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Netherlands Journal of Critical Care Bi-monthly journal of the Dutch Society of Intensive Care Volume 26 - No 4 - July 2018 REVIEW Auscultation for bowel sounds in patients with ileus: an outdated practice in the ICU? S.H.W. van Bree, M.M.C. Prins, N.P. Juffermans CASE REPORT Clostridium perfringens: a rare cause of postoperative septic shock N. Henning, R.K. Linskens, E.E.M. Schepers-van der Sterren, B. Speelberg CASE REPORT Small bowel obstruction after laparoscopic Roux-en-Y gastric bypass presenting as acute pancreatitis: a case report B.B.M. van der Woude, J. Berkhout, J.P. van Basten, J. Schouten

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Page 1: Netherlands Journal of Critical Care - NJCC 2018-4 Vol... · 2018-07-03 · Netherlands Journal of Critical Care Bi-monthly journal of the Dutch Society of Intensive Care Volume 26

Netherlands Journal of Critical CareBi-monthly journal of the Dutch Society of Intensive Care

Volume 26 - No 4 - July 2018

REVIEWAuscultation for bowel sounds in patients with ileus: an outdated practice in the ICU? S.H.W. van Bree, M.M.C. Prins, N.P. Juffermans

CASE REPORTClostridium perfringens: a rare cause of postoperative septic shockN. Henning, R.K. Linskens, E.E.M. Schepers-van der Sterren, B. Speelberg

CASE REPORTSmall bowel obstruction after laparoscopic Roux-en-Y gastric bypass presenting as acute pancreatitis: a case reportB.B.M. van der Woude, J. Berkhout, J.P. van Basten, J. Schouten

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NVIC NAJAARSCONGRES

De IC van de lange ademuitdagingen bij langliggers

Donderdag 13 september 2018Postillion Hotel Utrecht

Bunnik

2018

Nederlandse Vereniging voor Intensive Care - www.NVIC.nl

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Netherlands Journal of Critical Care

NETHERLANDS JOURNAL OF CRITICAL CARE

EXECUTIVE EDITORIAL BOARDN.P. Juffermans, editor in chiefI. van Stijn, managing editorH. Dupuis, language editorJ. Horn, editorial boardA.P.J. Vlaar, editorial boardM. Kuiper, associate editorP. Spronk, associate editor

[email protected]

C O P Y R I G H TNetherlands Journal of Critical CareISSN: 1569-3511NVIC p/a Domus MedicaP.O. Box 2124, 3500 GC UtrechtT: +31-(0)30 - 282 38 38

© 2018 NVIC. All rights reserved. Except as outlined below, no part of this publication may be reproduced, stored in a retrieval systemor transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher. Permission may be sought directly from NVIC.

DERIVATIVE WORKSSubscribers may reproduce tables of contentsor prepare lists of articles including abstracts for internal circulation within their institutions. Permission of the publisher is required for resale or distribution outside the institution. Permission of the publisher is also required for all other derivative works, including compilations and translations.

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SUBSCRIPTIONSAn annual subscription to the Netherlands Journal of Critical Care consists of 6 issues. Issues within Europe are sent by standard mail and outside Europe by air delivery. Cancellations should be made, in writing, at least two months before the end of the year.The annual subscription fee for the Netherlands is € 170, for Europe € 285, for the rest of the world € 380. Subscriptions are accepted on a prepaid basis only and are entered on a calendar year basis.Please transfer the fee to ABNAMRO NL55 ABNA 0524 5618 93, swift-code: ABNANL2A. Do not forget to mention the complete address for delivery of the Journal.

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C O N T E N T S

E DITORIAL140 It’s not a gut feeling: don’t listen to the bowels J.I. van der Spoel

REVIEW142 Auscultation for bowel sounds in patients with ileus: an outdated practice in the ICU? S.H.W. van Bree, M.M.C. Prins, N.P. Juffermans

CASE REPORT147 Clostridium perfringens: a rare cause of postoperative septic shock B.B.M. van der Woude, J. Berkhout, J.P. van Basten, J. Schouten

C A S E R E P O R T150 Severe pulmonary involvement in a case of drug reaction with eosinophilia and

systemic symptoms (DRESS) E. Bruwiere, N. Janssen, S. van Santen

C A S E R E P O R T156 Small bowel obstruction after laparoscopic Roux-en-Y gastric bypass presenting as

acute pancreatitis: a case report N. Henning, R.K. Linskens, E.E.M. Schepers-van der Sterren, B. Speelberg

C L I N I C A L I M A G E159 The great imitator, imitated C.M.W. Teunissen, J.E. Lopez Matta, J.J. Maas

C O R R E S P O N D E N C E161 Research Collaboration Critical Care in the Netherlands: RCCCNet L. Heunks, N.P . Juffermans, P. Pickkers, A. J.C. Slooter of the RCCCNet executive committee

164 NVIC conference and course agenda165 Editorial board 165 International advisory board166 Information for authors

Netherlands Journal of Critical Care is indexed in:

NETH J CRIT CARE - VOLUME 26 - NO 4 - JULY 2018 139

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Submitted June 2018; Accepted June 2018

E D I T O R I A L

It’s not a gut feeling: don’t listen to the bowels

J.I. van der SpoelDepartment of Intensive Care Medicine, Amsterdam UMC location VUmc.

Correspondence

J.I. van der Spoel - [email protected]

Keywords - ileus; ausculatation; physical examination; enteral feeding

In my 1973 copy of Hamilton Bailey’s Demonstration of Physical Signs in Clinical Surgery it is stated that auscultation of the abdomen is of ‘overriding importance’ in the investigation of ileus, be it obstructive of paralytic.[1] The doctor should be seated on a chair on the right side of the patient’s abdomen, command everybody in the vicinity to be quiet, apply the cup of the stethoscope firmly to the skin just below and to the right of the umbilicus, and listen – if necessary – for three full minutes. Only then can an ileus be diagnosed or the diagnosis can be discarded. In this issue of the Netherlands Journal of Critical Care, Van Bree reports a review of the literature on the utility of auscultation for bowel sounds in clinical decision-making.[2] It may be questionable whether the auscultation in the reported studies was executed as meticulously as prescribed by Hamilton Bailey - in the intensive care unit it will seldom be quiet, even if the doctors these days still have the authority to command silence - but the conclusion is firm: auscultation of the abdomen is useless, should be abandoned, and – most importantly – should not contribute to the process of clinical decision-making.

So, if auscultation of the abdomen does not lead to an impact on clinical decision-making and should be abandoned, could this mean that auscultation in general should be abandoned? Indeed, auscultation of the heart by experienced general practitioners has a sensitivity of only 32% and 44% for diagnosing mild and significant valvular heart disease with specificities of 67% and 69%, respectively.[3] Fifty-two patients admitted to the emergency room with symptoms of lower respiratory tract infection were evaluated by a general internist, a specialist in infectious diseases, and a pulmonologist. Without knowledge of the clinical histories, they performed a chest exam to determine whether the patients had pneumonia.[4] As compared with the gold standard chest radiography, the sensitivity of clinical diagnosis ranged from 47 to 69%, and the specificity from 58 to 75%. Now that we conclude that auscultation is, to say the least, not

a very useful part of physical examination, does this mean that performing a physical examination in general can be discarded? After all, it has low specificity and sensitivity, and for the intensivist ultrasound has become a reliable tool. Ultrasound performs much more accurately than physical examination on diagnosing pathological conditions of the lung (consolidation, pleural effusion, oedema), the heart (global dimensions and function, valve dysfunction, volume status) and the abdomen (gastric retention volume, ileus, intra-abdominal air and fluid). Probably, some medical specialists will have to continue doing direct hands-on examinations, e.g. the neurologist with reflex and sensitivity testing (although even pupillary size, symmetry, and reactivity nowadays can be tested automated by a pupilometer handled by a nurse), but for most specialists physical examination may not contribute to the diagnostic process. Even the surgeon will almost always rely on ultrasound and/or CT scanning of the abdomen instead of following the principles that Henry Hamilton Bailey described.[5]

All in all, following this line of reasoning, physical examination can be abolished - or can it? Of course not. History taking and physical examination have been the cornerstone of medicine since Hippocrates, and even though the diagnostic accuracy of physical examination is low compared with modern methods, it still has many valuable aspects - also for ICU patients. But the focus should change from organ-specific diagnosis to more general results and findings. Physical examination results in an intimate interaction between patient and physician, hopefully increasing the patient’s confidence and trust in the doctor’s abilities and therefore his treatment. A physical examination gives the physician insight into the mental state of the patient (delirium, depression), pain and anxiety, and the patient’s will to fight his disease and help in physical rehabilitation. Observing the patient reveals unwanted patient-ventilator interactions and could lead to relevant adjustments in the ventilator settings. Touching the patient provides relevant

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knowledge on the circulation.[6] Although auscultation of the heart is inferior to echocardiography, a (new) murmur could point to a new diagnosis such as endocarditis, an acute mitral valve insufficiency or a ventricular septal rupture. In contrast to ultrasound and CT/MRI, physical examination is always available, is cheap, and might reveal conditions that would otherwise go unnoticed, such as decubitus, an infected catheter, petechiae and so on.

In conclusion, I have gone from auscultation of bowel sounds in patients with an ileus to physical examination in general. Returning to the starting point that auscultation for bowel sounds is useless, we - and our nurses! - should stop doing it. This is in line with existing guidelines: enteral feeding should not be withheld in ICU patients with absent bowel sounds.[7,8]

Together with auscultation of bowel sounds, other rituals which hamper optimal enteral feeding, such as measuring gastric retention volume, are to be abolished as well.[9] The authors are to be complemented with their research, and expanding on ‘test everything, retain what is good’ it is up to us not only to retain what is good, but to discard what is not good, to begin with rituals that hamper optimal feeding.

DisclosuresThe author declares no conflict of interest. No funding or financial support was received.

References

1. Hamilton Bailey H. Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery. Fifteenth ed. Bristol: John Wrigth & sons LTD; 1973:pp 309 and 319-20.

2. Van Bree SHW, Prins MMC, Juffermans N. Ausculatation for bowel sounds in patients with ileus: an outdated practice in the ICU? Neth J Crit Care. 2018. 142-146

3. Gardezi SKM, Myerson SG, Chambers J, et al. Cardiac auscultation poorly predicts the presence of valvular heart disease in asymptomatic primary care patients. Heart. 2018:Published Online First: 24 May 2018. doi: 10.1136/heartjnl-2018-313082.

4. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997;278:1440-5.

5. Gans SL, Pols MA, Stoker J, Boermeester MA. Guideline for the diagnostic pathway in patients with acute abdominal pain. Dig Surg. 2015;32:23-31.

6. Lima A, Jansen TC, van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009;37:934-8.

7. McClave SA, DiBaise JK, Mullin GE, Martindale RG. ACG Clinical Guideline: Nutrition Therapy in the Adult Hospitalized Patient. Am J Gastroenterol. 2016;111:315-34; quiz 35.

8. Reintam Blaser A, Starkopf J, Alhazzani W, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43:380-98.

9. Marshall AP, West SH. Enteral feeding in the critically ill: are nursing practices contributing to hypocaloric feeding? Intensive Crit Care Nurs. 2006;22:95-105.

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Netherlands Journal of Critical CareSubmitted November 2017; Accepted February 2018

R E V I E W

Auscultation for bowel sounds in patients with ileus: an outdated practice in the ICU?

S.H.W. van Bree1,2, M.M.C. Prins3, N.P. Juffermans4

1Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, the Netherlands2Department of Internal Medicine, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands3 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC location AMC,

University of Amsterdam, Amsterdam, the Netherlands4Department of Intensive Care Medicine, Amsterdam UMC location AMC, Amsterdam, the Netherlands

Correspondence

S. van Bree - [email protected]

Keywords - auscultation; bowel sounds; intestinal motility; ileus; bowel obstruction

Abstract Background: Ileus can be the consequence of multiple factors, including an operation, a side effect of drugs or the result of an obstruction requiring direct operative correction. Although auscultation for bowel sounds is routinely performed in the ICU and a well-established part of the physical examination in patients, its clinical value remains largely unstudied.Methods: To determine whether auscultation for bowel sounds helps in clinical decision-making in ICU patients with ileus, a literature search of PubMed, Embase and Cochrane was performed to study the diagnostic value of auscultation for bowel sounds. Results: The inter-observer variability for the assessment of the quantity, volume and pitch of bowel sounds was high, with a moderate inter-observer agreement for discerning postoperative ileus, bowel obstruction and normal bowel sounds (kappa value 0.57). The intra-observer reliability of duplicated recordings for distinguishing between patients with normal bowels, obstructed bowels or postoperative ileus was 54%. No clear relation between bowel sounds and intestinal transit was found. Sensitivity and positive predictive value were low: 32% and 23% respectively in healthy volunteers, 22% and 28% in obstructive ileus, and 22% and 44% in postoperative ileus.Conclusions: Auscultation with the aim to differentiate normal from pathological bowel sounds is not useful in clinical practice. The low sensitivity and low positive predictive value together with a poor inter- and intra-observer agreement demonstrate the inaccuracy of utilising bowel sounds for clinical decision-making. Given the lack of evidence and standardisation of auscultation, the critically ill patient is more likely to benefit from abdominal imaging.

IntroductionIleus can be the consequence of multiple factors, including an operation, or medications such as opiates, but can also result from an obstruction that may require direct operative correction. As the pathogenesis of ileus is complex, there are more causes of ileus in intensive care patients such as critical illness itself,[1] ischaemia, diverticulitis and peritonitis, contributing at various times during the development of this entity.[2] Therefore, the decreased propulsive ability in patients with ileus may be broadly classified as caused either by bowel obstruction or intestinal atony/paralysis.Reported clinical symptoms of ileus include nausea, vomiting, bloating, abnormal or loss of peristaltic bowel sounds, delayed passage of flatus and stool, and inability to progress to an oral diet.[3,4] Gastrointestinal problems occur frequently and are associated with adverse outcomes in intensive care patients.[5-8] Different gastrointestinal symptoms and complications [e.g. decreased bowel sounds and delayed gastric emptying) may occur in up to 50% of mechanically ventilated patients.[5,9] Despite this, there is no consensual means for obtaining a precise assessment of gastrointestinal function,[8] and it remains unclear which symptoms most reliably reflect recovery of the gastrointestinal tract in the intensive care unit (ICU).[3,10-12] Clinical parameters to diagnose ileus, such as return of bowel sounds and time to first flatus, may lack accuracy, while other clinical parameters such as nausea, vomiting and tolerance of solid food strongly depend on patient reporting.[13] Thus, it is questionable to what extent these parameters reflect recovery of intestinal motility. Thereby, it may not be surprising that studies assessing ileus have used various clinical parameters as primary outcome measure.[13,14]

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In the ICU, diminished bowel peristalsis and the absence of bowel sounds are common in mechanically ventilated patients receiving sedatives, opiates and/or catecholamines. Data suggest that bowel sounds may be decreased or absent in half of the patients in the intensive care.[4-6,15] There are contradictory data in the literature about what constitutes normal bowel sounds; however, what is consistent throughout is the reported abnormality of a complete lack of bowel sounds. Auscultation for bowel sounds is routinely performed in the ICU and a well-established part of the physical examination in patients with suspected ileus,[16-18] while its clinical value remains largely unstudied.[19-23] In this review, the following clinical question is addressed: Does auscultation for bowel sounds help in clinical decision-making in critically ill patients with ileus?

MethodsTo identify studies and case series that report on the utility of bowel sounds in clinical decision-making in intensive care patients with ileus, we searched MEDLINE (1950 to September 2017), EMBASE (1980 to Sept 2017, ISI Web of Science (1964 to September 2017), and the Cochrane Library (2005 to September 2017). The following subheadings were used: (“intestinal obstruction” OR “bowel obstruction” OR "ileus”) AND (“auscultation” OR “bowel sounds” OR "gastrointestinal motility” OR “peristalsis” OR “diagnosis” OR “ICU” OR “critically ill”). Two authors independently reviewed the titles and abstracts yielded by this comprehensive search. All titles and abstracts were screened to identify manuscripts for eligibility. Based on the initial screening, selected full-text articles were obtained for second stage screening of the whole article. Randomised controlled trials, prospective and retrospective cohorts and case series were all eligible for inclusion, irrespective of publication status, date of publication and blinding status. Language was limited to English. Quality assessment was done with the methodological index for non-randomised studies (MINORS) checklist.[24]

Results The search yielded 947 articles. After elimination of irrelevant titles and duplicates, 172 abstracts were evaluated. A total of 21 publications were retrieved for further assessment and finally seven full-text articles were included in the results section of this review. There were no systematic reviews or meta-analyses of randomised controlled trials on this topic.

Accuracy and variability in assessment of bowel sounds in bowel obstruction, healthy controls and in postoperative ileusOnly two studies have determined whether an accurate diagnosis of mechanical small bowel obstruction, postoperative ileus and normal intestinal motility can be made based on bowel sound characteristics (table 1).[25,26] Bowel sounds were recorded for 30 seconds using an electronic stethoscope and were randomly replayed to clinicians of the departments of internal medicine and surgery without providing any clinical information. The clinicians were instructed to categorise the patient recordings as small bowel obstruction, ileus or normal. The study by Gu et al. determined the accuracy of bowel sounds in 9 patients with small bowel obstruction, 7 patients with ileus and 10 healthy volunteers.[25] Recordings of patients with obstructive ileus were correctly labelled in only 42%. However, recordings of healthy volunteers and those of patients with ileus yielded a sensitivity of 78% and 84% respectively. If the physician believed she or he was hearing a bowel obstruction, this had a positive predictive value (PPV) of 72%, while for ileus and normal intestinal motility the PPV was 93% and 54% respectively. The inter-observer agreement was moderate (kappa value 0.57). The subsequent study by Felder et al. was a more elaborate reproduction of the earlier published study by Gu et al. with similar results, but also included the level of training of the clinicians.[26] The study cohort consisted of recordings of bowel sounds of 19 patients with mechanical small bowel obstruction, 156 patients with postoperative ileus and 177 healthy volunteers. A total of 45 recordings were played consecutively to physicians, with 15 of the recordings duplicated. Over 78% of the recordings of

Table 1. Accuracy and inter/intra-observer variability in bowel obstruction, ileus and healthy volunteers

Author Design & MI-NORS score

Patients Outcome Results (%) Limitations

Gu, 2010 [25] Prospective13

A: Healthy volunteersB: Intestinal obstructionC: Postoperative ileus

Correct classification of bowel sounds: Sensitivity/PPV

A: 78/54B: 42/72C: 84/93

- Electronic recordings- Patient characteristics unknown- Small selection of bowel recordings

Felder, 2014 [26] Prospective20

A: Healthy volunteersB: Intestinal obstructionC: Postoperative ileus

Correct classification of bowel sounds & reliability:Sensitivity/PPV /intra-observer reliability

A: 32/23/59B: 22/28/52C: 22/44/53

- Electronic recordings

Breum, 2015 [28] Prospective19

Patients with clinically suspected bowel obstruction:A: Intestinal obstruction (n=37) B: Without obstruction (n=61)

Sensitivity, specificity, PPV and NPV of pathological bowel sounds with respect to intestinal obstruction & Inter-observer agreement (median kappa (κ)-value)

- Sens.: 42- Spec.: 78- PPV: 48- NPV: 76 - κ-value: 0.29 (low)

- Shorter duration of electronic recordings (25 seconds)

PPV = positive predictive value, NPV = negative predictive value; MINORS = methodological index for non-randomised studies score. The global ideal score is 24: 12 items are scored 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate)[24]

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obstructive ileus were incorrectly labelled and not recognised as obstructive ileus, yielding a sensitivity of less than 22%. Recordings of healthy volunteers and those of patients with postoperative ileus yielded a sensitivity of just 32% and 22%, respectively. The PPV of bowel obstruction recordings was 28% and for normal and postoperative ileus recordings 23% and 44% respectively. This indicates that when a clinician judged the recording to match obstructive ileus, this was actually true in only 28% of cases. Auditory characteristics (tinkling, high pitched and rushes) in each bowel sound category were highly variable. Of all physicians, 58% reported tinkling as normal bowel sounds. However, high-pitched sounds and rushes, characteristics often associated with small bowel obstruction, were reported in 23% to 73% of normal bowel sounds recordings. High-pitched sounds and rushes were reported to be heard less frequently in the obstructed recordings, 28% and 23%, respectively, than in the normal recordings, 60% and 46%, respectively. For the postoperative ileus recordings, clinicians reported hearing tinkling, high-pitched sounds or rushes approximately one-third of the time. The intra-observer reliability for normal bowel sounds was 59%, for obstructive ileus recordings 51% and for postoperative ileus 56%. The overall intra-observer reliability of duplicated recordings was only 54%.The question remains whether physicians are able to determine by stethoscope whether bowel sounds are normal in their patients suspected of bowel obstruction. Durup-Dickenson et al. assessed inter- and intra-observer agreement in physicians' evaluation of quantity, volume and pitch of bowel sounds. A total of 100 physicians were presented with 20 bowel sound recordings in a blinded set-up. The recordings had been made in healthy volunteers and patients in the emergency department presenting with peritonitis or bowel obstruction. Inter-observer agreement regarding pitch, intensity and quantity yielded κ-values of 0.19, 0.30 and 0.24 (p<0.0001), respectively, corresponding to slight, fair and fair agreement. With regard to the intra-observer agreement, the probability of agreement was only 0.55, 0.45 and 0.41 for pitch, intensity and quantity respectively, which approximates flipping a coin.[20] Hyperactive bowel sounds were thought to be useful in diagnosing obstructive ileus, as suggested by a cohort study performed by Bohner et al. in patients presenting with abdominal pain lasting less than seven days, and with no history of abdominal injury including surgery.[27] Investigating which data from history and physical examination may help to exclude bowel obstruction and thereby avoid the additional request of abdominal radiographs, they found that ‘increased’ bowel sounds was one of the six variables with the highest sensitivity to exclude bowel obstruction. However, a more recent study investigating the accuracy of bowel sounds to diagnose obstructive ileus was performed by Breum et al., in which 53 physicians listened to electronically recorded bowel sounds from 98 patients admitted with clinically suspected

intestinal obstruction. A low accuracy and low inter-observer-agreement for bowel obstruction was found.[28] Moreover, using a simulation model, Mehmood et al. found that healthcare professionals of the internal medicine department and the ICU had a correct detection rate of hyperdynamic bowel sounds of 50%.[29]

Relationship between bowel sounds and intestinal transit The presence of audible peristalsis as a sign of intestinal contraction is routinely used in postoperative patients. However, until recently it was not known whether this actually correlates with effective intestinal transit.[30,31] Intestinal transit was analysed by scintigraphy in 60 patients to determine which clinical symptoms best reflect postoperative intestinal motility.[13] Postoperative defecation together with tolerance of solid food proved to be the best clinical composite endpoint of postoperative ileus. This was in accordance with a recent systematic review determining the best clinical endpoint for postoperative ileus.[32] Strikingly, seven patients had developed a major postoperative complication, with paralytic ileus requiring a nasogastric tube. In these patients, the indium-111 tracer had not reached the colon at day 2, demonstrating no significant intestinal propulsive activity. Interestingly, in six out of these seven patients with a paralytic ileus, there was still presence of audible peristalsis (table 2).[33] These data indicate that the reported absence of audible peristalsis poorly reflects postoperative dysmotility.

Discussion There are practical difficulties in determining whether bowel sounds are hyperactive, hypoactive or truly absent, considering that normal bowel sounds occur intermittently between 5 and 35 times a minute in an irregular pattern.[34-37] The minimum amount of time to auscultate before concluding that no bowel sounds are present varied from 30 seconds to 7 minutes, with most authors advising practitioners to auscultate for at least 5 minutes if no sounds are heard initially.[35,38-41] In addition, bowel sounds demonstrate a large variation in sound distribution and

Table 2. Auscultation for the presence of bowel sounds audible peristalsis in relation with intestinal transit

Postoperative day 2 Auscultation of bowel sounds n =

No Yes

GC = 0 (paralytic ileus) 1 6 7

GC < 2 (no recovery of colonic transit)

0 41 41

GC ≥ 2 (recovery of colonic transit)

1 11 12

In the patients without ileus, the recovery of colonic transit (defined as geometrical centre (GC) of radioactivity ≥ 2) was significantly correlated with clinical recovery[33]

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intensity in healthy subjects. Along with this, the terminology commonly used for normal and pathological bowel sounds is variable and the labelling of bowel sounds is often subjective.[17] Thereby, the diagnostic ability of bowel sounds to discern normal and pathological conditions is not well characterised, and aberrant bowel sounds may be of limited value for the diagnosis of small bowel obstruction.[42] Despite these issues, bowel sounds are claimed to help us develop our differential diagnosis.[16,35,36,39-41,43] However, for a diagnostic test to be of value, it not only has to be well interpretable and accurate but, most importantly, also reproducible.[23] In the study by Felder et al. the intra-observer reliability for normal bowel sounds, obstructive ileus recordings and postoperative ileus was low at 50-60%.[26] This makes it unlikely that the diagnostic value of auscultation increases with the addition of patient history and physical findings. Furthermore, several studies have reported no differences between junior and senior doctors, contradicting the assumption that the diagnostic value of auscultation may be further improved by increasing systematic training.[26,28]

Previous studies have demonstrated low to moderate inter-observer agreement for bowel sounds assessment in various motility disorders.[19,20,22,25,28,44] Variation in the intensity of the volume and pitch of the sound further challenges the clinician trying to determine whether bowel sounds are overly loud or soft. A partial obstruction may provoke a hollow, very high-pitched tinkling sound as a result of liquid and gas accumulating under pressure in the dilated bowel.[41] However, there is no clear evidence that very high-pitched bowel sounds have clinical pertinence.[45]

Besides a lack of accuracy, there are specific conditions in the ICU that may further hamper the utility of auscultating bowel sounds in critical care. Contact precautions are part of the standard care in the ICU to prevent the spread of multidrug resistant bacteria from infected or colonised patients. These precautions include the use of disposable or patient-dedicated simple stethoscopes. As previously demonstrated by Mehmood et al., these low-end stethoscopes perform poorly, hampering reliable auscultation in the ICU. Physicians differ in how long they listen for bowel sounds, and they listen for a shorter time compared with nurses in the ICU. As a result, different conclusions about the presence of normal bowel sounds can be made within the same patient in the same department.[21,29]

Had abdominal auscultation not been such a cheap commonly practised investigation, it would probably not have survived in clinical practice for more than 150 years, given the very limited documentation of its clinical value.[28,46] The practice of auscultation therefore appears to be more a reflection of tradition and anecdotal evidence, and begs the question whether it may be better to abandon this routine procedure in order to avoid delayed diagnosis or even misjudgement of patients with suspected bowel obstruction.[28] We are strong

supporters of the history and physical exam and advocate for the use of hands, ears, nose and eyes to interpret the patient’s condition. However, intensivists must be progressive, embracing new modalities and letting go of less reliable methods. For example, the bedside ultrasound for the diagnosis of small bowel obstruction might be a more suitable alternative. In line with this, a recent systematic review of the diagnostic modalities used to identify bowel obstruction found ultrasound to be superior to all other modalities.[47] The lack of consensus, standardisation and evidence may encourage educators and physicians in the ICU to discuss the efficacy and utility of this manoeuvre during clinical training. Especially, in an era of expanding diagnostic possibilities,[48] the intensive care patient is more likely to benefit from abdominal imaging than auscultation if the suspicion of an ileus requiring operative intervention arises.[49]

For many years, the dogma was not to give patients any oral or enteral feeds unless bowel sounds were present. However, a number of studies have shown that ileus is not equated with intestinal failure and that bowel function and nutrient-absorbing capacity may be suppressed in patients with ileus, but are not absent.[50] Moreover, the sounds made by the bowel are evidence of contractility, not absorptive capacity or mucosal integrity. Thus, the intestine can still produce loud bowel sounds while its mucosa is eroded and denuded of villi.[51,52] In fact, the use of bowel sounds to drive any clinical decision has never been validated and nowadays guidelines support the use of early enteral nutrition, stating there is no need to wait for bowel sounds.[52,53] Moreover, the presence of bowel sounds poorly reflects postoperative dysmotility as bowel sounds are still audible in the majority of patients with a paralytic ileus. These findings are in line with a recently published prospective study in 124 adult patients undergoing major abdominal surgery. In this blinded observational study, Read et al. found no association between bowel sounds and flatus, bowel movement, or tolerance of oral intake.[54] This further underlines that clinical decisions in intensive care patients with ileus should not be based on auscultatory assessment of bowel sounds.[3,33,45]

ConclusionThe low sensitivity and positive predictive value, together with a poor inter- and intra-observer agreement, demonstrate low accuracy of utilising bowel sounds for clinical decision-making. Thereby, the diagnostic utility of auscultation in differentiating normal from pathological bowel sounds in ICU patients is useless and should be abandoned.

DisclosuresAll authors declare no conflicts of interest. No funding or financial support was received.

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3. van Bree SHW, Nemethova A, Cailotto C, Gomez-Pinilla PJ, Matteoli G, Boeckxstaens GE. New therapeutic strategies for postoperative ileus. Nat Rev Gastroenterol Hepatol. 2012;9:675-83.

4. Reintam A, Parm P, Kitus R, Kern H, Starkopf J. Gastrointestinal symptoms in intensive care patients. Acta Anaesthesiol Scand. Blackwell Publishing Ltd; 2009;53:318-24.

5. Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest. 2001;119:1222-41.

6. Mentec H, Dupont H, Bocchetti M, Cani P, Ponche F, Bleichner G. Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk factors, and complications. Crit Care Med. 2001;29:1955-61.

7. Montejo JC, Grau T, Acosta J, et al. Multicenter, prospective, randomized, single-blind study comparing the efficacy and gastrointestinal complications of early jejunal feeding with early gastric feeding in critically ill patients. Crit Care Med. 2002;30:796-800.

8. Reintam A, Parm P, Kitus R, Starkopf J, Kern H. Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care. 2008;12:R90.

9. Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units. Crit Care Med. 1999;27:1447-53.

10. Collins TC, Daley J, Henderson WH, Khuri SF. Risk factors for prolonged length of stay after major elective surgery. Ann Surg. 1999;230:251-9.

11. Hiranyakas A, Bashankaev B, Seo CJ, Khaikin M, Wexner SD. Epidemiology, pathophysiology and medical management of postoperative ileus in the elderly. Drugs Aging. 2011;28:107-18.

12. Reintam Blaser A, Malbrain MLNG, Starkopf J, et al. Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems. Intensive Care Med. 2012;38:384-94.

13. van Bree SHW, Bemelman WA, Hollmann MW, et al. Identification of clinical outcome measures for recovery of gastrointestinal motility in postoperative ileus. Ann Surg. 2014;259:708-14.

14. Reintam A, Kern H, Starkopf J. Defining gastrointestinal failure. Acta Clin Belg. 2007;62 Suppl 1:168-72.

15. Dark DS, Pingleton SK. Nonhemorrhagic gastrointestinal complications in acute respiratory failure. Crit Care Med. 1989;17:755-8.

16. Li B, Tang S, Ma Y-L, Tang J, Wang B, Wang J-R. Analysis of bowel sounds application status for gastrointestinal function monitoring in the intensive care unit. Crit Care Nurs Q. 2014;37:199-206.

17. De Dombal F. The physical examination revisited. Diagnosis of acute abdominal pain. 2nd ed. Churchill Livingstone; 1991. p. 47-62.

18. Reintam Blaser A, Starkopf J, Malbrain MLNG. Abdominal signs and symptoms in intensive care patients. Anaesthesiol Intensive Ther. 2015;47:379-87.

19. Bjerregaard B, Brynitz S, Holst-Christensen J, et al. The reliability of medical history and physical examination in patients with acute abdominal pain. Methods Arch. 1983;22:15-8.

20. Durup-Dickenson M, Christensen MK, Gade J. Abdominal auscultation does not provide clear clinical diagnoses. Dan Med J. 2013;60:A4620.

21. Baid H. A critical review of auscultating bowel sounds. Br J Nurs. 2009;18:1125-9. 22. Gade J, Kruse P, Andersen OT, Pedersen SB, Boesby S. Physicians’ abdominal

auscultation. A multi-rater agreement study. Scand J Gastroenterol. 1998;33:773-7. 23. Sackett D. Clinical epidemiology. A basic science for clinical medicine. 2nd ed.

Lippincott Williams and Wilkins; 1991. p. 52-8. 24. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological

index for non-randomized studies (MINORS): development and validation of a new instrument. ANZ J Surg. 2003;73:712-6.

25. Gu Y, Lim HJ, Moser MAJ. How useful are bowel sounds in assessing the abdomen? Dig Surg. 2010;27:422-6.

26. Felder S, Margel D, Murrell Z, Fleshner P. Utility of bowel sound auscultation: a prospective evaluation. J Surg Educ. 2014;71:768-73.

27. Böhner H, Yang Q, Franke C, Verreet PR, Ohmann C. Simple data from history and physical examination help to exclude bowel obstruction and to avoid radiographic studies in patients with acute abdominal pain. Eur J Surg. 1998;164:777-84.

28. Breum BM, Rud B, Kirkegaard T, Nordentoft T. Accuracy of abdominal auscultation for bowel obstruction. World J Gastroenterol. 2015;21:10018-24.

29. Mehmood M, Abu Grara HL, Stewart JS, Khasawneh FA. Comparing the auscultatory accuracy of health care professionals using three different brands of stethoscopes on a simulator. Med Devices (Auckl). 2014;7:273-81.

30. Maffezzini M, Campodonico F, Canepa G, Gerbi G, Parodi D. Current perioperative management of radical cystectomy with intestinal urinary reconstruction for muscle-invasive bladder cancer and reduction of the incidence of postoperative ileus. Surg Oncol. 2008;17:41-8.

31. Bungard TJ, Kale-Pradhan PB. Prokinetic agents for the treatment of postoperative ileus in adults: a review of the literature. Pharmacotherapy. 1999;19:416-23.

32. Wu Z, Boersema GSA, Dereci A, Menon AG, Jeekel J, Lange JF. Clinical endpoint, early detection, and differential diagnosis of postoperative ileus: a systematic review of the literature. Eur Surg Res. 2015;54:127-38.

33. van Bree, Sjoerd HW, Bemelman W, et al. Auscultation of bowel sounds to assess intestinal motility? In: Poster 0198. 2015. p. Neurogastro 2015, European Society of NeuroGastroenterology.

34. Rhoads J. Advanced Health Assessment and Diagnostic Reasoning. Philadelphia: Lippincott Williams & Wilkins; 2006.

35. Seidel, HM, Ball JW, Dains, JE, Benedict G. Mosby’s Guide to Physical Examination. 6th edn. St Louis: Mosby Elsevier; 2006.

36. Bickley, LS. Szilagyi P. Bates’ Guide to Physical Examination and History Taking. 10th edn. Philadelphia: Lippincott Williams & Wilkins; 2009.

37. Kahan S, Miller R, Smith E. In a Page: Signs and Symptoms. 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 2009.

38. Smith C. Assessing bowel sounds - more than just listening. Nursing (Lond). 1988;18:42-3.

39. Estes M. Health Assessment and Physical Examination. 3rd edn. Clifton Park, New York: Thomson Delmar Learning; 2006.

40. Jarvis C. Physical Examination and Health Assessment. 5th edn. St Louis: Saunders Elsevier; 2008.

41. Epstein O, Perkin, GD. Cookson J. Clinical Examination. The abdomen. 4th edn. Edinburgh: Mosby Elsevier; 2008. p.186-225.

42. Ching SS, Tan YK. Spectral analysis of bowel sounds in intestinal obstruction using an electronic stethoscope. World J Gastroenterol. 2012;18:4585-92.

43. Khan KS, Bachmann LM, ter Riet G. Systematic reviews with individual patient data meta-analysis to evaluate diagnostic tests. Eur J Obstet Gynecol Reprod Biol. 2003;108:121-5.

44. Yen K, Karpas A, Pinkerton HJ, Gorelick MH. Interexaminer reliability in physical examination of pediatric patients with abdominal pain. Arch Pediatr Adolesc Med. 2005;159:373-6.

45. Moll van Charante EP, de Jongh TOH. [Physical examination of patients with acute abdominal pain]. Ned Tijdschr Geneeskd. 2011;155:A2658.

46. Hooker C. An Essay on Intestinal Auscultation. Bost Med Surg J. 1849;1439-40. 47. Taylor MR, Lalani N. Adult Small Bowel Obstruction. Carpenter CR, editor. Acad

Emerg Med. 2013;20:527-44. 48. Godfrey A. Listening to Bowel Sounds: An Outdated Practice? https://blogs.

jwatch.org/frontlines-clinical-medicine/2017/03/01/listening-bowel-sounds-outdated-practice

49. Rami Reddy SR, Cappell MS. A Systematic Review of the Clinical Presentation, Diagnosis, and Treatment of Small Bowel Obstruction. Curr Gastroenterol Rep. 2017;24;19:28.

50. McCarter MD, Gomez ME, Daly JM. Early postoperative enteral feeding following major upper gastrointestinal surgery. J Gastrointest Surg. 1:278-85; discussion 285.

51. Deranged Physiology [Internet]. http://www.derangedphysiology.com/main/required-reading/endocrinology-metabolism-and-nutrition/Chapter 5.1.1.3/when-and-how-start-enteral-nutrition

52. Heighes PT, Doig GS, Simpson F. “Timing and Indications for Enteral Nutrition in the Critically Ill.” Nutrition. Springer International Publishing, 2016.; p.55-62.

53. Farkas J. PulmCrit- New guidelines simplify ICU nutrition [Internet]. Available from: https://emcrit.org/pulmcrit/enteral-nutrition-intubated/

54. Read TE, Brozovich M, Andujar JE, Ricciardi R, Caushaj PF. Bowel Sounds Are Not Associated With Flatus, Bowel Movement, or Tolerance of Oral Intake in Patients After Major Abdominal Surgery. Dis Colon Rectum. 2017;60:608-13.

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Submitted August 2017; Accepted November 2017

C A S E R E P O R T

Clostridium perfringens: a rare cause of postoperative septic shock

B.B.M. van der Woude1, J. Berkhout2, J.P. van Basten3, J. Schouten4

Departments of 1Emergency Medicine, 2Medical Microbiology and Infectious Diseases, 3Urology and 4Intensive Care Medicine, Canisius

Wilhelmina Hospital, Nijmegen, the Netherlands

Correspondence

B.B.M. van der Woude – [email protected]

Keywords - clostridium perfringens, laparoscopic nephrectomy, septic shock

AbstractPostoperative infections with Clostridium perfringens are rare. We report a case of a 59-year-old male, admitted to our ICU for postoperative monitoring after an elective retroperitoneoscopic radical nephrectomy. This patient developed septic shock within 22 hours after laparoscopic surgery. Due to clinical deterioration, he was intubated and taken to the operating room, after a CT scan was performed. Surgery revealed an infected retroperitoneal haematoma, which was drained. Cultures identified C. perfringens as the causative pathogen. Postoperative C. perfringens infection is potentially life-threatening and rapid antibiotic treatment and surgical drainage play a pivotal role in its management.

IntroductionPostoperative infections with Clostridium perfringens are rare but have been reported.[1-4] C. perfringens is an anaerobic, spore forming, Gram-positive rod,[5] present in nature and often found as a normal component of the human intestinal flora. It has an optimal growing temperature of 37 ºC. It is the main cause of clostridial myonecrosis after traumatic injury, an acute and very painful infection in which muscles and subcutaneous tissues become filled with gas and exudate. Occasionally, this clinical picture can be caused by other Clostridial subtypes as well (C. novyi, C. septicum, C. histolyticum, C. bifermentans and C. fallax). Clostridial myonecrosis is more commonly known as gas gangrene. Gas gangrene is a key symptom and is easily confused with the usual intraoperative gas used during laparoscopic surgery. It is of the utmost importance to consider C. perfringens in a patient with fulminant septic shock and intraperitoneal and/or retroperitoneal gas post laparoscopic surgery, because patients may die before the diagnosis of gas gangrene has been made. To our knowledge, we present the first case of C. perfringens infection after a retroperitoneoscopic radical nephrectomy.

Case reportOur 59-year-old patient was admitted to our ICU after left-sided retroperitoneoscopic nephrectomy. Surgery was indicated because of suspected renal cell carcinoma. Past medical history of this patient includes: right-sided nephron-urethrectomy due to urothelial cell carcinoma and chronic intermittent haemodialysis, diabetes and morbid obesity. To remove the specimen at the end of the surgical procedure, a lumbotomy was performed. No perioperative antibiotic prophylaxis was given. The surgical procedure was uncomplicated so far and the patient was extubated in the operating room, prior to transfer to the ICU. On admission to the ICU, the only symptoms were local postoperative pain and hypotension (80/40 mmHg). This low blood pressure was within the normal range for this patient and had frequently been reported prior to haemodialysis sessions. Approximately 20 hours after arrival on the ICU, he developed progressive local pain, fever, chills and bruise-like coloration of the skin. The blood pressure dropped further, and the patient became unresponsive. Physical examination revealed subcutaneous emphysema in the left flank. Noradrenaline was started through a central line, empirical antibiotic therapy (piperacillin/tazobactam 4500 mg 3 times daily) was commenced and one dose of gentamycin (6 mg per kg) was administered. Hydrocortisone (100 mg 3 times daily) was added because of the septic shock. Blood cultures were drawn before starting antibiotic therapy. The patient was intubated later that day.

A CT scan (figure 1) was performed and confirmed subcutaneous emphysema in the left flank. Furthermore, free air was seen in the intra-abdominal and left renal fossa space, with some fluid, but no signs of an abscess. The subcutaneous emphysema and intraperitoneal and retroperitoneal air were interpreted as post laparoscopic surgery. After consulting with the urologist,

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Figure 1. Coronal (left) and axial view of the first CT abdomen.

Subcutaneous and free intra-abdominal air is indicated by green arrows.

we chose to manage this patient conservatively. During the following hours, however, further clinical deterioration was noted. Laboratory analysis revealed a CRP of 458 mg/l (144 mg/l, 24 hours earlier) and a lactate of 3.9 mmol/l. The patient was then taken to the operating room (approximately 48 hours after the first surgical intervention) for surgical exploration of the wound. During surgery, an infected deep wound haematoma was found and drained. Intraperitoneal exploration revealed no signs of bowel perforation. The wound was closed leaving two drains and the patient was transferred back to the ICU. During the next 48 hours, the results of cultures (retroperitoneal fluid and tissue, separate cultures) were reported positive for C. perfringens (as determined by MALDI-TOF-MS). Repeated blood cultures remained negative. The drains were removed after two days because of no drainage. Piperacillin/tazobactam was continued for six consecutive days. Five days post-surgery, the patient developed worsening pain in his left flank and his recovery stagnated. A repeated CT scan revealed fluid in the nephrectomy area, the wound was – again – surgically drained. A new drain was placed, but fell out spontaneously the day after. From the second operation on, the patient steadily recovered. We started piperacillin/tazobactam per protocol (this is our hospital’s protocol in abdominal sepsis without positive cultures). Susceptibility testing revealed C. perfringens which was sensitive to piperacillin/tazobactam, so we chose to continue this treatment. Pathology of the renal specimen revealed multiple benign cysts, without signs of carcinoma. Negative pressure wound therapy was started in order to improve wound healing because the past medical history included multiple factors that might restrict wound healing, for example: obesity, diabetes etc. The patient was discharged to the urology ward 11 days after admission to the ICU.

DiscussionOur case illustrates a fulminant septic shock due to a postoperative infection with C. perfringens. After C. perfringens enters the body (in our case, most likely via the surgical site), the usual manifestation is a necrotising infection of the abdominal wall, often accompanied by hypotension and renal failure due to septic shock.

C. perfringens consists of five serotypes, A-E. They differ in the types of extracellular toxins they make and their form of tropism. Alpha toxin is a haemolytic toxin which is largely responsible for the tissue necrosis. Under optimal conditions for the bacterium, its multiplying time is as little as eight minutes and is accompanied by gas production. This is the reason why the progression of the infection is so fulminant. Because C. perfringens is an anaerobic bacterium, blood supply must be impaired in some way in order for it to thrive. When the ability of the host to mount an inflammatory response involving phagocytes is not suppressed, infection with C. perfringens may progress into a fulminant septic shock.

Most cases of gas gangrene arise after penetrating trauma and therefore it is often considered to be a typical military disease: during World War I an estimated 10% of soldiers lost their lives as a direct result.[6] Postoperative complications account for approximately 30% of the cases and are most frequently associated with surgery to the appendix, intestine or biliary tract. Known risk factors include: diabetes, coronary artery disease, obesity, malnutrition and intravenous drug use.[1] It seems difficult to determine the incidence of the disease;[7] however, when haemolysis occurs, mortality rates are as high as 70%.[8] Since C. perfringens has the ability to spread very fast, it is of the utmost importance to recognise and treat early. This provides the patient the best chance of recovery.

Harmsen et al.[1] described a case of postoperative infection with C. perfringens after laparoscopic cholecystectomy. They report that trocar port infections are rare, only nine cases were reported until 2016. Trocar port wounds are considered ideal sites for infections. A penetrating wound is made, CO2 is insufflated for creating a pneumoperitoneum. This positive intra-abdominal pressure (12-15 mmHg) and continuous CO2 flow reduces blood flow in the abdominal wall, making it relatively hypoxic. Trocars damage the abdominal muscles, and cause a ‘chimney effect’[9] (gas passing alongside the trocars, leaving the body), by leakage of CO2 from the abdominal cavity into the subcutis. This results in subcutaneous emphysema with an environment in which anaerobic bacteria might thrive easily. A trocar infection may have been present in this case. One of the clinical dilemmas we encountered in this case was to evaluate whether the amount of gas, as visualised by a CT scan, was within the ‘normal range’ for the given time post-laparoscopic surgery. To our knowledge, there are no studies or guidelines elucidating this issue. During retroperitoneoscopic surgery about 3 litres of CO2 are insufflated in the retroperitoneal space. If there happens to be a tear in the peritoneal membrane, this amount easily doubles.[10] The total amount of CO2 used during surgery depends on the duration and leakage alongside the trocars. Within 72 hours post-surgery, the CO2 has usually resolved. Visible intraperitoneal or retroperitoneal gas 72 hours after surgery is considered an ominous finding.

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Conclusion When a patient rapidly develops severe abdominal septic shock following laparoscopic surgery, and subcutaneous emphysema and intra-abdominal air are present, gas gangrene must be considered. These signs should not always easily be attributed to peroperative carbon dioxide insufflation. The treatment of choice for C. perfringens infection is surgical debridement of all involved gangrenous tissue, intravenously administered high-dose penicillin, combined with clindamycin[11] and supportive measures. This approach might provide the patient with a better chance for survival.

AcknowledgementsWe thank Dr. R.O.A. van Os, radiologist, for providing the scan images.

Disclosures All authors declare no conflict of interest. No funding or financial support was received.

References

1. Harmsen AMK, van Tol E, Giannakopoulos GF, de Brauw LM. Clostridial Gas Gangrene of the Abdominal Wall After Laparoscopic Cholecystectomy: A Case Report and Review. Surg Laparosc Endosc Percutan Tech. 2016;26:278-81.

2. Carbonetti F, Cremona A, Guidi M, Carusi V. A case of postsurgical necrotizing fasciitis invading the rectus abdominis muscle and review of the literature. Case Rep Med. 2014;2014:479057.

3. Mihaylov P, Powelson JA, Goggins WC. Fulminant Clostridium perfringens Sepsis in Kidney Transplant: A Case Report. Transplant Proc. 2016;48:3112-4.

4. van Bunderen CC, Bomers MK, Wesdorp E, Peerbooms P, Veenstra J. Clostridium perfringens septicaemia with massive intravascular haemolysis: A case report and review of the literature. Neth J Med. 2010;68:343-6.

5. Murray PR, Baron EJ, Jorgensen JA, et al. Manual of Clinical Microbiology, 11th Edition. Washington: ASM Press; 2015.

6. Pailler JL, Labeeu F. Gas gangrene: a military disease? Acta Chir Belg. 1986;86:63-71. 7. Titball RW. Gas gangrene: An open and closed case. Microbiology. 2005;151:2821-8. 8. Simon TG, Bradley J, Jones A, Carino G. Massive Intravascular Hemolysis From

Clostridium perfringens Septicemia. J Intensive Care Med. 2014;29:327-33. 9. Ba MC, Long H, Zhang XL, et al. Port-site metastases and chimney effect of

B-ultrasound-guided and laparoscopically-assisted hyperthermic intraperitoneal perfusion chemotherapy. Yonsei Med J. 2017;58:497-504.

10. van Basten, JP, Tuut M. Recommendations in laparoscopic and robotic surgery. Dutch Urological Association; 2017.

11. Stevens DL, Bisno AL, Chambers HF, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections : 2014 Update by the Infectious Diseases Society of America. 2017;59 (September).

CURS

US

CURS

US

CURS

US

CURS

US

www.nvic.nl

Woensdag 14 november en donderdag 15 november 2018

Luchtwegmanagement op IC

Hotel Houten / OSGHouten

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Submitted October 2017; Accepted December 2017

C A S E R E P O R T

Severe pulmonary involvement in a case of drug reaction with eosinophilia and systemic symptoms (DRESS)

E. Bruwiere1, N. Janssen2, S. van Santen1* Department of 1Intensive Care and 2Infectiology, Radboud University Medical Centre, Nijmegen, the Netherlands

*current address: Maastricht University Medical Centre, Maastricht, the Netherlands

Correspondence

S. van Santen - [email protected]

Keywords - drug reaction with eosinophilia and systemic symptoms (DRESS), shock, acute respiratory distress syndrome (ARDS), intensive care unit, multi-organ failure

AbstractDrug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, but potentially lethal disorder characterised by fever, exanthema and systemic organ involvement. We present a young woman with a complex medical history, including endocarditis and DRESS, suffering from fever for which antibiotics were prescribed. After initial recovery the fever returned, along with a rash. Her condition progressively deteriorated into shock, requiring ICU admission. Soon after, an acute respiratory distress syndrome (ARDS) evolved, which called for mechanical ventilation with deep sedation and prone positioning. After extensive investigations excluding most autoimmune, infectious and haematological aetiologies, DRESS was considered. Antibiotics were withdrawn and prednisone treatment was started after which the patient eventually recovered.This case demonstrates the importance for intensivists to recognise DRESS, a potentially life-threatening syndrome, in patients with shock and multi-organ failure, due to its non-infectious process. Awareness is pivotal to discontinuing the causative drugs.

BackgroundDRESS is the acronym for ‘drug reaction with eosinophilia and systemic symptoms’ and is also known as a drug-induced hypersensitivity syndrome (DIHS).[1] DRESS/ DIHS (further denoted as DRESS) belongs to a family of severe cutaneous drug reactions, together with Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN) and acute generalised exanthematous pustulosis (AGEP). Symptoms, including fever, enlarged lymph nodes, skin and/or internal organ involvement, mimic various systemic diseases. Exclusion of these other diseases and fulfilling the criteria of the RegiSCAR scoring system (table 1) are essential in the diagnosis of DRESS.[1,2] DRESS is rare: prevalence ranges from 1 case per 1,000 to

10,000 drug exposures. In particular, the burden of DRESS on intensive care admissions is largely unknown. However, it is important that intensivists are aware of this syndrome, as this case will demonstrate.

Case ReportA 35-year-old female presented to the emergency ward of a university hospital with fever, cold chills and tenderness in the right knee joint for three days. Almost a year before, she was admitted for four months because of pneumococcal pneumonia complicated by aortic valve endocarditis for which an aortic valve replacement had been performed. This episode was furthermore complicated by septic emboli to the brain and thoracic vertebrae and an aortic root abscess for which a Bentall procedure was needed. She received long-term antibiotic therapy. During that admission she had a drug reaction with eosinophilia and systemic symptoms for which she was successfully treated with prednisone. She was prescribed piperacillin/tazobactam, benzylpenicillin, ceftriaxone, vancomycin, diclofenac and tramadol, but careful evaluation at the allergology department could not reveal the culprit agent. Finally, she recovered completely.At the current admission, her vital signs were normal except for a low-grade fever (38.0°C) and local knee joint swelling with tenderness. Her medication was limited to acenocoumarol and acetaminophen. Empirical therapy with teicoplanin and moxifloxacin was started, aimed to cover a possible bacterial endocarditis, graft infection or arthritis (see figure 1A for an overview of antibiotic use). Knee arthrocentesis resulted in a dry tap and ultrasound of the knee was normal. Soon after admission she developed gastrointestinal symptoms, attributed to moxifloxacin which was therefore switched to ciprofloxacin.Early after administration of intravenous ciprofloxacin, however, a subtle but pruritic skin rash with a papular erythematous

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Severe pulmonary involvement with DRESS

aspect developed. Quinolones were stopped and teicoplanin was continued. Blood cultures were repetitively negative as were further investigations including cardiac ultrasound, and MRI of the knee, heart and aortic graft. An infection was thus considered unlikely and the antibiotics were stopped after six days. The skin eruptions had improved and the fever had resolved.However, nine days after admission, there was a sudden recurrence of fever, an increase in C-reactive protein, mild eosinophilia of 590 cells per µl and atypical lymphocytes on the blood smear. Meropenem was prescribed targeting a possible vascular graft infection or endocarditis, which would have been insufficiently treated in the earlier prescribed antibiotic regimen. However, the fever persisted and a few days later a new skin rash appeared with generalised erythematous eruptions on her back, torso and extremities. To cover the more resistant Gram-positive species as well, teicoplanin was added to the antibiotic regimen. At day 14 her condition, however, worsened with haemodynamic instability and respiratory distress for which she was transferred to the ICU and immediately intubated. Consistent with ARDS, severe hypoxaemia was present with a PaO2/FiO2 ratio declining under 100 mmHg, in association with the development of bilateral infiltrates (figure 1B) and normal cardiac function on echocardiography. With further respiratory deterioration, neuromuscular blockade and prone positioning was required after lung protective mechanical ventilation was set up. Concomitantly there was evidence of liver and kidney involvement with respectively elevated serum transaminases and creatinine, although the latter developed after ICU admission and could just as well be secondary to the patient’s state of shock. Our differential diagnosis was broad and included ARDS due to recurrent endocarditis with septic pulmonary involvement,

a pulmonary infection or a haematological or autoimmune disease. PET-CT scan showed bilateral pulmonary opacities and widespread lymphadenopathy, but no signs of graft infection (figure 1B). Pathological examination of bone marrow and lymph node ruled out haemophagocytic lymphohistiocytosis and lymphoma. Cultures and microbial testing of blood and bronchoalveolar lavage, including a viral panel, Pneumocystis jiroveci and Aspergillus were negative. In addition, no herpes viruses were detected and autoimmune serology was also negative, making an autoimmune disease unlikely.Because of the continuing deterioration under antibiotic treatment DRESS was considered and rated as a ‘definite case’ in compliance with the RegiSCAR criteria (table 1) as a diagnosis by exclusion.[1,2] All antibiotics were discontinued and prednisone treatment was started at 1 mg/kg, resulting in a gradual recovery. Extubation followed after 12 days of mechanical ventilation and eventually our patient was discharged to a rehabilitation clinic with a tapering prednisone regimen. Six months after the initial presentation she returned home. Follow-up in the outpatient clinic again included evaluation of the possible culprit drug which was thought to be teicoplanin. However, she received a relative contraindication for beta-lactam antibiotics in the future as well.

DiscussionWe present a young woman who was admitted to the ICU with multi-organ failure and severe ARDS as manifestations of DRESS. This diagnosis was supported by negative test results for infectious, haematological or autoimmune disease in combination with the ‘definite’ categorisation according to the RegiSCAR criteria (table 1). In addition, her gradual recovery after withdrawal of all antibiotics and initiation of prednisone

Figure 1A. Outline of medication use in relation to symptoms. Schematic representation of medication use in relation to fever (°C), extension of rash and U: ICU admission, V: prone positioning and W: extubation during current admission.

Figure 1B. Radiological and nuclear imaging studies. X: Chest X-ray at admission (1) and at the time of intubation showing bilateral diffuse consolidations. (2). Y: PET-CT of multiple enlarged lymph nodes suggesting widespread adenopathy. Z: CT thorax at intubation showing bilateral dense consolidations merging in peripheral groundglass opacifications suggestive of (early) ARDS.

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therapy favoured the diagnosis of DRESS. This is one of the few reports linking DRESS with ARDS (search on Medline and PubMed with search criteria “DRESS,” “drug reaction with eosinophilia and systemic symptoms,” “DIHS,” “drug-induced hypersensitity syndrome,” “drug induced ARDS,” “drug pulmonary involvement,” “drug hypersensitivity lung” and “drug hypersensitivity pulmonary”).Awareness is critical as DRESS is potentially life threatening but, as this case demonstrates, it may often go unrecognised for several reasons: symptoms are non-specific, it is a diagnosis by exclusion requiring expert-based criteria and the time of dosage to symptoms may vary greatly.[1] Symptoms may occur 2-6 weeks after prescription of the culprit drug, or in hours to days in case of a rechallenge.[2] Based on the temporal relationship between the onset of symptoms and the initiation of the drug (figure 1A), the glycopeptide and quinolone antibiotics could have been the culprit drug. Quinolone antibiotics, however, have not been reported to cause DRESS,[1] although they have been implicated in SJS/TEN and AGEP.[2]

It is thus reasonable to specify only teicoplanin as the culprit agent. DRESS due to a combination of vancomycin and teicoplanin has recently been described by Miyazu et al.[3] The possibility of the patient’s initial presentation being a relapse of the previous episode of DRESS a year before was considered, but could not be proven since the criteria (table 1) were not met at that time. In the last eight months there had been no other drug exposure, including possible over-the-counter drugs, than acenocoumarol and acetaminophen making the initial phase as a prodromal stage of DRESS unlikely as well. However amoxicillin-induced flares have been reported, implying a relative contraindication for beta-lactam antibiotics in patients with DRESS.[4]

In general, severe cutaneous drug reactions are elicited by excessive or inappropriate activation of an immune response, due to the binding of foreign antigens (i.e. the drug) to T- cell receptors.[5] This leads to a dramatic expansion of functional T-lymphocytes and the appearance of autoantibodies to various epidermal proteins. This drug-specific T-cell proliferation may have an important role in the known association with reactivation of latent human herpesvirus (HHV) 6, and to lesser extent with HHV7, Epstein-Barr virus and Cytomegalovirus reactivation.[1,3,5,6]

Pulmonary involvement in drug reactions is well known and characterised by pulmonary oedema and interstitial lung disease, and rarely with a severe presentation consistent with ARDS at the extremity of the spectrum of pulmonary involvement.[7,8]

Data regarding the course and outcome of patients with severe DRESS admitted to the ICU are limited to one retrospective study in 23 French ICUs.[9] The researchers identified 21 patients with a probable or definite diagnosis of DRESS in ten years’ time (based on the RegiSCAR score, table 1). All had fever and erythematous exanthema (part of database search criteria);

more than half were associated with shock (15/21), acute renal failure (18/21), mechanical ventilation (13/21; no information about ARDS diagnosis in this population) and acute hepatitis (11/21). The disease severity of this highly restricted population selection is further demonstrated by a mortality rate of almost 50%.[9] DRESS is rare, but the low incidence may be explained by underreporting or unawareness of the syndrome with diagnostic hallmarks such as fever, eosinophilia, generalised rash with typical mucosal involvement, and multi-organ involvement. Nevertheless, the high mortality compatible with severe shock and multi-organ failure emphasises the importance for intensive care physicians to consider DRESS in their differential diagnosis. This is imperative, as early recognition with prompt withdrawal of the culprit drug to stop the harmful exposure is considered the key treatment. In addition, corticosteroids are advised, but future studies are needed to explore their role in the treatment of DRESS.[1]

ConclusionThis case demonstrates that intensive care physicians should include DRESS in their differential diagnosis of ARDS in patients with a distributive shock accompanied by systemic symptoms without evidence of definite aetiology. This is important as it has treatment implications, namely the withdrawal of the possible causative agent. Thus earlier recognition implies shorter exposure. It is possible that this could have led to a shortened period of mechanical ventilation and haemodynamic

Table 1. The RegiSCAR group diagnosis score for drug reaction with eosinophilia and systemic symptoms (DRESS)[1,2]

No Yes Unknown Case

Fever (≥38.5°C) -1 0 -1 0

Enlarged lymph nodes (≥2 sites, >1 cm) 0 1 0 1a

Atypical lymphocytes 0 1 0 1

Eosinophilia 700-1499x109/l or 10-19.9% ≥1500 x109/l or ≥50%

012

0 0

Skin rash Extent >50% At least 2 of: oedema, infiltration, purpura, scaling Biopsy suggesting DRESS

00-1-1

110

0000

0100b

Internal organ involvement One 2 or more

012

0

2c

Resolution in >15 daysAt least 3 biological investigations done and negative to exclude alternative diagnosis

-10

01

-10

01

A schematic scoring system to grade the possibility of DRESS: <2 no case; 2-3 possible case; 4-5 probable case; > 5 definite case.[1,2] The last column represents the scoring for our patient, 6 points in totala Generalised lymphadenopathy on computed tomography (CT), see

also figure 1 b Biopsy of the skin was not performedc Including pulmonary, hepatic and possibly renal involvement, although this could also be secondary to shock

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instability; however, this is mere speculation. Nonetheless, our patient recovered and at present, six months after the initial presentation, has finished her rehabilitation. She has received a list of contraindicated medications with high and intermediate probability of eliciting a severe drug reaction.

DisclosuresAll authors declare no conflicts of interest. No funding or financial support was received.

References

1. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588-97.

2. Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169:1071-80.

3. Miyazu D, Kodama N, Yamashita D, et al. DRESS syndrome caused by cross-reactivity between vancomycin and subsequent teicoplanin administration: A Case Report. Am J Case Rep. 2016;17:625-31.

4. Mardivirin L, Valeyrie-Allanore L, Branlant-Redon E, et al. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro. Eur J Dermatol. 2010;20:68-73.

5. Descamps V, Valance A, Edlinger C, et al. Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch dermatol. 2001;137:301-4.

6. Yoshikawa T, Fujita A, Yagami A, et al. Human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug-induced hypersensitivity syndrome. Clin Diagn Virol. 2006;37 Suppl 1:S92-6.

7. Schwaiblmair M, Behr W, Haeckel T, Markl B, Foerg W, Berghaus T. Drug induced interstitial lung disease. Open Respir Med J. 2012;6:63-74.

8. Camus PH, Foucher P, Bonniaud PH, Ask K. Drug-induced infiltrative lung disease. Eur Respir J Suppl. 2001;32:93s-100s.

9. Kimmoun A, Dubois E, Perez P, Barbaud A, Levy B. Shock state: an unrecognized and underestimated presentation of drug reaction with eosinophilia and systemic symptoms. Shock. 2013;40:387-91.

▼ Dit geneesmiddel is onderworpen aan aanvullende monitoring. NAAM VAN HET GENEESMIDDEL: CRESEMBA 200 mg poeder voor concentraat voor oplossing voor infusie, of CRESEMBA 100 mg harde capsules. KWALITATIEVE EN KWANTITATIEVE SAMENSTELLING: Elke fl acon bevat 200 mg isavuconazol (in de vorm van 372,6 mg isavuconazoniumsulfaat); elke capsule bevat 100 mg isavuconazol (in de vorm van 186,3 mg isavuconazoniumsulfaat). Voor de volledige lijst van hulpstoffen, zie rubriek 6.1 SPC. FARMACEUTISCHE VORM: Poeder voor concentraat voor oplossing voor infusie: wit tot geel poeder. Harde capsule: Roodbruin capsulelichaam met het getal 100 erop in zwarte inkt en een witte capsuledop met een C erop in zwarte inkt. Lengte van de capsule: 24,2 mm. KLINISCHE GEGEVENS: Therapeutische indicaties: CRESEMBA is geïndiceerd voor gebruik bij volwassenen voor de behandeling van: invasieve aspergilloses; mucormycose bij patiënten voor wie amfotericine B niet geschikt is (zie rubrieken 4.4 en 5.1 SPC). Er moet rekening gehouden worden met de offi ciële richtlijnen voor het juiste gebruik van antischimmelgeneesmiddelen. Dosering en wijze van toediening: Dosering: Infusie: Startdosering: De aanbevolen startdosering is één fl acon na reconstitutie en verdunning (equivalent aan 200 mg isavuconazol) elke 8 uur gedurende de eerste 48 uur (6 toedieningen in totaal). Onderhoudsdosering: De aanbevolen onderhoudsdosering is één fl acon na reconstitutie en verdunning (equivalent aan 200 mg isavuconazol) eenmaal daags, vanaf 12 tot 24 uur na de laatste startdosering. De duur van de behandeling moet worden vastgesteld op basis van de klinische respons (zie rubriek 5.1 SPC). Bij langdurige behandelingen die langer duren dan 6 maanden, dienen de voordelen en risico’s zorgvuldig tegen elkaar te worden afgewogen (zie rubrieken 5.1 en 5.3 SPC). Overstappen op orale toediening van isavuconazol: CRESEMBA is ook beschikbaar in harde capsules die 100 mg isavuconazol bevatten, wat equivalent is aan 186 mg isavuconazoniumsulfaat. Op basis van de hoge orale biobeschikbaarheid (98%, zie rubriek 5.2 SPC) is afwisselen van intraveneuze en orale toediening geschikt wanneer daar een klinische indicatie voor is. Orale toediening: Startdosering: De aanbevolen startdosering is twee capsules (equivalent aan 200 mg isavuconazol) elke 8 uur gedurende de eerste 48 uur (6 toedieningen in totaal). Onderhoudsdosering: De aanbevolen onderhoudsdosering is twee capsules (equivalent aan 200 mg isavuconazol) eenmaal daags, vanaf 12 tot 24 uur na de laatste startdosering. De duur van de behandeling moet worden vastgesteld op basis van de klinische respons (zie rubriek 5.1 SPC). Bij langdurige behandelingen die langer duren dan 6 maanden, dienen de voordelen en risico’s zorgvuldig tegen elkaar te worden afgewogen (zie rubrieken 5.1 en 5.3 SPC). Overstappen op intraveneuze infusie: CRESEMBA is ook beschikbaar als poeder voor concentraat voor oplossing voor infusie dat 200 mg isavuconazol bevat, wat equivalent is aan 372 mg isavuconazoniumsulfaat. Op basis van de hoge orale biobeschikbaarheid (98%, zie rubriek 5.2 SPC) is afwisselen van intraveneuze en orale toediening geschikt wanneer daar een klinische indicatie voor is. Ouderen: Het is niet noodzakelijk om de dosis aan te passen voor oudere patiënten, hoewel de klinische ervaring met oudere patiënten beperkt is. Nierinsuffi ciëntie: Het is niet noodzakelijk om de dosis aan te passen voor patiënten met nierinsuffi ciëntie, ook niet bij patiënten met eindstadium nierfalen (zie rubriek 5.2 SPC). Leverinsuffi ciëntie: Het is niet noodzakelijk om de dosis aan te passen voor patiënten met lichte of matige leverinsuffi ciëntie (Child-Pugh A en B) (zie rubrieken 4.4 en 5.2 SPC). CRESEMBA werd niet onderzocht bij patiënten met ernstige leverinsuffi ciëntie (Child-Pugh klasse C). Het gebruik wordt voor deze patiënten niet aanbevolen, tenzij de mogelijke voordelen opwegen tegen de risico’s. Zie rubrieken 4.4, 4.8 en 5.2 SPC. Pediatrische patiënten: De veiligheid en werkzaamheid van CRESEMBA bij kinderen die jonger zijn dan 18 jaar zijn nog niet vastgesteld. Er zijn geen gegevens beschikbaar. Wijze van toediening: Infusie: Intraveneus gebruik. Te nemen voorzorgen voorafgaand aan gebruik of toediening van het geneesmiddel: CRESEMBA moet voor de toediening worden gereconstitueerd en dan verder worden verdund tot een concentratie die overeenkomt met ongeveer 0,8 mg/ml isavuconazol. CRESEMBA wordt toegediend via een intraveneuze infusie van ten minste 1 uur om het risico op infusiegerelateerde reacties te beperken. De infusie moet worden toegediend met een infusieset met een in de lijn geplaatst fi lter dat een membraan met microporiën heeft dat is gemaakt van polyethersulfon (PES) en waarvan de poriën tussen 0,2 µm en 1,2 µm groot zijn. CRESEMBA mag alleen als intraveneuze infusie worden toegediend. Voor gedetailleerde instructies voor de reconstitutie en verdunning van CRESEMBA voorafgaand aan toediening, zie rubriek 6.6 SPC. Orale toediening: CRESEMBA-capsules kunnen met of zonder voedsel worden ingenomen. CRESEMBA-capsules moeten in hun geheel worden doorgeslikt. Er mag niet op de capsules worden gekauwd en ze mogen niet worden vermalen, opgelost of geopend. Contra-indicaties: Overgevoeligheid voor de werkzame stof of voor een van de in rubriek 6.1 vermelde hulpstoffen. Gelijktijdige toediening met ketoconazol (zie rubriek 4.5 SPC). Gelijktijdige toediening met een hoge-dosis ritonavir (elke 12 uur 200 mg of hoger) (zie rubriek 4.5 SPC). Gelijktijdige toediening met krachtige CYP3A4/5-inductoren, zoals rifampicine, rifabutine, carbamazepine, langwerkende barbituraten (bv. fenobarbital), fenytoïne en sint-janskruid, of met matige CYP3A4/5-inductoren, zoals efavirenz, nafcilline en etravirine (zie rubriek 4.5 SPC). Patiënten met het aangeboren korte QT-syndroom (zie rubriek 4.4 SPC). Bijzondere waarschuwingen en voorzorgen bij gebruik: Overgevoeligheid: Er is voorzichtigheid geboden bij het voorschrijven van isavuconazol aan patiënten die overgevoelig zijn voor andere azool-antischimmelgeneesmiddelen. Overgevoeligheidsreacties op isavuconazol kunnen resulteren in: hypotensie, respiratoir falen, dyspneu, geneesmiddeleneruptie, pruritus en huiduitslag. Infusiegerelateerde reacties: Tijdens intraveneuze toediening van isavuconazol werden infusiegerelateerde reacties vastgesteld, waaronder hypotensie, dyspneu, duizeligheid, paresthesie, misselijkheid en hoofdpijn (zie rubriek 4.8 SPC). Als deze reacties optreden, moet de infusie beëindigd worden. Ernstige bijwerkingen aan de huid: Er zijn ernstige bijwerkingen aan de huid, zoals het syndroom van Stevens-Johnson, gemeld tijdens de behandeling met azool-antischimmelgeneesmiddelen. Als een patiënt ernstige bijwerkingen aan de huid heeft, moet de behandeling met CRESEMBA worden beëindigd. Cardiovasculair: Verkorting van het QT-interval: CRESEMBA is gecontra-indiceerd voor gebruik bij patiënten met familiaal kort-QT-syndroom (zie rubriek 4.3 SPC). In een QT-onderzoek bij gezonde proefpersonen verkortte isavuconazol het QTc-interval steeds meer bij toenemende concentraties. Bij een dosering van 200 mg was het gemiddelde van de kleinste kwadraten (LSM) vergeleken met de placebo 13,1 ms 2 uur na toediening [90% Cl: 17,1; 9,1 ms]. Een verhoging van de dosis naar 600 mg resulteerde in een LSM-verschil van de placebo van 24,6 ms 2 uur na toediening [90% Cl: 28,7; 20,4 ms]. Er is voorzichtigheid geboden bij het voorschrijven van CRESEMBA aan patiënten die andere geneesmiddelen gebruiken waarvan bekend is dat ze het QT-interval verkorten, zoals rufi namide. Verhoogde levertransaminasen: In klinische onderzoeken zijn verhoogde waarden voor levertransaminasen waargenomen (zie rubriek 4.8 SPC). De verhoogde waarden voor levertransaminasen leidden zelden tot de beëindiging van de behandeling met CRESEMBA. Monitoring van leverenzymen moet overwogen worden, indien klinisch geïndiceerd. Ernstige leverinsuffi ciëntie: CRESEMBA werd niet onderzocht bij patiënten met ernstige leverinsuffi ciëntie (Child-Pugh klasse C). Het gebruik wordt voor deze patiënten niet aanbevolen, tenzij de mogelijke voordelen opwegen tegen de risico’s. Deze patiënten moeten nauwgezet worden gemonitord op mogelijke toxiciteit van het geneesmiddel. Zie rubrieken 4.2, 4.8 en 5.2 SPC. Gelijktijdig gebruik met andere geneesmiddelen: CYP3A4/5-remmers: Ketoconazol is gecontra-indiceerd (zie rubriek 4.3 SPC). Voor de krachtige CYP3A4-remmer lopinavir/ritonavir werd een verdubbelde blootstelling aan isavuconazol waargenomen. Andere sterke CYP3A4/5-remmers zullen naar verwachting een minder uitgesproken effect hebben. De dosering CRESEMBA hoeft niet te worden aangepast wanneer het gelijktijdig wordt toegediend met sterke CYP3A4/5-remmers, maar er is wel voorzichtigheid geboden omdat de bijwerkingen kunnen toenemen (zie rubriek 4.5 SPC). CYP3A4/5-inductoren: Gelijktijdige toediening met lichte CYP3A4/5-inductoren, zoals aprepitant, prednison en pioglitazon, kan resulteren in lichte tot matige daling van de plasmaspiegels van isavuconazol; gelijktijdige toediening met lichte CYP3A4/5-inductoren moet worden vermeden, tenzij de mogelijke voordelen opwegen tegen de risico’s (zie rubriek 4.5 SPC). CYP3A4/5-substraten, waaronder immunosuppressiva: Isavuconazol kan worden beschouwd als een matige remmer van CYP3A4/5 en de systemische blootstelling aan geneesmiddelen die door CYP3A4 worden gemetaboliseerd, kan hoger zijn wanneer ze gelijktijdig met CRESEMBA worden toegediend. Gelijktijdig gebruik van CRESEMBA met CYP3A4-substraten, zoals de immunosuppressiva tacrolimus, sirolimus of ciclosporine, kan de systemische blootstelling aan deze geneesmiddelen verhogen. Gepaste therapeutische geneesmiddelenmonitoring en aanpassing van de dosering kan noodzakelijk zijn wanneer er sprake is van gelijktijdige toediening (zie rubriek 4.5 SPC). CYP2B6-substraten: Isavuconazol is een inductor van CYP2B6. De systemische blootstelling aan geneesmiddelen die worden gemetaboliseerd door CYP2B6 kan lager zijn wanneer er sprake is van gelijktijdige toediening met CRESEMBA. Daarom is voorzichtigheid geboden wanneer er sprake is van gelijktijdige toediening van CYP2B6-substraten, vooral geneesmiddelen met een kleine therapeutische breedte zoals cyclofosfamide, en CRESEMBA. Het gebruik van het CYP2B6-substraat efavirenz met CRESEMBA is gecontra-indiceerd, omdat efavirenz een matige inductor is van CYP3A4/5 (zie rubriek 4.3 SPC). Pgp-substraten: Isavuconazol kan de blootstelling aan geneesmiddelen die Pgp-substraten zijn, vergroten. Aanpassing van de dosering van geneesmiddelen die Pgp-substraten zijn, vooral geneesmiddelen met een kleine therapeutische breedte, zoals digoxine, colchicine en dabigatranetexilaat, kan noodzakelijk zijn wanneer ze gelijktijdig worden toegediend met CRESEMBA (zie rubriek 4.5 SPC). Beperkingen van de klinische gegevens: De klinische gegevens voor isavuconazol voor de behandeling van mucormycose zijn beperkt. Ze omvatten de gegevens van één prospectieve, niet-gecontroleerde klinische studie bij 37 patiënten met bewezen of waarschijnlijke mucormycose die isavuconazol kregen als hoofdbehandeling of omdat andere antischimmelbehandelingen (voornamelijk amfotericine B) ongeschikt waren. Voor afzonderlijke Mucorales-soorten zijn de klinische werkzaamheidsgegevens zeer beperkt. Vaak zijn er maar gegevens van één of twee patiënten (zie rubriek 5.1 SPC). Er waren slechts voor een kleine subgroep gevoeligheidsgegevens beschikbaar. Deze gegevens wijzen erop dat de concentraties isavuconazol die in vitro nodig zijn voor de remming zeer sterk variëren tussen de soorten/klasses binnen de orde van de Mucorales, en dat de concentraties in het algemeen hoger zijn dan de concentraties die nodig zijn om de Aspergillus-soorten te remmen. Opgemerkt dient te worden dat er in het geval van mucormycose geen specifi eke studie ter vaststelling van de dosis is uitgevoerd, en dat de patiënten dezelfde dosis isavuconazol kregen als de dosis die werd gebruikt voor de behandeling van invasieve aspergillose. Bijwerkingen: Samenvatting van het veiligheidsprofi el: De frequentie van de bijwerkingen die staan beschreven in de lijst met bijwerkingen is gebaseerd op 403 patiënten met invasieve schimmelinfecties die werden behandeld met CRESEMBA in fase 3-studies. De meest voorkomende behandelingsgerelateerde bijwerkingen waren verhoogde uitslagen in levertests (7,9%), misselijkheid (7,4%), braken (5,5%), dyspneu (3,2%), buikpijn (2,7%), diarree (2,7%), reactie op de injectieplaats (2,2%), hoofdpijn (2,0%), hypokaliëmie (1,7%) en uitslag (1,7%). De bijwerkingen die het vaakst leidden tot permanente beëindiging van de behandeling met CRESEMBA waren verwardheid (0,7%), acuut nierfalen (0,7%), verhoogde bilirubinespiegels in het bloed (0,5%), convulsie (0,5%), dyspneu (0,5%), epilepsie (0,5%), respiratoir falen (0,5%) en braken (0,5%). Lijst van bijwerkingen: In de lijst hieronder staan de bijwerkingen van isavuconazol tijdens de behandeling van invasieve schimmelinfecties, op volgorde van systeem/orgaanklasse en frequentie. De frequentie van de bijwerkingen wordt als volgt gedefi nieerd: zeer vaak (≥1/10); vaak (≥1/100 tot <1/10); en soms (≥1/1.000 tot <1/100). Binnen elke frequentiegroep staan de bijwerkingen gesorteerd op volgorde van afnemende ernst. Samenvatting van bijwerkingen op volgorde van systeem/orgaanklasse volgens MedDRA en frequentie: Bloed- en lymfestelselaandoeningen: Soms: Neutropenie, trombocytopenie^, pancytopenie, leukopenie^, anemie^. Immuunsysteemaandoeningen: Soms: Overgevoeligheid^. Voedings- en stofwisselingsstoornissen: Vaak: Hypokaliëmie, verminderde eetlust; Soms: Hypomagnesiëmie, hypoglykemie, hypoalbuminemie, ondervoeding^. Psychische stoornissen: Vaak: Delirium^#; Soms: Depressie, insomnia^. Zenuwstelselaandoeningen: Vaak: Hoofdpijn, somnolentie; Soms: Convulsie^, syncope, duizeligheid, paresthesie^ Encefalopathie, presyncope, perifere neuropathie, dysgeusie. Evenwichtsorgaan- en ooraandoeningen: Soms: Vertigo. Hartaandoeningen: Soms: Atriumfi brilleren, tachycardie, bradycardie^, palpitaties; Atriumfl adderen, QT-interval verkort in elektrocardiogram, supraventriculaire tachycardie, ventriculaire extrasystole, supraventriculaire extrasystole. Bloedvataandoeningen: Vaak: Trombofl ebitis^; Soms: Circulatoire collaps, hypotensie. Ademhalingsstelsel-, borstkas- en mediastinumaandoeningen: Vaak: Dyspneu^, acuut respiratoir falen^; Soms: Bronchospasmen, tachypneu, hemoptyse, epistaxis. Maagdarmstelselaandoeningen: Vaak: Braken, diarree, misselijkheid, buikpijn^; Soms: Dyspepsie, constipatie, abdominale distensie. Lever- en galaandoeningen: Vaak: Verhoogde uitslagen in levertests^#; Soms: Hepatomegalie. Huid- en onderhuidaandoeningen: Vaak: Huiduitslag^, pruritus; Soms: Petechiën, alopecia, geneesmiddeleneruptie, dermatitis^. Skeletspierstelsel- en bindweefselaandoeningen: Soms: Rugpijn. Nier- en urinewegaandoeningen: Vaak: Nierfalen. Algemene aandoeningen en toedieningsplaatsstoornissen: Vaak: Pijn op de borst^, vermoeidheid, reactie op de injectieplaats^; Soms: Perifeer oedeem^, malaise, asthenie. ^ Geeft aan dat groepering heeft plaatsgevonden van gepaste voorkeurstermen in één enkel medisch concept. # Zie de rubriek Beschrijving van geselecteerde bijwerkingen, hieronder. Beschrijving van geselecteerde bijwerkingen: Delirium omvat reacties van verwardheid. Verhoogde uitslagen in levertests omvatten verhoogde alanineaminotransferase, verhoogde aspartaataminotransferase, verhoogde bloedspiegel van alkalinefosfatase, verhoogde bloedspiegel van bilirubine, verhoogde bloedspiegel van lactaatdehydrogenase, verhoogde gamma-glutamyltransferase, verhoogde leverenzymen, afwijkende leverfunctie, hyperbilirubinemie, afwijkende leverfunctietests en verhoogde transaminasen. Laboratoriumeffecten: In een dubbelblinde, gerandomiseerde, actief gecontroleerde klinische studie van 516 patiënten met een invasieve schimmelinfectie die werd veroorzaakt door een Aspergillus-schimmel of een andere fi lamenteuze schimmel werden verhoogde levertransaminasen (alanineaminotransferase of aspartaataminotransferase) > 3 x Normale Bovenste Grenswaarde (ULN) gemeld aan het eind van de studiebehandeling bij 4,4% van de patiënten de CRESEMBA kregen. Bij 1,2% van de patiënten die met isavuconazol werden behandeld, werden verhogingen van levertransaminasen van > 10 x ULN waargenomen. Melding van vermoedelijke bijwerkingen: Het is belangrijk om na toelating van het geneesmiddel vermoedelijke bijwerkingen te melden. Op deze wijze kan de verhouding tussen voordelen en risico’s van het geneesmiddel voortdurend worden gevolgd. Beroepsbeoefenaren in de gezondheidszorg wordt verzocht alle vermoedelijke bijwerkingen te melden via Bijwerkingencentrum Lareb, www.lareb.nl. HOUDER VAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN: Basilea Medical Ltd (p/a Cox Costello & Horne Limited), Langwood House, 63–81 High Street, Rickmansworth Hertfordshire WD3 1EQ, Verenigd Koninkrijk. NUMMER(S) VAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN: EU/1/15/1036/001. DATUM VAN HERZIENING VAN DE TEKST: 26/09/2017. AFLEVERINGSTATUS: Receptplichtig. Voor medische informatie over dit product belt u met 0800-MEDINFO (6334636). Neem voor correspondentie en inlichtingen contact op met : Pfi zer, Postbus 37, 2900 AA Capelle a/d IJssel. Raadpleeg vóór prescriptie eerst de volledige tekst van de Samenvatting van de Productkenmerken van Cresemba. PP-GEP-NLD-0044 (juni 2018)

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SE

CU

RE

-ST

UD

IE: V

OR

ICO

NA

ZO

L V

ER

SU

S IS

AV

UC

ON

AZ

OL

Invasieve schim

melinfecties

Invasieve schimm

elinfecties, zoals invasieve aspergillose, kom

en vaak voor bij patiënten met een verm

inderde weer-

stand, met nam

e bij patiënten met hem

atologische aandoe-ningen, patiënten die een hem

atopoïetische stamcel- of

orgaantransplantatie hebben ondergaan en patiënten op de intensive care unit. 1 Voriconazol is de huidige gouden standaard voor prim

aire behandeling van invasieve aspergillose en kan zow

el oraal als intraveneus w

orden toegediend. 2-4 Interacties met andere

medicatie, farm

acokinetische variabiliteit en bijwerkingen

op zowel de korte als de lange term

ijn (o.a. nefrotoxiciteit) m

aken het gebruik van voriconazol echter uitdagend. 5

Isavuconazol heeft daarentegen een voorspelbare en lineaire farm

acokinetiek m

et lage

variabiliteit tussen

patiënten. 6 Zow

el isavuconazol als voriconazol inhiberen CYP3A4/5,

maar de rem

mende w

erking van isavuconazol is zwakker. 7

In tegenstelling tot voriconazol remt isavuconazol C

YP2C9

en CYP2C

19 bovendien niet. Hierdoor is het risico op inter-

acties met andere geneesm

iddelen kleiner bij isavuconazol.

SE

CU

RE

-studie

De fase III SEC

UR

E-studie vergeleek de effectiviteit en vei-ligheid van isavuconazol m

et voriconazol bij volwassen pati-

enten met (verdenking op) invasieve schim

melinfecties. 8

Patiënten kregen gerandomiseerd isavuconazol of voricona-

zol toegediend (zie Tabel 1). De m

aximale behandeltijd w

as 84 dagen. In de ‘intention-to-treat’ (IT

T) populatie (alle patiënten die m

instens 1 dosis medicatie toegediend hebben gekregen)

kregen 258 patiënten isavuconazol en 258 patiënten vorico-nazol. D

e meeste patiënten (84%

) hadden als onderliggende aandoening een hem

atologische maligniteit. D

e gemodifi-

ceerde ITT (m

ITT) populatie bestond uit IT

T-patiënten met

een bewezen of w

aarschijnlijke invasieve schimm

elinfectie. In deze groep kregen 143 patiënten isavuconazol en 129 patiënten voriconazol.

Resultaten

Mortaliteit vanaf de eerste dosis tot aan dag 84 w

as niet ver-schillend tussen isavuconazol en voriconazol, in zow

el de ITT-populatie (-1,1%

[95% BI: -8,9%

-6,7%]) als de m

ITT-po-

pulatie (-5,7% [95%

BI: -16,9%-5,5%

], zie Figuur 1). Bijna alle patiënten rapporteerden m

instens één bijwerking die tij-

dens de behandelperiode optrad: 247 (96%) bij isavuconazol

en 255 (98%) bij voriconazol (p=

0,122). Significant minder

patiënten (42%) uit de isavuconazol-groep rapporteerden

echter medicatie gerelateerde bijw

erkingen vergeleken met

patiënten uit de voriconazol-groep (60%, p<

0,001). Aan-

doeningen aan de ogen (15% versus 27%

, p=0,002), de

lever (9% versus 16%

, p=0,016) en de huid (33%

versus 42%

, p=0,037) kw

amen m

inder vaak voor bij patiënten die w

aren behandeld met isavuconazol.

Isavuconazol wordt dus goed verdragen vergeleken m

et vori-conazol. D

eze resultaten ondersteunen het gebruik van isa-vuconazol

voor de

primaire

behandeling van

invasieve schim

melaandoeningen.

Muco

rmyco

seN

aast de behandeling van invasieve aspergillose, kan isa-vuconazol ook w

orden ingezet bij mucorm

ycose indien de standaardbehandeling am

fotericine B niet geschikt is, bij-voorbeeld door het verhoogde risico op nefrotoxiciteit. D

e recente V

ITAL-studie toonde vergelijkbare m

ortaliteit aan bij patiënten m

et mucorm

ycose die waren behandeld m

et isavuconazol (33%

) vergeleken met patiënten die am

foteri-cine B toegediend kregen (39%

, p=0,775). 9 Bovendien w

as er geen verschil in overleving op dag 84 van beide behande-lingen: 57%

bij isavuconazol versus 50% bij am

fotericine B (H

R 0,831 [95% C

l: 0,367–1,882]; p=0,653).

DR

. BA

RT

RIJN

DE

RS

OV

ER

HE

T G

EB

RU

IK

VA

N IS

AV

UC

ON

AZ

OL

IN D

E P

RA

KT

IJKD

r. Bart

Rijnders,

internist-infectioloog in

het Erasm

us M

edisch Centrum

(Rotterdam), is gespecialiseerd in infecties

bij hematologiepatiënten. H

ij vertelt over zijn ervaringen met

isavuconazol en voriconazol.

Heeft u isavuconazol al eens b

ij een patiënt geb

ruikt?Tot nu toe heb ik isavuconazol bij 1 patiënt m

et cerebrale aspergillose toegepast en bij 1 patiënt m

et zygomycose. Bij

deze laatste patiënt zijn we volgens de richtlijn gestart m

et de standaardbehandeling m

et liposomaal am

fotericine B. Dit

kan echter alleen intraveneus gegeven worden en geeft na

langdurig gebruik vaak bijwerkingen. D

oordat de behande-ling van zygom

ycose maandenlang duurt, w

erden de bijwer-

kingen (met nam

e nefrotoxiciteit) dermate belastend, dat w

e hebben besloten om

over te schakelen naar orale toediening van isavuconazol. D

e behandeling met isavuconazol sloeg

aan, waardoor w

e de therapie hebben kunnen voortzetten en verdere verslechtering van de nierfunctie hebben kunnen voorkom

en.

Zijn er o

ok situaties w

aarbij u d

irect zou starten

met isavuco

nazol?

De richtlijn in N

ederland stelt dat liposomaal am

fotericine B bij zygom

ycose de voorkeursbehandeling is. Alleen indien

deze behandeling niet gegeven kan worden, is direct starten

met isavuconazol een optie. Bij aspergillose zijn voriconazol

en isavuconazol even effectief gebleken op basis van de SECU

-R

E-studie, maar ook bleek dat isavuconazol m

inder bijwer-

kingen geeft dan voriconazol. Of een patiënt die behandeld

wordt m

et voriconazol bijwerkingen zal krijgen, w

eet je echter niet op voorhand. D

aarom is het m

ijns inziens door het grote prijsverschil tussen generieke voriconazol- en isavuconazolta-bletten logisch om

te starten met voriconazol, indien een pati-

ent oraal behandeld kan worden. Voor intraveneuze behande-

ling kan het ontbreken van sulfobutylether-β-cyclodextrine een reden zijn om

isavuconazol te verkiezen boven voricona-zol bij patiënten m

et nierinsufficiëntie.

Wat zijn uw

ervaringen

met vo

riconazo

l?Ik heb goede ervaringen m

et voriconazol, m

aar je moet w

el w

eten hoe je het gebruikt. Zo m

oet je bijvoorbeeld rekening houden

met

fototoxiciteit. Patiënten

die voriconazol

langdurig thuis

gebruiken, dienen zich goed te bescher-m

en met de hoogst m

ogelijke beschermingsfactor om

ver-branding door de zon te voorkom

en. Verder geeft voricona-zol

af en

toe bijw

erkingen zoals

neuropsychiatrische bijw

erkingen (kleurveranderingen en hallucinaties) en lever-toxiciteit (hepatitis). D

aarom is het fijn dat er nu een alterna-

tief beschikbaar is, indien deze bijwerkingen zich voordoen.

Waaro

m is isavuco

nazo

l een go

ed altern

atief?Isavuconazol geeft m

inder medicatie gerelateerde bijw

erkingen, bevat geen cyclodextrine en heeft een bew

ezen gelijkwaardige

effectiviteit vergeleken met de gouden standaard. Bovendien

omvat het antifungale spectrum

naast Aspergillus ook een deel van de Zygom

yceten. Dit kan handig zijn bij patiënten w

aarbij een schim

melinfectie w

ordt vermoed, die niet verder geconcre-

tiseerd kan worden. Tenslotte dringt isavuconazol net als vori-

conazol goed door de bloed-hersenbarrière. Hierdoor zou het

als alternatief kunnen dienen bij de behandeling van cerebrale aspergillose w

anneer een patiënt voriconazol niet kan verdra-gen.

Voorheen w

as hiervoor

geen aantrekkelijk

alternatief beschikbaar.

SE

CU

RE

-ST

UD

IE: V

OR

ICO

NA

ZO

L S

EC

UR

E-S

TU

DIE

: VO

RIC

ON

AZ

OL

pulatie (-5,7% [95%

BI: -16,9%-5,5%

], zie Figuur 1). Bijna

AD

VE

RTO

RIA

L – DE

ZE B

IJDR

AG

E VA

LT NIE

T ON

DE

R D

E V

ER

AN

TWO

OR

DE

LIJKH

EID

VAN

DE

HO

OFD

RE

DA

CTIE

RA

AD

DE

ZE B

IJDR

AG

E W

ER

D M

ED

E M

OG

ELIJK

GE

MA

AK

T DO

OR

FINA

NC

IELE

ON

DE

RS

TEU

NIN

G VA

N P

FIZER

.

PP-ERA-NLD-0183 (MEI 2018).

Tabel 1. Doseringsschem

a isavuconazol en voriconazol.

Gro

epD

ag 1

Dag

2V

anaf d

ag 3

Isavuco

nazo

lD

riemaal daags 200 m

g intraveneus

Driem

aal daags 200 m

g intraveneusD

agelijks 200 mg

intraveneus of oraal

Vo

ricon

azol

Tweem

aal daags 6 m

g/kg intraveneusTw

eemaal daags

4 mg/kg intraveneus

Tweem

aal daags 4 mg/kg

intraveneus of 200 mg oraal

Strijd

tegen

infec

ties

Isavuco

nazo

l bij invasieve asp

ergillo

se

• Isavuconazol

• Voriconazol

Aangep

ast behand

elverschil:-1,4%

(95% B

l: -9,2–

6,3)

Aangep

ast behand

elverschil:-5,5%

(95% B

l: -16,1–5

,1)

ITT

mIT

T

29%

(75/2

58

)

31%(8

0/2

58

)3

0%(4

3/14

3)

37%

(48

/129

)

ITT = ‘intention-to-treat’ p

opulatie; m

ITT = gem

odificeerd

e ITT-pop

ulatie

Figuur 1. Mortaliteit op d

ag 84

RE

FE

RE

NT

IES

1. B

itar D, et al. E

merg Infect D

is 2014;20(7):1149

-55.

2. W

alsh TJ, et al. Clin Infect D

is 200

8; 46: 327–60.

3. M

aertens J, et al. Bone M

arrow Transp

lant 2011;46:709

-18.

4. Tortorano A

M, et al. C

lin Microb

iol Infect 2014;20(sup

pl 3):27–46.

5. M

ikulska M1, et al. J C

hemother. 2012;24(6):311-27.

6. Falci D

R, et al. Infect D

rug Resist 2013;6:163

–74.

7. P

ettit NN

, et al. Ann P

harmacother. 2015;49(7):825

–842.

8. M

aertens JA, et al. Lancet 2016;387(10

020):760

-9.

9. M

arty FM, et al. Lancet Infect D

is 2016;16(7):828–37.

AD

VERTORIA

L

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Netherlands Journal of Critical Care

NETH J CRIT CARE - VOLUME 26 - NO 4 - JULY 2018 155

Submitted January 2018; Accepted April 2018

C A S E R E P O R T

Small bowel obstruction after laparoscopic Roux-en-Y gastric bypass presenting as acute pancreatitis: a case report

N. Henning1, R.K. Linskens2, E.E.M. Schepers-van der Sterren3, B. Speelberg1 Department of 1Intensive Care, 2Gastroenterology and Hepatology, and 3Surgery, Sint Anna Hospital, Geldrop, the Netherlands.

Correspondence

N. Henning - [email protected]

Keywords - Roux-en-Y, gastric bypass, pancreatitis, pancreatic enzymes, small bowel obstruction, biliopancreatic limb obstruction.

AbstractSmall bowel obstruction is a common and potentially life-threatening complication after laparoscopic Roux-en-Y gastric bypass surgery. We describe a 30-year-old woman who previously underwent gastric bypass surgery. She was admitted to the emergency department with epigastric pain and elevated serum lipase levels. Conservative treatment was started for acute pancreatitis, but she showed rapid clinical deterioration due to uncontrollable pain and frequent excessive vomiting. An abdominal computed tomography scan revealed small bowel obstruction and surgeons performed an exploratory laparotomy with adhesiolysis. Our patient quickly improved after surgery and could be discharged home. This case report emphasises that in post-bypass patients with elevated pancreatic enzymes, small bowel obstruction should be considered and early computed tomography scan is required in these patients.

IntroductionLaparoscopic gastric bypass surgery is the most commonly performed bariatric procedure worldwide.[1] In the Netherlands alone, approximately 8,139 gastric bypass operations are performed annually. Laparoscopic Roux-en-Y gastric bypass (LRYGB) is considered the gold standard for the treatment of severe obesity in patients with a body mass index (BMI) >40 kg/m2 or >35 kg/m2 with obesity-related comorbidity.[2] General surgeons, emergency physicians and other clinicians will more frequently encounter postoperative LRYGB complications because of the increasing number of patients undergoing bariatric surgery.[1-4]

Small bowel obstruction is described as a common complication after LRYGB surgery and has an incidence of 1.27-5%.[1,4-6] The obstruction can be difficult to diagnose due to the changed anatomy of the gastrointestinal tract and symptoms may vary. During LRYGB, the upper part of the stomach is stapled to form a small pouch and is connected to the jejunum, bypassing the remnant stomach, duodenum, bile ducts and a proximal part of the jejunum (figure 1). This bypassed part forms the biliopancreatic limb, which delivers bile and pancreatic enzymes to the common intestinal channel. Physicians should have a thorough knowledge of post-bypass anatomy and should be extra attentive to suspecting small

bowel obstruction within this population, because misdiagnosis can have disastrous outcomes.[1,3-5,7] In this report we describe the difficulty of diagnosing small bowel obstruction in post-LRYGB patients and why elevated pancreatic enzymes can indicate an obstruction in these patients. The purpose of this manuscript is to emphasise that in post-bypass patients with abdominal pain and elevated pancreatic enzymes, small bowel obstruction should be considered and that this condition requires

rapid diagnosis using computed tomography. Contrary to other conditions, such as acute pancreatitis, surgical intervention is needed in most cases.

Case reportA 30-year-old woman was referred by a general practitioner to our emergency department (ED) with complaints of continuous epigastric pain, despite 10 mg of morphine intramuscularly one hour prior to presentation. Her medical history revealed that she had undergone more than 15 abdominal operations, including gastric band placement (2011), laparoscopic Roux-en-Y gastric bypass (2013), laparoscopic cholecystectomy (2017) and laparotomic adhesiolysis due to obstruction of the biliopancreatic limb (2017). In the ED we saw a woman in severe pain, with nausea and vomiting. Her last bowel movement was that day and her vital signs were normal. Physical examination revealed a soft abdomen with normal bowel sounds, but maximal abdominal tenderness in the epigastric region and rebound tenderness. Laboratory tests revealed hyperlipasaemia with hyperamylasuria and a minor elevation of liver function tests (table 1). Unfortunately, serum amylase levels were not measured. Abdominal radiography showed mildly dilated small bowel loops with some air-

Figure 1. Roux-en-Y gastric bypass

©Ethicon, Inc. 2017. Reproduced

with their kind permission.

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Netherlands Journal of Critical Care

156 NETH J CRIT CARE - VOLUME 26 - NO 4 - JULY 2018

Small bowel obstruction after gastric bypass presenting as pancreatitis

fluid levels. An abdominal ultrasound did not expose gallstones or dilated intrahepatic or extrahepatic bile ducts. The pancreas could not be visualised due to intestinal gas, but slightly dilated bowel loops were seen with normal peristalsis. We considered that our patient was suffering from acute pancreatitis. She did not use alcohol or eliciting drugs, had not recently undergone an endoscopic retrograde cholangiopancreatography and her calcium and triglyceride levels were normal. Therefore, the cause of the pancreatitis could be gallstones that were not visualised on ultrasound. She was admitted to the ward with conservative treatment: nil by mouth, intravenous fluids, pantoprazole, antiemetics and analgesics. The patient refused a nasogastric tube due to unpleasant experiences with previous tubes. On the ward, our patient had uncontrollable abdominal pain, despite paracetamol, diclofenac and pethidine. She had severe persistent vomiting and on physical examination her abdomen was rigid and bowel sounds were absent. The patient was transferred to the intensive care unit (ICU) because of this clinical deterioration, where she received morphine intravenously. At the ICU, her laboratory tests revealed progressively elevated liver function tests (table 1), suggesting that acute biliary pancreatitis might still be the cause of our patient’s symptoms. However, the severity of pain, the excessive vomiting and the new findings on physical examination did not match this diagnosis. At this point we considered a torsion or obstruction of the biliopancreatic limb.An abdominal computed tomography scan was ordered and showed dilated small bowel loops with a change in calibre and collapsed loops in the pelvic area (figure 2), suggesting small bowel obstruction. No signs of pancreatitis were observed. The patient required surgical treatment that same day. Surgeons performed an exploratory laparotomy with adhesiolysis 50 cm distal to the jejunojejunostomy. The patient quickly showed clinical improvement after surgery; she was no longer vomiting and her pain diminished. Also, her lipase level and liver function tests returned to normal (table 1). The patient could be transferred to the surgical ward and was discharged home on postoperative day 4.

DiscussionWe present a case of a young woman with a history of Roux-en-Y gastric bypass surgery, who presented with epigastric pain, vomiting, hyperlipasaemia and elevated liver function tests. These findings were misinterpreted as acute biliary pancreatitis and the patient was treated conservatively, as is required in acute pancreatitis. However, after clinical deterioration, computed tomography revealed small bowel obstruction without any signs of pancreatitis. The patient underwent an exploratory laparotomy with adhesiolysis, after which she rapidly improved and could be discharged home on postoperative day 4. Small bowel obstruction after Roux-en-Y gastric bypass Small bowel obstruction after LRYGB can be difficult to diagnose. The most common symptoms include abdominal pain, nausea and vomiting.[1,3-6] Our patient vomited upon admission and progressed to excessive vomiting on the ward despite antiemetics. A variety in the expression of symptoms is described among post-bypass patients. Vomiting is reported as retching or small amounts of

clear emesis, due to the small stomach pouch.[1,7] Bilious vomiting indicates an obstruction at or below the site of the jejunojejunostomy.[1,5] However, vomiting might also be absent when the obstruction only involves the biliopancreatic limb.[7] This illustrates the difficulty in recognising symptoms of small bowel obstruction in post-bypass patients and why attending physicians should have knowledge of the post-bypass anatomy. The diagnosis can also be challenging because of the low sensitivity of radiological studies in post-LRYGB patients.[1] The abdominal radiograph of our patient did show some signs of small bowel obstruction, but the computed tomography scan diagnosed the adhesive obstruction. This corresponds with a study which found a sensitivity of 33.3% for plain abdominal radiography to diagnose small bowel obstructions in the post-LRYGB population, compared with a sensitivity of 70-80% in the general population. This study also found a sensitivity of 51.1% for computed tomography scans to diagnose obstruction in the post-LRYGB population, compared with 80-90% in the general population.[1] This means that negative radiological studies do not rule out small bowel obstruction in the post-bypass population. Therefore, in this case where abdominal radiography did not explain the symptoms, a computed tomography scan should have been performed immediately. In case of negative radiological studies, a strong clinical suspicion is leading in decisions to perform laparoscopic exploration and should be done without delay.[1,6,7]

Our patient developed small bowel obstruction four years after her LRYGB, caused by adhesions that obstructed the common intestinal channel. The reported interval between LRYGB surgery

Table 1. Laboratory results

t0 t1 t2

Haemoglobin 7.3 6.8 6.4 mmol/l

Leukocytes 14.4 6.4 7.5 10^9/l

Thrombocytes 264 234 258 10^9/l

Sodium 141 139 140 mmol/l

Potassium 3.6 3.6 3.6 mmol/l

Urea 3.0 3.9 mmol/l

Creatinine 65 47 60 µmol/l

eGFR >90 >90 >90 ml/min

Calcium 2.41 2.30 mmol/l

Bilirubin 14.5 69.3 µmol/l

Bilirubin (conjugated) 82 %

ASAT 89 701 192 U/l

ASAT 39 473 338 U/l

GGT 11 37 37 U/l

Alkaline phosphatase 173 268 263 U/l

LDH 275 483 318 U/l

Triglycerides 0.53 mmol/l

Albumin 43.9 40.8 g/l

Lipase 8600 2168 U/l

CRP <2 47 81 mg/l

Urine amylase 18596 U/l

t=0 presentation at the ED, t=1 admission at the ICU, t=2 postoperative.

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Small bowel obstruction after gastric bypass presenting as pancreatitis

and surgical intervention for small bowel obstruction varies between 1 to 1,215 days after surgery, but seven years is also mentioned.[1,3] Our patient developed the obstruction quite late. However, she had already undergone adhesiolysis due to an obstruction earlier that year. This case also corresponds with studies stating that early small bowel obstructions mainly result from technical problems with the anastomosis, whereas late obstructions tend to affect the common channel and generally originate from internal herniation or adhesions.[4,6] Adhesions cause 13.7-27.5% of all obstructions.[1,4-6,8] Small bowel obstruction should have been suspected earlier, because of the patient’s medical history of adhesions.

Elevated pancreatic enzymes as an indicator of small bowel obstruction after Roux-en-Y gastric bypass An association between small bowel obstruction after LRYGB and elevated amylase or lipase levels has been reported before.[4,7] The lipase level in our patient was 8,600 IU/l with elevated amylase urine levels and slightly elevated liver function tests. This mislead us in diagnosing acute (biliary) pancreatitis in our patient. One study measured elevated serum amylase and/or lipase levels in 48% of small bowel obstructions after LRYGB. In 28.6% of patients both enzymes were elevated, whilst some patients only had amylase (46.4%) or lipase (25%) elevation. The range of amylase levels in this study was between 127-328 IU/l (mean 152.1) and lipase levels between 53-148 IU/l (mean 87.9), which is lower compared with the levels in acute pancreatitis.[7] The same study concludes that elevated pancreatic enzymes have a high sensitivity for detecting acute small bowel obstructions (64%), especially in the biliopancreatic limb (94%).[7] Although our patient had an acute obstruction of the common intestinal channel, the elevated lipase level should have suggested small bowel obstruction. In small bowel obstructions, elevated pancreatic enzymes result from the inability of the pancreas to secrete its enzymes against the increased intraluminal pressure in the duodenum. The same aetiology exists for elevated liver function tests.[5,7,8] In this case, the extremely high level of lipase could imply some inflammation of the pancreas due to stasis of pancreatic enzymes, despite the normal aspect of the pancreas on computed tomography. Thereby, elevation of these markers in post-bypass patients may be misleading and can indicate an obstruction of the biliopancreatic limb or distal to the jejunojejunostomy.[5]

Misdiagnosis of small bowel obstruction as acute pancreatitis can have disastrous consequences because of the non-surgical management, whilst the obstruction can rapidly worsen to bowel ischaemia, perforation and even death.[5,7] Guidelines for acute pancreatitis recommend a computed tomography scan when there is diagnostic uncertainty, when clinical findings suggest severe acute pancreatitis, when there is no response to conservative treatment or in case of clinical deterioration. The initial scan should be performed at least 72-96 hours after the onset of symptoms, because necrosis may not yet be visible and early imaging does not affect the management or prognosis.[9] In post-bypass patients with elevated pancreatic enzymes, computed tomography should be performed early due to diagnostic uncertainty and the possible life-threatening complications of small bowel obstruction that require direct operative management.

ConclusionAn increasing number of patients undergo laparoscopic Roux-en-Y gastric bypass, so complications will be seen more frequently at the emergency department and intensive care unit. A well-known complication is small bowel obstruction. This can be difficult to diagnose, due to the altered gastrointestinal anatomy that gives a variety of symptoms and a lower sensitivity of radiological studies. Misdiagnosis of small bowel obstruction as acute pancreatitis can be catastrophic due to the non-surgical management. Elevated pancreatic enzymes can indicate small bowel obstruction in post-LRYGB patients and a computed tomography scan early in the course of the illness is mandatory in these patients because of diagnostic uncertainty and possible bowel ischaemia or perforation. In case of negative laboratory or radiological results, high clinical suspicion should be leading in the decision for surgical exploration.

DisclosuresAll authors declare no conflict of interest. No funding or financial support was received.

References

1. Husain S, Ahmed A, Johnson J, Boss T, O’Malley W. Small-Bowel Obstruction After Laparoscopic Roux-en-Y Gastric Bypass. Arch Surg. 2017;142:988-93.

2. Dutch Institute for Clinical Auditing. DATO Jaarrapportage 2014 en 2016. 3. Rogula T, Yenumula PR, Schauer PR. A complication of Roux-en-Y gastric bypass: Intestinal

obstruction. Surg Endosc Other Interv Tech. 2007;21:1914-8. 4. Cho M, Carrodeguas L, Pinto D, et al. Diagnosis and management of partial small bowel

obstruction after laparoscopic antecolic antegastric Roux-en-Y gastric bypass for morbid obesity. J Am Coll Surg. 2006;202:262-8.

5. Brooks S, Phelan MP, Chand B, Hatem S. Markedly elevated lipase as a clue to diagnosis of small bowel obstruction after gastric bypass. Am J Emerg Med. 2009;27:7-9.

6. Hwang RF, Swartz DE, Felix EL. Causes of small bowel obstruction after laparoscopic gastric bypass. Surg Endosc. 2004;18:1631-5.

7. Spector D, Perry Z, Shah S, Kim JJ, Tarnoff ME, Shikora SA. Roux-en-Y gastric bypass: Hyperamylasemia is associated with small bowel obstruction. Surg Obes Relat Dis. 2015;11:38-43.

8. Vettoretto N, Pettinato G, Romessis M, Bravo AF, Barozzi G, Giovanetti M. Laparoscopy in afferent loop obstruction presenting as acute pancreatitis. JSLS. 2006;10:270-4.

9. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatol Off J Int Assoc Pancreatol. 2013;13:e1-15.

Oesophagus Gastric pouch Excluded stomach

Change in calibre between dilated small bowel loops and collapsed loops in the pelvic area.

Figure 2. Computed tomography scan, made in a lateral position due to vomiting and risk of aspiration, demonstrating a small bowel obstruction in the patient

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BEST ARTICLEOF THE YEAR AWARD

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OF THE YEAR AWARDAWARD

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The NVIC will award a prize for the best Review and the best Original Article in 2018. In both categories the top 3 papers in 2018 will be nominated by the executive board of the Netherlands Journal of Critical Care. NVIC members may vote and the prizes will be awarded during the Intensivistendagen in February 2019. The executive board invites you to submit your article to the Netherlands Journal of Critical Care.

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Submitted November 2017; accepted February 2018

C L I N I C A L I M A G E

The great imitator, imitated

C.M.W. Teunissen, J.E. Lopez Matta, J.J. MaasDepartment of Intensive Care Medicine, Leiden University Medical Center, Leiden, the Netherlands

Correspondence

J.J. Maas - [email protected]

Keywords - tuberculosis, miliary, hydrocephalus, carcinoma

CaseA 72-year-old female, born in Surinam, presented to the emergency unit of a general hospital after a month of non-productive coughing and a week of being unwell. Except for increasing chronic lower back pain, she had no other complaints and there was no fever. She had no history of tobacco use and her medical history was unremarkable other than insulin-dependent diabetes and dyslipidaemia. A chest X-ray showed uniformly distributed miliary deposits (commonly defined as: innumerable, uniformly distributed, 1-4 mm pulmonary nodules) and consolidation in the left lower lobe (figure 1). With the hypothesis of miliary tuberculosis, the patient was admitted to the pulmonology ward. A bronchoscopy showed no endobronchial abnormalities and a bronchoalveolar lavage was performed in the right upper lobe. Both the auramine-rhodamine stain and the Ziehl-Neelsen stain turned out positive, after which treatment with tuberculostatic drugs (isoniazid 300 mg/day, rifampicin 600 mg/day, ethambutol 1000 mg/day and pyrazinamide 1500 mg/day) was initiated and a PCR on Mycobacterium tuberculosis was ordered. The PCR later turned out to be negative. A PCR on non-tuberculous mycobacteria was not performed. The HIV test was negative.After two days of treatment, the patient’s consciousness deteriorated. A CT and MRI scan of the brain showed hydrocephalus with dilated lateral and third ventricles, a normal aqueduct and fourth ventricle and extensive leukoaraiosis. This was interpreted as impaired resorption of cerebrospinal fluid due to tuberculous meningitis.

Because of progressively deteriorating consciousness and nuchal rigidity, dexamethasone was started and the patient was transferred to our centre for placement of an external ventricular drain.After the transfer, a previously obtained interferon-gamma release assay (IGRA, QuantiFERON) test turned out negative which, even though there are many cases of active tuberculosis

with a negative IGRA, initiated doubt about the diagnosis of tuberculosis. Repeated cerebrospinal fluid samples showed no leucocytosis or low glucose and the auramine-rhodamine stains and PCR on Mycobacterium tuberculosis was negative.

False-positive results from both the auramine and Ziehl-Neelsen stains are rare. This can result from technical errors during the staining process, such as the re-use of containers or positive slides, contamination of the stain by using water containing environmental mycobacteria, use of scratched slides, inadequate decolourisation, etc. We consulted the microbiologist of the referring hospital about the discrepancies in the results and learned that the initial auramine-rhodamine

Figure 1. Chest X-ray.

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Figure 2. CT-scan showing miliary deposits. Figure 3. CT-scan showing consolidation in the left lower lobe.

and Ziehl-Neelsen stains were only doubtfully positive and that a second stain on a new glass had turned out negative. After insertion of the external ventricular drain her consciousness improved. A CT scan of the lungs was performed, confirming the miliary deposits previously suggested on the chest X-ray (figure 2), a pulmonary embolism in the left lower lobe segmental artery, consolidation in the left lower lobe being interpreted as pulmonary infarction (figure 3) and no significant mediastinal lymphadenopathy. A bronchoscopy was repeated to obtain transbronchial biopsies from the left lower lobe. Unfortunately, 24 hours later our patient needed to be intubated because of respiratory insufficiency. The results of the transbronchial biopsies showed an adenocarcinoma of which the immunohistochemical profile fitted a primary lung malignancy.

The cytology of the cerebrospinal fluid showed atypical cells, which in this context were most likely a metastasis of an adenocarcinoma. Together these results took us to the final diagnosis of a primary lung carcinoma with diffuse miliary pulmonary and leptomeningeal metastasis.Neurologically the patient did not improve, she was localising to pain, but not obeying commands and was therefore maintained on mechanical ventilation. Together with the neurologist and the pulmonologist, we concluded that the prognosis was grave and life support, including mechanical ventilation, was terminated, after which our patient died. Autopsy was not performed.

All cultures from the bronchoalveolar lavage, cerebrospinal fluids and the pulmonary biopsy turned out negative for mycobacteria.

ConclusionIn conclusion, we present a patient with miliary pulmonary abnormalities suspect of tuberculosis. Tuberculosis is known as the ‘great imitator’ since the disease may mimic a variety of other diseases. In this case, however, the great imitator was imitated itself since the patient was diagnosed with pulmonary adenocarcinoma, with miliary pulmonary metastases and leptomeningeal metastasis. While the primary thought is often tuberculosis when confronted with miliary pulmonary abnormalities, it is important to realise that there is quite an extensive differential diagnosis. The differential diagnosis of a miliary pattern on a chest X-ray in an afebrile patient is: tuberculosis, fungal infection, viral infection (such as varicella pneumonia), sarcoidosis, silicosis, haemosiderosis, hypersensitivity pneumonitis, (eosinophilic) granulomatosis with polyangiitis ((e)GPA), eosinophilic pneumonia, pulmonary alveolar proteinosis, Langerhans cell histiocytosis and miliary metastasis of cancer (melanoma, sarcoma, carcinoma). As always, we need to keep an open mind and realise the importance of pulmonary biopsy.

DisclosuresThe author declares no conflict of interest. No funding or financial support was received.

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Submitted June 2018; Accepted June 2018

C O R R E S P O N D E N C E

Research Collaboration Critical Care in the Netherlands: RCCCNet

The RCCCNet executive committee

Correspondence

A. Slooter - [email protected]

Keywords - ICU, research, collaboration, organisation, funding

Several breakthroughs in medicine, such as the discovery of penicillin,[1] have been the merit of a single individual. Those days are over and will not return, as current medical research is more than ever a team effort. Multiple disciplines are involved due to the complexity of the studied topics and the need to use advanced research methodology that comes with very specific expertise. This holds particularly true for intensive care medicine, with heterogeneous patient populations, time-dependent determinants and outcomes, and numerous confounders. As patient-centred outcomes in intensive care medicine usually have a multifactorial aetiology, clinical studies in this field must be large enough to demonstrate meaningful effects. Large multicentre investigations are therefore needed, both for inclusion of a sufficient number of patients and for high-level scientific input.To achieve this, collaboration is essential. However, multicentre studies are costly, to a large extent due to legal regulations that have become more and more complex. Obviously, this poses a challenge on how to optimise resources for medical research. This does not imply it is time to cut down on research efforts in our field. On the contrary, it calls for organisation of our efforts to improve the quality of intensive care medicine and to be able to compete with other medical specialties for the limited research funding. Intensive care is at the heart of modern medicine. Without intensive care units (ICUs), high-risk therapies such as cardiac surgery or trauma surgery would take their death toll. The increase in demand for ICU facilities further underlines that modern intensive care is indispensable in modern medicine. However, fundamental issues in intensive care medicine are currently unresolved. For many routine treatments, it is currently unclear whether these are effective. New tools for diagnosis and management raise new questions, and emerging therapies need to be tested. Other medical disciplines and intensive care medicine abroad have shown how much can be gained with collaboration.[2-6]

Examples of successful research collaborations from other disciplines in the Netherlands and from intensive care medicine abroadSeveral medical disciplines have been very successful in establishing research consortia in the Netherlands, such as the Dutch Pancreatitis Study Group and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).[2,3] The resulting synergy of research-based patient care and clinical research have led to impressive breakthroughs. These have boosted quality of care and research, and have also given rise to opportunities to acquire new research funding.Examples can also be found in intensive care medicine, as shown by the Australian and New Zealand Intensive Care Society (ANZICS), Canadian Critical Care Trials Group (CCCTG) and the Scandinavian Critical Care Trials Group (SCCTG).[4-6] In the Netherlands, several important investigator-initiated multicentre studies have been performed in intensive care medicine.[7-9] However, these efforts were isolated and lacked long-term organisation and structural funding.

Aims of a collaborative research networkTo improve research opportunities in the Netherlands, the Research Collaboration Critical Care in the Netherlands (RCCCNet) has recently been founded. The overall aim of RCCCNet is to improve opportunities for research in the field of intensive care medicine in the Netherlands. The first objective is to facilitate collaboration between participating ICUs in our country. We aim to create a network of ICUs from both academic and non-academic hospitals, as well as researchers active in intensive care medicine, related fields and/or research methodology. Infrastructure and expertise that has grown locally can thus be shared within the network to facilitate future collaborative efforts. This not only refers to research methodology, but also to knowhow regarding complex regulations, and the process of obtaining research funding.The second aim is to increase the financial means to execute

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Netherlands Journal of Critical CareResearch Collaboration Critical Care in the Netherlands

these investigations. We realise that it is challenging to get a ‘bigger part of the cake’ as current research budgets are under pressure. Compared with many other fields of medical research (such as oncology, cardiovascular medicine and dementia) intensive care medicine has significantly less resources for research. There are no funds solely dedicated to intensive care medicine and intensivists are usually not in key positions in general funding agencies where scientists from all disciplines compete for a limited number of grants.To increase resources, we need to bring together organisations that are relevant for research in intensive care medicine. These include the Dutch Society of Intensive Care (NVIC), public parties (The Netherlands Organisation for Health Research and Development, ZonMW; Netherlands Organisation for Scientific Research, NWO) and industry (pharmaceutical companies and manufacturers of devices used in the ICU). Public and private parties are part of society, and at present society may not be sufficiently aware of what intensive care medicine entails, nor what its relevance is in modern medicine. We therefore need to reach out to the public to improve awareness of intensive care medicine. Important in this regard is that intensive care medicine is very expensive and that cost-effectiveness has great societal impact. As fundamental issues in intensive care medicine are currently unresolved, research should not, however, be limited to health economic studies alone. We envision that in the near future, two or three large-scale, non-commercial multicentre studies could be running simultaneously, with participation of a large number of Dutch ICUs. These studies could be interventional randomised clinical trials, but also observational investigations. In selected centres, sub-studies could be performed on separate outcomes. In addition, we wish to enhance collaboration in critical care translational research. We envision that the already high standard of translational research can be further improved by exchanging ideas and collaborative investment in expensive, highly-specialised laboratories, equipment and personnel.Our aims to facilitate collaboration and to increase financial means are closely connected. A research network with a high-level infrastructure, expertise and knowhow will be extremely helpful in obtaining new funding for future investigations. An active research network will further mature Dutch intensive care medicine, and improve visibility towards fundraisers and society. On the other hand, any increase in financial means for research will strongly stimulate collaboration and ultimately clinical care.

Organisational structureTo achieve these goals, an executive committee has been established. To be effective and decisive, the executive committee will have a limited number of members to lead RCCCNet and to coordinate the efforts of the steering committee.

The steering committee will consist of representatives from participating ICUs from academic and non-academic hospitals, scientists from related fields such as intensive care epidemiology or sepsis biology, as well as representatives of former patients such as Family and Patient Centred Intensive Care (FCIC). All RCCCNet members will have the opportunity to contribute to the research agenda, as described below. In addition, steering committee members will be able to give input to new study proposals and become principle investigators, trial coordinators, members of a Data Safety Monitoring Board, or contributing investigators by enrolling patients for a certain study. Membership of the steering committee provides the opportunity to be involved in large and relevant trials and to publish in top-ranked journals. Importantly, credits such as authorship of resulting publications, will be shared among everyone who has made a substantial contribution.RCCCNet has been endorsed by the NVIC board and will regularly report to the NVIC members. A formal statement will be put in the statutes to ensure scientific independence of RCCCNet. NVIC will provide administrative support.

The research agendaA broadly supported research agenda may help to keep the focus on the topics that are considered most urgent by the research community. In contrast to other medical disciplines, there is currently no research agenda on intensive care medicine in the Netherlands. This is unfortunate, as important funding agencies such as ZonMW may have a preference for research proposals of topics that are listed on the research agenda of the involved medical discipline.We envision that all RCCCNet members will have the opportunity to contribute to the development of a research agenda for intensive care medicine. We propose that members choose a subfield of their interest and make a short list of topics with a high priority for investigation. It is encouraged to focus new grant proposals on one of these topics. When a grant proposal is finalised, it will be distributed among all steering group members for input and feedback to improve the chances of a successful competitive bid to a funding agency. If the proposal is granted, representatives of each centre can decide whether or not to participate in this specific investigation.Importantly, it is envisioned that the consortium is not meant to act as a ‘trial bureau’, only to facilitate the conduct of randomised clinical trials. RCCCNet aims to facilitate interaction between investigators, to provide a platform for new and clinically relevant research ideas, and eventually to improve the chances of successful applications to funding agencies. In addition, RCCCNet aims to facilitate the conduct of studies. Commitment, investment of time and financial resources will be needed.

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Research Collaboration Critical Care in the Netherlands

Kick-offOn the 21 September 2018, a meeting will be organised to which all intensive care physicians and researchers interested in this collaboration effort are invited. An invitation will also be sent by email, with the exact location. We hope to be able to welcome you all in order to start mapping relevant research topics. Now is the time to improve research collaboration in critical care in the Netherlands.

L. Heunks1, N.P . Juffermans2, P. Pickkers3, A. J.C. Slooter4 1Department of Intensive Care Medicine, Amsterdam UMC location

Vumc, Amsterdam, the Netherlands2Department of Intensive Care Medicine, Amsterdam UMC location

AMC, Amsterdam, the Netherlands3Department of Intensive Care Medicine, Radboud University

Medical Center, Nijmegen, the Netherlands4 Department of Intensive Care Medicine and Brain Center Rudolf

Magnus, University Medical Center Utrecht, Utrecht University,

Utrecht, the Netherlands

References

1. Shama G, La Moisissure et la Bactérie: Deconstructing the fable of the discovery of penicillin by Ernest Duchesne. Endeavour. 2016;40:188-200.

2. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371:651-9.

3. Löwenberg B, van Putten W, Theobald M, et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 ;349:743-52.

4. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356:2139-43.

5. Cameron JI, Chu LM, Matte A, et al. One-Year Outcomes in Caregivers of Critically Ill Patients. N Engl J Med. 2016;374:1831-41.

6. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367:124-34.

7. de Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med. 2009 ;360:20-31.

8. van Vught LA, Klein Klouwenberg PM, Spitoni C, et al. Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. JAMA. 2016 ;315:1469-79.

9. van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial. JAMA. 2018;319:680-9

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Netherlands Journal of Critical CareBi-monthly journal of the Dutch Society of Intensive Care

Volume 24 - No 5 - September 2016

ORIGINAL ARTICLEAgreement of blood glucose levels between venous blood test and arterial blood glucometer in the ICUR. Bhurayanontachai

REVIEWCorticosteroids for cardiac surgery: a summary of two large randomised trialsJ.M. Dieleman, D. van Dijk

CASE REPORTThyrotoxic hypokalaemic periodic paralysis in a Caucasian man who had already started treatment for hyperthyroidismM.J.A. Biemans, J.C. van Westreenen

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ORIGINAL ARTICLEAgreement of blood glucose levels between venous blood test and arterial blood glucometer in the ICUR. Bhurayanontachai

www.njcc.nl

Netherlands Journal of Critical Care

Bi-monthly journal of the Dutch Society of Intensive Care

Volume 25 - No 1 - January 2017

REVIEWCardioprotective and anti-inflammatory effects

of glutamine in parenteral nutrition

A. Leguina-Ruzzi

CASE REPORT

A complicated case of Kingella kingae

endocarditis and review of the literature

L.M. van den Berg, A-C de Pont, P.H.J. van der Voort

CASE REPORT

Use of two continuous venovenous

haemofiltration devices in metformin-

associated lactic acidosis

J.E. Schopman, C.S. Bouman, C.M. Canté, S. Kouwen,

F. Holleman, N.P. Juffermans

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COURSES AND CONFERENCES | NVIC

NVIC Basiscursus echografie

Monday 10 September - Tuesday 11 September 2018

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Friday 21 September 2018 (VUmc Amsterdam)

Friday 14 December 2018

NVIC Cursus Luchtwegmanagement op de IC

Wednesday 14 November - Thursday 15 November 2018

NVIC FCCS cursus

Tuesday 10 July - Wednesday 11 July 2018

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Wednesday 5 September - Thursday 6 September 2018

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Thursday 13 September 2018

NVIC Intensivistendagen 2019

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NETH J CRIT CARE - VOLUME 26 - NO 4 - JULY 2018 165

Jan BakkerProfessor of Intensive CareColumbia University Medical Center, New York University Medical Center, New York, USAPontificia Universidad Católica de Chile, Santiago, ChileErasmus MC University Medical Center, Rotterdam, Netherlands

Charles GomersallDept. of Anaesthesia and IntensiveCareThe Chinese University of HongKong, Prince of Wales HospitalHong Kong, China

Frank van HarenA/ Professor, Australian NationalUniversity Medical SchoolDepartment of Intensive CareMedicineThe Canberra HospitalPO Box 11, Woden, ACT 2606Canberra, Australia

Charles HindsProfessor of Intensive CareMedicineSt. Bartholomew’s HospitalWest Smithfield, London, UK

Patrick HonoréProfessor of ICU MedicineDirector of Critical CareNephrology PlatformICU departmentUniversitair Ziekenhuis Brussel,VUB UniversityBrussels, Belgium

Alun HughesProfessor of Clinical PharmacologyUniversity College LondonLondon, UK

Manu MalbrainDept. of Intensive Care UnitHospital Netwerk AntwerpCampus StuivenbergAntwerp, Belgium

Paul MarikAssociate ProfessorDept. of Medicine and MedicalIntensive Care UnitUniversity of MassachusettsSt. Vincent’s Hospital, Worcester, USA

Greg MartinDept. of MedicineDivision of Pulmonary, Allergy andCritical CareEmory University School ofMedicineAtlanta, USA

Ravindra MehtaProfessor of Clinical MedicineAssociate Chair for ClinicalResearchDepartment of MedicineUCSD Medical CentreSan Diego, USA

Xavier MonnetService de réanimation médicaleCentre Hospitalier Universitairede BicêtreLe Kremlin-Bicêtre, France

Jean-Charles PreiserDept. Intensive CareErasme University HospitalBrussels, Belgium

Yasser SakrDept. of Anaesthesiology andIntensive CareFriedrich-Schiller UniversityHospitalJena, Germany

Hannah WunschDept. of AnaesthesiaNew York Presbyterian ColumbiaNew York, USA

International advisory board

Nicole Juffermans, Editor in ChiefDept. of Intensive CareAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Walter van den Bergh, Section Editor GeneralDept. of Critical CareUniversity of GroningenHanzeplein 19700 RB Groningen

Dennis Bergmans, Section Editor Infection and Inflammation Dept. of Intensive CareMaastricht University Medical Center+P. Debyelaan 256229 HX Maastricht

Frank Bosch, Section Editor ImagingDept. of Internal MedicineRijnstate HospitalPO Box 95556800 TA Arnhem

Diederik van Dijk, Section Editor CardioanesthesiaDept. of Intensive Care Medicine,Div. of Anesthesiology, IntensiveCare and Emergency MedicineUniversity Medical Center UtrechtPO Box 855003508 GA Utrecht

Dirk Donker, Section Editor CardiologyDept. of Intensive Care Medicine,Div. of Anesthesiology, IntensiveCare and Emergency MedicineUniversity Medical Center UtrechtPO Box 855003508 GA Utrecht

Janneke Horn, Section Editor GeneralDept. of Intensive CareAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Leo Heunks, Section Editor Mechanical ventilationDept. of Intensive Care MedicineAmsterdam UMC location VumcPO Box 70571007 MB Amsterdam

Can Ince, Section Editor PhysiologyDept. of PhysiologyAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Evert de Jonge, Section Editor Scoring and quality assessmentDept. of Intensive Care MedicineLeiden University Medical CenterPO Box 96002300 RC Leiden

Michael Kuiper, Associate Editor NeurologyDept. of Intensive Care MedicineMedical Center LeeuwardenPO Box 8888901 BR Leeuwarden

Matijs van Meurs, Section Editor AnesthesiologyDept. of Critical CareUniversity of GroningenHanzeplein 19700 RB Groningen

Marike van der Schaaf, Section Editor RehabilitationDept. of RehabilitationAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Arjen Slooter, Section Editor Mental healthDept. of Intensive CareUniversity Medical Center UtrechtPO Box 855003508 GA Utrecht

Peter Spronk, Associate Editor GeneralDept. of Intensive Care MedicineGelre Hospital, location LukasPO Box 90147300 DS Apeldoorn

Ilse van Stijn, Managing EditorDept. of Intensive Care MedicineOLVG, location OostPO Box 955001090 HM Amsterdam

Eleonora Swart, Section Editor Pharmacology Dept. of PharmacyAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ AmsterdamDept. of Clinical Pharmacology and Pharmacy Amsterdam UMC location VumcDe Boelelaan 11171081 HV Amsterdam

Pieter Roel Tuinman, Section Editor GeneralDept. of Intensive Care MedicineAmsterdam UMC location VumcPO Box 70571007 MB Amsterdam

Alexander Vlaar, Section Editor GeneralDept. of Intensive CareAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

David van Westerloo, Section Editor GeneralDept. of Intensive Care MedicineLeiden University Medical CenterPO Box 96002300 RC Leiden

Job van Woensel, Section EditorPediatricsPediatrics Intensive Care UnitEmma children’s hospitalAmsterdam UMC location AMCUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Editorial board of the Netherlands Journal of Critical Care

Netherlands Journal of Critical Care

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Information for authors

The Netherlands Journal of Critical Care (NJCC) is the official journal of the Dutch Society of Intensive Care (Nederlandse Vereniging voor Intensive Care-NVIC). The journal has a circulation of about 1750 copies bimonthly in the Netherlands and Belgium.High-quality reports of research related to any aspect of intensive care medicine, whether laboratory, clinical, or epidemiological, will be considered for publication in the NJCC. This includes original articles, reviews, and meta-analyses. Case reports, clinical images, book reviews, editorials, letters to the editor, clinical problem solving, research news and correspondence are also welcome. All manuscripts pass through an independent review process managed by the editorial board. The journal does not have any publication fees, and colour figures are reproduced free of charge.The journal is indexed by Embase, Emcare and Scopus. A Medline annotation is in preparation.

Ethical standardsManuscripts reporting original research must contain a statement that all human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Where appropriate, it should also be stated in the text that all persons gave their informed consent prior to their inclusion in the study. If possible, the Journal aims to also include informed consent of individuals described in case reports. Details that might disclose the identity of the subjects under study should be omitted. The editors reserve the right to reject manuscripts that do not comply with the above-mentioned requirements. The author will be held responsible for false statements or failure to fulfil the above-mentioned requirements. The editors adhere to the guidelines laid down by the International Committee of Medical Journalist Editors (www.icmje.org), concerning authorship and scientific conduct.

Types of papers The following manuscript types are considered for publication: original articles, review articles, systematic reviews, meta-analyses, editorials, case reports, clinical images, book reviews, letters to the editor, clinical problem solving, research news and correspondence.

Original articles Original articles should not exceed 3000 words (excluding abstract, references, tables and legends). The manuscript should be clear in outline (with subheadings) for maximum clarity. The text should follow the IMRAD format and contain an abstract, introduction, materials (patients) and methods, results, discussion section and references. This should be followed by tables and figures (maximum of 6 in total) with titles above and legends below these elements. The abstract should not exceed 250 words and should be structured: background, methods, results, conclusions. Do not include references in the abstract. Authors should provide a minimum of 3 keywords, a running title, and a list of not more than 30 references.Original articles must meet the following criteria:- the manuscript presents the results of primary scientific research; - the results have not been published in full elsewhere; - analyses are described in full in the manuscript; - conclusions are presented in a clear and concise manner and are supported

by the data; - the research meets all applicable ethical standards; - the article adheres to appropriate reporting guidelines and community

standards for full data disclosure; - when reporting the results of a randomised controlled trial, author(s)

should use the CONSORT statement as a guide to preparing the manuscript (http://www.consort-statement.org/);

- conflicts of interest should be clearly stated in the manuscript (see below).

The authors are encouraged to refer to national and international registries of trials in their papers (such as clinicaltrials.gov), where applicable.

Review articlesReview articles, systematic reviews and meta-analyses should not exceed 3000 words (excluding abstract, references, tables and legends). The manuscript should contain subheadings. A maximum of 6 tables and figures (in total) are allowed. Please provide titles above and legends below these elements. The abstract should not exceed 250 words and should be structured: background, methods, results, conclusions, with the exception of a non-systematic review, which may contain a non-structured abstract. No references should be included in the abstract. Authors should provide a minimum of 3 keywords, a running title, and a list of not more than 70 references. The authors are encouraged to refer to national and international registries of trials in their papers (such as clinicaltrials.gov), where applicable.

EditorialsEditorials are always commissioned by the Editors and comment on one or more articles in the same issue of the Journal or to a subject with high news value. Editorials should not exceed 1500 words and may include up to 15 references. Editorials have a maximum of 3 authors and no abstract. Please provide 2-3 key words.

Case reportsThe text of a case report should include an abstract, introduction, case report/case history, discussion, tables and figures (2 in total), and references. The main text may be up to 2000 words; the abstract should not exceed 150 words and may be unstructured. Please provide a minimum of 3 keywords and a list of not more than 30 references. Please include an informed consent statement from the patient described in the case.

Clinical problem-solving These manuscripts consider the step-by-step process of clinical decision-making. Information about a patient is presented to an expert clinician or clinicians in stages (indicated by boldface type in the manuscript) to simulate the way such information emerges in clinical practice. The clinician responds (in regular type) as new information is presented, sharing his or her reasoning with the reader. The text should not exceed 2500 words, and there should be no more than 15 references. Please include an informed consent statement from the patient described in the case.

Research newsResearch news should be a review of a manuscript which has appeared in the past two months. It contains sections on why this study was done, the research question, how this was investigated, conclusions and the impact of the study on clinical practice. The text should not exceed 800 words with a maximum of 5 references. Contributions for this section will be commissioned; however, inquiries about contributions can be sent to [email protected].

Clinical imagesA clinical image should contain one or two pictures with a legend and a short case history, and should preferably not be referenced. The manuscript should succinctly present relevant clinical information, including a short description of the patient’s history, relevant physical and laboratory findings, clinical course, response to treatment (if any), and condition at last follow-up. Please provide a minimum of 3 keywords. The text should not exceed 500 words. Please include an informed consent statement from the patient described in the case.

Photo quizIn this section relevant images for critical care medicine (e.g. flow and pressure curves of mechanical ventilation or haemodynamic indices, radiological images or laboratory results) will be accompanied by a short introduction of the context. The introduction will be followed by ‘what is your diagnosis?’. The answer will include a brief discussion of the literature. A photo quiz should not exceed 500 words and contain no more than two figures, and five references conform the Vancouver style. Abbreviations of measurements should be quoted in SI units.

Book reviewsA book review should not exceed 300 words. Please mention in the header: title, author, edition and year. Scan the cover in high resolution (300 dpi/1 mb) and send with the text. With an online review, the cover can usually be downloaded. Details with the cover: title, author, edition, year, publisher, number of pages, price and ISBN number. Conclude with the name and affiliation(s) of the reviewer.

Letters to the editorLetters to the editor provide an opportunity to present results of scientific value where a short format is most appropriate. They should not exceed 1000 words, 5 references and 1 figure or table.

CorrespondenceCorrespondence provides an opportunity to debate published articles. This should not exceed 500 words, 5 references and 1 figure or table. Correspondence is sent to the authors for rebuttal, and a final decision on publication is made at the end of this process, by the editor.

General informationEach manuscript should be accompanied by a cover letter stating the following: the complete postal address, email address and telephone number of the corresponding author and, if it is a re submission, the previous Neth J Crit Care number and year. The language of the journal is British English. Authors who are unsure of proper English usage should have their manuscript checked by someone proficient in the English language. All text should be double spaced. The manuscript pages, including references and legends, should be sequentially numbered throughout

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General guidelines on house style- The title of the manuscript should be in typeface Times New Roman, size 20.

With the exception of the first word and proper nouns, initial capitals are not used in the title.

- The names of departments should be in typeface Times New Roman, size 12.- The names of hospitals should be written in English.- Write ‘the Netherlands’, without capitalising the t.- Generally, abbreviations should not be used in the title (see Table of standard

abbreviations for exceptions).- The corresponding author only provides his/her email address on the title page.- Please provide a minimum of three keywords and a running title.- The abstract of original and review articles should be written in a structured format.- Unstructured abstracts should take the form of a single paragraph.- Headings must be in bold. Use no more than two levels of headings. - Paragraphs starting immediately under headings and subheadings should begin

at the left margin. Subsequent paragraphs should be indented. - Non-standard abbreviations (see table of standard abbreviations) should always

be explained and their use kept to a minimum.- Use British English spelling – except in titles of institutions that have chosen to

use US spelling, e.g. Academic Medical Center, Amsterdam. Examples: anaemia (instead of anemia), oesophagus (instead of esophagus), litre (instead of liter), colour (instead of color), labelling (instead of labeling), practice (noun), and practise (verb). This should be used consistently. Use the s-form spelling, e.g. minimise, randomisation.

- Do not use full stops in initials, abbreviations and academic titles.- References are numbered sequentially in the text and placed in square brackets

after the punctuation. [..]- Genus names should be written in italics, e.g. Staphylococcus aureus, S. aureus.- Numbers under 10 are spelled out except for measurements with a unit (10

mmol/l) or age (4 weeks old), or when in a list with other numbers (5 mice, 6 rats, 12 gerbils).

- When referring to tables or figures in the text, use italics; do not use a capital letter, e.g. see table 2.

TablesTables are to be numbered independently of the figures with Arabic numbers and are uploaded as separate documents.- Tables should be laid out in Word, using the table function. Other tables (e.g.

in pdf format or PowerPoint) will not be accepted;- Do not use internal horizontal or vertical lines;- Do not use spaces, tabs or hard returns in tables;- Each piece of data must be contained in its own cell;- Numbers and percentages are presented in the same cell;- Tables should always be cited in the text in consecutive numerical order;- For each table, please supply a title explaining the components of the table;- Any abbreviations used in the table must be defined in a legend; - Tables should not exceed the printed area of the page (174 x 234 mm).

FiguresFigures should also be numbered with Arabic numbers and are uploaded in separate documents. Legends should be given in the document that contains the text, references, and tables. Authors wishing to include figures or tables that have already been published elsewhere are required to obtain permission from the copyright owner and provide evidence that such permission has been granted when submitting their paper. Colour figures can be published. Short, clear legends make additional description in the text unnecessary. Figures should be provided in electronic format (TIFF or JPEG).

Conflict of interest Authors must indicate any conflict of interest. This includes a financial relationship with an organisation that sponsored the research (funding, speakers fee, consultancy fee), management relations with the organisation that sponsored the research (consultant, member of board). All sources of funding obtained for the research should also be stated. A conflict of interest statement can be downloaded from the website. The completed and signed form should be uploaded as a separate document when submitting the manuscript. If no conflict exists, authors should state: All authors declare no conflicts of interest. No funding or financial support was received.

Author agreement All authors must certify they have seen and approved the manuscript being submitted. All authors warrant that the article is the authors’ original work, has not been published previously and is not under consideration for publication elsewhere. The author agreement form can be downloaded from the website. An article will only be published when this form is completed, signed and returned.

CopyrightCopyright ownership is to be transferred in a written statement, which must accompany all manuscript submissions and must be signed by all authors. The agreement should state: ‘The undersigned authors transfer all copyright

ownership of the manuscript (title of article) to the Netherlands Journal of Critical Care’. Any relevant papers that may be considered as duplicating in part the current submission should be reported.

ReferencesNeth J Crit Care uses the Vancouver style of referencing. Only articles cited in the text are to be listed. They should be arranged in order of appearance in the text and numbered consecutively. Only the reference number should appear in the text between brackets. […] Include all author names (unless there are more than six, in which case abbreviate to three and add ‘et al.’), and page numbers. Use the Medline abbreviation for names of journals.Article in journals: Calandra T, Cometta A. Antibiotic therapy for Gram-negative bacteremia. Infect Dis Clin North Am. 1991;5:817-34.Books (sections): Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent J L (eds). Clinical trials for the treatment of sepsis. (Update in intensive care and emergency medicine, volume 19). Berlin Heidelberg New York: Springer; 1995, pp 167-90.Conference meetings: Rijneveld AW, Lauw FN, te Velde AA, et al. The role of interferon gamma in murine pneumococcal pneumonia. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, Ca.; 1998, pp 290.Article/ information on website: Samenwerken aan duurzame zorg, landelijke monitor proeftuinen: Rijksinstituut voor Volksgezondheid en Milieu, 2015. (Accessed 11 August 2015, at http://www.rijksoverheid.nl/documenten-en-publicaties/rapporten/2015/07/10/samen-werken-aan-duurzame-zorg.html.)

How to submitPlease submit manuscripts directly to the Editorial Office through our online submission system at www.njcc.nl.

Peer reviewAll papers are subject to a peer-review system handled by the editors. Authors are encouraged to resubmit, when invited, the revised paper within two weeks after the editorial decision. The changes made in the revised paper should be highlighted and the manuscript accompanied by a letter with a point-to-point rebuttal.

ProofsThe corresponding author will receive proofs of accepted papers by email. Corrected proofs should be returned within 48 hours of receipt.

Production processDecisions of the editors are final. All material accepted for publication is subject to copyediting. The Neth J Crit Care reserves the right to edit for house style, clarity, precision of expression, and grammar. Authors review these changes at the proof stage but must limit their alterations in the proof to correcting errors and to clarifying misleading statements.

Table of commonly used abbreviationsAIDS acquired immunodeficiency syndromeALI acute lung injuryARDS adult respiratory distress syndromeAPACHE acute physiology and chronic health evaluationBIPAP biphasic positive airways pressureCCU coronary care unitCOPD chronic obstructive pulmonary diseaseCPAP continuous positive airway pressureCT computed tomographyECG electrocardiogramECMO extracorporeal membrane oxygenationEEG ElectroencephalogramELISA enzyme-linked immunosorbent assayETCO2 end-tidal carbon dioxideHIV human immunodeficiency virusIC intensive careICU intensive care unitIM IntramuscularINR international normalised ratioIPPV intermittent positive pressure ventilationIV IntravenousMAP mean arterial pressureMODS multiorgan dysfunction syndromeMRI magnetic resonance imagingPACU post anaesthesia care unitPEEP positive end expiratory pressurePET positron emission tomographySARS severe adult respiratory syndromeSIRS systemic inflammatory response syndromeSOFA sequential organ failure assessmentSPECT single-photon emission computed tomography TIA transient ischaemic attackTRALI transfusion-related acute lung injury

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