes and neutrophil activation as a measure of the formation of neutrophil extracellular traps (NETs) during sickle cell painful crisis M. Schimmel 1, E. Nur 1,2, B.J. Biemond 2, G.J. van Mierlo 3, S. Solati 3, D.P. Brandjes 1, H.M. Otten 1, S. Zeerleder 2,3 1 Slotervaart Hospital, Department of Hematology, AMSTERDAM, the Netherlands, 2 Academic Medical Centre, AMSTERDAM, the Netherlands, 3 Sanquin Research and Landsteiner laboratory, Academic Medical Centre/University of Amsterdam, AMSTERDAM, the Netherlands Introduction: Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive painful crisis frequently leading to SCD related complications, like acute chest syndrome. The pathophysiology of painful crisis is complex, with an important role for polymorphonuclear neutrophils (PMN). Recently, PMN have been demonstrated to form NETs upon activation. Nucleosomes and histones, together with neutrophil proteases, exposed on these NETs have been shown to be bactericidal, but can 15

17 also be strongly procoagulant and cytotoxic to endothelial cells. In sepsis, the level of circulating nucleosomes has been reported to correlate with severity of inflammation, organ dysfunction and mortality. The Aim of this case-control study was to assess plasma levels of circulating nucleosomes and human neutrophil elastase-a 1 -antitrypsin (EA) complexes, as measure of NET formation and systemic PMN activation. Methods: Blood samples of healthy controls (24) and sickle cell patients during steady state (74) and painful crisis (70) were analyzed using ELISA. For statistical analysis, patients were divided in two groups with patients with the relatively severe genotypes HbSS and HbSb 0 -thalassemia grouped together (HbSS/HbSb 0 -thal) and patients with the relatively milder HbSC and HbSß + -thalassemia genotypes in the other group (HbSC/HbSß + -thal). Results: Plasma levels of nucleosomes in both patients with HbSS/HbSb 0 -thal and HbSC/HbSb + -thal were significantly higher during painful crisis (median; IQR, 20.2 U/ml; , p < 0.001, and 11.7 U/ml; , p = 0.045) as compared to those in steady state (6.0 U/ ml; and 7.1 U/ml; ). An increment in EA levels was seen in HbSS/HbSb 0 -thal and HbSC/ HbSb + -thal patients during painful crisis (75.1 ng/ml; , p < 0.001; 62.0 ng/ml; ; p = 0.051) as compared to levels during steady state (45.7 ng/ml; and 50.2 ng/ml; ), which just failed to reach statistical significance in HbSC/HbSb + -thal patients. During painful crisis, EA levels correlated strongly with levels of nucleosomes in both HbSS/HbSb 0 -thal (Sr = 0.55, p < 0.001) and HbSC/HbSb + -thal patients (Sr = 0.90, p < 0.001). In steady state HbSS/HbSb 0 -thal patients, levels of nucleosomes correlated with endothelial markers svcam-1 and vwf:ag (Sr = 0.421, p = 0.003; Sr = 0.452, p < 0.001). Six patients who developed an acute chest syndrome during painful crisis were among the patients with the highest nucleosome and EA levels. A moderate (Sr = 0.431, p < 0.001) correlation was found between levels of nucleosomes and duration of hospitalization. Conclusion: We demonstrate for the first time increased levels of circulating nucleosomes in sickle cell patients with painful crisis reflecting NET formation which strongly correlates with PMN activation and disease severity. 1 Academic Medical Centre, Department of Internal Medicine, Meibergdreef 9, 1105 AZ AMSTERDAM, the Netherlands, 2 Wageningen university and research Centre, WAGENINGEN, the Netherlands, 3 Leids University Medical Centre, LEIDEN, the Netherlands, 4 Haga Hospital, DEN HAAG, the Netherlands Background: Recurrent clostridium difficile infection is difficult to treat, and failure rates for antibiotictherapy are high. We studied the effect of duodenal infusion of donor fecesin patients with recurrent C. difficile infection. Methods: We randomly assigned patients to receive one of three therapies: an initial vancomycin regimen (500 mg orally four times per day for 4 days), followed by bowellavage and subsequent infusion of a solution of donor feces through a nasoduodenaltube; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage. The primary end pointwas the resolution of diarrhea associated with C. difficile infection without relapseafter 10 weeks. Results: The study was stopped after an interim analysis. Of 16 patients in the infusiongroup, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion.the 3 remaining patients received a second infusion with feces from a differentdonor, with resolution in 2 patients. Resolution of C. difficile infection occurredin 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (p < for both comparisons with theinfusion group). No significant differences in adverse events among the three studygroups were observed except for mild diarrhea and abdominal cramping in the infusiongroup on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increasein Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species. Conclusion: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.) 13 Duodenal infusion of donor feces for recurrent clostridium difficile infection E. van Nood 1, A. Vrieze 1, M. Nieuwdorp 1, S. Fuentes 2, E. Zoetendal 2, W.M. de Vos 2, C.E. Visser 1, E.J. Kuijper 3, J. Bartelsman 1, J. Tijssen 1, P. Speelman 1, M. Dijkgraaf 1, J.J. Keller 4 14 Reduced prevalence of arterial thrombosis in von Willebrand disease Y.V. Sanders 1, J. Eikenboom 2, E.M. de Wee 1, J.G. van der Bom 2, B.A.P. Laros-van Gorkom 3, K. Fijnvandraat 4, M.H. Cnossen 1, M.E.L. Degenaar-D ujard in 5, K. Meijer 6, E.P. Mauser-Bunschoten 7, F.W.G. Leebeek 1 16

18 1 Erasmus University Medical Centre Rotterdam, Department of Hematology, P.O. box 2040, 3000 CA ROTTERDAM, the Netherlands, 2 Leiden University Medical Centre, LEIDEN, the Netherlands, 3 St Radboud University Nijmegen Medical Centre, NIJMEGEN, the Netherlands, 4 Emma Children s Hospital, Academic Medical Centre, AMSTERDAM, the Netherlands 5 Nederlandse Vereniging van Hemofilie-Patiënten, BADHOEVEDORP, the Netherlands, 6 University Medical Centre Groningen, GRONINGEN, the Netherlands, 7 Van Creveldkliniek/UMCU, UTRECHT, the Netherlands Introduction: Von Willebrand factor (VWF) plays an important role in primary hemostasis by facilitating adhesion of platelets to the endothelium, thereby initiating aggregation of platelets to form a platelet plug. Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by reduced levels or activity of VWF and is characterized by recurrent mucocutaneous bleeding. It is well known that high VWF levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that VWD patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. Aim of the study: To investigate the prevalence of arterial thrombosis in a large cohort of VWD patients and to compare this with the general population. Materials and Methods: We studied clinical history of arterial thrombosis in 635 adult VWD patients with VWF levels 30 U/dl (aged years, 36.6% men), participating in a large nation-wide multicentre cross-sectional study (Willebrand in the Netherlands WiN study). Clinical history of acute myocardial infarction, ischemic stroke, transient ischemic attack (TIA), unstable angina pectoris or peripheral arterial disease and cardiovascular risk factors were obtained by a questionnaire. For each patient with arterial thrombosis the diagnosis was confirmed using medical records from the hospital of treatment or the general practitioner. The prevalence of arterial thrombosis was compared with two reference populations from the general Dutch population (CBS and RIVM) adjusted for age and sex as standardized morbidity ratios (SMRs). Results: Twenty-nine arterial thrombotic events occurred in twenty-one VWD patients (21 out of 635; 3.3%; 95% CI ). Five patients (0.8%; 95% CI ) suffered acute myocardial infarction and three patients (0.5%; 95% CI 0-1.0) ischemic stroke, unstable angina pectoris in twelve patients, TIA in nine. None of the VWD patients suffered from peripheral arterial disease. The prevalence of cardiovascular disease in VWD patients was lower than observed in the general population, SMR 0.60 (95% CI ) for coronary heart disease and SMR 0.40 (95% CI ) for acute myocardial infarction. For ischemic stroke the prevalence was 35-67% lower compared to two reference populations, SMR 0.65 (95% CI ) and 0.33 (95% CI ), respectively. The reduction in prevalence of all arterial thrombotic events combined (acute myocardial infarction, ischemic stroke and coronary heart disease) was 39% and 63%. Conclusion: This is the first study that indicates that VWD patients have a reduced prevalence of arterial thrombosis and provides important insights into the role of VWF in the pathogenesis of arterial thrombosis. 15 Skin autofluorescence as a measure of advanced glycation end products deposition predicts mortality in patients with peripheral artery disease L.C. de Vos, D.J. Mulder, A.J. Smit, R.P.F. Dullaart, P.W. Kamphuisen, C.J. Zeebregts, J.D. Lefrandt University Medical Centre Groningen, Department of Vascular Medicine, Hanzeplein 1, 9713 GZ GRONINGEN, the Netherlands, Introduction: Patients with peripheral artery disease (PAD) suffer from widespread atherosclerosis and an increased risk of cardiovascular events. Advanced Glycation End products (AGEs) play an important role in the development of atherosclerosis and cardiovascular disease. Earlier, we reported the independent predictive value of AGEs for mortality in patients with diabetes mellitus and patients with renal failure. Recently, we reported that AGEs are increased in PAD patients, independent from cardiovascular risk factors. In the present study we hypothesized that AGEs deposition predicts mortality in patients with PAD. Methods: PAD patients were recruited from the outpatient clinic of vascular surgery of our hospital. PAD was established by a resting ankle-brachial index 0.90 and confirmed by computed tomographic angiography, magnetic resonance angiography, catheter angiography, or duplex ultrasonography. Patients with renal failure (egfr < 15 ml/min per 1.73 m 2 ) were excluded. Cardiovascular risk factors were assessed. Primary end-point was all-cause mortality. The follow-up was performed by evaluating hospital records and contact with the general practitioner. AGEs level was assessed by skin autofluorescence (SAF) using the AGE-reader, a previously validated non-invasive method. SAF results were split into quartiles. Kaplan- Meier analysis with log-rank test and Cox regression analysis were performed. Data are shown as mean ± SD, number (%) or median (Q1-Q3). Results: Between 2007 and 2008, 258 PAD patients (188 men and 70 women) were included with a mean age of 66 ± 10 year. Patients had a mean body mass index of 27 ± 4 kg/m 2. Systolic and diastolic blood pressure were 140 ( ) and 80 (70-85) mmhg, respectively. A total of 17

19 199 (77%) patients were on lipid lowering drugs and 213 (83%) used blood pressure lowering drugs. 61 (24%) had diabetes mellitus and 131 (51%) were smokers. Mean SAF was 2.77 ± 0.66 arbitrary units (AU). Median follow-up time was 4.0 ( ) years. A total of 47 (18%) patients died. Kaplan-Meier analysis showed that SAF predicted mortality (log-rank test p = 0.015). Cox regression showed that patients with a higher SAF value (4th quartile, mean SAF of 3.66 ± 0.35 AU) had a 5.0-fold (95% CI ), p = increased risk for mortality (crude model) as compared to the patients with lower SAF values (1st quartile, mean SAF of 1.97 ± 0.27 AU), and 3.5-fold (95% CI ), p = after correction for cardiovascular risk factors. Conclusion: AGEs deposition, measured by SAF, predicts mortality in PAD patients, independent from cardiovascular risk factors. Possibly, SAF can identify patients at highest cardiovascular risk that may benefit from more aggressive treatment of all modifiable risk factors. 16 Efficacy of repeat duplex ultrasound in patients with suspected deep venous thrombosis B.M.J. Scholtes, F.L.G. Erdkamp, R.J.W. van Kampen, F.P.J. Peters Orbis Medical Centre, Department of Internal Medicine, Dr H. van der Hoffplein 1, 6162 BG SITTARD-GELEEN, the Netherlands, Introduction: About 300 patients a year are referred to our outpatient clinic at Orbis Medical Centre for suspected DVT. Referring general practitioners (GP s) use a primary decision rule combined with D-dimer testing to stratify patients who should undergo a duplex ultrasound to safely exclude a deep vein thrombosis (DVT). In all patients with a negative duplex ultrasound but elevated D-dimer test and/or high clinical suspicion, guidelines advice to perform a second duplex ultrasound. In this study, we investigate prevalence of DVT after GP referral and the effectiveness of repeat ultrasound in case of elevated D-dimer test in these patients. Methods: We performed a single centre, prospective analysis of GP referred patients suspected of DVT. Inclusion was started at July 17th 2012 and still ongoing, a preliminary analysis was performed after inclusion of 150 patients. All patients underwent clinical investigations to determine Wells-score, D-dimer testing and a duplex ultrasound. In case of elevated D-dimer test and/ or a persisting clinical suspicion for DVT repeat duplex ultrasound after 5-7 days was performed in all patients. Results: During a period of 5.5 months, 153 GP referred patients were seen to rule out a DVT. Of these 153 patients effectively 28.8% had a DVT and in 7.8% of cases a thrombophlebitis was diagnosed. Negative duplex ultrasound. Results for thrombosis were seen in 97 patients. In these patients 56 had a repeat duplex ultrasound 5-7 days later. The repeat ultrasound was positive for DVT in 3.6% (n = 2) of cases. All patients with a primary Wells score > 4 had a positive duplex ultrasound, in two cases only the second duplex ultrasound. 41 patients had no repeat ultrasound performed; 29.3% had a normal D-dimer test, 43.9% had an alternative diagnosis and 19.5% had low Wells scores in combination with a D-dimer test < 750. Two patients refused additional ultrasound. Conclusion: At our outpatient clinic 28.8% of GP referred patients had a comfirmed deep vein thrombosis by duplex ultrasound. Deep venous thrombosis was diagnosed in only 3.6% of patients after repeat duplex ultrasound. All patients with a Wells score above 4 had a positive duplex ultrasound, including the patients with a positive second duplex ultrasound. In conclusion a repeat duplex ultrasound seems effective in GP referred patients with high Wells scores (> 4) and a primary negative duplex ultrasound. Efficacy and effectiveness of repeat ultrasound will be further analysed in our prospective cohort study. 17 Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism P.L. den Exter 1, J. van Es 2, P. Erkens 3, M. van Roosmalen 1, P. van den Hoven 1, M.M.C. Hovens 4, P.W. Kamphuisen 5, F.A. Klok 1, M.V. Huisman 1 1 Leiden University Medical Centre, Department of Thrombose & Hemostase, Albinusdreef 2, 2333 ZA LEIDEN, the Netherlands, 2 Academic Medical Centre, AMSTERDAM, the Netherlands 3 Maastricht University Medical Centre, MAASTRICHT, the Netherlands, 4 Rijnstate Hospital, ARNHEM, the Netherlands, 5 University Medical Centre Groningen, GRONINGEN, the Netherlands Introduction: The non-specific clinical presentation of pulmonary embolism (PE) frequently leads to delay in its diagnosis. Aim of the study: To assess the impact of delay in presentation on the diagnostic management and clinical outcome of patients with suspected PE. Methods: For this post-hoc analysis, we used the combined data of two large multicentre, prospective studies that investigated the diagnostic management of patients with suspected PE. Patients presenting > 7 days from the onset of symptoms were contrasted to those presenting within 7 days as regards the safety of excluding PE on the basis of a clinical decision rule (CDR) combined with D-dimer testing. Patients were followed for three months to assess the rates of recurrent venous thromboembolism (VTE) and mortality. 18

20 Results: Diagnostic delay (presentation >7 days) was present in 754 (18.6%) of the total of 4044 patients. The failure rate of an unlikely clinical probability and normal D-dimer test was 0.5% (95% CI ) for patients with and 0.5% (95% CI ) for those without diagnostic delay. D-dimer testing yielded a sensitivity of 99% (95% CI 96-99%) and 98% (95% CI 97-99%) in these groups respectively. PE patients with diagnostic delay more frequently had centrally located PE (41% vs. 26%, p < 0.001). The cumulative rates of recurrent VTE (4.6% vs. 2.7%, p = 0.14) and mortality (7.6% vs. 6.6%, p = 0.31) were not different for patients with and without diagnostic delay. Conclusion: PE can be safely excluded based on a CDR and D-dimer testing in patients with a delayed clinical presentation. Diagnostic delay for PE was associated with a more central PE location although this did not affect the clinical outcome at 3 months. 18 Advantages and disadvantages of incorporating C-reactive protein levels, age and D-dimer levels in diagnosing pulmonary embolism M.J. Crop 1, C. Siemes 2, P. Berendes 1, F. van der Straaten 1, M-D. Levin 1 1 Albert Schweitzer Hospital, Department of Internal Medicine, Albert Schweitzerplaats 25, 3318 AT DORDRECHT, the Netherlands, 2 Erasmus MC, ROTTERDAM, the Netherlands Introduction: Over the past several years the number of performed radiological scans to diagnose pulmonary embolism (PE) increased dramatically, while the incidence of PE hardly increased. This resultated in an increased number of patients exposed to radiation and higher costs. Recently, the use of an age-adjusted D-dimer cut-off value was suggested to increase specificity of D-dimer testing. Aim of the study: This study investigated the impact of incorporating age and levels of C-reactive protein (CRP) and D-dimer on the sensitivity and specificity to diagnose PE. Methods: This observational study ( ) included all consecutive patients suspected for PE presenting on the Emercency Department and with simulatanously measured levels of CRP and D-dimer. Only patients who received pulmonary CT angiography were further analysed. We studied the correlation between age, CRP, D-dimer and the effect of using an age-adjusted cut-off values for D-dimer (age in years/100 mg/l). Moreover, the predictive value of these parameters for PE was calculated. Results: Of 4609 patients suspected for PE, 1164 patients underwent radiological imaging. PE was demonstrated in 309 patients (26.5%). Increased levels of D-dimer were modestly positively correlated with CRP levels (r s = 0.42; p < 0.001). In addition, D-dimer levels were positively correlated with age (r s = 0.33; p < 0.001). Interestingly, in patients < 50 years D-dimer and CRP were strongly correlated (r s = 0.47; p < 0.01), whereas in elderly the correlation was only 0.24 (p < 0.01). Thus, in young patients 22% of elevated D-dimer levels can be explained by an elevated level of CRP. While age, D-dimer levels and age*d-dimer (i.e. age-adjusted D-dimer) significantly contributed to the prediction model of PE. Based on area-under-the-curve odds-ratios (OR, 95% confidence interval) were ( ), ( ) and ( ), respectively. CRP did not significantly contribute to the model. Using an age-adapted D-dimer cut-off value for patients 50 years the negative predictive value decreased from 96% to 93%, while specificity increased from 37% to 50%, Moreover, in patients (> 70 years), 40% more patients had D-dimers levels below the age-adjusted cut-off level compared to the conventional cut-off level, thus reducing the need of performing CT scans. Conclusion: In the prediction of PE, age and dimer levels are relevant, while CRP levels are not. CRP levels only modestly effected D-dimer levels. Using an age-adjusted D-dimer cut-off in patients 50 years modestly reduces the negative predictive value, but dramatically increases the specificity of D-dimer testing. 19 Protocolised inpatient care of diabetes mellitus C. van Noord, S. Kos, R.W. Wulkan, M. Alkemade, K. Dekker, L.J.D.M. Schelfhout, J. van der Linden Maasstad Hospital, Department of Internal Medicine, Maasstadweg 21, 3079 DZ ROTTERDAM, the Netherlands, Introduction: The prevalence of hyperglycaemias in patients with diabetes mellitus during admission is high. Prevention and treatment is important to prevent further clinical complications. We have conducted a study evaluating implementation of a new protocol to standardize inpatient care of patients with diabetes mellitus. Methods: A retrospective study including all glucose measurements of adult patients with diabetes mellitus type 1 or 2 admitted to a surgery department, was performed before and after implementation of the new protocol, which acquired direct consultation of an internist and diabetes specialist nurse at admission, who made a daily treatment program and adjustment scheme based on glucose measurements four times a day by HemoCue201DM glucose point of care (POC) device. We compared the prevalence of hyperglycaemias and hypoglycaemias before and after implementation with logistic regression analyses adjusted for age and gender. Results: Overall, 360 patients with diabetes mellitus type 1 or 2 with 5322 glucose measurements were included. The risk 19

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