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Bi-monthly journal of the Dutch Society of Intensive Care

Netherlands Journal of Critical Care

Volume 17 - No 5 - December 2013

ReviewGlomerular hyperfiltration of antibioticsD.W. de Lange

Clinical imagePeriodic SvO2 fluctuations in a patient with severe pulmonary emboliP.E. Spronk

Case reports and abstracts Intensivistendagen 2014

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Referenties:* Invasieve aspergillose bij volwassene patienten en kinderen die niet reageren op amfotericine B, toedieningsvormen van amfotericine B met lipiden en/of itraconazol of deze niet verdragen.1. D.W. Denning: Echinocandin antifungal drugs. The Lancet 362: 1142-51, 2003.

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Evidence. Experience. Confi dence.

Cancidas® Breed toepasbaar bij• Invasieve candidiasis• Invasieve aspergillose*

• Empirische antifungale therapie

Antifungale therapie zonder compromis• Voor volwassenen én kinderen• Voor neutropenen én niet-neutropenen• Goed verdragen1

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1Ne th j cr it c ar e – volume 17 – no 5 – december 2013

Netherlands journal of critical care

ed I To r IAl s

3 Glomerular hyperfiltration, the devil in disguiseH.M. Oudemans-van Straaten

5 Video-laryngoscopy: the eye of the beholder?T.M. van den Berg, D. Gommers

o r I g I nAl Ar T I cle

7 Endotracheal intubation by inexperienced registrars in internal medicine: a comparison of video-laryngoscopy versus direct laryngoscopyH. Biermann, E. van der Heiden, A. Beishuizen, A.R.J. Girbes, M.C. de Waard

r e v I e W

10 Glomerular hyperfiltration of antibioticsD.W. de Lange

c A se r ePo r T s

15 Cryoglobulinemia complicated by diffuse alveolar haemorrhageJ.E.M. Schilders, A.J.B.W. Brouwers, H.C.T. van Zaanen

19 Severe anti NMDA encephalitis and EBV infectionS.J. Derksen, B. Goraj, J.P. Molenaar, J.G. van der Hoeven

clI n I c Al I m Ag e

22 Periodic SvO2 fluctuations in a patient with severe pulmonary emboliP.E. Spronk

24 c A se r eP o r T s I n T ensI v Is T en dAg en 2014

42 Abs T r Ac T s I n T ensI v Is T en dAg en 2014

66 Editorial Board

66 International Advisory Board

67 Information for authors

c o n T e n T se x e c u T I v e e d I T o r I A l b o A r dA.b.J. groeneveld, editor in chiefmw. I. van stijn, managing editorJ. box, language editor

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Accepted november 2013

Glomerular hyperfiltration is an underdiagnosed condition leading to augmented renal clearance. This condition passes unnoticed, and can lead to serious underdosing of renally excreted antibiotics. In the present issue, Dylan de Lange pays attention to this condition. His contribution is worth reading for its clinical relevance.1 A typical case of glomerular hyperfiltration is as follows. A 24-year-old previously healthy man was admitted to hospital after a severe motor accident. At the trauma site he was found to be comatose and was intubated. Apart from an instable thoracic-3 vertebral fracture, which was fixated at day three, and some other less important injuries, his cerebral trauma was the most severe of his injuries. He underwent early hemicraniectomy to evacuate an acute subdural hematoma with mass effect. After repositioning of the cranial bone flap three weeks later, a subduro-peritoneal drain was inserted, because his neurological condition deteriorated. He subsequently developed fever. Several blood cultures showed growth of S. epidermidis and the pre-emptive vancomycin treatment was continued. The patient’s renal function appeared to be normal, on admission his serum creatinine was 73 µmol/L and after five weeks of intensive care treatment with persistently decreased consciousness (maximal EMV score of 8), the serum creatinine decreased to 40 µmol/L. Vancomycin blood levels were measured. Initial intravenous dose was twice 1000 mg but this dose had to be increased to 4-times 1300 mg to attain trough levels above 15 mg/L. Of note, this patient additionally exhibited intermittent sympathetic hyperactivity (fever, tachycardia, hypertension, tachypnoea, hyperhidrosis and dystonic posturing) which was successfully treated with hydration, enteral propanolol and intravenous clonidine.2

This young patient with severe traumatic brain injury had augmented renal clearance with subtherapeutic vancomycin concentrations. In such cases, augmented renal clearance is a devil in disguise. The first reason for this is that the condition passes unnoticed with routine clinical monitoring. Therefore,

Glomerular hyperfiltration, the devil in disguise

awareness on the part of the physician is crucial. Patients at risk include younger patients with apparently ‘normal’ renal function who exhibit sympathetic hyperactivity after major trauma, especially head injury, burns or during early sepsis. The precise mechanism is not well known, but the condition is associated with high catecholamine concentrations, fluid loading and low plasma albumin concentration and is reported in up to forty percent of septic and eighty five percent of the young trauma patients with normal renal function.3-7. The second pitfall is the augmented renal clearance of water soluble antibiotics and other solutes. For example, subtherapeutic concentrations of vancomycin8-9, β-lactam antibiotics,10 meropenem,11 piperacilline/tazobactam11 and levetiracetam9 are reported in the literature.How do we incorporate this knowledge into daily practice? Several measures seem necessary. First, in younger patients with trauma, early sepsis and burns, a higher initial dose of antibiotics should be considered to saturate an increased distribution volume. Subsequently, the non-toxic renally excreted antibiotics such as β-lactams, carbapenems and fluoroquinolones should be dosed more frequently or continuously (β-lactams), to prevent concentrations falling below the minimum inhibitory concentration due to augmented renal clearance. With non-toxic drugs, the risk of underdosing is higher than that of overdosing. Second and ideally, therapeutic drug monitoring should be performed. If this option is not available, creatinine clearance from a 2-4-hours urine collection period should be done at regular intervals to monitor augmented renal clearance and guide antibiotic dosing. Glomerular filtration may be markedly increased, creatinine clearances of 310 and of 375 mL/min/ 1.73 m2 have been reported.11,12 Third and finally, toxic antibiotics such as aminoglycosides, which demonstrate concentra-tion-dependent killing, should be given more frequently in cases of augmented renal clearance, and therapeutic drug monitoring should be performed, not only in patients with diminished renal function but also in those with apparently

H.M. Oudemans-van Straaten

correspondence

H. oudemans-van straaten – e-mail: [email protected]

Keywords – antibiotic, renal clearance, trauma, sepsis, pharmacokinetics

e d I T o r I A l

4 Ne th j cr it c ar e – volume 17 – no 5 – december 2013


normal renal function. The same strategy is recommended for vancomycin for which continuous infusion may be considered as well.4

The message here is, be aware of glomerular hyperfiltration in younger patients with trauma, sepsis and burns with apparently normal renal function; measure 2-4 hours creatinine clearance regularly, administer antibiotics more frequently and perform therapeutic drug monitoring, not only in patients with diminished but also in those with apparently normal renal function. This strategy is likely to increase treatment success.

references

1. De Lange DW. Glomerular hyperfiltration of antibiotics. Neth J Crit Care 2013;17:10-4.

2. Rabinstein AA, Benarroch EE. Treatment of paroxysmal sympathetic hyperactiv-ity. Curr Treat Options Neurol. 2008;10:151-7.

3. Fuster-Lluch O, Geronimo-Pardo M, Peyro-Garcia R, Lizan-Garcia M. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth Intensive Care. 2008;36:674-80.

4. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clear-ance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49:1-16.

5. Udy A, Boots R, Senthuran S, Stuart J, Deans R, Lassig-Smith M, Lipman J. Augmented creatinine clearance in traumatic brain injury. Anesth Analg. 2010;111:1505-10.

6. Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. Crit Care. 2013;28:695-700.

7. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care. 2013;17:R35.

8. Minkutė R, Briedis V, Steponavičiūtė R, Vitkauskienė A, Mačiulaitis R. Augmented renal clearance – an evolving risk factor to consider during the treatment with vancomycin. J Clin Pharm Ther. 2013; in press doi: 10.1111/jcpt.12088.

9. Cook AM, Arora S, Davis J, Pittman T. Augmented renal clearance of vanco-mycin and levetiracetam in a traumatic brain injury patient. Neurocrit Care. 2013;19:210-4.

10. Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, et al. Subtherapeutic initial beta-lactam concentrations in select critically ill patients association between augmented renal clearance and low trough drug concen-trations. Chest. 2012;142:30-9.

11. Carlier M, Carrette S, Roberts JA, Stove V, Verstraete AG, Hoste E, et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/ pharmacodynamic target attainment when extended infusions are used? Crit Care. 2013;17:R84.

12. Lonsdale DO, Udy AA, Roberts JA, Lipman J. Antibacterial therapeutic drug monitoring in cerebrospinal fluid: difficulty in achieving adequate drug con-centrations. J Neurosurg. 2013;118:297-301.



Accepted november 2013

In this issue of the Netherlands Journal of Critical Care, Biermann et al. report on a trial in which they compared the use of direct laryngoscopy using the classical Macintosh laryngoscope (DL) with video-laryngoscopy using the GlideScope (GS) in the hands of inexperienced registrars. The registrars all had to intubate a manikin with both tools, after which the intubation success and time needed for successful intubation were compared. Results showed that intubation using the GS technique had a higher success rate (92% vs 69%, P<0.05). However, it took the registrars more time to successfully intubate the manikin with the GS (75 seconds versus 39 seconds).The GS has been commercially available since 2001. The first major clinical study using the new video-laryngoscope was performed in 2005. In 133 patients in whom both direct laryngoscopy and video-laryngoscopy using the GS were performed, the use of GS resulted in superior or comparable view of the vocal cords. In 35 patients classified as Cormack-Lehane (C/L) 3/4 by DL, the use of GS reclassified them as C/L 1 in 24 and C/L 2 in three patients. Intubation with the GS was successful in 96.3% of patients.1 Later that year the first randomized clinical trial comparing DL and GS in 200 elective surgical patients was performed. The results showed that GS improved the C/L grade in the majority of patients by G/L > 1. The time needed for intubation was longer in the GS group than in the DL group, but not for patients with G/L 3.2

The intubations in these first studies were performed by experienced anesthetists. Because of the better laryngeal view obtained by using GS, the technique has since been investigated in numerous situations with expected difficult intubation: in patients with reduced mouth opening,3, in patients with immobilized spine,4 out-of-hospital intubations,5 and in simulated difficult airway-intubation in a manikin.6 In all these situations the GS technique proved to be better than DL in terms of intubation success. In obese patients, better glottis views were achieved with the GS but the intubation time

Video-laryngoscopy: the eye of the beholder?

was longer. No difference was found in intubation success rate or complications.7 The fact that it takes longer to intubate a patient with GS, especially when the C/L grade is low, has been reported frequently. This seems to be due to the more difficult advancement of the tube through the mouth.8

However, the most difficult skill to learn when intubating patients is obtaining a good view of the glottis. Since the GS has proven to give these better views, it is reasonable to examine the functionality of its use in the hands of relatively inexperienced doctors. Nouruzi-Sedeh et al. performed a study in which inexperienced volunteers, who had only had a tracheal intubation training on a manikin, intubated elective surgical patients either with GS or DL. The success rate of GS was 93% versus 51% for DL. The intubation time for GS was shorter than for DL (63 seconds versus 89 seconds).9 The same result was found by Ayoub et al.: inexperienced medical students were briefly trained using GS or DL, and subsequently intubated patients with normal airways. The students being trained with, and using the GS achieved higher success rates in less time.10

A recently published study by Kory et al. is closer to every day hospital reality. A cohort of critical care fellows using a GS in urgent endotracheal intubations in critical ill patients was compared with a historical cohort of critical care fellows using direct laryngoscopy. The rate of first-attempt success was higher in the group using GS (91% vs 68%). Also, the rate of unintended oesophageal intubation and the average number of attempts required for successful intubation were lower in the GS group.11

Randomized studies on the use of the GlideScope in emergency situations are scarce. The studies that have been performed on urgent intubation in the Emergency Department or in critically ill patients are mostly observational, and they do not show uniform results. Some find intubation with the GS leading to fewer attempts before successful intubation and less time needed for intubation 5, or fewer oesophageal intubations.12.

T.M. van den Berg, D. GommersDepartment of intensive care Medicine, erasmus Medical center, rotterdam

correspondence

T.m. van den berg – e-mail: [email protected]

Keywords – Laryngoscopy, video-laryngoscopy

e d I T o r I A l



Others find similar success rates for both methods of intubation, and suggest the use of GS for difficult airways.13 The study by Platts-Mills et al. shows no difference between success rate and longer time needed for intubation in the GS group.14 That the prolonged time needed for intubation is not always harmless in an emergency situation is suggested by the only randomized controlled study by Yeatts et al. performed in trauma patients: they retrospectively found longer intubation times and higher mortality among patients with severe neurotrauma who were intubated with GS.15

The most important limitation of the study by Biermann et al. is, as the authors mention themselves, that it has not been performed in a real life situation. Given the fact that outside office hours the vast number of intubations are required in emergency situations, there are many difficulties including hemodynamic and respiratory deterioration, aspiration and other complications that may be encountered by an inexperienced doctor trying to intubate a patient. Most of these problems will not be less when GS is used. Therefore, all doctors responsible for emergency stabilization of patients need to be thoroughly trained in the management of the acute patient. Emphasis should be placed on the ability to use the balloon, and other noninvasive methods of maintaining airway and breathing in an emergency situation. Once these prerequisites have been met and if the patient is still in urgent need of intubation, or the (thus probably not so inexperienced) doctor feels comfortable with the technique, the GS can be used as an initial means of intubation. This is particularly reasonable if the patient is expected to have a difficult airway. It is too early to say that the GS is superior in these situations; more randomized studies to prove this in a real life emergency situation are needed.

references

1. Cooper RM, Pacey JA, Bishop MJ, McCluskey SA. Early clinical experience with a new videolaryngoscope (GlideScope) in 728 patients. Can J Anaesth. 2005;52:191-8.

2. Sun DA, Warriner CB, Parsons DG, Klein R, Umedaly HS, Moult M. The GlideScope Video Laryngoscope: randomized clinical trial in 200 patients. Br J Anaesth. 2005;94:381-4.

3. Schumann M, Biesler I, Börgers A, Pförtner R, Mohr C, Groeben H. Tracheal intu-bation in patients with odentogenous abscesses and reduced mouth opening. Br J Anaesth. 2013 in press.

4. Kill C, Risse J, Wallot P, Seidl P, Steinfeldt T, Wulf H.. Videolaryngoscopy with gli-descope reduces cervical spine movement in patients with unsecured cervical spine. J Emerg Med. 2013;44:750-6.

5. Wayne MA, McDonnell M. Comparison of traditional versus video laryngoscopy in out-of-hospital tracheal intubation. Prehosp Emerg Care. 2010;14:278-82.

6. Savoldelli GL, Schiffer E, Abegg C, Baeriswyl V, Clergue F, Waeber JL. Comparison of the Glidescope, the McGrath, the Airtraq and the Macintosh laryngoscopes in simulated difficult airways*. Anaesthesia. 2008;63:1358-64.

7. Andersen LH, Rovsing L, Olsen KS. GlideScope videolaryngoscope vs. Macintosh direct laryngoscope for intubation of morbidly obese patients: a randomized trial. Acta Anaesthesiol Scand. 2011;55:1090-7.

8. Wetsch WA, Carlitscheck M, Spelten O, Teschendorf P, Hellmich M, Genzwürker HV, Hinkelbein J. Success rates and endotracheal tube insertion times of experi-enced emergency physicians using five video laryngoscopes: a randomised trial in a simulated trapped car accident victim. Eur J Anaesthesiol. 2011;28:849-58.

9. Nouruzi-Sedeh P, Schumann M, Groeben H. Laryngoscopy via Macintosh blade versus GlideScope: success rate and time for endotracheal intubation in untrained medical personnel. Anesthesiology. 2009;110:32-7.

10. Ayoub CM, Kanazi GE, Al Alami A, Rameh C, El-Khatib MF. Tracheal intubation following training with the GlideScope compared to direct laryngoscopy. Anaesthesia. 2010;65:674-8.

11. Kory P, Guevarra K, Mathew JP, Hegde A, Mayo PH. The impact of video laryn-goscopy use during urgent endotracheal intubation in the critically ill. Anesth Analg. 2013;117:144-9.

12. Sakles JC, Mosier JM, Chiu S, Keim SM). Tracheal intubation in the emergency department: a comparison of GlideScope® video laryngoscopy to direct laryn-goscopy in 822 intubations. Emerg Med. 2012;42:400-5.

13. Choi HJ, Kang HG, Lim TH, Chung HS, Cho J, Oh YM, Kim YM; Korean Emergency Airway Management Registry (KEAMR) Investigators). Endotracheal intubation using a GlideScope video laryngoscope by emergency physicians: a multicentre analysis of 345 attempts in adult patients. Emerg Med J. 2010;27:380-2.

14. Platts-Mills TF, Campagne D, Chinnock B, Snowden B, Glickman LT, Hendey GW. A comparison of GlideScope video laryngoscopy versus direct laryngoscopy intubation in the emergency department. Acad Emerg Med. 2009;16:866-71.

15. Yeatts DJ, Dutton RP, Hu PF, Chang YW, Brown CH, Chen H, Grissom TE, Kufera JA, Scalea TM. Effect of video laryngoscopy on trauma patient survival: a rand-omized controlled trial. J Trauma Acute Care Surg. 2013;75:12-9.



Accepted october 2013

AbstractOne of the most important tasks involved in the management of critically ill patients is to secure the airway. The preferred method for securing the airway is tracheal intubation followed by mechanical ventilation, but intubation is a difficult skill to acquire. When tracheal intubation using direct laryngoscopy is carried out by inexperienced personnel, there is a high risk of failure. Indirect laryngoscopy which uses a video-la-ryngoscope requires fewer skills to successfully secure the airway. We hypothesized that the use of the classical Macintosh laryngoscope is less effective in inexperienced hands compared with the video-laryngoscope GlideScope®, both in terms of successful intubation of the trachea and the time needed to achieve it. We asked thirty-nine registrars in internal medicine with negligible intubation experience to intubate a manikin airway model using a Macintosh laryngoscope and a video-la-ryngoscope GlideScope®. Inexperienced registrars with a mean duration of clinical experience as medical doctor of 1.7±1.0 years had a higher intubation success rate using the GlideScope® technique compared to the Macintosh technique (92% versus 69% respectively, P<0.05). However, the mean time needed for successful intubation was longer using the video-la-ryngoscope GlideScope® compared to the classical Macintosh laryngoscope (75±40 versus 39 ± 12 seconds respectively, P<0.05). In this study inexperienced registrars in internal medicine were able to intubate a manikin with a very high success rate using indirect video-laryngoscopy; however, the technique took more time to complete when compared with direct laryngoscopy.

IntroductionTo obtain a secure airway is of vital importance in the management of a critically ill patient. The preferred method of securing the airway is endotracheal intubation followed by mechanical ventilation. Direct laryngoscopy with intubation

Endotracheal intubation by inexperienced registrars in internal medicine: a comparison of video-laryngoscopy versus direct laryngoscopy

remains difficult for medical personnel who do not have sufficient clinical experience with the technique. Indirect video-laryngoscopy may require a lower level of technical expertise and experience to successfully intubate and these laryngoscopes are now commercially available. The image obtained by the video-laryngoscope GlideScope® is displayed on a monitor1 and provides better laryngeal views than conventional laryngoscopes.2-3 In a meta-analysis of Griesdale et al. the GlideScope® video technique was associated with improved glottis visualisation compared to direct laryngoscopy.2 Several studies have assessed the use of video and conventional laryngoscopes in terms of success rate. A manikin study for emergent intubation during cardiopulmonary resuscitation by inexperienced medical practitioners demonstrated that when the GlideScope® video-laryngoscope was used, the time to successful intubation was shorter and the success rate higher than when the Macintosh laryngoscope was used.3 Controversially, data from studies in the emergency department suggest that the success rate of intubation by emergency medicine residents on the first attempt did not differ between GlideScope® and Macintosh6-7 and that intubation using GlideScope® required more time.4 Also, studies with inexperienced medical students5 and experienced anaesthe-siologists6 showed that intubation with the GlideScope® took more time when a manikin was used and with easy intubation conditions. After extensive training of medical personnel and under close supervision of an anaesthesiologist, the intubation success rate in a manikin was over 90% when the GlideScope® technique was used.10 In this study we compared the use of the classical Macintosh laryngoscope and the GlideScope® video-laryngoscope by inexperienced untrained registrars in internal medicine in terms of successful endotracheal intubation, using an airway model.

H. Biermann*, E. van der Heiden*, A. Beishuizen, A.R.J. Girbes, M.C. de WaardDepartment of intensive care, institute for cardiovascular research, VU University Medical centre, amsterdam, the Netherlands,

*equal contribution

correspondence

m.c. de Waard – e-mail: [email protected]

Keywords – Video-laryngoscope, GlideScope®, Macintosh, inexperienced personnel, successful tracheal intubation

o r I g I n A l A r T I c l e



Materials and methodsProtocolRegistrars in internal medicine, with no or negligible prior experience of laryngoscopy, performed tracheal intubation on an airway model (SimMan®, Laerdal Benelux B.V., Netherlands) using a conventional laryngoscope (Macintosh, Welch Allyn Inc., USA) and a video-laryngoscope (GlideScope®, Verathon Inc., USA). Whole-class explanation and demonstration of both intubation scenarios was given by an experienced specialist. Before the first intubation attempt, the registrars were randomly assigned to either the Macintosh or GlideScope® group by lot. When the GlideScope® was used in the first attempt, the Macintosh was used in the second attempt, and vice versa. The time from the first insertion of the laryngoscope in the mouth until successful intubation was recorded. A maximum time of three minutes was allowed for each intubation attempt. The registrars were allowed to perform only one intubation attempt for each laryngoscope type. For each registrar, age, gender, number of years of clinical experience as medical doctor, previous anaesthesiology training and estimated total number of performed intubations and those performed during the last year were recorded. Time (seconds) needed to intubate and success of the intubation (yes/no) were scored. Intubations were scored as successful when the endotracheal tube was inserted in the trachea and the intubation attempt was finished within a three-minute timeframe. Failed attempts like unsuccessful intubation or oesophageal intubation and whether the registrar recognized this failed attempt were recorded.

Statistical analysisContinuous variables are presented as mean ± standard deviation (sd). Categorical variables are reported as counts and percentages. To test for significant differences between the two groups we used the Student’s t-test for continuous variables and the Fisher exact test for categorical variables. A wo-sided P≤0.05 was considered to indicate statistical significance.

ResultsThe group of participants consisted of 25 female and 14 male registrars in internal medicine of 29±3 years old, with no or negligible intubation experience. The mean duration of clinical experience as medical doctor was 1.7±1.0 years. All 39 participants performed two intubation attempts in an airway model using both the Macintosh laryngoscope and the GlideScope® video-la-ryngoscope. Eighteen of the 39 participants started with the Macintosh laryngoscope followed by the GlideScope® and 21 the other way round. The order in which the laryngoscopes were used did not affect intubation time or the intubation success rate. Furthermore, no effect of years of clinical experience as a medical doctor or estimated number of performed intubations in the past on intubation time was observed.

Intubation time using the Macintosh laryngoscope was 39±12 seconds (n=39) compared to 75±40 seconds (n=39) for the GlideScope® (P<0.05; figure 1A). However, more intubations failed within the three-minute time frame in the Macintosh group (12 out of 39 = 31%) compared to the GlideScope® group (3 out of 39 = 8%; P<0.05; figure 1B). All twelve unsuccessful intubations within the Macintosh group were identified as oesophageal intubations, of which only two were recognized as intubation failures by the participants. The three failed intubations in the GlideScope® group were due to exceeding the three minutes intubation attempt timeframe. Time needed for successful intubation was 35±10 seconds (n=27) in the Macintosh group and 66±24 seconds (n=36) using the GlideScope® (P<0.05).

DiscussionEndotracheal intubation is the preferred technique for securing an airway in compromised patients. Accordingly, the skill required to perform tracheal intubation is taught to both medical and paramedical healthcare professionals. Mulcaster et al. have shown that it takes approximately 50 intubations to acquire a 90% or higher success rate using direct laryngoscopy.7 Taking into account that many of the trained health care professionals perform intubations infrequently, it would be beneficial to rely on a technique that is easy to learn, perform, and has a high success rate. Our manikin study shows that the GlideScope® technique led to a higher intubation success rate in registrars in internal medicine inexperienced in performing laryngoscopy, compared to direct laryngoscopy. However, the time needed to successfully intubate was longer using the GlideScope® technique. This was consistent with another study that compared success rate and speed of intubation by novices

Figure 1A. mean intubation time using the macintosh laryngoscope (39±12 seconds, n=39, white bar) was shorter compared to the glidescope® (75±40 seconds, n=39, black bar). Figure 1B. more intubation attempts failed in the macintosh group (12 out of 39 = 31%) compared to the glidescope® group (3 out of 39 = 8%). * P<0.05 versus the glidescope® group.



endotracheal intubation by inexperienced registrars in internal medicine: a comparison of video-laryngoscopy versus direct laryngoscopy

using the GlideScope® technique on manikins.3 Nouruzi-Sedeh et al.8 showed that medical personnel untrained in intubation were more successful in tracheal intubation of patients using the GlideScope compared to direct laryngoscopy, however, this study showed no difference in intubation time. It should be noted that these untrained personnel had already received manikin training for tracheal intubation in the past, which was likely to have a positive effect on intubation time. Another study also reported no difference in intubation time comparing the GlideScope® technique with direct laryngoscopy by novices on manikins;9 this is in contrast to another study in which the GlideScope® technique was faster by novice personnel when compared to direct laryngoscopy.10 A recent meta-analysis showed that the use of the GlideScope® video-laryngoscope is associated with improved glottis visualisation, particularly in patients with potential or simulated difficult airways.3 One of the limitations of our study is the fact that it is a manikin study and does not involve real-life patients. Airway management in critically ill patients is more difficult and likely to be associated with complications, especially in acute situations when accompanied by desaturation periods and aspiration.11 With respect to this point, the airway model is not truly representative of an acute real-life situation. Another limitation of this study is the time frame of maximal three minutes which was used to perform a successful intubation. In an acute life threatening situation in critically ill patients you may not have a three minute time frame to attempt a successful intubation because of serious adverse events caused by hypoxemia during the attempt. Although the times required to perform airway interventions are generally quicker in a manikin model than in patients,12 three out of 39 intubation attempts with the GlideScope® failed due to exceeding the three minutes allowed. With regard to this, we are unable to comment on how the results of this study could be extrapolated on patients in an acute life threatening situation. Therefore, larger studies with longer follow-up of skill improvement in patients during acute situations are needed to validate our results.In conclusion, the use of a video-laryngoscope by inexperienced registrars in an airway manikin model appeared to be superior in terms of success rate. Although using the GlideScope® technique takes more time, a failed attempt might be more strenuous on a patient. Therefore, for health care professionals who need to acquire the skill to secure an airway but have limited time and infrequent exposure to do so, it may be advantageous to learn how to use a video assisted technique rather than the direct laryngoscope technique, which is still common practice. Currently, in our teaching level III ICU the fellows and residents who are not anaesthesiologists in training, are trained to use the GlideScope® primarily, and the GlideScope® technique has become the preferred method for intubations.

references

1. Benjamin FJ, Boon D and French RA. An evaluation of the GlideScope, a new video laryngoscope for difficult airways: a manikin study. Eur J Anaesthesiol. 2006;23:517-21.

2. Griesdale DE, Liu D, McKinney J and Choi PT. Glidescope(R) video-laryngoscopy versus direct laryngoscopy for endotracheal intubation: a systematic review and meta-analysis. Can J Anaesth. 2012;59:41-52.

3. Xanthos T, Stroumpoulis K, Bassiakou E, Koudouna E, Pantazopoulos I, Mazarakis A, et al. Glidescope((R)) videolaryngoscope improves intubation success rate in cardiac arrest scenarios without chest compressions interruption: a randomized cross-over manikin study. Resuscitation. 2011;82:464-7.

4. Platts-Mills TF, Campagne D, Chinnock B, Snowden B, Glickman LT and Hendey GW. A comparison of GlideScope video laryngoscopy versus direct laryngos-copy intubation in the emergency department. Acad Emerg Med. 2009;16:866-71.

5. Lim Y, Lim TJ and Liu EH. Ease of intubation with the GlideScope or Macintosh laryngoscope by inexperienced operators in simulated difficult airways. Can J Anaesth. 2004;51:641-2.

6. Lim TJ, Lim Y and Liu EH. Evaluation of ease of intubation with the GlideScope or Macintosh laryngoscope by anaesthetists in simulated easy and difficult laryn-goscopy. Anaesthesia. 2005;60:180-3.

7. Mulcaster JT, Mills J, Hung OR, MacQuarrie K, Law JA, Pytka S, et al. Laryngoscopic intubation: learning and performance. Anesthesiology. 2003;98:23-7.

8. Nouruzi-Sedeh P, Schumann M and Groeben H. Laryngoscopy via Macintosh blade versus GlideScope: success rate and time for endotracheal intubation in untrained medical personnel. Anesthesiology. 2009;110:32-7.

9. Xanthos T, Bassiakou E, Koudouna E, Stroumpoulis K, Vlachos I, Johnson EO, et al. Inexperienced nurses and doctors are equally efficient in managing the airway in a manikin model. Heart Lung. 2011.

10. Malik MA, Hassett P, Carney J, Higgins BD, Harte BH and Laffey JG. A comparison of the Glidescope, Pentax AWS, and Macintosh laryngoscopes when used by novice personnel: a manikin study. Can J Anaesth. 2009;56:802-11.

11. Nolan JP and Kelly FE. Airway challenges in critical care. Anaesthesia. 2011;66 Suppl 2:81-92.

12. Gatward JJ, Thomas MJ, Nolan JP and Cook TM. Effect of chest compressions on the time taken to insert airway devices in a manikin. Br J Anaesth. 2008;100:351-6.




AbstractNormal glomerular filtration rate (GFR) declines with age and in disease. Diminished GFRs are seen in many patients on the ICU. The clearance of toxins and pharmaceuticals might be (temporarily) diminished especially in patients with septic or circulatory shock. Most physicians are aware of this and adjust the dosage of antibiotics accordingly: the dosage is reduced or the administration interval is prolonged. However, some patients have an increased clearance of antimicrobials, so-called glomerular hyperfiltration. Glomerular hyperfiltration is present whenever the GFR exceeds 160 ml/min/1.73 m2 in men and 150 ml/min/1.73 m2 in women. This is especially seen in young, male patients after neurotrauma, polytrauma or burn patients. The consequences of glomerualr hyperfiltration might be that antibiotics are cleared more rapidly and concentrations fall below optimal levels. This compromises effective antimicrobial therapy when it is most important: directly from the beginning of treatment. Therapeutic Drug Monitoring (TDM) of all classes of antibiotics is needed in ICUs that treat critically ill patients at risk of glomerular hyperfiltration.

Acute kidney injury on the ICU Acute kidney injury is a common complication of acute illness, affecting approximately 2-7% of hospitalised patients and more than 35% of critically ill patients.1 Acute kidney injury (AKI) consists of a rapid and sustained decline in the glomerular filtration rate (GFR) that results in the inability of the kidneys to eliminate waste products, toxins, antibiotics and other medications, or to maintain proper fluid and electrolyte balances.2 Most ICUs measure creatinine levels on a daily basis. Whenever creatinine levels increase (and estimated GFRs diminish) we interpret these changes as renal dysfunction, particularly in combination with oliguria (urine output <0.5 mL/kg/h). Whenever this occurs, most clinicians are quite

Glomerular hyperfiltration of antibiotics

eager to modify their dosage schemes of renally excreted antibiotics: either the dosage is reduced or the administration interval is prolonged. However, it remains questionable whether this is a sound decision in all circumstances.

Hyperdynamic circulation and glomerular hyperfiltration The hemodynamic manifestations Systemic Inflammatory Response Syndrome (SIRS) are low systemic vascular resistance and a high cardiac output. The impact of this hyperdynamic circulation upon renal function is still being studied. In animal models of early sepsis, renal blood flow has been documented to increase parallel to cardiac output.10 In a later phase of sepsis the renal blood flow is diminished, resulting in decreased creatinine clearance.11 One of the first measures to improve cardiovascular function in patients with SIRS is fluid resuscitation followed by the application of vasopressors. Again, animal research has shown that crystalloids and vasoactive drugs can result in an increase of creatinine clearance.12,13 Data from these studies suggest that in critically ill patients without significant renal dysfunction and in whom adequate resuscitation has been achieved, renal clearance might actually be increased in the acute phase: this is known as glomerular hyperfiltration.

How do we measure GFR when renal function is unstable?The gold standard estimations of GFR include urinary clearance of iohexal and clearance of various radionuclide markers, among which 99mTc-labeled diethylenetriaminepen-taacetic acid (DTPA), 51Cr-labeled EDTA, and 125I-labeled iothalamate.9 However, these test methods are cumbersome and are almost never used in daily practice. Numerous equations have been used to estimate the GFR from serum creatinine levels in patients with chronic kidney diseases. The Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and

D.W. de LangeDepartment of intensive care Medicine and the National Poison information center (NPic), University Medical center, University Utrecht,

the Netherlands

correspondence

d.W. de lange – e-mail: [email protected]

Keywords – antibiotic, renal clearance, icU, pharmacokinetics, pharmacodynamics

r e v I e W



glomerular hyperfiltration of antibiotics

Cockcroft-Gault formula are the most widely used estimations for GFR in patients with chronic but stable kidney disease. Unfortunately, all have a poor application in the critically ill, especially when renal function is not stable.3-5 Although these calculations are somewhat more useful than a single creatinine concentration, the use of such equations to estimate the GFR should be discouraged in critically ill patients.3,6,7 A possible better way to estimate GFR in critically ill patients is a urinary creatinine collection taken over 4 to 12 hours.8,9 However, the optimal time period in which creatinine clearance should be measured in unstable critically ill patients is still debatable. The GFR is influenced by circadian rhythm and intra-individual variability is likely to be substantial. Because rapid changes in renal function might occur in the critically ill, more frequent sampling of urine creatinine collection has been advocated.

What is glomerular hyperfiltration?One of the most important functions of the kidney is to excrete circulating metabolites, toxins, waste products and pharmaceutical products such as antibiotics. This can be achieved by a combination of glomerular filtration, tubular secretion and reabsorption. Glomerular hyperfiltration means that the renal clearance of waste products and antibiotics is above normal limits. Accurately defining this is difficult because we cannot agree upon “normal renal function” in any population, let alone in critically ill patients! However, the most accepted definition of “normal renal function” is the GFR of approximately 130 mL/min/1.73 m2 in young, healthy, adult males and 120 ml/min/1.73 m2 in young, healthy, adult females.14 Importantly, these values decline over age (figure 1). One of the most sensible definitions of “glomerular hyperfiltration” is a GFR >10% higher than the normal limits. This means a GFR of >160 mL/min/1.73 m2 in young men and a GFR >150 mL/min/1.73 m2 in young women.8 These conservative thresholds are likely to identify patients that truly have “glomerular hyperfiltration”. In a single-centre observational cohort (n=89) 17.9% of the patients had such “glomerular hyperfiltration” on admission and 75% had hypoalbuminaemia.15 During the first week of admission, the percentage of patients with glomerular hyperfiltration rose to 30%. The patients with an elevated GFR were primarily younger, polytrauma victims or postoperative patients, were less severely ill (lower APACHE II scores) and had higher urine outputs. In a subgroup of patients with traumatic brain injury, who received norepinephrine treatment, increased creatinine clearance had been noticed. These increased GFRs (>150 mL/min/1.73 m2) were already present before the initiation of norepinephrine treatment and remained elevated for the duration of this study (24 hours).16 Quite similar results had been found in a much older study. Here the effects of a combination of dopamine and norepinephrine were studied in 20 young, stable patients with brain trauma. The mean GFR at

the beginning of the study was 152 mL/min/1.73 m2.17 Recently these results have been confirmed in another study involving patients with brain trauma.7 Based upon the definitions of glomerular hyperfiltration as stated above, they found that in 17 out of 20 (85%) patients, renal clearance was clearly increased (mean GFR of 179 with interquartile range of 159-198 mL/min/1.73 m2). The mean age of this population was 26 years and they were receiving 3% NaCl infusions and vasopressor therapy to maintain a cerebral perfusion pressure >60 mmHg. From these small and uncontrolled case series, which all used proper creatinine clearance in urine samples, it follows that younger patients, admitted after trauma and/or brain trauma are at particular risk of developing glomerular hyperfiltration. However, higher than normal antimicrobial clearances have been documented in patients with sepsis18,19, haematological malignancies20,21 and patients with burns22,23 as well.

What are the consequences of glomerular hyperfiltration?Why should we be bothered with glomerular hyperfiltration? A faster excretion of waste products and toxins is a good thing and the effects of other pharmaceuticals can be dosed according to their pharmacodynamic effect. If midazolam metabolites are excreted in a more rapid fashion, we will just increase the infusion rates until the patient is sufficiently sedated. Unfortunately, not all effects of pharmaceuticals are directly evident. If antibiotics are administered inadequately

Figure 1. declining creatinine clearances over age.

normal values for inulin clearance are shown for men and women of various ages, with the gFr measured as the urinary clearance of inulin. A gFr value of 60 ml/min/1.73 m2 is the threshold for the defi-nition of chronic kidney disease. solid lines represent the mean value of gFr per decade of age, and dashed lines represent the value 1 standard deviation from the mean value of gFr per decade of age. A gFr >160 ml/min/1.73 m2 in men and >150 ml/min/1.73 m2 in women is considered glomerular hyperfiltration (grey area). Adapted from stevens et al. neJm 2006;354:2473-2483. With permission from the massachusetts medical society.



this might result in slower eradication of the infection or even introduce resistance.24 Unfortunately, resolution of infection takes time and recognizing whether the antibiotics are working properly will take days. Therefore, glomerular hyperfiltration might be the cause of ineffective antimicrobial therapy just at the time when it counts most: at the start of treatment!

Pharmacodynamics and glomerular hyperfiltrationDifferent classes of antibiotics possess different pharmacodynamic properties. Some antibiotics have concentration dependent killing, while others typically demonstrate time depending killing (see figure 2). Aminoglycosides, like gentamicin and tobramycin, are classical examples of antibiotics that exhibit concentration dependent killing properties. The higher the peak concentration (also called maximum concentration, Cmax) in relation to the minimum inhibitory concentration (MIC) of a bacterium the better the killing.25 The killing of bacteria is optimal whenever the Cmax/MIC >10. This means that the peak concentration of an aminoglycoside, in the organ you are trying to treat, should be 10x higher than the MIC of the bacterium. The peak concentration depends on the loading dose of the aminoglycoside and its immediate dilution in the extracellular

fluid compartment (the so-called volume of distribution, Vd). Aminoglycosides are hydrophilic, rather large molecules. Therefore, their apparent Vd is rather small (no penetration into cells, no penetration into lipophilic compartments) and almost the entire aminoglycoside loading dose is present in a free and unbound fashion. Modern dosage schemes are >7 mg/kg once daily.25,26 Glomerular hyperfiltration will not influence the Vd and therefore have no influence on the loading dose. However, the clearance of aminoglycosides might be faster than in patients with a normal GFR. Therefore, the frequency of the maintenance dose might be increased to once every 18 hours instead of once daily.8 Indeed, the Vd of aminoglycosides is unpredictable in critically ill patients and the penetration into organs (like the lung and the abdominal cavity) is limited.27,28 As a consequence, the pharmacodynamic goal (Cmax/MIC>10) is often not attained in critically ill patients.27

Beta-lactam antibiotics (penicillins, cephalosporins, monobactams and carbapenems) demonstrate time dependent killing (see figure 2). This means that the killing of bacteria by beta-lactam antibiotics is maximal whenever the free and unbound concentration of beta-lactams is higher than the minimum inhibitory concentration ( fuT>MIC) during 70-100% of the time.7,25 Again, the direct concentration depends on the loading dose and its immediate dilution into the Vd. Unfortunately, the Vd can be highly variable in critically ill patients. Just consider a patient in septic shock who is being aggressively resuscitated with fluids. In such patients, the Vd for hydrophilic antimicrobials (like aminoglycosides, beta-lactams, and vancomycin) might even be doubled. For this reason, a one-size-fits-all loading dose cannot be established in critically ill patients. However, the trough levels (also called minimum levels, Cmin) are dependent on binding to proteins and excretion by the liver and kidneys. Whenever there is glomerular hyperfiltration, the beta-lactams will be excreted more efficiently and minimal levels will be reached earlier. Given the pharmacodynamic goal of keeping the trough level above the MIC for as long as possible, the dosage frequency may have to be increased. Just giving higher dosages might lead to higher free fractions and more clearance of antibiotics. An alternative is to administer beta-lactams by continuous infusion. Theoretically the trough levels will be above MIC for all of the time ( fuT>MIC = 100%). Again, in critically ill patients the volume of distribution and renal clearance are not stable over time. The range of protein binding of beta-lactams is enormous. Some beta-lactams are predominantly bound to albumin, like ceftriaxone (85-95% is protein bound), while others are hardly bound to albumin, like amoxicillin (17-20% is protein bound).29 Unfortunately, critically ill patients often have hypoalbu-minaemia. In the Saline versus Albumin Fluid Evaluation (SAFE)-study, hypoalbuminaemia (<25 g/L) was seen in 40.5% of the patients on admission to the ICU.30 Hypoalbuminaemia

Figure 2. concentration dependent killing and time dependent killing.

some antibiotics exhibit so-called concentration-dependent killing properties. This means that the higher the peak concentration in relation to minimum inhibitory concentration where 90% of the bacteria are killed (mIc90) the better bacteria are killed (peak/mIc-ratio). A peak/mIc-ratio >10 results in optimal killing for aminoglyco-sides, like gentamicin and tobramycin.other antimicrobials exhibit time dependent killing properties (e.g. beta-lactam antibiotics, like penicillins, cephalosporins, monobac-tams and carbapenems). This means that the longer the concentra-tion stays above the mIc the better the bacteria are killed. Peak con-centrations are not needed. The free and unbound concentration of beta-lactams (fuT>mIc) needs to be above the mIc 70-100% of the time for optimal killing.



glomerular hyperfiltration of antibiotics

results in a higher free and unbound antibiotic fraction. Although this means that the “active fraction” has increased it also means that the fraction available for renal clearance is higher. This is particularly true for beta-lactam antibiotics with a high protein binding, like ceftriaxone. In patients with hypoalbuminaemia (and normal GFR) ceftriaxone clearance might be doubled, leading to trough levels below the MIC too early.31 The pharmacodynamic goal ( fuT>MIC 70-100%) might, therefore, not be reached. Clearly, we cannot predict the initial Vd, the GFR and the hypoalbuminaemia in critically ill patients and changes over time are commonplace on the ICU. A prerequisite for the administration of beta-lactams in critically ill patients is therapeutic drug monitoring (TDM). We have to assure whether the free and unbound trough levels remain above the MIC whenever something changes in our patients. Additionally, TDM can minimise the risk of toxicity in excessive dosing. At present only very few hospitals in the Netherlands are able to provide this necessary TDM.

ConclusionsGlomerular hyperfiltration (>150 ml/min/1.73m2 in women and >160 ml/min/1.73 m2 in men) is seen in a substantial subpopulation on the ICU. Especially younger patients with neurotrauma, polytrauma, burns or sepsis, appear to be at risk of higher than normal clearance of antibiotics. In addition, hypoalbuminaemia causes higher free and unbound fractions of antibiotics, and thereby further increases renal clearance of protein bound antibiotics. Both lead to suboptimal concentrations of antibiotics and possibly less effective antimicrobial therapy. Creatinine concentrations and estimations of the glomerular filtration rate (GFR) are

inadequate for measuring such elevated clearance in clinical practice. Because rapid changes in renal function might occur in the critically ill, measuring creatinine clearance with short period urine collections seems the best available option. All kinds of pharmacokinetic conditions, like hypoalbu-minaemia, clearance and volume of distribution, are constantly changing in critically ill patients. Therefore, Therapeutic Drug Monitoring (TDM) of all antimicrobials (including beta-lactam antibiotics) should be available in hospitals treating critically ill patients.

references

1. VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359:7-20.

2. Valette X, du Cheyron D. A critical appraisal of the accuracy of the RIFLE and AKIN classifications in defining “acute kidney insufficiency” in critically ill patients. J Crit Care. 2013;28:116-25.

3. Bragadottir G, Redfors B, Ricksten SE. Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury – true GFR versus urinary creatinine clearance and estimating equations. Crit Care. 2013;17:R108.

4. Poggio ED, Wang X, Greene T, Van Lente F, Hall PM. Performance of the modifica-tion of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol. 2005;16:459-66.

5. Hoste EA, Damen J, Vanholder RC, et al. Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol Dial Transplant. 2005;20:747-53.

6. Baptista JP, Udy AA, Sousa E, et al. A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care. 2011;15:R139.

7. Udy A, Boots R, Senthuran S, et al. Augmented creatinine clearance in traumatic brain injury. Anesth Analg. 2010;111:1505-10.

8. Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clear-ance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49:1-16.

9. Martin JH, Fay MF, Udy A, et al. Pitfalls of using estimations of glomerular filtra-tion rate in an intensive care population. Intern Med J. 2011 Jul;41:537-43.

10. Di Giantomasso D, May CN, Bellomo R. Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis. Intensive Care Med. 2003;29:1774-81.

11. Prowle JR, Molan MP, Hornsey E, Bellomo R. Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation. Crit Care Med. 2012;40:1768-76.

12. Wan L, Bellomo R, May CN. The effects of normal and hypertonic saline on regional blood flow and oxygen delivery. Anesth Analg. 2007;105:141-7.

13. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney injury. Crit Care Med. 2008l;36:S179-S186.

14. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med. 2006;354:2473-83.

15. Fuster-Lluch O, Gerónimo-Pardo M, Peyró-García R, Lizán-García M. Glomerular hyperfiltration and albuminuria in critically ill patients. Anaesth Intensive Care. 2008;36:674-80.

16. Albanèse J, Leone M, Garnier F, Bourgoin A, Antonini F, Martin C. Renal effects of norepinephrine in septic and nonseptic patients. Chest. 2004;126:534-9.

17. Benmalek F, Behforouz N, Benoist JF, et al. Renal effects of low-dose dopamine during vasopressor therapy for posttraumatic intracranial hypertension. Intensive Care Med. 1999;25:399-405.

18. Udy AA, Varghese JM, Altukroni M, et al. Subtherapeutic initial β-lactam con-centrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest. 2012;142:30-9.

19. Tröger U, Drust A, Martens-Lobenhoffer J, Tanev I, Braun-Dullaeus RC, Bode-Böger SM. Decreased meropenem levels in Intensive Care Unit patients with augmented renal clearance: benefit of therapeutic drug monitoring. Int J Antimicrob Agents. 2012;40:370-2.

20. Pea F, Viale P, Candoni A, et al. Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages. Clin Pharmacokinet. 2004;43:405-15.

Table 1. suggested reading

Suggested readingmarta ulldemolins and co-authors emphasise how often hypoalbuminaemia is seen in the Icu. They highlight the consequences of hypoalbuminaemia on different classes of antibiotics. A list of antibiotics with their estimated protein binding is included.

clin Pharmacokinet. 2011;50:99-110.

Frederico Pea and Pierluigi viale describe which chemical properties are important for an antimicrobial in order to reach its target organ. They also explain the concentration needed for optimal killing and conclude that certain antimicrobials (especially the aminoglycosides) do not attain sufficient concentrations in target organs. This seriously limits their use. A list with proposed antimicrobial dosage schemes is included.

crit care. 2009;13:214.

Andrew udy and co-authors describe the consequences of augmented renal clearance (=glomerular hyperfiltration) of various antibiotic classes. They describe the difficulties of assessing glomerular filtration rate in critically ill patients and suggest that creatine clearance in urine is probably the best estimation.

clin Pharmacokinet. 2010;49:1-16.



21. Lamoth F, Buclin T, Csajka C, Pascual A, Calandra T, Marchetti O. Reassessment of recommended imipenem doses in febrile neutropenic patients with hemato-logical malignancies. Antimicrob Agents Chemother. 2009;53:785-7.

22. Conil JM, Georges B, Lavit M, et al. A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation. Br J Clin Pharmacol. 2007;64:27-35.

23. Dailly E, Le Floch R, Deslandes G, Pannier M, Jolliet P. Influence of glomeru-lar filtration rate on the clearance of vancomycin administered by continuous infusion in burn patients. Int J Antimicrob Agents. 2008;31:537-9.

24. Chytra I, Stepan M, Benes J, et al. Clinical and microbiological efficacy of con-tinuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16:R113.

25. Pea F, Viale P. Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock--does the dose matter? Crit Care. 2009;13:214.

26. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS. Optimizing aminoglyco-side therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43:623-9.

27. Rea RS, Capitano B, Bies R, Bigos KL, Smith R, Lee H. Suboptimal aminoglycoside dosing in critically ill patients. Ther Drug Monit. 2008;30:674-81.

28. Gonçalves-Pereira J, Martins A, Póvoa P. Pharmacokinetics of gentamicin in crit-ically ill patients: pilot study evaluating the first dose. Clinical Microbiology and Infection. 2010;16:1258-63.

29. Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoal-buminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011;50:99-110.

30. Finfer S, Bellomo R, McEvoy S, et al. Effect of baseline serum albumin concentra-tion on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. 2006;333:1044.

31. Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong EL, Gin T. The pharmacoki-netics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother. 2001;47:421-9.

VERKORTE PRODUCTINFORMATIECANCIDAS® 50 mg poeder voor concentraat voor oplossing voor intraveneuze infusie.CANCIDAS® 70 mg poeder voor concentraat voor oplossing voor intraveneuze infusie.SamenstellingCANCIDAS 50 mg bevat 50 mg caspofungin (als acetaat). CANCIDAS 70 mg bevat 70 mg caspofungin (als acetaat).Indicaties• Behandeling van invasieve candidiasis bij volwassen patiënten

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kinderen die niet reageren op amfotericine B, toedieningsvormen van amfotericine B met lipiden en/of itraconazol of deze niet verdragen.

• Empirische therapie voor vermoede schimmelinfecties (zoals Candida of Aspergillus) bij volwassen patiënten of kinderen met koorts en neutropenie.

Contra-indicatiesOvergevoeligheid voor het actieve bestanddeel of één van de hulpstoffen.Waarschuwingen en voorzorgen De werkzaamheid van caspofungine tegen de minder vaak voorkomende niet-Candida-gisten en niet-Aspergillus-schimmels is niet vastgesteld.Bij gelijktijdig gebruik van CANCIDAS met ciclosporine werden geen ernstige bijwerkingen aan de lever opgemerkt. Sommige gezonde volwassen vrijwilligers die ciclosporine samen met caspofungine kregen, vertoonden een voorbijgaande verhoging van het alaninetransaminase (ALT) en aspartaattransaminase (AST) van minder dan of gelijk aan 3 maal de bovenste waarde van het normale bereik (ULN), die bij stopzetting van de behandeling verdween. CANCIDAS kan gebruikt worden bij patiënten die ciclosporine krijgen als de mogelijke voordelen opwegen tegen de potentiële risico’s. Zorgvuldige controle van de leverenzymen moet worden overwogen als CANCIDAS en ciclosporine gelijktijdig worden gebruikt.Bij een matige leverfunctiestoornis wordt een verlaging van de dagelijkse dosis naar 35 mg aanbevolen. Er is geen klinische ervaring met ernstige leverinsufficiëntie of bij kinderen met elke mate van leverinsufficiëntie. Te verwachten valt dat de blootstelling hoger is dan bij matige leverinsufficiëntie; bij deze patiënten moet CANCIDAS voorzichtig worden toegepast.De gegevens over de veiligheid van een behandeling die langer duurt dan 4 weken zijn beperkt.BijwerkingenVolwassen patiëntenFlebitis was in alle patiëntpopulaties een vaak gemelde lokale bijwerking op de injectieplaats. Andere lokale reacties waren erytheem, pijn/gevoeligheid, jeuk, afscheiding, en een brandend gevoel. De gemelde klinische en laboratoriumafwijkingen bij alle met CANCIDAS behandelde volwassenen waren over het algemeen licht en maakten zelden stopzetting noodzakelijk.De volgende bijwerkingen zijn gemeld:[Zeer vaak (≥1/10), Vaak (≥1/100 tot <1/10), Soms (≥1/1.000 tot <1/100)]Vaak: verlaagd hemoglobine, verlaagd hematocriet, verminderd aantal leukocyten, hypokaliëmie, hoofdpijn, flebitis, dyspnoe, misselijkheid, diarree, braken, verhoogde leverwaarden (AST, ALT, alkalische fosfatase, direct en totaal bilirubine), uitslag, pruritus, erytheem, hyperhidrose, artralgie, koorts, rillingen, pruritus op infusieplaats.Soms: anemie, trombocytopenie, coagulopathie, leukopenie, verhoogd aantal eosinofielen, verminderd aantal trombocyten, verhoogd aantal trombocyten, verminderd aantal lymfocyten, verhoogd aantal leukocyten, verminderd aantal neutrofielen, vochtophoping, hypomagnesiëmie, anorexia, gestoorde elektrolytenbalans, hyperglykemie, hypocalciëmie, metabole acidose, angst, desoriëntatie, slapeloosheid, duizeligheid, dysgeusie, paresthesie, slaperigheid, tremoren, hypo-esthesie, oculaire icterus, wazig zien, oedeem van het ooglid, verhoogde traanvorming, palpitaties, tachycardie, aritmieën, atriumfibrilleren, hartfalen, tromboflebitis, flushing, opvliegers, hypertensie, hypotensie, verstopte neus, faryngolaryngeale pijn, tachypnoe, bronchospasmen, hoest, paroxysmale dyspnoe ‘s nachts,

hypoxie, rhonchi, wheezing, buikpijn, pijn in de bovenbuik, droge mond, dyspepsie, last van de maag, opgezwollen buik, ascites, constipatie, dysfagie, winderigheid, cholestase, hepatomegalie, hyperbilirubinemie, geelzucht, gestoorde leverfunctie, hepatotoxiciteit, leveraandoening, erythema multiforme, maculaire uitslag, maculopapulaire uitslag, pruritische uitslag, urticaria, allergische dermatitis, gegeneraliseerde pruritus, erythemateuze uitslag, gegeneraliseerde uitslag, morbilliforme uitslag, huidlaesie, rugpijn, pijn in extremiteiten, botpijn, spierzwakte, myalgie, nierfalen, acuut nierfalen, pijn, pijn rond catheter, vermoeidheid, koud gevoel, warm gevoel, erytheem op infusieplaats, verharding op infusieplaats, pijn op infusieplaats, zwelling op infusieplaats, flebitis op injectieplaats, perifeer oedeem, gevoeligheid, ongemak op de borst, pijn op de borst, aangezichtsoedeem, gevoel van andere lichaamstemperatuur, verharding, extravasatie op infusieplaats, irritatie op infusieplaats, flebitis op infusieplaats, uitslag op infusieplaats, urticaria op infusieplaats, erytheem op injectieplaats, oedeem op injectieplaats, pijn op injectieplaats, zwelling op injectieplaats, malaise, oedeem.Onderzoeken:Vaak: verlaagd kalium in bloed, verlaagd bloedalbumine.Soms: verhoogd bloedcreatinine, positief voor rode bloedcellen in urine, verlaagd totaal eiwit, eiwit in urine, verlengde protrombinetijd, verkorte protrombinetijd, verlaagd natrium in bloed, verhoogd natrium in het bloed, verlaagd calcium in bloed, verhoogd calcium in bloed, verlaagd chloride in bloed, verhoogd glucose in bloed, verlaagd magnesium in bloed, verlaagd fosfor in bloed, verhoogd fosfor in bloed, verhoogd ureum in bloed, verhoogd gamma-glutamyltransferase, verlengde geactiveerde partiële tromboplastinetijd, verlaagd bicarbonaat in bloed, verhoogd chloride in bloed, verhoogd kalium in bloed, verhoogde bloeddruk, verlaagd urinezuur in bloed, bloed in urine, afwijkende ademgeluiden, verlaagd kooldioxide, verhoogde concentratie immunosuppressivum, verhoogde INR, cilinders in urinesediment, positief op witte bloedcellen in urine, en verhoogde pH van urine.KinderenHet algehele veiligheidsprofiel van CANCIDAS bij kinderen is over het algemeen vergelijkbaar met dat bij volwassenen.Zeer vaak: koorts.Vaak: verhoogd aantal eosinofielen, hoofdpijn, tachycardie, flushing, hypotensie, verhoogde leverenzymen (AST, ALT), uitslag, pruritus, rillingen, pijn op de injectieplaats.Onderzoeken:Vaak: verlaagd kalium, hypomagnesiëmie, verhoogd glucose, verlaagd fosfor en verhoogd fosfor. Post-marketingervaringSinds de introductie van het product zijn de volgende bijwerkingen gemeld:leverfunctiestoornis, zwelling en perifeer oedeem, hypercalciëmie.

Farmacotherapeutische groepAntimycotica voor systemisch gebruik, ATC-code: J 02 AX 04AfleverstatusURVerpakkingCANCIDAS 50 mg is beschikbaar in een verpakking met 1 injectieflacon.CANCIDAS 70 mg is beschikbaar in een verpakking met 1 injectieflacon.VergoedingCANCIDAS wordt volledig vergoed. Raadpleeg de volledige productinformatie (SPC) voor meer informatie over CANCIDAS.

Merck Sharp & Dohme BVWaarderweg 39 2031 BN HaarlemTel.: 0800-9999000www.msd.nl

Mei 2012 (SmPC datum 19 juli 2012)




AbstractObjective: This case report describes a 58-year old man with respiratory insufficiency caused by a systemic immune complex vasculitis. A brief review of the literature is given.Patient/Subject: A 58-year old man presented with respiratory insufficiency caused by a systemic immune-complex vasculitis. His symptoms were haemoptysis due to alveolar haemorrhage, a leukocytoclastic vasculitis of the skin and glomerulo-nephritis. He was diagnosed with cryoglobulinemia and was successfully treated with prednisone and rituximab. Conclusion: Cryoglobulinemia should be considered in small vessel vasculitis. Diffuse alveolar haemorrhage is a rare complication of type 2 cryoglobulinemia.

Introduction Immunoglobulin M (IgM) associated disorders, such as cold agglutinin disease, cryoglobulinemia and peripheral neuropathy, are caused by autoreactivity of IgM paraproteins. Waldenström macroglobulinemia or signs of lymphoma are usually absent and the M-protein is low.Cold agglutinin disease is characterized by antibodies directed against the I/i antigens on erythrocytes. This can be induced by viral infections (i.e. EBV, CMV) or Mycoplasma pneumoniae, for example. Clinical features consist of acrocyanosis and haemolytic anemia.Cryoglobulinemia is defined as presence of one or more immunoglobulins in the serum that precipitate at temperatures below 37ºC and dissolve again on rewarming. Cryoglobulinemia is usually classified into three types according to Brouet’s classification. Type 1 is characterized by the presence of a monoclonal immunoglobulin which can be seen in lymphopro-liferative disorders such as chronic lymphatic leukaemia, multiple myeloma or non-Hodgkin lymphoma. Type 2 has a monoclonal component (mostly IgM) and polyclonal immunoglobulin which can lead to immune-complex vasculitis. Type 3 has polyclonal immunoglobulins of different isotypes. Types 2 and 3 are also called mixed type cryoglobulinemia.1 There is a wide range of

Cryoglobulinemia complicated by diffuse alveolar haemorrhage

symptoms. Patients can be asymptomatic, but they can also have a hyperviscosity syndrome and on rare occasions present with multi organ failure. Criteria for the classification of cryoglob-ulinemia patients are based on serologic, pathologic and clinical findings. 70% of cases classify as a mixed type cryoglobulinemia (type 2), which has a strong association with the hepatitis C virus (HCV) infection. We present a patient with hepatitis C negative mixed type cryoglobulinemia with alveolar haemorrhage caused by vasculitis.

Case reportA 58-year old male was admitted with erythematous lesions on his lower extremities and decreased renal function. Skin biopsy showed a leukocytoclastic vasculitis, immunofluorescence was not performed. On the ward the patient’s renal function declined with creatinine levels increasing from 92 to 170 µmol/L (normal 70-106 µmol/L). Over 40% dysmorphic erythrocytes, proteinuria and hyaline casts were present in the urine, suggesting glomerulonephritis. Unfortunately, renal biopsy was inconclusive since it did not contain enough glomeruli. C-reactive protein was 14 mg/L, haemoglobin 5.5 mmol/L, thrombocytes 174 x109/L and leukocytes 15.1x109/L with a normal differentiation. Liver enzymes were normal. Before admission to the ward he was treated with clarithromycin for a presumed pulmonary infection that showed on his chest X ray (figure 1). All cultures remained negative.A few days after admission the patient developed progressive hypoxemia and haemoptysis and was admitted to the Intensive Care for intubation and mechanical ventilation. CT scan of the lungs showed bilateral thickening of interlobular septa with cysts and ground-glass opacification (figure 2). Bronchoalveolar lavage showed red blood cells, 67% T-lymphocytes, 6% granulocytes and 14% alveolar macrophages. Because of the haemorrhage a biopsy was not performed. All tests for auto-immune diseases (ANA, ENA, ANCA, anti-GBM and anti-CCP) were negative except for a positive IgM rheumatoid factor. Decreased levels of C3 (0.59 gr/L), C4 (<0.1 gr/L) and

J.E.M. Schilders1, A.J.B.W. Brouwers2, H.C.T. van Zaanen1

Departments of internal Medicine, Division of 1haematology and 2intensive care, Sint Franciscus Gasthuis rotterdam

correspondence

H.c.T. van Zaanen – e-mail: [email protected]

Keywords – alveolar haemorrhage, cryoglobulinemia, vasculitis

c A s e r e P o r T



an elevated C1q-binding test of 93% (normal <8%) suggested an immune complex disease. The viral serology including hepatitis B, C, EBV, CMV and HIV were also negative. Because of a suspected seronegative granulomatosis with polyangiitis he was started on prednisone 1dd 60mg, cyclophosphamide 1dd 100mg for a total of ten days (1.5mg/kg adjusted for acute kidney injury) and plasmapheresis, with poor result. Decreased levels IgG (0.6 g/L) and IgA (0.6 g/L) were found with a slightly increased IgM (2.33 g/L), however, this test was performed after initial treatment. Morphology of the bone marrow biopsy showed no abnormalities. Immunological examination showed 1% plasma cells and 15% monoclonal B-lymphocytes with an increased kappa/lambda ratio of 47 (normal <4.9).

The level of free light chains kappa in the serum was elevated (109 mg/L), the ratio of kappa/lambda free light chains was also increased (ratio 23, normal 0.26-1.65) and cryoglobulins were present. Hepatitis C RNA could not be detected. We concluded that clinical and laboratory findings suggested a hepatitis C virus negative mixed cryoglobulinemia (type 2) with multi organ involvement including diffuse alveolar haemorrhage, which led to respiratory failure, leukocytoclastic vasculitis of the skin and glomerulonephritis caused by an immune complex vasculitis.The patient was treated with prednisone 1mg/kg daily and rituximab 375 mg/m2, a monoclonal antibody against CD20 on B-lymphocytes, initially weekly for four weeks and later every three months for a total of two years according to the Non Hodgkin Lymphoma protocol. After several weeks of treatment his clinical condition improved. Chest X-rays improved significantly and normalized over time. Currently, 17 months later, he is no longer on steroids and is doing well. Kappa/lambda ratios, IgM, complement levels etc. normalized and cryoglobulins can not be detected anymore.

Discussion Our patient was diagnosed with cryoglobulinemia after initial treatment with prednisone, cyclophosphamide and plasmapheresis for presumed granulomatosis with polyangiitis. We found decreased levels of IgG and IgA plus a slightly increased IgM with cryo-activity. It is possible that IgM levels were even higher prior to this treatment. Free light chains kappa in the serum were elevated and a low concentration of monoclonal B-lymphocytes in the bone marrow was found. CT scan did not show lymphadenopathy or organomegaly and an underlying malignancy could not be detected despite a population of monoclonal B-cell lymphocytes in the bone marrow. Our patient had several minor and major criteria to support the diagnosis of cryoglob-ulinemia, including a positive IgM rheumatoid factor, an activated immune system, detection of cryoglobulins and a monoclonal B-lymphocyte population.There are three subtypes of cryoglobulinemia.1,2 Type 1 is characterized by the presence of a monoclonal immunoglobulin which can be seen with lymphoproliferative disorders such as multiple myeloma, NHL or chronic lymphatic leukemia. Patients with type 1 cryoglobulinemia are typically asymptomatic but can have a hyperviscosity syndrome. Type 2 has a monoclonal component, mostly IgM, and polyclonal immunoglobulins, type 3 has polyclonal immunoglobulins of different isotypes. Type 2 and 3 (mixed types) are associated with different infectious, immunological or malignant disorders. Mixed type cryoglobulinemia is rare and the prevalence is unknown. The M:F sex ratio of type 2 is 1:3.7 with an onset normally between the fourth and sixth decade. In 70-100% of cases hepatitis C virus antibodies are

Figure 1. chest x-ray before admission showing diffuse pulmonary lesions.

Figure 2. cT scan on admission showing bilateral thickening of inter-lobular septa with cysts and ground-glass opacification. This could be due to alveolar haemorrhage.



cryoglobulinemia complicated by diffuse alveolar haemorrhage

present, HCV RNA is usually positive.3,4 In the Netherlands, however, this association is much lower than in other countries.5

Pathophysiology Chronic stimulation of the immune system by lymphopro-liferative disorders, infections or autoimmune diseases cause clonal expansion of B cells which can create cryoglobulins. This can lead to vascular occlusion and hyperviscosity syndrome which is frequently observed in type 1 cryoglobulinemia.6 In mixed cryoglobulinemias immune complex mediated vasculitis is more often observed, mainly affecting arterioles, capillaries and venules. Very rarely this involves alveoli.6,7 Mixed type cryoglobulinemia is related to the hepatitis C virus. The HCV E1/E2 glycoprotein is able to bind to CD81 on the B-lymphocyte which leads to proliferation of B-lymphocytes.8 The pathophysiology in hepatitis C virus negative patients remains unclear.

Clinical manifestations and diagnosis In over 50% of cases clinical features are mild and slowly progressive, but in over 30% of cases patients have severe vasculitis with involvement of multiple organs. In a series of over 200 patients, the most common symptoms were found to be purpura, arthralgias and neuropathies. 70% of patients have hepatitis while glomerulonephritis is present in about 30%. Alveolar vasculitis has been described in about 3% of cases, so it is very rare.3,6,7

To assess for cryoglobulins, blood should be drawn into tubes that are placed directly into warm water (37 ºC), after this the serum is separated by centrifugation at the same temperature. To see if precipitation occurs, the serum is kept at 4 ºC for a maximum of three days. Criteria for the classification and diagnosis of cryoglobulinemia are based on serologic, pathologic and clinical findings. The presence of cryoglobulins in the serum together with major criteria like activation of the immune system, purpura and leukocytoclastic vasculitis confirm the diagnosis. Minor criteria include a positive IgM rheumatoid factor, positive screening for HCV/HBV, a clonal B-cell population in the bone marrow, chronic hepatitis, glomerulonephritis, peripheral neuropathy and skin ulcers. Based on previous major and minor criteria in our patient, the diagnosis of mixed cryoglobulinemia was made. Although this patient had monoclonal B-lymphocytes in the bone marrow without a HCV infection, he did not fulfil the criteria for multiple myeloma, CLL, Waldenströms macroglobulinemia or NHL and he did not have symptoms of hyperviscosity. Immune complex mediated vasculitis, as seen in this patient, is typically more frequent in type 2 cryoglob-ulinemia. Together with the other results we concluded that this patient had a type 2 cryoglobulinemia without evidence of HCV infection.

There are no standardized diagnostic or classification criteria for cryoglobulinemic vasculitis with diffuse alveolar haemorrhage. To start with the more common disorders like infections, malignancies and chronic heart failure should be ruled out. In patients with pulmonary abnormalities, clues that can lead to the diagnosis of cryoglobulinemia, are typically skin purpura, glomerulonephritis, unexplained low C4 levels, monoclonal gammopathy and neuropathy.

Prognosis and treatment Treatment depends on the clinical features; patients who are asymptomatic do not need any treatment. Early manifestations may respond to low doses of corticosteroids. In patients with an active Hepatitis C infection, antiviral therapy is indicated with PEG interferon-alpha and ribavirin.9 HCV serology alone is not sufficient, HCV RNA is necessary to confirm an HCV infection and to start treatment. More severe symptoms like vasculitis need to be treated with high doses of corticosteroids, immunosuppressive drugs or even plasmapheresis when patients suffer from the hyperviscosity syndrome. Rituximab plays an important role in treating B-cell NHL and has also proved to be effective in treating mixed cryoglobulinemia.10,11 Malignancy is a late complication of cryoglobulinemia and occurs in 10-15% of patients; B-cel NHL is most common but also hepatocellular carcinoma and papillary thyroid carcinoma can occur.2,3 Due to complications like liver cirrhosis, renal failure and malignancies, the survival rates of patients with this condition are significantly low.3

The role of rituximab for treatment in the long term is uncertain, but given the analogy with low grade NHL, in this patient, we will continue rituximab every three months for two years, according to low grade NHL protocol.In summary, the diagnosis of cryoglobulinemia should be considered in small vessel vasculitis. Diffuse alveolar haemorrhage due to vasculitis caused by cryoglobulinemia is very rare. Rituximab is effective in the treatment of (mixed) type 2 cryoglobulinemia. Follow up of patients with cryoglobulinemia is required because of an increased risk of malignancies.

AcknowledgmentThe authors have no competing interests.

references

1. Brouet JC, Clauvel JP, Danon F et al. Biological and clinical significance of cryo-globulins. A report of 86 cases. Am J Med. 1974;57:775-88.

2. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol. 2002;55:4-13.

3. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serological features and survival in 231 patients. Semin Arthritis Rheum. 2004;33:355-74.

4. Abel G, Zhang QX, Agnello V. Hepatitis C virus infection in type II mixed cryo-globulinemia. Arthritis Rheum. 1993;36:1341-9.



5. Cohen Tervaert JW, Van Paassen P, Damoiseaux J. Type ll cryoglobulinemia is not associated with hepatitis C infection: the Dutch experience. Ann NY Acad Sci. 2007;1107:251-8.

6. Ramos-Casals M, Stone JH, Cid MC, et al. The cryoglobulinaemias. Lancet. 2012;379:348-60.

7. Amital H, Rubinow A, Naparstek Y. Alveolar hemorrhage in cryoglobulinemia – an indicator of poor prognosis. Clinical and Experimental Rheumatology. 2005;23:616-20.

8. Pileri P, Uematsu Y, Campagnoli S et al. Binding of hepatitis C virus to CD81. 1998;282:938-41.

9. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobuline-mia associated with hepatitis C virus. N Engl J Med. 1994;330:751-6.

10. Terrier B, Launay D, Kaplanski G et al. Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French Autoimmunity and Rituximab registry. Arthritis Care Res. 2010;62:1787-95.

11. Ferri C, Cacoub P, Mazzaro C, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011;11:48-55.

Verkorte productinformatie ECALTA (september 2012). De volledige productinformatie (SPC van 23 augustus 2012) is op aanvraag verkrijgbaar.Samenstelling: ECALTA bevat 100 mg anidulafungin per injectieflacon, overeenkomend met een 3,33 mg/ml oplossing na reconstitutie met water voor injecties. De verdunde oplossing bevat 0,77 mg/ml anidulafungin. Indicaties: Behandeling van invasieve candidiasis bij volwassen niet-neutropenische patiënten. ECALTA is hoofdzakelijk onderzocht bij patiënten met candidemie en slechts bij een beperkt aantal patiënten met diepgelegen Candida infecties of met abcesvorming. Farmacotherapeutische groep: Antimycotica voor systemisch gebruik, andere antimycotica voor systemisch gebruik, ATC-code: JO2 AX 06. Dosering: De behandeling met ECALTA moet worden uitgevoerd door een arts die ervaring heeft met de behandeling van invasieve schimmelinfecties. De eenmalige aanvangdosis van 200 mg dient op dag 1 te worden toegediend, daarna gevolgd door dagelijks 100 mg. Er zijn onvoldoende gegevens beschikbaar om een behandeling van langer dan 35 dagen met de 100 mg dosis te onderbouwen. De veiligheid en werkzaamheid van ECALTA bij kinderen jonger dan 18 jaar zijn niet vastgesteld. Op basis van de momenteel beschikbare gegevens kan geen doseringsadvies worden gedaan. Het wordt aanbevolen om ECALTA toe te dienen met een infusiesnelheid die niet hoger is dan 1,1 mg/minuut (overeenkomend met 1,4 ml/minuut wanneer gereconstitueerd en verdund conform instructies). ECALTA mag niet worden toegediend als een bolusinjectie. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen; overgevoeligheid voor andere geneesmiddelen uit de groep van echinocandinen. Waarschuwingen en voorzorgen: De werkzaamheid van ECALTA bij neutropenische patiënten met candidemie en bij patiënten met diepgelegen Candida infecties of intra-abdominaal abces en peritonitis is niet vastgesteld. De klinische werkzaamheid is hoofdzakelijk beoordeeld bij niet-neutropenische patiënten met C. albicans infecties en bij een kleiner aantal patiënten met niet-albicans infecties, voornamelijk C. glabrata, C. parapsilosis en C. tropicalis. Patiënten met Candida-endocarditis, -osteomyelitis of -meningitis en bekende C. krusei infectie zijn niet onderzocht. Verhoogde waarden van leverenzymen zijn waargenomen bij gezonde personen en patiënten die met anidulafungin werden behandeld. Bij een aantal patiënten met een ernstige onderliggende medische aandoening die gelijktijdig meerdere geneesmiddelen kregen naast anidulafungin, zijn klinisch significante leverafwijkingen opgetreden. Gevallen van significante leverstoornis, hepatitis en leverfalen kwamen soms voor tijdens klinische onderzoeken. Bij patiënten met verhoogde leverenzymen tijdens behandeling met anidulafungin dient te worden gecontroleerd op tekenen van verslechterende leverfunctie en dient het risico/voordeel van voortzetting van behandeling met anidulafungin geëvalueerd te worden. Anafylactische reacties, waaronder shock, zijn gemeld bij het gebruik van anidulafungin. Indien deze reacties voorkomen, dient de behandeling met anidulafungin te worden stopgezet en dient passende behandeling te worden gegeven. Infusiegerelateerde bijwerkingen zijn gemeld bij het gebruik van anidulafungin, waaronder uitslag, urticaria, blozen, pruritus, dyspneu, bronchospasmen en hypotensie. Infuusgerelateerde bijwerkingen komen weinig voor wanneer de snelheid waarmee anidulafungin wordt geïnfundeerd niet hoger is dan 1,1 mg/minuut. In een onderzoek bij ratten is verergering van infusie-gerelateerde reacties door gelijktijdige behandeling met anesthetica waargenomen waarvan de klinische relevantie onbekend is. Men dient voorzichtig te zijn bij het gelijktijdig toedienen van anidulafungin en anesthetica. Patiënten met een zeldzame erfelijke fructose-intolerantie dienen dit geneesmiddel niet te gebruiken. Bijwerkingen: Bijwerkingen in klinische studies waren meestal licht tot matig en leidden zelden tot stopzetting van de behandeling. De meest gerapporteerde, vaak voorkomende bijwerkingen (≥1/100 tot <1/10) zijn: coagulopathie, convulsies, hoofdpijn, diarree, braken, misselijkheid, verhoogd creatininegehalte in het bloed, uitslag, pruritus, hypokaliëmie, flushing, verhoogde alanine-aminotransferase, verhoogde alkalische fosfatase in het bloed, verhoogde aspartaat-aminotransferase, verhoogd bilirubine in het bloed, verhoogde gamma-glutamyltransferase. Soms (≥1/1000, < 1/100) zijn waargenomen: pijn in de bovenbuik, urticaria, hyperglykemie, hypertensie, opvliegers, pijn op de infusieplaats, cholestase. Bijwerkingen uit spontane meldingen met frequentie niet bekend (kan met de beschikbare gegevens niet worden bepaald) zijn: anafylactische shock, anafylactische reactie (zie “Waarschuwingen en voorzorgen”), hypotensie, bronchospasmen, dyspneu. Afleveringsstatus: UR. Verpakking en Registratienummer: ECALTA, 100 mg poeder voor concentraat voor oplossing voor intraveneuze infusie: EU/1/07/416/002 (1 injectieflacon met 100 mg poeder). Vergoeding en prijzen: ECALTA wordt vergoed volgens de ‘Beleidsregel dure geneesmiddelen in ziekenhuizen’. Voor prijzen wordt verwezen naar de Z-Index taxe. Voor medische informatie over dit product belt u met 0800-MEDINFO (6334636). Registratiehouder: Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, Verenigd Koninkrijk. Neem voor correspondentie en inlichtingen contact op met de lokale vertegenwoordiger: Pfizer bv, Postbus 37, 2900 AA Capelle a/d IJssel.

1. Reboli AC et all; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. New England Journal of Medicine 2007;356(24):2472-82*. 2. Glöckner et all, Treatment of invasive candidiasis with echinochandines. Mycoses 2009 pag 476-486. 3. Ecalta Sept 2011 Summary of Product Characteristics. 4. www.cvz.nl. 5. Taxe April 2012, WMG-geneesmiddelen Z-Indez, 13e jaargang nr. 8. 6. Stichting Werkgroep Antibioticabeleid (SWAB), Optimaliseren van het antibioticabeleid in Nederland XII, SWAB-richtlijnen voor de behandeling van invasieve schimmelinfecties,September 2008. 7. Joseph J.M et all; Anidulafungin: a drug evaluation of a new echinocandin; Expert opinion Informa health care 2008; 2339-2348.*In deze studie werd anidulafungin-IV vergeleken met fl uconazol-IV bij 245 patienten met invasieve candidiasis. Het primaire eindpunt was globale respons (microbiologisch en klinisch) aan het eind van de IV-behandelperiode.

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Verkorte productinformatie Mycamine® 50 mg/100 mg (januari 2013) Samenstelling: Mycamine® 50 mg/100 mg poeder voor oplossing voor infusie (in natriumvorm). De toe te dienen hoeveelheid na reconstitutie is 10 mg/ml en 20 mg/ml, resp. (in natriumvorm). Farmacotherapeutische groep: Overige antimycotica voor systemisch gebruik, ATC-code: J02AX05. Therapeutische indicaties: Volwassenen, adolescenten ≥ 16 jaar en ouderen: Behandeling van invasieve candidiasis; Behandeling van oesofageale candidiasis bij patiënten voor wie intraveneuze therapie geschikt is; Profylaxe van Candida infectie bij patiënten die allogene hematopoiëtische stamceltransplantatie ondergaan of van wie wordt verwacht dat ze aan neutropenie lijden gedurende 10 dagen of langer. Kinderen (inclusief neonaten) en adolescenten < 16 jaar: Behandeling van invasieve candidiasis; Profylaxe van Candida infectie bij patiënten die allogene hematopoiëtische stamceltransplantatie ondergaan of van wie wordt verwacht dat ze aan neutropenie lijden gedurende 10 dagen of langer. Bij de beslissing Mycamine te gebruiken dient rekening gehouden te worden met het potentiële risico voor de ontwikkeling van levertumoren. Mycamine dient daarom uitsluitend te worden gebruikt als andere antifungale middelen niet in aanmerking komen. Dosering en wijze van toediening: Behandeling van invasieve candidiasis: 100 mg/dag, 2 mg/kg/dag bij een lichaamsgewicht < 40 kg. Als de patiënt in onvoldoende mate reageert, bv. indien de kweken positief blijven of de klinische toestand niet verbetert, dan mag de dosis worden verhoogd tot 200 mg/dag bij patiënten met een lichaamsgewicht > 40 kg of tot 4 mg/kg/dag bij patiënten met een lichaamsgewicht ≤ 40 kg. Profylaxe van Candida infectie: 50 mg/dag, 1 mg/kg/dag bij een lichaamsgewicht < 40 kg. Behandeling van oesofageale candidiasis: 150 mg/dag, 3 mg/kg/dag bij een lichaamsgewicht < 40 kg. Contraindicaties: Overgevoeligheid voor het werkzame bestanddeel, voor andere echinocandines of voor één van de hulpstoffen. Waarschuwingen en voorzorgen bij gebruik: De ontwikkeling van foci van veranderde hepatocyten (FAH) en hepatocellulaire tumoren werd bij ratten waargenomen na een behandelperiode van 3 maanden of langer. De leverfunctie dient zorgvuldig te worden gecontroleerd tijdens behandeling met micafungine. Om het risico op adaptieve regeneratie en mogelijk daaropvolgende levertumorvorming te minimaliseren, wordt vroegtijdig staken aanbevolen indien significante en persisterende verhoging van ALT/AST optreedt. De micafungine behandeling dient uitgevoerd te worden na een zorgvuldige risico/voordelen bepaling, met name bij patiënten met ernstige leverfunctiestoornissen of chronische leverziekten die preneoplastische aandoeningen vertegenwoordigen, of bij het tegelijkertijd ondergaan van een behandeling met hepatotoxische en/ of genotoxische eigenschappen. Er zijn onvoldoende gegevens beschikbaar over de farmacokinetiek van micafungine bij patiënten met ernstige leverfunctiestoornis. Er kunnen anafylactische/anafylactoïde reacties optreden, waarna de infusie met micafungine moet worden stopgezet en de juiste behandeling moet worden ingesteld. Exfoliatieve huidreacties zijn gemeld; als patiënten uitslag ontwikkelen, dienen zij nauwkeurig geobserveerd te worden. De therapie dient gestopt te worden als de laesies verergeren. In zeldzame gevallen is er hemolyse gerapporteerd. In dit geval dient nauwlettend te worden gevolgd of er geen verslechtering optreedt en er dient een risico/baten analyse gedaan te worden van voortzetting van de therapie. Patiënten dienen nauwlettend te worden gecontroleerd op verslechtering van de nierfunctie. Patiënten met zeldzame galactose intolerantie, Lapp lactasedeficiëntie of glucosegalactose malabsorptie dienen dit middel niet te gebruiken. Interacties: Patiënten die Mycamine in combinatie met sirolimus, nifedipine of itraconazol ontvangen, dienen te worden gecontroleerd op toxiciteit van sirolimus, nifedipine of itraconazol. Gelijktijdige toediening van micafungine met amfotericine B-desoxycholaat is alleen toegestaan wanneer de voordelen duidelijk opwegen tegen de risico’s, met een scherpe controle op mogelijke toxiciteit van amfotericine B-desoxycholaat. Bijwerkingen: De volgende bijwerkingen deden zich vaak (≥ 1/100 tot < 1/10) voor: leukopenie, neutropenie, anemie, hypokaliëmie, hypomagnesiëmie, hypocalciëmie, hoofdpijn, flebitis, misselijkheid, braken, diarree, buikpijn, verhoogd bloedalkaline-fosfatase, verhoogd aspartaataminotransferase, verhoogd alanineaminotransferase, verhoogd bilirubine in het bloed (inclusief hyperbilirubinemie), afwijkende leverfunctietest, uitslag, pyrexie, koude rillingen. Naast bovengenoemde bijwerkingen zijn bij kinderen tevens vaak thrombocytopenie, tachycardie, hypertensie, hypotensie, hyperbilirubinemie, hepatomegalie, acuut nierfalen en verhoogd bloedureum gemeld. In de volledige SPC tekst worden de soms, zelden voorkomende bijwerkingen en bijwerkingen die niet met de beschikbare gegevens kunnen worden bepaald gemeld. Afleverstatus: UR. Overige productinformatie: Astellas Pharma B.V. Sylviusweg 62, 2333 BE Leiden, PO Box 344, 2300 AH Leiden, phone: +31(0)71 545 57 45, fax: +31(0)71 545 58 00

Referenties: 1. Sinds 2002; aantal patiëntendagen berekend over aantal verkochte Kg (Bron: IMS 12/02- 09/12)/gemiddelde dagdosering gedurende 14 aanbevolen behandeling (bron: SmPC).Veronderstelde behandelduur is 14 dagen. 2. SmPC Mycamine 25042008.13-MYC-003




AbstractN-methyl-D-aspartate (NMDA) receptor antibody encephalitis is an immunotherapy-responsive panencephalitis. Patients usually present with characteristic clinical features in a specific order. We describe a patient who developed anti NMDA receptor encephalitis with a positive liquor EBV titer, suggesting formation of antibodies including anti NMDA. After a prolonged ICU stay the patient had a slow but full recovery. Despite severe neurological symptoms, in general, the prognosis of anti NMDA receptor encephalitis is good and warrants prolonged intensive care treatment when indicated.

IntroductionN-methyl-D-aspartate (NMDA) receptor antibody encephalitis is an immunotherapy-responsive panencephalitis.1-3 Patients usually present with characteristic clinical features in a specific order.1,2,4 After a prodomal flu-like illness, patients develop psychiatric symptoms with short term memory loss followed by orofacial dyskinesias, limb choreoathetosis, catatonia and autonomic instability. Another characteristic feature is a persistent amnesia of the entire process.5 This report describes a patient with chronic use of immunosuppressants and with a positive spinal fluid Epstein Barr virus (EBV) titer who developed anti NMDA encephalitis.

Case reportFor eight weeks a 26-year-old male had experienced several episodes with blackouts and strong feelings of romantic love and joy, lasting several minutes. These episodes increased in frequency and the patient showed signs of confusion. Two weeks before admission in the referring hospital the patient developed anxiety attacks, became confused and exhibited echolalia. There was also indecisiveness, sleepiness and difficulties with speech. Eight weeks after the first symptoms arose, the patient was admitted to the referring hospital. An EEG was consistent with encephalopathy. Neural imaging including an MRI showed no abnormalities but spinal fluid

Severe anti NMDA encephalitis and EBV infection

analysis showed a mild lymphocytic pleocytosis. Cultures of both spinal fluid and blood were negative. The patient became bedridden and because of further deterioration that included inability to walk or speak and increasing confusion, he was transferred to our hospital for evaluation.The patient had had a renal transplant in 2003 for reflux nephropathy. His medication consisted of prednisone 10 mg once daily and mycofenolatemofetil 500 mg twice daily. After transplantation the patient had multiple urinary tract infections due to kidney stones.On arrival in our hospital, 12 days after admission in the referring hospital, neurologic examination showed non-fluent speech with difficulty finding words and following more complex commands. The patient had a cautious and broad-based gait and there was a slight tremor of both hands without myoclonus. Deep tendon reflexes were symmetrical and lively, with bilateral clonus of the ankle reflex and Babinski’s sign. Testing of cranial nerves, strength, sensibility and coordination showed no abnormalities.The patient was admitted to the neurology ward. After admission his symptoms progressed. He developed catatonia with dyskinesias in the face and mouth, manifesting as orofacial movements with clenching of the teeth or forcefully opening his mouth for several minutes. Because of catatonia and dyskinesias he was transferred to our medium care unit five days after admission, where he was given midazolam intravenously. Thyroid and adrenal function were normal. Kidney and liver function tests as well as a full blood count were normal. CSF showed lymphocytic pleocytosis and an increased protein concentration (95% lymphocytes, protein 864 mg/l). Cultures of blood and CSF were negative. Viral studies of blood and CSF for neurotropic viruses, HSV, CMV, enterovirus, parechovirus and varicella zoster were negative. However, a PCR for EBV from CSF became positive with 30,000 copies per ml and EBV ebna IgG 152 U/ml and EBV vca IgG >200 U/ml in blood became positive a few days later. A diagnosis of EBV encephalitis was made and ganciclovir 200 mg twice daily

S.J. Derksen1, B. Goraj2, J.P. Molenaar3, J.G. van der Hoeven1

Departments of 1intensive care, 2radiology, 3Neurology, radboud University Medical centre, Nijmegen, the Netherlands

correspondence

s.J. derksen – e-mail: [email protected]

Keywords – anti NMDa encephalitis, eBV and limbic encephalitis

c A s e r e P o r T



was started and mycofenolatemofetil discontinued. An initial MRI showed no abnormalities, but a second T2-FLAIR* MRI showed a subtle diffuse increase of signal intensity of the white matter bilaterally (figure 1). An EEG showed slow delta-theta activity.After an initial improvement and despite aggressive treatment of the EBV encephalitis with ganciclovir and immunoglobulins, given at a dose of 0.4 gr/kg/day for five days, epileptic seizures continued and the patient became catatonic for longer periods. During the following four weeks the patient deteriorated further and needed continuous sedation to treat the seizures and catatonia. Three weeks after admission, the patient was transferred to the ICU for mechanical ventilation. Since there had been no improvement after the start of antiviral treatment and because of the sequence of symptoms and by now nearly permanent catatonia – only interrupted by seizures – limbic encephalitis was suspected. CSF auto-antibody testing was performed and was positive for anti N-methyl-D-aspartate (NMDA) receptor antibodies. Subsequently a diagnosis of anti NMDA (receptor) encephalitis was made. The patient was treated with immunoglobulins, in the same dose as mentioned, and methylprednisolone, with little improvement. For two weeks the patient exhibited signs of autonomic instability, with fluctuations of blood pressure, cardiac rhythm and fever and he was eventually treated with rituximab (700 mg; 375 mg/m2) weekly for four weeks. Thereafter the patient improved slowly

and was extubated after four weeks and discharged eight days later. The patient continued to improve but on discharge he still showed apathy, marked rigidity and short term memory loss. A few months after discharge the patient had made a full recovery. An extensive work up (abdominal/scrotal ultrasound; CT scan thorax/abdomen; PET-CT) showed no evidence of an underlying tumor.

DiscussionN-methyl-D-aspartate receptor antibody encephalitis is an immunotherapy-responsive limbic panencephalitis.1-3 This disorder is associated with a misdirected autoimmune response with formation of antibodies against the NR1 subunit of the NMDA receptor.4-6 NMDA receptors are ligand-gated cation channels on neural cell membranes with crucial roles in synaptic transmission and plasticity and are predominantly concentrated in the hippocampus and forebrain.4,5 About 60% cases occur as a paraneoplastic process, most commonly an ovarian teratoma.1 Anti NMDA limbic encephalitis affects young people, predominantly young women.1 In male patients the detection of a tumor is rare, but testicular germ cell tumors, teratoma of the mediastinum, small cell lung carcinoma, Hodgkin’s lymphoma and neuroblastoma have been found.5,6 Patients present with characteristic clinical features in a specific order and many patients have initially been seen by psychiatrists but subsequently developed seizures and complex symptoms requiring multidisciplinary care.4,5,7 The

Figure 1. T2-FlAIr mrI with subtle diffuse increase of signal intensity of white matter bilaterally.

FlAIr stands for Fluid-Attenuated Inversion recovery and is the most sensitive mrI sequence. It provides a better contrast range with more conspicuous delineation of pathology. by suppressing csF intensity (which appears black) and increasing the intensity of edema, even subtle (periventriculair) vasogenic and cytotoxic oedema will be clearly visible.



severe anti nmdA encephalitis and ebv infection

development of autonomic instability and stupor may require mechanical ventilation for weeks or even months and seizures should be treated aggressively.1,2 Symptoms usually start with a prodomal flu-like illness with fever, malaise, headache or fatigue, after which psychiatric symptoms develop, the most common being anxiety, agitation, delusions and hallucinations with short term memory loss followed by orofacial dyskinesias, limb choreoathetosis, catatonia and autonomic instability with fluctuations of blood pressure, temperature and cardiac rhythm. Another characteristic feature is a persistent amnesia of the entire process.1,2,5

CSF reveals inflammatory changes in >90% of cases with an elevated white cell count, mainly lymphocytes and mildly elevated protein content with oligoclonal bands.2-4,8 EEG studies are abnormal in >90% of cases and usually show diffuse delta-theta activity.5,7,9 Brain MRI is often normal initially, but 55% of cases will show non-focal cortical hyper intensity in FLAIR setting, predominantly in the medial temporal lobes.2-4,8 These findings can be asymmetric. MRI abnormalities are not prerequisite for the diagnosis. The finding of N-methyl-D-aspartate receptor antibodies in CSF, however, together with the characteristic clinical picture confirms the diagnosis.The concentration of NMDA receptor antibodies correlates well with the clinical state in individual patients.5,8 Therefore, the major aim of therapy is to reduce NMDA receptor antibodies.4,5,8 For patients with an underlying tumor, removal of the malignancy is of paramount importance.1,2,6 In addition, immunotherapies appear to hasten recovery. In nonparaneoplastic cases immunotherapies are administered, again with the aim of reducing NMDA receptor antibody levels. Commonly used immunotherapies in this case series include corticosteroids, intravenous immunoglobulins and plasma exchange. Patients who do not improve with these first line therapies may improve with rituximab and/or cyclophosphamide.4-6

Our patient who was known to have a chronic use of immunosuppressants and a positive spinal fluid EBV titer, developed anti NMDA receptor encephalitis. Patients with long term immunosuppressant therapies are typically at risk for infection or reactivation of EBV. A typical aspect of EBV infection is proliferation of B cells with accompanying antibody formation. These antibodies may be directed against the NMDA receptor. Although extensive studies of CSF, brain biopsies and autopsies in other cases of anti NMDA receptor encephalitis were negative for viruses 5,6, a viral pathogenesis in general is suggested by the prodomal flu-like illness and in this case particularly by a concurrent high spinal EBV load (104). This does not mean that EBV encephalitis per se is the cause of anti NMDA receptor encephalitis, but strongly suggests pathogenicity of the anti NMDA receptor antibody itself.

Conclusion We describe a specific neurological syndrome (limbic encephalitis) associated with auto antibodies against the NMDA receptor temporarily related to EBV encephalitis. Despite severe neurological symptoms, anti NMDA receptor encephalitis generally has a good prognosis and warrants prolonged intensive care treatment if indicated.

references

1. Graus F, Dalmau J. Paraneoplastic neurological syndromes: diagnosis and treat-ment. Curr Opin Neurol. 2007;20:732-7.

2. Dalmau J. Limbic encephalitis and variants related to neuronal cell membrane autoantigens. Rinsho Shinkeigaku. 2008;48:871-4.

3. Ishiura H, Matsuda S, Dalmau J. Response of anti-NMDA receptor enceph-alitis without tumor to immunotherapy including rituximab. Neurology. 2008;71:1921-3.

4. Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13:261-71.

5. Dalmau J, Gleichman, Hughes EG et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091-8.

6. Graus F, Saiz A, Dalmau J et al. Neuronal surface antigen antibodies in limbic encephalitis. Neurology. 2008;71:930-6.

7. Bien CG, Scheffer IE. Autoantibodies and epilepsy. Epilepsia. 2011;52(suppl.3):18-22.

8. Irani SR, Vincent A. NMDA receptor antibody encephalitis. Curr Neurol Neurosci Rep. 2011;11:298-304.

9. Caplan JP, Binius T, Lennon VA, Pittock SJ, Rao MS. Pseudopseudoseizures: Conditions that mimic psychogenic non-epileptic seizures. Psychosomatics. 2011;52:501-6.




After a long flight from Asia, a 44-year-old woman was admitted to our hospital following collapse and with dyspnoea. CT-scanning confirmed the diagnosis of pulmonary emboli. A “saddle embolus” bridging across both pulmonary arteries provided the explanation for her symptoms. Thrombolysis was started immediately and she was admitted to the ICU. After being admitted for 12 hours, she developed severe shock with an extended right cardiac ventricle. An ultrasound guided continuous SvO2 central venous catheter was inserted into the right internal jugular vein. After a few hours, the image in figure 1 was obtained.We were puzzled by the periodic fluctuations in SvO2 with decreasing amplitude and zoomed in to analyze the duration of the periodicity. This proved to be 10 minutes (figure 2), exactly the default time used by the anti-decubitus mattress to inflate/deflate. After shutting down the mattress the periodicity disappeared (data not shown). The patient fully recovered and was successfully discharged from the ICU three days later.

Periodic SvO2 fluctuations in a patient with severe pulmonary emboli

An explanation of the observed phenomenon may be the periodic sequential inflation of the mattress in a caudal-cranial direction with concomitant increase in venous return, thus influencing the SvO2. However, the mattress does not inflate in this way, i.e. areas distributed amongst all body areas are intermittently inflated and deflated. One could also hypothesize that the periodic inflation of the mattress intermittently decreased the patient’s thoracic wall compliance. This may in turn have resulted in an increase in intrathoracic pressure with subsequent decrease in venous return and a drop in the SvO2. The patient was given IV fluids during the same period to maintain an adequate preload with a concomitant decrease in the amplitude of the periodic SvO2 fluctations. We think this case description may be of importance for intensive care nurses and physicians when they make bedside observations in patients with continuous SvO2 monitoring.

P.E. SpronkDepartment of intensive care Medicine, Gelre hospitals, apeldoorn, the Netherlands

correspondence

P.e. spronk – e-mail: [email protected]

Keywords - SvO2, periodicity, matrass

c l I n I c A l I m A g e

Figure 1. Periodic fluctuation in svo2.

Figure 2. Periodic fluctuation in svo2 is similar to matrass inflation periodicity.

6 en 7 februari 2014, s-Hertogenbosch

UITNODIGING INTENSIVISTENDAGEN

Op 6 en 7 februari 2014 worden de jaarlijkse Intensivistendagen gehouden in ’s-Hertogenbosch. Niet alleen een nieuwe locatie, maar ook een nieuw tweedaags programma!

Bekende onderdelen• een selectie van nationale wetenschap in de vorm van abstracts en proefschriften• de postersessies• de thematische ‘year in review’ presentaties

Nieuwe onderdelen• de internationale keynote lecture door professor mervyn singer • de nvIc erelezing door een gerenommeerde collega

Verder• interactieve workshops over het omgaan met ethisch-culturele dilemma’s en het

beoordelen van wetenschappelijke artikelen

OntmoetingTussen de bedrijven door is er natuurlijk tijd om u door de vertegenwoordigers van de industrie te laten bijpraten.de Intensivistendagen zijn de gelegenheid bij uitstek om kennis te nemen van de nieuwste ontwikkelingen in de Intensive care geneeskunde, maar ook om elkaar te ontmoeten en bij te praten tijdens de borrel of het feest.

Tot ziens in Den Bosch!



1.

Disastrous consequences: Influenza A and pneumococcal co-infection

A. Ruiter, M.L.J. Scheer

Department of Intensive Care Medicine, Martini Hospital Groningen, The Netherlands

Introduction: Pneumococcal infection after influenza A infection lead

more frequently to an invasive pneumonia. We describe a patient with

influenza A and a pneumococcal co-infection who developed a severe

septic shock with cavitary pneumonia and multi organ failure. early rec-

ognition and treatment of a co-infection is important in the prevention

of a more serious course of the disease.

Case history: A 64-year-old female, was admitted to the Icu with

respiratory failure en septic shock with multiple organ failure. Her

medical history compromised atrial fibrillation and hyperthyroidism.

she suffered from fever, coughing and dyspnoea which started one

week before admission. The chest radiograph showed bilateral infil-

trates (figure 1).

diagnostic tests showed positive Pcr for pneumococcus and influenza

A. complementary blood cultures showed Streptococcus pneumoniae.

Immediately after taking blood cultures and viral Pcr, we started anti-

biotic and antiviral therapy.

Intubation, inotropic support and continuous venous hemofiltration

were required.

The patient underwent prolonged postural drainage, prone position

and several bronchoscopies treating sputum retention. A computed

tomography of the chest revealed cavitating pneumonia (figure 2).

After a few weeks the patient recovered from the multiple organ failure

and started weaning from the ventilator. she was discharged from the

Icu after two months of admission (figure 3).

After two months of rehabilitation the patient restarted her work as a nurse.

Discussion: Approximately 250.000-500.000 people die of influenza

worldwide, of which a significant fraction of influenza deaths can be

attributed to bacterial infections, either during, or closely following

influenza infection. An important influenza co-infection is pneumonia,

caused primarily by Streptococcus pneumonia.1

Although the mechanisms underlying the association between the

severity of influenza and pneumococcal infections are still poorly

understood, there are a number of mechanisms involved. viral infec-

tions facilitate bacterial colonization, adhesion and translocation

through the epithelial barrier. In fact, clearing the way for bacterial

disease. Pneumococcal infection after influenza infection lead more

frequently to invasive pneumonia. In conclusion, it is clinically relevant

to start with the combination of antiviral and antibacterial treatment

in case of suspicion of a co-infection. This is of particular importance

during the influenza season.2 The co-treatment is only beneficial

Case Reports Intensivistendagen 2014

when the antiviral therapy is started within the first few days of onset

of pneumonia. This can prevent the occurrence of a serious invasive

pneumonia.1

Conclusion: This case showed a severe cavitary pneumonia following

Influenza A and pneumococcal co-infection. We successfully treated

this patient with prompt administration of antibiotics combined with

antiviral therapy. nevertheless a cavitary pneumonia developed with

a prolonged treatment on the Icu. In conclusion, doctors should be

aware of the fulminant course of the disease due to influenza and

pneumococcal co-infection.

Figure 1. chest radiograph at admission showed bilateral effusion

Figure 2. computed Tomography: severe cavitary lung destruction air-fluid levels: confirmed lung abscesses



case reports Intensivistendagen 2014

Figure 3. chest radiograph at discharge: improved with only a few abnormalities left

References 1. shresta s, Foxman b, dawid s, et al. Time and dose-dependent risk of pneu-

mococcal pneumonia following influenza: a model for within-host inter-action between influenza and Streptococcus pneumoniae. J r soc Interface. 10:20130233.

2. Hament J, kimpen Jll, Fleer A, Wolfs TFW. respiratory viral infection pre-disposing for bacterial disease: a concise review. Fems Immunology and medical microbiology 26 (1999) 189-95.

2.

Hypokalemic paralysis and profound metabolic acidosis in a

woman with Sjögren’s diseaseY.J. Beijer1, T. Tobé2, M. Otten1, C.M. Pleizier3, J.H. van der Werf4,

J.W. Fijen1, L.E.M. Haas1

1Department of Intensive Care, Diakonessenhuis, Utrecht, The Netherlands, 2Department of Internal Medicine, Nephrology, Diakonessenhuis, Utrecht,

The Netherlands, 3Department of Neurology, Diakonessenhuis, Utrecht, 4Department of Rheumatology, Diakonessenhuis, Utrecht, The Netherlands

Case: A 52-year-old woman presented with a rapid progressive proximal

muscle weakness in both upper (medical research council (mrc) grade

3-4) and lower (mrc 2) extremities and neck flexors (mrc 3) as well, since

last week. she also documented anorexia, weight loss and constipation,

for which she had used laxatives last week but abuse was not suspected.

she was diagnosed with sjögren’s syndrome (ss) four months before.

The diagnosis was based on xerostomia, keratoconjunctivitis sicca, a

positive schirmer test and positive antinuclear antibodies with both

positive anti-ro/ssA and anti-la/ssb.

The laboratory results and the ecg on admission are shown in table 1

and figure 1. remarkable was the severe hypokalemia (1.5 mmol/l), the

profound non-aniongap acidosis (bicarbonate 4.6 mmol/l, anion gap

13.6 mmol/l, albumin 41 g/l) and elevated creatine kinase (ck). despite

the profound metabolic acidosis, urine pH was 6.5. The anion gap in

urine was 31 mmol/l with a urine osmolgap of 14 mosm/kg.

both the urinary anion gap and the urine osmolgap suggested the ina-

bility to produce ammonium. In combination with low bicarbonate and

hypokalaemia, renal tubular acidosis (rTA) type I was diagnosed.

The woman received high doses intravenous potassium via a central

venous catheter and when serum level was raised above 3.0 mmol/l,

supplementation of bicarbonate was added. Her myopathy recovered

soon after normalization of serum potassium and subsequently she

was successfully treated with potassium citrate tablets (tid 1500 mg).

Discussion: distal (type 1) rTA is an uncommon disorder, particularly in

adults. The primary defect is impaired distal acidification with reduced

urinary ammonium excretion. The hallmark features of rTA are hyper-

chloremic metabolic acidosis with a normal anion gap and a urine pH

above 5.5, with or without associated defects in potassium homeostasis.

The major causes of distal rTA in adults are autoimmune diseases, e.g.

ss (table 2).1 In up to 25 per cent of patients with ss, interstitial nephritis

with a defect in distal acidification occurs.2 The underlying mechanism

is incompletely understood.

differential diagnosis included multiple myeloma, but in our patient a

recent protein electrophoresis was normal. This is important, because

particularly haematological malignancies are more frequent in patients

with ss and can also cause rTA type I.

differential diagnosis of normal anion gap (hyperchloremic) metabolic

acidosis also included diarrhea, but there was no history of diarrhea

or intoxication in this patient who did not use diuretics. normal anion

gap metabolic acidosis due to laxative abuse exists in the presence of

normal distal acidification, and hence it was unlikely to be the case of

acidosis in this case.

The aim of therapy is to achieve a relatively normal serum bicarbonate

concentration. Adults with distal rTA can be treated with 1 to 2 meq/

kg/day sodium bicarbonate or sodium citrate. Potassium citrate is indi-

cated when hypokalaemia persists despite correction of the serum

bicarbonate, like in this case.

Conclusion: Although rTA is a rare disorder, it is quite common in ss

patients and these patients can present with profound hypokalaemia

and metabolic acidosis.

Figure 1. ecg, showing characteristic changes; depression of the sT segment and a prolonged QT interval



Table 1. laboratory results

LABORATORY TEST VALUE REFERENCE VALUE

c-reactive protein (crP) 17 mg/l < 10 mg/l

esr 50 mm/hr 2-12 mm/hr

Hemoglobin 6.6 mmol/l 7.0-9.2 mmol/l

mcv 87 fl 82-98 fl

leucocytes count 13.4 x109/l 4.0-10.0 x109/l

sodium 134 mmol/l 135-145 mmol/l

Potassium 1.5 mmol/L 3.5-5.0 mmol/l

urea 11 mmol/l 2.5-6.4 mmol/l

creatinin 173 µmol/l 44-80 µmol/l

chloride 116 mmol/l 98-108 mmol/l

calcium 2.25 mmol/l 2.10-2.55 mmol/l

magnesium 1.12 mmol/l 0.65-1.05 mmol/l

gamma-glutamyltransferase (ggT) 20 u/l < 38 u/ll

Alkaline phosphatase (AlP) 50 u/l < 98 u/l

Alanine aminotransferase (AlT) 40 u/l < 34 u/l

Aspartate aminotransferase (AsT) 80 u/l < 31 u/l

lactase dehydrogenase (ldH) 167 u/l < 220 u/l

creatine kinase 1264 U/L < 145 u/l

Albumin 41 g/l 35-55 g/l

glucose 5.9 mmol/l 3.0-7.0 mmol/l

TsH 3.37 mu/l 0.35-4.50 mu/l

pH 7.22 7.35-7.45

pco2 1.5 kPa 4.7-6.4 kPa

po2 16.0 kPa 10.0-13.3 kPa

Bicarbonate 4.6 mmol/L 22-29 mmol/l

base excess -20.6 mmol/l -3.0-3.0 mmol/l

urinary pH 6.5 4.0-8.0

urinary sodium 14 mmol/l 25-135 mmol/l

urinary potassium 12 mmol/l 16-67 mmol/l

urinary chloride 13 mmol/l 110-250 mmol/l

glucose in urine negative

Table 2. major causes of distal renal tubular acidosis (type 1)

PrimaryIdiopathic (sporadic)

Familial

Autosomal dominant mainly due to mutations causing defects in the kidney anion exchanger – kAe1 in distal tubule intercalated cells.

Autosomal recessive mainly due to mutations causing defects in v-ATPase in distal tubule intercalated cells.

SecondaryAutoimmune disorders• sjogren’s syndrome• Autoimmune hepatitis/primary biliary cirrhosis• systemic lupus erythematosus• rheumatoid arthritis

drugs• lithium• Amphotericin b• Toluene inhalation• Ifosfamide

Hypercalciuric conditions• sarcoidosis• Hyperparathyroidism• vitamin d intoxication• Idiopathic hypercalciuria

other• sickle cell disease• obstructive uropathy• renal transplant rejection• Wilson’s disease• medullary sponge kidney

References1. van daele Pl, Zanen Al, de ronde W, et al. severe hypokalaemia with para-

lysis in a patient with distal renal tubular acidosis as an initial expression of sjögren’s syndrome. [ernstige hypokaliëmie met paralyse bij een patiënte met een distale renale tubulaire acidose als eerste uiting van het syndroom van sjögren]. ned Tijdschr geneeskd. 2002;146;218-21.

2. ren H, Wang Wm, chen xn, et al. renal involvement and follow up of 130 patients with primary sjogren’s syndrome. J rheumatol. 2008;35:278-84.

3.

The powerful double-edged sword of thrombolysis

Y.J. Beijer1, M. Otten1, L.H. Conemans2, H. Doğan3, J.W. Fijen, L.E.M. Haas1

1Intensive Care Unit, Diakonessenhuis, Utrecht, The Netherlands, 2Department of Pulmonology, University Medical Center, Utrecht, The Netherlands, 3Department of

Radiology, Diakonessenhuis, Utrecht, The Netherlands

Background: We present a case in which the direct therapeutic effects

of thrombolysis in massive pulmonary embolism are made visible,

clinically as well as by diagnostic imaging and invasive haemody-

namic measurements. Thereby, we show the feared side effect, severe

bleeding, which unfortunately occurred.

Case: An 82-year-old diabetic male was admitted to the Icu with a

hyperosmolar hyperglycemic syndrome, luxated by prednisone use

for a recent myasthenic crisis. He was treated with intravenous fluids,

insulin and low molecular weight heparin (lmWH) in a prophylactic dose.

glucose and electrolytes normalized and no myasthenic crisis occurred.

Patient was hypoxemic at admission, but further clinical examination

and chest x-ray (cxr) were non-diagnostic. The next day he became

severely hypoxic and haemodynamically unstable and therefore invasive

mechanical ventilation was started. An electrocardiogram (ecg) showed

a sinus tachycardia with s1Q3T3 pattern en incomplete rbbb (figure

1) and beds ide echocardiography revealed a dilated right ventricle.

Pulmonary embolism (Pe) was suspected and subsequently computed

tomography (cT) pulmonary angiography confirmed extended saddle

embolisms (figure 2a), with signs of severe right ventricular dilatation and

left sided shift of the interventricular septum (rv/lv diameter ratio 2.8).

The patient was treated with alteplase (rtPA), in the absence of any con-

traindications to thrombolysis, and subsequent lmWH in therapeutic

dose. significantly increased dead space ventilation with a vd/vt ratio of

70%,normalized after thrombolysis (about 24%).

The patient recovered well, but suffered an arterial bleeding after radial

artery puncture. He was resuscitated with crystalloids, erythrocytes,

platelets and Fresh Frozen Plasma. The lmWH was discontinued for the

time coming. nevertheless, he also developed a large hematoma in the

right pectoral muscle (figure 2b). since no extravasation of contrast was

seen with cT imaging, no endovascular intervention was performed.

notably on cT, the large pulmonary embolism was almost completely

dissolved and pulmonary artery catheterization measurements, after

resuscitation, showed no elevated pulmonary artery pressures (figure

3). The next week, patient developed a ventilator-associated pneumo-

nia (vAP) with refractory septic shock and eventually he died.




Figure 3. Invasive haemodynamic measurements

Graphic with mean pulmonary artery pressures (PAP) measured by Swan-Ganz catheter one week after thrombolysis.

Conclusion: This case demonstrates the effectiveness of thrombolytic

therapy in predominantly dissolving massive pulmonary embolism

with normalization of PAP pressures, but at cost of the feared side

effect. because of this massive bleeding risk and the absence of strong

evidence of mortality improvement, thrombolytic therapy should be

used only in carefully selected cases.

References1. Wan s, Quinlan dJ, Agnelli g, eikelboom JW. Thrombolysis compared with

heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. circulation. 2004;110:744.

2. kearon c, Akl eA, comerota AJ, et al. American college of chest Physicians. Antithrombotic therapy for vTe disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American college of chest Physicians evidence-based clinical Practice guidelines. chest 2012;141:e419s.

4.

Giant-cell myocarditis – a giant challengeB.M.A. Pieters, D.W. Donker

University Medical Center Utrecht, Utrecht, The Netherlands

Introduction: giant-cell myocarditis (gcm) is a rare disease carrying an

unfavourable prognosis. A majority develops progressive heart failure

and life-threatening arrhythmias. Thus, a timely diagnosis is essential

and can only be obtained by myocardial biopsy. If medical therapy fails,

only cardiac mechanical support and transplantation can be consid-

ered, although their therapeutic benefit in gcm remains to be debated.

Here, we describe the clinical challenges one faces when managing a

patient with gcm.

Case: A 22-year-old male without any medical history was referred

in cardiogenic shock after complaining of general malaise for days.

After stabilization upon medical treatment and routine diagnos-

tics, right-ventricular endomyocardial biopsies revealed gcm. Yet,

despite immunosuppressive therapy (steroids, cyclosporine and aza-

thioprine) and intensified heart failure therapy, cardiac contractility

deteriorated, necessitating the implantation of a bi-ventricular assist

device (Thoratec®centrimag®). Weaning from mechanical support

was impossible, and 6 weeks after presentation cardiac transplanta-

tion was performed, allowing clinical discharge (day 65). Follow-up

Discussion: since it is generally known that the adverse effects of

thrombolytic therapy can be devastating, the indication and potential

benefits must be carefully weighed against the risks in each patient.

contraindications to thrombolytic therapy are recent (intracranial)

surgery or head trauma, an active intracranial neoplasm, a history

of stroke, severe hypertension, an active or recent internal bleeding,

bleeding diathesis and thrombocytopenia.

Although thrombolytic therapy can be lifesaving and leads to early

haemodynamic improvement, it has not been proven to improve mor-

tality in unselected patients.1 However, in patients with major pulmo-

nary embolism who are haemodynamically compromised, a consistent

trend toward improved mortality has been repeatedly found. but as

said, with a significant increased risk for major bleeding, compared to

anticoagulation alone.2

Figure 1. ecg

Typical ECG withS1Q3T3 pattern en incomplete RBBB

Figure 2. chest computed tomography

Computed tomography scan of the chest, before (a. and c.) and after (b. and d.) thrombolysis. Figure a & c: show the saddle embolus with concomitant right ventricular (RV)dilatation en shift of the septum to the left. The calculated RV/LV diameter ratio is significantly elevated; 2.8.Figure b & d: show that the saddle embolus is almost completely dissolved after thrombolysis and the calculated RV/LV ratio decreased (although it was still elevated; 1.16). Thereby, it shows a large hematoma of 14 x 8 cm underneath the right M. Pectoralis.

A

c

b

d



biopsies revealed gcm recurrence 2 months after transplantation in

the absence of heart failure and was successfully treated with methyl-

prednisolon (3 days) and intensified prednisolone therapy.

Discussion: This exceptional case of recent-onset, unexplained heart

failure emphasizes the incremental diagnostic value of an early endo-

myocardial biopsy (emb). The diagnosis of gcm cannot be established

by any other diagnostic means. Therefore, it is of utmost importance to

consider emb early in the diagnostic work-up.

Although gcm is a rare, idiopathic disease, the diagnosis has important

therapeutic implications, i.e., the initiation of immunosuppressants. In our

case, combined immunosuppression and adjuvant medical unloading

did not reverse clinical deterioration due to terminal bi-ventricular failure.

generally, cardiac transplantation is the treatment of choice in refrac-

tory gcm, but this therapeutic option is limited by the paucity of

donor organs. Alternatively, short-term mechanical support as a

‘bridge-to-transplantation’ can be considered, as we did. Yet, bi-ven-

tricular support is cumbersome and bears significant risks of bleeding,

thromboembolism and infection. moreover, modern bi-ventricu-

lar short-term support devices, e.g., veno-arterial extracorpor-

eal membrane oxygenation orextracorporeal centrifugal pumps

(Thoratec® centrimag®), are designed for limited use (a few weeks).

Thus, the time interval to transplantation may exceed the durability

of the short-term device. In contrast, long-termpulsatile bi-ventricular

support devices disqualify for a ‘high-urgency’ waiting list and carry

unacceptably high complication rates including irreversible pulmonary

hypertension after months of support which precludes cardiac trans-

plantation.

moreover, gcm is well-known to potentially recur in the transplanted

heart, but has been reported to allow successful treatment by adapting

immunosuppressants, as in this case.

Conclusion: severe, idiopathic heart failure of recent onset should

prompt emb in order to establish a diagnosis. rarely, gcm may be

encountered which carries a poor prognosis but may be treated by

employing a challenging therapeutic strategy combining medical and

mechanical cardiac support towards transplantation.

References1. cooper lT Jr, et al. Idiopathic giant-cell myocarditis – natural History and

Treatment. n engl J med. 1997;336:1860-6.

2. murray lk, et al. ventricular assist device support as a bridge to heart transplantation in patients with giant cell myocarditis. eur J Heart Fail. 2012;14:312-8.

5.

Shock after colonoscopyJ. Boddé, M. Scheer

Department of Critical Care, Martini Hospital Groningen, The Netherlands

Introduction: An increase in intra-abdominal-pressure (IAP) can lead

to an abdominal compartiment syndrome (Acs) with obstructive shock

en multiple organ failure. one of the causes is a pneumoperitoneum.

We present a case where a patient is referred to the Icu with obstruc-

tive shock following colonoscopy.

Case: A 69-year-old man was admitted to the Icu with tachypnea,

hypotension and abdominal discomfort following gastro- and colo-

noscopy. He had a history of urolithiasis, dvT and non-insulin-de-

pendent type 2 diabetes mellitus. He was referred to the hospital for

analysis of microcytic anaemia. With gastroscopy no explanation was

found, biopsies from duodenum where taken. during colonoscopy a

narrowing colon tumor is observed, biopsies are taken and the tumor

is marked proximal and distal of the tumor. Within a few hours the

patients deteriorates with abdominal pain and shock and is admitted

to the Icu. At physical examination we find extreme abdominal dis-

tension with redness of the lower limbs and an erection of the penis.

Perforation or bleeding with obstructive shock is suspected. A radi-

ograph of the chest shows a massive amount of intra-abdominal air

(figure 1). With prompt needle decompression of the abdomen the

patients circulation dramatically improved. subsequent laparotomy

show s a pneumoperitoneum with a perforation of the tumor. After

sigmoid resection and antibiotics the patient recovered.

Figure 1. Plain radiograph of the chest: a massive amount of intrabdominal free air is striking

Discussion: Acs is defined as an increase in IAP which is associated

with new organ failure or dysfunction.1 especially in Icu patients Acs is

a known complication in trauma-patients, burn-victims, intra-abdom-

inal surgery, polytransfusion, intra-abdominal bleeding and ascites

and edema due infection, inflammation or malignancies.1 We present

a rare cause of Acs caused by perforation of a colontumor after biopsy

during colonoscopy. Perforation during colonoscopy is a rare com-

plication itself with an estimated incidence of 0.03% to 2%.2 during

colonoscopy insufflation of air is used to visualize the intestinal wall. If

perforation occurs but not recognized, it can lead to a tension-pneu-

moperitoneum.2 Probably the omentum acts as a one-way-valve pre-

venting air to flow back into the intestine.

The use of needle-decompression is usefull as a salvage procedure




during resuscitation, although it has been described as sole therapy in

one case.2 This is well reflected by our case in which circulation dramat-

ically improved after decompression by needle, before further surgical

intervention was planned. In general colonic perforation is associated

with high morbidity, up to 50%. Therefore surgical management is

widely recommended.2

Conclusion: Acs as a result of perforation following colonoscopy is

a rare but most serious complication. It should be considered in the

patient in shock after colonoscopy. endoscopists but intensivists

as well, should be aware of this complication and its clinical signs.

Although not a definitive therapy needle-decompression is quick,

readily available and particular helpful in resuscitation of acute Acs

due to pneumoperitoneum. Afterwards swift surgical intervention is

still warranted.

References3. Papavramidis Ts, marinis Ad, Pliakos I, et al. Abdominal compartment syn-

drome-Intra abdominal hypertension: defining, diagnosing, and managing. J emerg Trauma shock. 2011;4:279-91.

4. souadka A, mohsine r, Ifrine l, et al. Acute abdominal compartment syndrome complicating a colonoscopic perforation: a case report. J med case reports. 2012;6:51.

6.

Unexplained hypoxia and Budd Chiari syndrome in a patient with

antiphospholipid syndromeJ.J.H. Bunge1, U.S. Wiersema2, A. Moelker3, E.T.T.L. Tjwa2,

J. van Bommel1

1Department of Intensive Care, Erasmus MC, Rotterdam, The Netherlands, 2Department of Hepatology, Erasmus MC, Rotterdam, The Netherlands,

3Department of Radiology, Erasmus MC, Rotterdam, The Netherlands

Case report: A 23-year-old woman was admitted for analysis and

treatment of a suspected budd-chiari syndrome. Her medical history

reported antiphospholipid syndrome, complicated by pulmonary

emboli and thrombosis of the superior vena cava (svc) and brachioce-

phalic vein in the previous year. The budd-chiari syndrome was caused

by a suprahepatic inferior vena cava (Ivc) thrombus. on admission she

already complained of dyspnoea d’effort. A day after admission, there

was progressive respiratory failure. she was transferred to the Intensive

care, where she soon needed to be intubated and ventilated. on sus-

picion of pneumonia, antibiotics were started. However, her condition

did not improve and marked hypoxia persisted despite high Fio2 and

ventilation pressures. A cT scan, with iodine contrast injected through

the femoral vein, ruled out new pulmonary embolism, and showed

only marginal pleural effusion and atelectasis, and no signs of intersti-

tial lung disease.

The differential diagnosis, in the setting of budd-chiari syndrome,

included portopulmonary hypertension, or shunting due to hepato-

pulmonary syndrome. However, pulmonary artery catheterization

revealed normal pressures. contrast echocardiography was unre-

markable and showed no signs of a right-left shunt. In addition, (99

m)Technetium-macro aggregated albumin (mAA) perfusion scanning

showed 22% mAA-capture in cerebrum/kidney, possibly indicating

pulmonary shunting.

upon further respiratory deterioration over time, a cT scan was

repeated to rule out new pulmonary embolism. This time the iodine

contrast was administered through the right arm, revealing a totally

occluded svc and a severe stenosis of the distal azygos vein due to

thrombosis. There were extensive chest wall collaterals, as well as col-

laterals that appeared to have a close relation with the right pulmonary

veins. There was hardly any contrast in the right atrium and pulmonary

arteries, but dense contrast enhancement in the right pulmonary veins,

left atrium and left ventricle, suggesting direct shunting between

systemic veins and pulmonary veins based on a svc syndrome, rather

than hepatopulmonary syndrome. based on these findings a stent

was placed to dilate the azygos-svc junction. In the same procedure,

a stent was placed over the calcified stenosis in the Ivc. oxygenation

markedly improved directly after stent placement and the patient

was weaned from the ventilator within 24 hours. she was discharged

to from the Icu 4 days after the procedure. The ascites resolved com-

pletely within two weeks.

This case illustrates the different diagnostic steps in a patient with

refractory hypoxia. The diagnosis was only made after (co-incidentally)

altering the route of contrast administration. In the end, there was a

relatively simple solution for the clinical problem.

7.

Massive airembolus after LVAD placement in a patient with dilating

end-stage heart failureJ.V. Dikkeboer, P.R. Wijnandts


Background: In the treatment of end-stage heart failure left ventricu-

lar assist devices (lvAd) are well-known therapeutic options as a bridge

to transplantation or even a bridge to destination in patients deterio-

rating under maximal inotropic therapy. early complications include

perioperative hemorrhage, air embolism, and right ventricular failure.

beyond the perioperative period, late complications consist primarily

of infection, thromboembolism, and primary device failure.

In this case report we would like to share our experience in one of the

severe complications that might appear after implantation of an lvAd.

Methods/Case: A 65-year-old female was admitted at our hospital suffer-

ing from dilating cardiomyopathy. In the previous decade she had been

treated repeatedly for heart failure. despite resynchronization therapy

with pacemaker the estimated left ventricular function decreased from

25 to 10 %. because of atrial fibrillation there was a progressive deteriora-

tion of right and left ventricular function, with pronounced clinical dete-

rioration despite inotropic support. Patient underwent an aortic valve

repair, a tricuspid valve repair because of severe aortic- and tricuspid



regurgitation and implantation of a centrimag lvAd. After weaning from

cardiopulmonary bypass, haemodynamic support was provided by low

dose dobutamine, milrinone, amiodarone and high dose norepineph-

rine. At admittance to the Intensive care unit (Icu) patient showed signs

of low cardiac output, which was corrected by fluid resuscitation. Trans

esophageal ultrasound (Tee) showed no evidence of cardiac tamponade.

Aproximally an hour after arrival at the Icu there was a sudden drop of

cardiac output (co). measured blood flow dropped below 1 l/min, with

preservation of lvAd rpm. Pulmonary artery catheter showed a drop of

co, with only a slight increase in cvd or PAP. resuscitation started imme-

diately by fluid therapy and increasing inotropic support. Patient was

hypoxic with poor circulation of the extremities. Physical examination

showed normal bilateral lung sounds. Inspection of the lvAd showed

massive amounts of air in the cannula, with an airlock at the pump.

Patient was immediately put in Trendelenburg position to try to avoid

air-embolus to the brain.Tee showed marginal right- and left ventricu-

lar movement, with no evident opening of the aortic valve. There was a

pronounced air-embolus in the ascending and descending aorta (figure

1). re-thoracotomy performed on the Icu did not show a luxation of the

apex-cannula. After advancing of the cannula into the left ventricle cir-

culation swiftly restored. Tee showed increased right and left ventricular

movement, with no evidence of outflow obstruction (figure 2). negative

pressure in the trabecular system of the left ventricle could have caused

the aspiration of air in the apex-cannula. Patient recovered haemody-

namically in the next days. she did not regain consciousness and devel-

oped epileptic seizures. cT-cerebrum showed widely spread ischemia.

Patient died shortly after discontinuation of treatment.

Results/Conclusion: Air was aspirated into the lvAd. causing airlock in

the pump, outflow obstruction and fatal air-emboli to the brain. There

was no evidence of displacement of the cannula during re-thoracot-

omy. Advancement of the apex-cannula caused swift haemodynamic

stabilization. special care should be taken positioning of the cannula

and testing for air-emboli, because of possibly fatal consequences.

Reference1. Igor d, et al. management of Air embolism during Heartmate® xve

exchange. Tex Heart Inst J. 2007;34:19-22.

Figure 1. Air in the ascending aorta

Figure 2. After repositioning of apex-cannula

8.

Blinded by septic shockK. Kooning¹, M. Otten¹, R. v.d. Ploeg ², L. Lelyveld¹

1Department of Intensive Care Medicine, Diakonessenhuis, Utrecht, The Netherlands, ²Department of Ophthalmology, Diakonessenhuis, Utrecht, The Netherlands

Introduction: The majority of patients discharged from critical care

experience problems with physical, non-physical and social function-

ing. We report on bilateral blindness as a rare and disabling complica-

tion in a young survivor of septic shock.

Case report: A 42-year-old male with a history of psoriatic arthritis, for

which he used methotrexate, presented to our emergency department

with abdominal discomfort two days after an inguinal hernia repair.

ultrasound showed abdominal wall hematoma and he was admitted

to the surgical ward. Within 12 hours of admission he developed septic

shock. The patient was admitted to the Intensive care unit (Icu), was

resuscitated with fluids and vasopressors and treated with antibiot-

ics (ceftriaxone and metronidazole). emergency surgical exploration

showed necrotizing fasciitis and aggressive surgical debridement was

performed. cultures revealed hemolytic group A streptococcus and anti-

biotic treatment was switched to penicillin and clindamycin. Intravenous

immunoglobulin was added for treatment of toxic shock syndrome.

The patient suffered from severe septic shock with multiple organ

failure, including diffuse intravascular coagulation (dIc) and acute

respiratory distress syndrome. High dose vasopressor therapy was

needed (noradrenaline 2.7 mcg/kg/min and adrenaline 0.08 mcg/kg/

min). After extubation he reported blindness with both eyes. His pupils

were dilated and unresponsive to light. ophthalmological evaluation

revealed peripapillary retinal hemorrhages without signs of papillary

edema. magnetic resonance imaging showed fluid surrounding the

optic nerves. visually evoked potentials were negative. The patient was

diagnosed with bilateral posterior ischemic optic neuropathy (PIon). A

course of steroids was considered to treat optic nerve edema but was

found unsafe at that moment since he still had an active infection. Two

weeks after diagnosing PIon a course of dexamethasone was started




without improvement of vision. Follow-up ophthalmological examina-

tion showed regression of retinal hemorrhages but four months after

diagnosis he still had no light perception or pupillary reaction to light

and fundoscopy revealed bilateral optic nerve pallor.

Discussion: PIon is a watershed infarction of the optic nerve and it is a

rare but serious complication of critical illness. blood supply to the pos-

terior optic nerve is almost entirely dependent on the pial vasculature,

which is very susceptible to ischemia. Factors associated with PIon are

hypotension, anemia, venous congestion, prone position, large blood

loss, use of vasopressors and preexisting vaso-occlusive disease. other

causes of PoIn are listed in table 1. A course of steroids can decrease

optic nerve edema and thereby improve outcome. spontaneous

recovery or improvement of PIon is unlikely.

The exact cause of PIon in this case remains unclear. The patient

suffered from severe septic shock with multiple organ failure and

received high dose vasopressor therapy. However, he did not exhibit

other signs of systemic hypoperfusion such as renal failure or gastro-

intestinal problems. He was never ventilated in prone position, did not

suffer from excessive blood loss or anemia and was not known to have

vaso-occlusive disease. The presence of retinal bleeds in the initial oph-

thalmologic examination leads us to think dIc played a contributing

role in causing PIon in our patient.

Conclusion: We report on a rare complication of septic shock: bilateral

irreversible complete vision loss due to PIon.

Reference1. lee lA, nathens Ab, sires bs, et al. blindness in the intensive care unit:

possible role for vasopressors? Anesth Analg. 2005;100:192-5.

Table 1.

Etiology of PION1) a combination of systemic hypotension and anemia (due to blood loss)

2) giant cell arteriitis, vasculitis (herpes zoster, polyarteritis nodosa, lupus erythematosis)

3) infiltrative causes

4) compression

5) idiopathic

9.

Ictal asystole: a rare complication of epilepsia

M.J. Boer, M.J. van Dam

Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

Background: epilepsy can be associated with a variety of cardiac

arrhythmias. Ictal asystole (IA) is a rare, and potentially fatal complication.

Methods: A 32-year-old, 17 weeks pregnant patient was brought to the

emergency room after return of spontaneous circulation after cardiac

arrest. she had a history of partial complex epilepsy. she used carba-

mazepine which was stopped at the beginning of her pregnancy. After

a seizure she remained unconscious and cardiopulmonary resuscita-

tion (cPr) was started. The ambulance arrived after 10 minutes and

continued cPr with a monitored asystole. she had return of sponta-

neous circulation and on arrival at the er her blood pressure (bP) was

170/100 mmHg, pulse of 131/min. Her glasgow coma scale (gcs) was 3

with normal brain stem reflexes. cT cerebrum showed diffuse swelling

with compressed ventricles and a hypodensity of the right parietal

lobe, considered to be preexistent. There were no signs of intracranial

hemorrhage nor signs of brain stem compression (picture 1). Her blood

work showed a bloodgas with a pH of 6,75 a pco2 of 71 mmHg and a

lactate of 16,6mmol/l. A transthoracic echocardiography (TTe) showed

a hyperdynamic left ventricle without regional wall motion abnormal-

ities and no valve abnormalities. There were no signs of pulmonary

embolism on a cT angiogram. she was admitted to the Icu for ther-

apeutic hypothermia according to protocol. After rewarming a soma-

tosensory evoked potential (sseP) was performed which was not con-

clusive due to technical difficulties so an electroencephalogram (eeg)

was performed which showed burst suppression without reactivity.

one day later the eeg showed an isoelectric trace, without any cortical

activity and no signs of non-convulsive state. Treatment was discontin-

ued and she died.

Results: epileptic seizures are accompanied by cardiac arrhythmias

2% of which are IA or bradycardia. schuele et al found an 0.27% inci-

dence after evaluating 6825 cases of epilepsy.1 schuele used eeg and

r-r interval monitoring and found asystole in 10 out of 6825 patients;

eight in patients with temporal epilepsy and two of other origin.

risk factors for IA are refractory epilepsy, most often temporal epilepsy,

cardiac abnormalities and some anti-epileptic drugs(Aed). There is

some debate whether epilepsy triggers a respiratory arrest and concur-

rent hypoxia causing cerebral hypoperfusion and myocardial hypoxia

and asystole or whether epilepsy alone is responsible through a auto-

nomic response and discharge of the vagal centers in the medulla

which leads to asystole resulting in cerebral hypoperfusion and atonia.

This latter cardio-inhibitory pathway may be associated with temporal

epilepsy.1

Treatment of IA or bradycardia requires better antiepileptic treatment

and sometimes pacemaker implantation. strzelczyk et al proposed the

following algorithm.2

Conclusion: Ictal asystole is a rare complication of epilepsy with dif-

ficult etiology but is potentially fatal. In our patient the asystole was

preceded by a seizure which probably led to cerebral hypoperfusion

and ischemia of both the heart and brain. surviving patients should

receive aggressive treatment with Aed, epilepsy surgery, pacemaker

implantation or a combination of treatments.

References1. schuele su, bermeo Ac, Alexopoulos Av, et al. video-electrographic and

clinical features in patients with ictal asystole. neurology 2007;69:434-41.

2. strzelczyk A, cenusa m, bauer s, et al. management and long-term outcome in patients presenting with ictal asystole or bradycardia. epilepsia. 2011;52:1160-7.



Picture 1.

Figure 1.

10.

A case of fatal asthma after use of a dietary supplement containing creatineM.P.M. Roukens1, E.S. Brugman1, H.W. Niessen2, A.R.J. Girbes1

1Department of Intensive care, VUMC, Amsterdam, The Netherlands, 2Department of Pathology, VUMC, Amsterdam, The Netherlands

A 49-year-old man, with a history of mild allergic asthma necessitating

occasional salbutamol inhalation therapy, developed a severe asthma

attack some 30 minutes after intensive workout and a first-time inges-

tion of a protein shake containing creatine. Following self-adminis-

tered incremental doses of salbutamol he was found unresponsive.

on arrival of the paramedics asystole and respiratory arrest were diag-

nosed. extensive successful resuscitation was initiated and the patient

was transported to our hospital. The ventilation during transport was

reported to be extremely difficult. on presentation at the emergency

room we saw a patient with a striking rash covering all body parts.

capnography could not be obtained; the eT tube appeared to be

placed in the oesophagus. After endotracheal reintubation the patient

developed again pulseless electric activity combined with unmeasur-

able high etco2, high ventilation pressures and expiratory wheezing,

suggesting a severe bronchusobstruction with dynamic hyperinfla-

tion. Initial bloodgas analysis revealed a severe combined respiratory

and metabolic acidosis: pH of 6.78 po2 282 kPa pco2 161 kPa Hco3- 23.8

mmol/l be-11.3 sao2 0.99. leucocyte count showed marked eosino-

philia. cardiac massage was combined with adrenaline iv and nebulisa-

tion, ketamine infusion, magnesium sulphate iv, as well as salbutamol,

ipratropium and steroids. The patient was mechanically ventilated with

low frequency and prolonged expiratory time allowing normalisation of

intrathoracic pressures. After restoration of circulation, mild therapeu-

tic hypothermia was induced. unfortunately, on rewarming patient was

found to have absent brain stem reflexes and brain death was declared

according to national protocol. Autopsy showed severe pulmonary

oedema with eosinophilic and neutrophilic infiltrates in the alveoli and

parabronchial tissue, consistent with fatal allergic asthma (figure 1).

Although findings at autopsy could not be specifically linked to a distinc-

tive allergenic cause, several clinical features in this case report are indic-

ative for an allergic reaction after a first time ingestion of a creatine sup-

plement. creatine has been widely used as the most effective nutritional

supplement with a proven ergogenic value in high-intensity exercise as

well as longer duration exercise tasks, increasing muscle strength and

lean body mass).1 Also creatine supplementation is used in conditions

where muscle wasting is a key feature like myopathies, neurodegener-

ative and brain disorders, heart failure and coPd.1 side effects seem to

be limited to water retention; however when the maximal daily dose is

exceeded, reports on kidney failure and hepatitis exist. In bodybuilder

communities on the internet however, worsening of allergic asthmatic

symptoms are frequently mentioned after use of creatine containing

supplement; no case-report is yet available in the current literature on

this matter. vieira and co-workers 2 were on different occasions able to

demonstrate in a model of sensitized mice that creatine supplementa-




tion exacerbates allergic inflammation, airway responsiveness, excessive

mucus production and airway remodelling through activation of Th2

and IgF -1 pathways, all of which also have been proven to play a role in

the development of human fatal asthma attacks. Therefore to our knowl-

edge this is the first case in literature where the use of creatine supple-

mentation can clinically be linked to a fatal allergic asthma.

References1. gualano b, roschel H, lancha AH, et al. In sickness and in health: the

widespread application of creatine supplementation. Amino Acids. 2012;519-29.

2. vieira rP, duarte Acs, claudino rc, et al. creatine supplementation exa-cerbates allergic lung inflammation and airway remodeling in mice. Am J respir cell mol biol. 2007;37:660-7.

Figure 1. cross-section of lungtissue, clearly visible are congested vessels, inflammatory infiltrate and invasion of neutrophils and eosinophils

11.

Mirizzi syndrome mimicking malignancy: the right sequence

in diagnostic interventionsA. Tel, P. Ott, R. Sayilir, M. Scheer

Department of Intensive Care Medicine, Martini Hospital Groningen, The Netherlands

Introduction: The mirizzi syndrome is a rare cause of obstructive

jaundice and should be considered in the differential diagnosis of all

patients with these signs. We describe a case of obstructive jaundice

with severe complications due to diagnostic interventions. The

sequence of these diagnostic and therapeutical interventions is impor-

tant as complications could be prevented.

Case: A 55-year-old male patient with a history of Helicobacter

Pylori gastritis presented with jaundice and itch since two weeks. on

physical examination he was icteric without pain, the remainder was

unremarkable. blood test showed serum total bilirubine level of 147

umol/l, direct bilirubine 88 umol/l, alkaline phosphatase 241 u/l and

γ-gT 97 u/l. Abdominal ultrasound revealed dilated intra- and extra-

hepatic biliary ducts, probably based on intraluminal obstruction of

the common bile duct (cbd). The patient underwent an endoscopic

retrograde cholangiopancreatography (ercP) which showed a

proximal dilatation of the cbd (figure 1). because of a stenosis in the

medial part of the cbd an endoprothesis was placed.

A few hours after ercP, the patient developed a hemorrhagic shock. He

was admitted to the Icu where he received blood transfusion and fresh

frozen plasma. Immediate cT angiography revealed a massive bleeding

in the area of the papilla duodeni from one of the branches of the arteria

hepatica propria (figure 2). Hemostatis was achieved by embolization.

The next day our patient developed fever and further elevated bilirubine

levels. reassessment of the cT scan revealed a large, layered gallstone (size

3-4.5 cm) in the gallbladder neck as the cause of the obstruction (figure

3). The patient underwent laparoscopic cholecystectomy which was con-

verted to an open procedure. A large gallstone was seen in the gallbladder

neck that caused erosion of the lateral wall of the common bile duct (figure

4). Two days after surgery the patient was discharged from the Icu.

Discussion: mirizzi’s syndrome is characterized by a compression of the

cbd or common hepatic duct caused by a gallstone which is impacted

in the cystic duct or neck of the gallbladder. It causes obstruction

and jaundice by an extrinsic compression of the cbd (type I) or may

be accompanied by a cholecystobiliary fistula compromising the cbd

wall (type II-Iv). The primary radiologic tests to diagnose the mirizzi

syndrome are computed tomography combined with ercP or mrcP.

Conclusion: In this case the patient went for ercP after dilated biliary

ducts were seen on abdominal sonography. If our patient went for

computed tomography before ercP a hemorrhagic shock could have

been prevented. In conclusion, the right sequence of diagnostic and

therapeutic interventions in obstructive jaundice should be accurately

chosen since it may lead to severe complications.

References1. beltrán mA. mirizzi syndrome: History, current knowledge and proposal of a

simplified classification. World J gastroenterol. 2012;18:4639-50.

2. Yun eJ, choi cs, Yoon dY, et al. combination of magnetic resonance cholan-giopancreatography and computed tomography for preoperative diagnosis of the mirizzi syndrome. J comput Assist Tomogr. 2009;33:636-40.

Figure 1. ercP with a proximal dilatation of the cbd and intrahepatic gallways with external compression in region of cystic duct



Figure 2. cT angiography reveals an active bleeding in the area of the papilla duodeni

Figure 3. computed Tomography showing a large, layered gall stone in the gallbladder neck, with compression of the common bile duct.

Figure 4. A large gallstone caused erosion of the lateral wall of the common bile duc

12.

Unexplained high lactate levels after long bone fractures: remember

cerebral fat embolism syndromeR. van Vugt1,2, B.P. Ramakers1, J.G. van der Hoeven1

1Department of Intensive Care, Radboudumc, Nijmegen, The Netherlands, 2Department of Anaesthesiology, Rijnstate Hospital, Arnhem, The Netherlands

Introduction: cerebral fat embolism is an uncommon but serious

complication of long-bone fracture. The classic fat embolism syndrome

is characterized by the clinical triad of respiratory insufficiency, altered

mental status and petechiae. Here we present two cases of cerebral

fat embolism syndrome (cFes) and isolated high lactate levels without

haemodynamic instability.

Patient A: A 26-year-old man was admitted to our hospital after

being hit by a car. on arrival he had a maximal glasgow coma score.

conventional radiology revealed fractures of both femura and a

fracture of the left tibia. Treatment was entirely conservative. The

patient was admitted to our intensive care unit (Icu) and within a few

hour his consciousness decreased to an eye motor verbal score of 3.

subsequently, his respiratory condition deteriorated quickly and the

clinical picture and mrI (figure 1) were most suspect for cFes. Although

there were no signs of sepsis, cardiac failure or ischemia, our patient

had an persistent isolated lactate level between 4.9-8.2 mmol/l (figure

2). The patient died within 48 hours after admission to our hospital.

Patient B: A 19-year-old man presented with multiple trauma after a

car accident. He had multiple fractures of the sacrum and femurs on

both sides, a fracture of the right lower leg, and a tibia plateau fracture

on the right. The patient underwent surgery and a total of three

external fixtures were placed on both legs. The patient had a maximal

eye and motor score while still on the ventilator. several hours later he

rapidly lost consciousness and within 20 minutes his eye motor verbal

score was e1m1vtube. Almost at the same time the pulmonary condi-

tion of our patient deteriorated quickly. given the neurological signs,

in combination with the pulmonary deterioration, a diagnosis of fat

embolism syndrome was suspected. Although there were no signs of

sepsis, cardiac failure, or ischemia, our patient had an isolated lactate

level of 3.1-5.5 mmol/l (figure 1). The patient died within 48 hours after

admission to our hospital.

Discussion: Although the diagnosis cFes is difficult, several scoring

systems have been developed to diagnose cFes. Here we suggest that

lactate in the absence of haemodynamic instability could additionally

be used in diagnosing cFes, adding it to its present criteria.

Although glucose is assumed to be the main energy source for all living

tissue, there are indications that lactate, and not glucose, is preferen-

tially metabolized by neurons in the brain. For example, lactate is an

important metabolic precursor for cerebral gluconeogenesis and ATP

under physiologic, but also pathological conditions.1 At rest, the human

brain releases a small amount of lactate. However, during cerebral acti-

vation, as seen during exercise, the plasma lactate increases and the

brain takes up lactate in proportion to the arterial concentration.2 It




is hypothesized that diffuse damage to the brain causes that neurons

cannot use lactate whereas astrocytes and oligodendrocytes keep pro-

ducing lactate with a net increase in lactate levels.

Possibly, adding lactate to the existing criteria for cFes, might increase

the sensitivity of diagnosing cFes.

References1. stein nr, mcArthur dl, etchepare m, vespa Pm. early cerebral metabolic

crisis after TbI influences outcome despite adequate hemodynamic resusci-tation. neurocrit care. 2012;17:49-57.

2. Quistorff b, secher nH, van lieshout JJ. lactate fuels the human brain during exercise. FAseb J. 2008;22:3443-9.

Figure 1. mrI

Figure 2. lactate levels

13.

Diffuse alveolar hemorrhage, a rare but possible fatal complication after

combined anticoagulant therapy for acute myocardial infarction

R.P.J. Segers, T.S.R. Delnoij, D.C.J.J. Bergmans

Maastricht University Medical Center, Maastricht, The Netherlands

Case report: diffuse alveolar hemorrhage (dAH) is a possible

life-threatening medical condition. bland pulmonary hemorrhage due

to elevated left ventricular end diastolic pressure is an underdiagnosed

cause. because of its low prevalence, dAH is a real diagnostic challenge.

A 69-year-old man with a past medical history of myocardial infarc-

tion, presented to our emergency department (ed) after a witnessed

out-of-hospital cardiac arrest while cycling. basic life support was started

immediately. upon arrival of the ambulance, the presenting rhythm was

ventricular fibrillation with subsequent return of spontaneous circula-

tion after defibrillation. He remained comatose and arrived intubated in

our ed. electrocardiogram showed an atrial flutter without sT-elevation.

Transthoracic echocardiography demonstrated an overall poor left ven-

tricular function with an estimated ejection fraction of 30%. Prasugrel

60 mg, acetylsalicylic acid 300 mg and 5000 units of heparin were given

because of the likelihood of a new ischemic event. A coronary angiogram

revealed a culprit lesion in the right coronary artery. A bare metal stent

was placed with good angiographic result. because the patient vomited

after administration of prasugrel in the ed, a loading dose of 600 mg

clopidogrel was administered. After the PcI the patient was admitted to

our intensive care unit. Therapeutic hypothermia was initiated. The res-

piratory situation deteriorated rapidly with a chest x-ray showing bilat-

eral consolidations. copious amounts of bloody secretions were aspi-

rated from the endotracheal tube. Therapeutic hypothermia was stopped

because of brady cardia and bleeding. bronchoscopy showed diffuse

bleeding in the distal regions of the bronchial tree suggesting dAH. chest

x-ray was repeated showing an increase in bilateral consolidations. The

patient succumbed to refractory respiratory failure due to massive dAH.

In cardiac asthma there is a disruption of the layers of the alveolar-cap-

illary unit due to elevated capillary hydrostatic pressures, a phenome-

non also known as pulmonary capillary stress failure. A rise in capillary

hydrostatic pressure favours the formation of edema in the interstitial

compartment removed from the critical gas-exchanging regions. once

fluid forms in the interstitium, it is transported to the interlobular septae,

the peribronchovascular space and finally to the hila and pleural space.

lymphatic vessels within these regions are highly recruitable and are able

to increase the clearance of lung water by more than 10-fold. When this

compensatory mechanism fails and all layers are disrupted, red blood

cells may be seen traversing the alveolar-capillary membrane, resulting in

the well-known pink frothy expectorations. Taking this pathophysiologi-

cal finding into account, we believe that administration of anticoagulant

therapy in patients with acute ischemic heart failure will increase the risk

of diffuse alveolar hemorrhage, in this case a fatal complication.



This case suggests that administration of anticoagulant therapy after

myocardial infarction can cause a fatal diffuse alveolar hemorrhage,

especially if the patient is in acute ischemic heart failure. diffuse

alveolar hemorrhage can be mistaken for acute heart failure with

similar radiological and clinical findings. Therapy should not only

consist of treating acute heart failure, but cessation of implicated drugs

and reversal of excess anticoagulation should be considered.

14.

Oxaliplatin induced multi organ failure: a condition intensivists should be aware of

S. Janssen, D.C.J.J. Bergmans, W.N.K.A. van Mook

Maastricht University Medical Center, Maastricht, The Netherlands

Background: oxaliplatin is increasingly used in both adjuvant and pal-

liative chemotherapy regimens for intestinal carcinoma. consequently,

more patients will be admitted to the intensive care unit (Icu) whilst

on such a regimen. common adverse effects include pancytopenia,

mucositis, neuropathy and anaphylaxis. less known are the potentially

lethal hepatic effects, which will be illustrated in the following case.

Case: A 70-year-old female was transferred to our Icu from another

hospital. Her medical history revealed non-metastasized rectum carci-

noma, treated with neo-adjuvant chemotherapy and radical resection.

Adjuvant treatment consisted of standard dose oxaliplatin and capecit-

abine. she was admitted with hypopotassaemia and metabolic acidosis

due to mucositis. This was complicated by a pulseless electrical activity,

resulting in an non-sT-elevation myocardial infarction. In the follow-

ing days, sepsis of unknown origin with respiratory, renal and liver

insufficiency with ascites developed. laboratory results showed biliru-

bin 200 µmol/l, AsAT 160 u/l, AlAT 76 u/l, AF 779 Iu/l and γ-gT 440

u/l. moreover, thrombocytopenia with secondary intestinal bleeding

occurred. she was intubated and platelet transfusion and antibiotics

were administered. gastroduodenoscopy showed multiple erosive

ulcerations likely due to mucositis.

she was then transferred to our hospital because of lack of contin-

uous venovenous haemodialysis capability in the referring center.

Thrombopenia persisted at 23 109/l, in spite of transfusion. diffuse intra-

vasal coagulation was deemed unlikely with fibrinogen at 2.1g/l, PT 16,1s

and aPTT 40s. Analysis of liver failure included extensive cultures, virus

assays, computed tomography and ultrasound imaging to rule out metas-

tasis or macrovascular obstruction and echocardiography to exclude

both forward and backward failure. besides the oxaliplatin, no other

cause was found for this multiple organ failure. In spite of maximal sup-

portive therapy, the patient died 6 days after admission. unfortunately,

postmortem confirmation of the diagnosis was declined by the family.

Discussion: Whereas the metabolic derangement due to diarrhea was

probably caused by capecitabine related mucositis, the ensuing symp-

tomatology is more likely due to oxaliplatin toxicity. literature reports

that oxaliplatin can cause sinusoidal injury syndrome (sos), with subse-

quent, potentially fatal liver damage. drug-induced thrombocytopenic

purpura has been also described with oxaliplatin use. However, no frag-

mentocytes were found. The thrombocytopenia might also have been

a drug-induced immune thrombocytopenia. This has however mainly

been described whilst on oxaliplatin treatment, and recovers after dis-

continuation. disseminated intravascular coagulation has also been

shown after oxaliplatin use, but was excluded in this case. sos there-

fore was the most likely diagnosis.

sos has been described after oxaliplatin use. most cases develop

mild to moderate symptoms, and have a good prognosis. severe sos

however, which accounts for 25-30% of cases, has a high mortality rate,

especially if renal failure occurs. Treatment consists mainly of support-

ive care. If multi organ failure has not yet developed, anticoagulation

may benefit outcome. defibrotide, a polydeoxyribonucleotide, may

benefit even those in severe sos, but is not yet commonly available.

Conclusion: In case of prolonged thrombocytopenia and liver insuffi-

ciency after administration of oxalipatin, intensivists should be aware

of the possibility of oxaliplatin toxicity as the causal entity.

References1. bautista, et al. Hypersensitivity reaction and acute immune-mediated

thrombocytopenia from oxaliplatin: two case reports and a review of the literature. Journal of Hematology and oncology. 2010;3:12

2. schouten van der velden AP. Hepatic veno-occlusive disease after neo-ad-juvant treatment of colorectal liver metastases with oxaliplatin: a lesson of the month. eur J surg oncol. 2008;34:353-5.

15.

First Pieris Japonica intoxication described in a humanS. van Roosmalen, J.A.H. van Oers

Department of Intensive Care Medicine, St Elisabeth Hospital, Tilburg, The Netherlands

Introduction: The Pieris Japonica (Japanese Pieris) plant is a member

of the ericaceae family, which also includes rhododendrons and

azaleas. It is a shrub or small tree with oval to lanceolate leaves with

finely serrated margins. They are more and more used as decoration in

european gardening. They are also known to be toxic to animals, espe-

cially ruminants. These animals are often exposed to these plants in

their grazing environment. A few reports have been published about

intoxications of goats. As far as we are aware, this is the first report ever

written about an intoxication in a human being.

Case: A 62-year-old woman was presented to the emergency room (er)

of the st elisabeth Hospital with salivation, nausea, vomiting, bradycar-

dia, hypotension and ‘different behaviour’. Four ours before presenta-

tion, during her daily walk, she ate two branches of the Pieris Japonica

plant. The woman is living in an environment for mentally disabled

people. Her mentally performance is estimated at 0.5 years old.

In the ambulance her heart rate began slowing down to 40 beats

per minute and her blood pressure dropped to 60/20. After one gift

of atropine (0.3 mg) her blood pressure and heart rate stabilized. no

further resuscitation was necessary.




on examination at the er blood pressure was 124/86, heart rate was 110

r/A. saturation was 98% (no extra oxygen), normal breath sounds. Her

behavior was different to normal. due to her pre-existent mentally perfor-

mance a gcs was not possible. she didn’t seem to be drowsy, both pupils

were equal (no enlargement) and reactive to light. Further clinical evalu-

ation showed no disturbances. laboratory studies showed biochemical

parameters within the normal range. The electrocardiogram revealed a

sinus tachycardia of 107 beats/minute, a normal Qrs axis, normal conduc-

tion times, no pathological Q waves and no sT segment changes.

due to the amount of time between ingestion and presentation in the

er, no gastric lavage was performed. she was treated with activated

coal and admitted to the Intensive care unit.

during her stay in the Intensive care unit she remained haemody-

namically stable; no hypotension or arrhythmias were observed. The

vomiting and salivation stopped. no neurological signs were observed

and her behavior went back to normal.

The next day she was discharged to her own living environment.

Discussion: The poisonous principle of the plant is the acetylan-

dromedol toxin. It binds to and modifies the sodium channels of cell

membranes, leading to prolonged depolarization and excitation. It

favors calcium movement into the cells and thereby results in a positive

inotropic effect, similar to that of digitalis (although structurally unre-

lated). bradycardia, hypotension and atrioventricular block are serious

cardiovascular effects that may be lethal. As little as 0.2% of the body

weight of leaves of the Pieris Japonica plant may be toxic and even lethal.

We should be aware of the risks of this plant, particularly because of

the low toxic dosage and the apparent increase in popularity in europe.

16.

Colchicine poisoning; hesitate before extubate?

L.C.M. Schenning, M.C.M. de Groot, J.J. Weenink

Department of Intensive Care, Spaarne Hospital, Hoofddorp, The Netherlands

Background: colchicine is an anti-inflammatory drug primarily used for

gout and familial mediterranean fever. The drug has a low therapeutic

index without a clear cut-off value between toxic and nontoxic dose.

Acute colchicine poisoning is rare but associated with poor outcome.

colchicine is rapidly absorbed from the gastro intestinal tract and under-

goes an extensive hepatic first-pass metabolism with significant entero-

hepatic re-circulation. mean elimination half-life of oral colchicine is

4-16h but its half-life in leucocytes is reported to be 60 h. colchicine

binds to intracellular tubulin impairing the microtubular network. This

predominantly affects cells with a high turnover rate and may subse-

quently lead to multi organ dysfunction revealing days after ingestion.

The typical clinical course of colchicine poisoning is summarized in table

1. Therapy consists of gastrointestinal decontamination in the first phase

and intensive supportive care.1 colchicine-specific Fab fragments are

described to be effective, but are not commercially available.2

Case report: A 50-year-old woman with a history of gout and an unspec-

ified psychiatric disorder was admitted comatose at an ed elsewhere

12-24h after an estimated ingestion of 15mg colchicine, 1600 mg clo-

mipramine, 600 mg fenobarbital and three different benzodiazepines.

she was intubated before transfer to our Icu. At admittance a e1m1v1

coma score persisted, without haemodynamically disturbances and

unaffected oxygenation. laboratory tests were unremarkable beside a

creatine kinase (ck) of 3668 u/l. ecg showed normal sinus rhythm with

prolonged Qrs and QTc. Treatment was started with activated charcoal,

magnesium sulphate and hyperhydration with saline and bicarbonate.

The next day patient fully awakened and appeared haemodynamic

and respiratory normal with minimal support. ck level decreased and

the conduction abnormalities normalized. Therefore it was decided to

extubate.

eight hours after extubation, 36-48h after ingestion, her condition

suddenly deteriorated with shock, bilateral inspiratory crackels and

severe hypoxemic respiratory failure not improving after applying

non-invasive positive pressure ventilation. chest x-ray showed bilat-

eral alveolar consolidations compatible with (non-)cardiogenic lung

edema. The patient was re-intubated and subsequently treated with

lung protective ventilation in prone position. The following week she

gradually improved although the Icu treatment was complicated by

pneumonia, delirium and hypophosphatemia. on day 7 she was extu-

bated and on day 9 she could be discharged from the hospital appar-

ently without any residual symptoms.

Conclusion: colchicine poisoning is a potential life-threatening condi-

tion. As our case report underlines, the initially mild clinical course may

be misleading and acute deterioration may reveal. It is important to be

aware of the subsequent clinical stages and patients should be closely

monitored for several days after colchicine poisoning.

References1. Finkelstein Y. clin Toxicol; 2010;48:407.

2. baud FJ. n engl J med. 1995;332:642.

Table 1. clinical stages of colchicine poisoning.1

Stage Time of onset Featuresgastrointestinal phase

0-24 hours post-ingestion

• nausea, vomiting, diarrhea, abdominal discomfort

• Hypovolemia• leukocytosis

multi-organ failure phase

1-7 days post-ingestion

• (Adult) Respiratory distress syndrome (ARDS)

• cardiac arrhythmias, failure, arrest• encephalopathy, brain edema,

convulsions• renal failure• liver failure• disseminated intravascular coagulation• bone marrow suppression,

pancytopenia• metabolic acidosis, hypokalemia,

hyponatremia, hypocalcemia, hypo(hyper)glycemia, hypophosphatemia

• myopathy, neuropathy• secondary sepsis

recovery phase 7-21 days post-ingestion

• resolution of organ system derangements

• rebound leukocytosis• Alopecia



17.

Microscopic polyangiitis with primary central nervous system manifestations

W.B. Prins1, H.L. Leavis2, M.J. van Dam1

1Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands, 2Department of Rheumatology and Clinical Immunology,


Background: vasculitis presenting with central nervous system mani-

festations is a rare diagnosis in the Icu.

Methods (Case): A 41-year-old woman with a medical history of mild

asthma developed sensory loss of her lower extremities after she was

admitted to hospital with acute onset of pain in the interscapular area.

eight months earlier she experienced paraesthesias and sensory loss of

her lower body, with no abnormalities detected by lumbar puncture or

magnetic resonance imaging (mrI). now, mrI of the spinal cord demon-

strated a subdural hematoma at the thoracic level (Th4-7) (figure 1) and

dexamethasone was started to treat the myelopathy. Two weeks later she

developed paralysis of her right leg and progressive general weakness

leading to respiratory insufficiency requiring mechanical ventilation.

consecutive mrI showed an additional hematoma at the cervical (c3-5)

level as well as ischemic areas (corpus callosum, medulla oblongata) in the

brain. one day later her state of consciousness decreased to a glasgow

coma scale of e4m4v1, with a fixed gaze to the right. A third mrI revealed

multifocal microinfarcts with magnetic resonance angiography (mrA)

demonstrating stenoses in multiple cerebral arteries (figure 2). differential

diagnosis included infective endocarditis, coagulation disorder, vasculi-

tis and lymphoma. diagnostic tests were performed accordingly. broad-

spectrum antibiotics were started after cultures had been taken. The

next day she developed an exanthematous rash. Although uncertain,

high dose methylprednisolone was started to treat the suspected vascu-

litis. In order to ascertain the diagnosis, biopsy of the affected brain tissue

was done. In the following days her condition did not improve and renal

function deteriorated. Haemodynamic instability occurred as a result of

gastrointestinal bleeding. unfortunately, none of the test results could

confirm the presence of vasculitis until one week after Icu admission.

P-AncA was present and directed against myeloperoxidase (AncA-mPo

> 100Iu/ml), indicative of microscopic polyangiitis (mPA). Treatment was

optimised by pulse cyclophosphamide. Plasmapheresis and rituximab

were added because of acute severe disease.

Results (discussion): mPA is a systemic vasculitis affecting small- and

medium-sized blood vessels and is associated with myeloperoxidase-an-

tineutrophil cytoplasm antibodies (mPo-AncA).1 Almost any organ

system can be affected and therefore symptoms can vary. Although

neurological involvement is not uncommon, this mainly concerns the

peripheral nervous system.1 The unusual presentation of mPA in our

case led to delay in diagnosis and irresoluteness about the most correct

therapy. early recognition and prompt therapy of vasculitis is crucial to

prevent serious morbidity and mortality. We would like to stress that

cns manifestations can be the first presentation of mPA. because the

majority of patients with mPA present with glomerulonephritis or lung

haemorrhage,1 clinical studies have focussed on this patient population

and even here the role of plasma exchange or other adjunctive therapies

remains unclear. recently, rituximab was proven at least as effective as

cyclophosphamide for the induction of remission in patients with severe

disease.2 unfortunately, our patient only partially recovered from her

cerebral ischaemic insults and remains severely disabled.

Conclusion: mPA is a systemic disorder that can present with primary

central nervous system manifestations. early recognition and therapy

are critical.

Figure 1. A mrI of the spinal cord showing a hematoma at the thoracic level

Figure 2. A mrA showing stenoses in multiple cerebral arteries

Thanks to doctor F.A.A. Mohamed Hoesein, Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands

References1. chung sA, seo P. microscopic polyangiitis. rheum dis clin north Am.

2010;36(3):545-58.

2. specks u, et al. for the rAve-ITn research group. efficacy of remission-induc-tion regimens for AncA-associated vasculitis. n engl J med. 2013;369:417-27.




18.

Inadvertent placement of a Central Venous Catheter (CVC) in the subclavian artery.

How to manage this problem?T.E. van der Krieken1, P.C. Hartman2, G.N.M. Stultiëns3, L.M. Keeris1

1Department of Intensive Care, Elkerliek Hospital, Helmond, The Netherlands, 2Department of Radiology, Elkerliek Hospital, Helmond, The Netherlands,

3Department of Vascular Surgery, Elkerliek Hospital, Helmond, The Netherlands

Background: Inadvertent puncture and catheterization of the subcla-

vian artery is a known complication of infraclavicular catheterization

for central venous access. removal of the cvc without precautions can

lead to severe complications.

Objectives: management of inadvertent placement of a cvc in the

subclavian artery.

Case report: A 74-year-old woman with an unremarkable medical

history was recently diagnosed with an adenocarcinoma of the

stomach. she received neo-adjuvantive chemotherapy and devel-

oped severe diarrhea. Patient was admitted to our Icu with deep hypo-

volemic shock due to dehydration. she was haemodynamically unstable

and, besides aggressive rehydration, required inotropy. Insertion of a 7

French left subclavian cvc procedure was uncomplicated.

no excessive backflow was noticed. While the x-ray showed a ‘correct’

position of the cvc, an arterial pressure curve was registered. The con-

sulted vascular surgeon advised not to remove the cvc and placement of a

endovascular stent in a clinically more stable situation. It was not ruled out

that the cvc had penetrated the vein prior entering the artery. Therefore,

the use of a percutaneous closure device would not be sufficient. A 59 x 7

mm stent-graft was placed via the right femoral artery without compro-

mising the vertebral and mammary artery. An indentation was dilated with

a 7mm balloon. The cvc was removed without complications.

Discussion: Arterial catheterization of a subclavian cvc occurs in 1% of

all infraclaviculair procedures. catheterization in hypovolemic patients

is difficult due to venous collapse. risk factor for inadvertent arterial

catheterization is, such as in our case, an emergency procedure.

Inadvertent arterial catheterization should be suspected when pulsatile

backflow or local hematoma occurs. control x-ray was performed and the

position of the cvc was reported “correct” by the radiologist. If arterial

catheterization is recognized, the catheter should be left in place and per-

cutaneous, endovascular or surgical management should be considered.

removal of an arterial positioned cvc without precautions can lead to

life-threatening complications. In our patient, stent placement was prefer-

able because of its safety, low incidence of complications and good long-

term results. A percutaneous closure device was contraindicated because

of its high failure rate, complications and to avoid venous damage.

ultrasound guidance reduces the risk of arterial puncture during place-

ment of a cvc. However, the subclavian approach benefits less from ultra-

sound guidance. Therefore knowledge of correct management, when an

accidental arterial catheterization occurs, is of great clinical importance.

Conclusion: Inadvertent arterial placement of a subclavian cvc is associ-

ated with emergency procedures. If arterial catheterization is recognized

the catheter should be left in place. A systematic approach is necessary

for planning the best treatment; endovascular, surgical or percutaneous.

References1. ruesch s, Walder b, Tramèr mr. complications of central venous catheters:

internal jugular versus subclavian access--a systematic review. crit care med. 2002;30:454-60.

2. Polderman kH, girbes AJ. central venous catheter use. Part 1: mechanical complications. Intensive care med. 2002;28:1-17. epub 2001 dec 4.

3. Pikwer A. Acosta s., kolbel T., malina m., sonessen b., Akeson J. management of inadvertent arterial catheterization associated with central venous access procedures. eur J vasc endovasc surg 2009. 38, 707-714

Figure 1. False correct position of the cvc

Figure 2. stentgraft in correct position



19.

An outbreak of Scabies norvegica in the intensive care; a challenging

diagnosis with severe consequencesM.R. Kruijt-Spanjer, J. Koeze

University Medical Center Groningen, Groningen, The Netherlands

Background: In contrast to scabies vulgaris caused by Sarcoptesscabiei

mites, variety hominis 1, crusted scabies or Scabies norvegica is a com-

plicated and far more contagious form with a higher mite load, con-

sequently making this type of scabies much easier to transmit.1,2

especially immunocompromised patients are vulnerable to this form

of scabies.2 If an intensive care unit is faced by this problem, adequate

management is essential to control institutional spread.

Objectives: To raise awareness for the possibility of Scabies norvegi-

ca-infection in immunocompromised patients, which is – of course –

often the case at an intensive care unit.

Methods: descriptive case and overview of the measures taken to

control and prevent this highly contagious infection.

Results: A 21-year-oldsomalian female with a known medical history

of cystic fibrosis (cF) was admitted to our Icu with severe respiratory

insufficiency, leading to a bilateral lung transplant one week later.

besides anticipated postoperative complications, a marked eosino-

philia was present, for which an extensive differential diagnosis was

investigated. under the diagnosis of allograft rejection or an allergic

reaction to medication (possibly morphine), she was treated with high-

dose steroids. despite this treatment, hypereosinophilia persisted.

Also, she suffered from a pre-existing itch over her entire body, which

persisted during further reconvalescence. Four months after admission

she had developed multiple hyperkeratotic skin lesions. dermatology

diagnosed Scabies norvegica, confirmed by skin scrapings revealing

several mites and eggs. Therapy with topical permethrin 5% and oral

ivermectin was started, under which regimen her skin lesions resolved

and the eosinophilia decreased. As a consequence, all patients close

to and all of the healthcare workers involved in this patient’s care

were informed. A total of 185 healthcare workers were screened, while

all symptomatic healthcare workers were treated with ivermectin.

Furthermore, there was a significant economical burden, which was

estimated at € 45,000, due to closure of Icu-beds and the costs of the

comprehensive screening program.

Conclusions: In the majority of scabies-outbreaks, the index patient

is an immunocompromised individual with unrecognized Scabies

norvegica, who is more prone to develop crusted scabies because

of masking of symptoms. Although rare, we therefore suggest that

scabies be considered early in patients with itching skin-lesions of

unknown origin, especially because of the burden and costs of the

consequences of such an outbreak in terms of institutional precaution

measures.

References1. choidow o. scabies. new engl J med. 2006;354:1718-27.

2. koene Prm, Tjioe m, Hoondert k, et al. uitbraak van scabies in 1 ziekenhuis en 8 zorginstellingen door een geriatrische patiënt met scabiës crustosa. ned Tijdschr geneesk. 2006;150:918-23.

20.

Fungal infection causing ischemia of the spinal cord

N. Ayub, M. Jak, M.D. Hazenberg, A.C. de Pont

AMC, Amsterdam, The Netherlands

Case report: A 62-year-old woman diagnosed with acute myeloid

leukemia was admitted to the intensive care unit with acute respiratory

failure after being treated with the second induction cycle according

to the Hovon 102b protocol. The chest-x-ray showed pleural effusion

in the left lower quadrant while the laboratory results showed a leuko-

cyte count of 0.1 x 109/l. The patient was intubated and mechanically

ventilated. she was treated with filgrastim, vancomycin and merope-

nem for a suspected pulmonary infection. during the course of the

treatment, she developed paraplegia of both legs with loss of sensa-

tion. An mrI of the spinal cord showed a paravertebral mass compress-

ing the artery of Adamkiewicz, thereby causing spinal cord ischemia. A

biopsy taken from this mass showed signs of a massive invasive fungal

infection. The treatment was changed to liposomal amphotericin-b, to

which the patient responded well. she was weaned from the ventila-

tor and discharged from the intensive care unit, albeit with persistent

paraplegia.

Discussion: Acute occlusion of the single artery of Adamkiewicz

results in an anterior spinal artery syndrome that involves paraplegia

with loss of reflexes, loss of pain and temperature sensation and loss of

sphincter control with sparing of vibration and position sensation. The

neurologic symptoms typically progress over a period of a few minutes

to a few hours and recovery is poor.

occlusion of the artery of Adamkiewicz has been described in a variety

of conditions: preexisting abnormalities of the aorta, surgery of aorta,

abdomen, spinal cord and lower limbs and spontaneous or trau-

matic thromboembolism. It has also been described in less common

conditions such as epidural analgesia, cartilage embolus after a

valsalva maneuver, sclerotherapy for esophageal varices, and acute

schistosomamansoni infection. The main etiology of the anterior spinal

artery syndrome during sepsis is compression of the anterior spinal

artery by an epidural abscess, the most common causative organism

being S. aureus.

Fungal infections causing paraplegia have been described only twice

before. A patient with crohn’s disease treated with tumor necrosis

factor antagonist therapy developed caseating granulomas in the

spinal cord, revealing fungal hyphae consistent with Aspergillus and

a patient with a prosthetic aortic valve experienced acute aortic occlu-

sion by thrombotic material containing Aspergillus niger. despite exten-

sive antifungal therapy, both patients died. To our knowledge, this is

the first report of an invasive fungal infection presenting as a mass




causing paraplegia by compressing the artery of Adamkiewizc, initially

successfully treated with an antifungal agent. voriconazole and lipos-

omal amphotericin b are the antifungal agents recommended for the

treatment of invasive fungal infections.1 In addition, surgical resection

may be curative, especially in case of persistent invasive aspergillosis

and in patients needing additional immunosuppressive therapy.2

In conclusion, the case above illustrates that an invasive fungal infec-

tion may present as a mass compressing other structures, in this case

leading to paraplegia due to spinal cord ischemia

References1. barberán J, mensa J. vallejo llamas Jc, et al. recommendations for the

treatment of invasive fungal infections caused by filamentous fungi in the haematological patient. rev esp Quimioter. 2011;24:263-70.

2. danner bc, didilis v, dörge H, et al. surgical treatment of pulmonary asper-gillosis/mycosis in imuunocompromised patients. Interact cardiovasc Thorac surg. 2008;7:771-6.

Figure1. mrI (T2-axial): the lumbar spinal cord showing a paravertebral mass compressing the artery of Adamkiewicz

21.

Stone Heart SyndromeH.G. Jongsma-van Netten1, L.C. Otterspoor1,2

1University Medical Centre Utrecht, Utrecht, The Netherlands, Catharina Hospital, Eindhoven, The Netherlands

Introduction: Fourty years ago, severe ischemic contracture of

the heart was a known, but uncommon complication of open-heart

surgery using cardiopulmonary bypass. since the introduction of

myocardial hypothermia during surgery, this stone Heart syndrome

is rarely seen anymore. However, to illustrate that this complication is

not just a problem from the past, we describe a patient who recently

underwent a standard mitral valve repair and developed a stone Heart.

Case description: A 50-year-old man with severe mitral valve regur-

gitation, was admitted for a mitral valve repair. After starting cardio-

pulmonary bypass and before cross-clamping the aorta, a refractory

ventricular tachycardia developed. The following mitral valve repair

was uncomplicated. Immediately after discontinuing the perfusion,

the left ventricle became thickened and hard as stone, the right ven-

tricle contracted only slightly. There were no signs of local infarction

or surgical complications. The electrocardiogram showed an asystole.

A peripheral extracorporeal membrane oxygenation (ecmo) support

system was implanted and the patient was transferred to a hospital

with heart transplantation facilities. The next day the ecmo was cen-

tralised and blood and thrombi were removed from the pericardium.

A large thrombus in the left atrium was left untouched because of the

risk of air embolism. In the following days the heart did not recover

and despite ecmo support he developed severe respiratory failure,

acute kidney failure, liver failure and a persistent coma after discontin-

uing the sedation. because of this multiple organ failure without ther-

apeutic options, treatment was stopped nine days after the first oper-

ation. Autopsy revealed a heavy and solid heart, with thrombi in the

left atrium, both ventricles and pulmonary veins and circular necrosis

of the myocardium of both ventricles. microscopy showed generalised

coagulation necrosis and typical contraction bands in the myocardium.

The coronary arteries were all open.

Discussion: The stone Heart syndrome was first described in 1972 and

is typically occurring in patients undergoing open-heart surgery using

cardiopulmonary bypass.1. during or after the extracorporeal perfu-

sion, a sudden irreversible ischemic contracture of the heart develops.

The hypothesis is that a combination of ATP depletion and intracellu-

lar calcium overload due to ischemia and reperfusion are responsible

for the extreme contraction and the lack of relaxation.2 because of the

contraction, intramyocardial coronary arteries are compressed, which

causes secondary ischemia. risk factors include left ventricular hyper-

trophy, aortic valve disease and pulmonary hypertension.1 There are no

therapeutic options, except for heart transplantation. because of the

contraction of the myocardium, no intraventricular assist device can

be implanted. Therefore, the only way to bridge to decision is implant-

ing an ecmo system. If the patient has no contraindications, the ecmo

can bridge the patient to a heart transplantation. Induced hypothermia

during surgery may prevent the stone heart.1

This case illustrates that even today, patients without any risk factors

undergoing a standard open-heart surgery procedure, may develop a

stone Heart syndrome. If confronted with this phenomenon, an ecmo

system may be implanted as a bridge to heart transplantation.

References1. cooley dA, reul gJ, Wukasch dc. Ischemic contracture of the heart: “stone

Heart”. Am J cardiology. 1972;29:575-7.

2. robinson rJ, Truong dT, mulder d, digerness sb, kirklin Jk. J cardiothorac Anesth. 1989 Jun;3:361-8.



1.

Delirium detection based on monitoring of blinks and eye movements

A.W. van der Kooi1, M.L. Rots1, G. Huiskamp2, F.A.M. Klijn3, H.L. Koek4, T. Numan1, J. Kluin5, F.S.S. Leijten2, A.J.C. Slooter1

1Department of Intensive Care Medicine, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands, 2Department of Neurology and

Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands, 3Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands, 4Department of Geriatrics, University

Medical Center Utrecht, The Netherlands, 5Department of Cardio-Thoracic Surgery, University Medical Center Utrecht, The Netherlands

Background: delirium is a common disorder in intensive care unit (Icu)

patients and associated with impaired long-term outcome. despite its

frequency and impact, delirium is poorly recognized in Icu patients

with current delirium screening tools as the confusion assessment

method for the Icu.1 numerous studies have shown by using actigra-

phy that delirium is associated with a change in motor activity level.2

However, actigraphy requires the patient to move the limbs sponta-

neously, which may be difficult in Icu patients because of pain, Icu

acquired weakness, and use of physical restraint. blinks and eye move-

ments are less affected by these issues, and a decrease in eye movement

velocity has been associated with a decrease of the level of conscious-

ness. As the level of consciousness and motor activity can be affected

in delirium, we hypothesized that monitoring of blinks and eye move-

ments could provide a new approach for delirium detection. The objec-

tive of this study was to investigate whether blinks and eye movements

are different in delirious patients compared to non-delirious patients.

Methods: electro-encephalography and electro-oculography record-

ings were made in 28 delirious- and 28 age- and gender-matched

non-delirious postoperative cardiac surgery patients. Patients were

evaluated for delirium by a geriatrician, psychiatrist or neurologist using

the diagnostic and statistical manual of mental disorders Iv criteria.

blinks were automatically extracted from electro-oculograms and eye

movements from electro-encephalography recordings using independ-

ent component analysis. The number and duration of eye movements

and blinks were compared between patients with and without delirium,

based on the classification of the delirium experts described above. eye

movements were assessed during eyes open and eyes closed condition.

Results: There were no significant differences between patients

with and without delirium in age (mean ± sd 76 ± 5.7 versus 74 ± 8.6;

p=0.21), gender (n=14 (54%) males versus n=16 (57%) males; p=0.81),

bypass time (median(interquartile range) 129 (95-158) versus 108 (77-

168); p=0.07) and euroscore (median(interquartile range) 7 (6-9) versus

7 (5-8); p=0.17).

during eyes open registrations, delirious patients showed, compared

to non-delirious patients, a significant decrease in the number of blinks

per minute and number of vertical eye movements per minute, as well

as an increase in the average duration of blinks (table 1). during eyes

closed, the average duration of horizontal eye movements was signif-

icantly increased in delirious patients compared to patients without

delirium (table 1).

Conclusion: This is the first study with automatic eye movement detec-

tion in delirious patients. We found that spontaneous eye movements,

in particular blinks, were affected in delirious patients, which holds

promise for the development of an objective tool to detect delirium.

References1. van eijk mm, van den boogaard m, van marum rJ, et al: routine use of the

confusion assessment method for the intensive care unit: A multicenter study. Am J respir crit care med. 2011;184:340-4.

2. osse rJ, Tulen JHm, Hengeveld mW, et al: screening methods for delirium: early diagnosis by means of objective quantification of motor activity patterns using wrist-actigraphy. Interact cardiovasc Thorac surg. 2009;8:344-8.

Table 1. eye movements in patients with and without delirium

Eyes Variable DeliriumMedian (IQR)

Non-deliriumMedian (IQR)

p-value

AUC (95% CI)

open number of eye movements

Horizontal 6 (0-51) n=23

26 (0-55) n=28

0.54 0.55 (0.39-0.71)

vertical 1 (0-13) n=23

15 (2-54) n=28

0.01 0.70 (0.55-0.85)

blinks 12 (5-18)n=23

18 (8-25)n=27

0.02 0.65 (0.50-0.80)

open duration of eye movements (s)

Horizontal 0.24 (0.10-0.56) n=14

0.14 (0.04-0.27) n=17

0.14 0.66 (0.47-0.85)

vertical 0.14 (0.06-0.49) n=10

0.07 (0.04-0.60) n=18

0.46 0.59 (0.37-0.81)

blinks 0.50 (0.36-0.96) n=20

0.34 (0.23-0.53) n=27

<0.01 0.74 (0.59-0.88)

closed number of eye movements

Horizontal 0 (0-42) n=27

0 (0-51) n=27

0.37 0.57 (0.41-0.72)

vertical 5 (0-47) n=27

10 (0-52) n=27

0.40 0.56 (0.41-0.72)

closed duration of eye movements (s)

Horizontal 0.41 (0.15-0.75) n=12

0.08 (0.06-0.22) n=13

<0.01 0.81 (0.64-0.99)

vertical 0.15 (0.07-0.29) n=15

0.07 (0.03-0.27) n=17

0.19 0.64 (0.44-0.84)

The number of patients differs per variable, due to the impossibility of determining the duration of eye movements when patients had no eye movements and exclusion of patients for specific conditions. Five delirious patients were unable to keep their eyes open during the registration and excluded for eyes open analysis. One delirious patient would not close his eyes and excluded for eyes closed analysis. The T8 electrode was defect during eyes closed registration in one non-delirious patient and therefore excluded from eyes closed analysis. The electro-oculography channel of one non-delirious patient was defect and therefore, excluded for the analysis of blinks. Abbreviations: AUC= Area Under the Curve; CI= Confidence Interval; IQR= Interquartile Range; n= Number of patients for which variable could be determined.

Abstracts Intensivistendagen 2014




2.

Delirium detection using EEG: what and how to measure?

A.W. van der Kooi1, I.J. Zaal1, F.A.M. Klijn2, H.L. Koek3, T. Numan1, R.C.A. Meijer4, F.S.S. Leijten5, A.J.C. Slooter1

1Department of Intensive Care Medicine, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands, 2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The

Netherlands,3Department of Geriatrics, University Medical Centre Utrecht, Utrecht, The Netherlands, 4Department of Cardiothoracic Surgery, University Medical Centre

Utrecht, Utrecht, The Netherlands, 5Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The

Netherlands

Background: despite its frequency and impact, delirium is poorly

recognized with current screening methods in critically ill patients.1

electro-encephalography (eeg) is a sensitive tool for delirium diagno-

sis, but inconvenient in routine patient care.2 To perform eeg-based

monitoring of delirium with a limited number of electrodes, we studied

the optimal electrode derivation and eeg characteristic to discriminate

delirium from non-delirium.

Methods: standard eegs were recorded in 28 delirious and 28 age- and

gender-matched non-delirious postoperative cardiac surgery patients.

A geriatrician, psychiatrist or neurologist evaluated the patient for

delirium using the diagnostic and statistical manual of mental disor-

ders Iv criteria.The first minute of artefact-free data with eyes closed

and with eyes open was selected. For eyes-closed recordings, all

possible bipolar derivations were studied, while for eyes-open only

occipital and parietal electrodes were used. For each derivation, 6 eeg

parameters were evaluated: relative power in the delta, theta, alpha

and beta frequency band, peak frequency and slow-fast ratio. using

a mann-Whitney u-test, all combinations of derivations and parame-

ters were compared between delirious and non-delirious patients and

p-values were ranked and corrected for multiple testing (eyes closed

alphaadjusted=4.0*10-5; eyes openalphaadjusted=5.6*10-4).

Results: There were no significant differences between patients

with and without delirium in age (mean ± sd 76 ± 5.7 versus 74 ± 8.6;

Table 2. listing the 10 combinations of eeg derivation and eeg characteristic that showed the lowest p-value in discriminating delirium from non-delirium for registration with eyes open.

Eyes OpenRank p-value* Derivation Characteristic Delirium, median (IQR) Non-delirium, median (IQR) AUC Sens (%) Spec (%)

1 2.0e-07 P7-P4 relative alpha 0.12 (0.09-0.15) 0.33 (0.19-0.39) 0.90 85 91


3 1.6e-06 P7-o1 relative delta 0.44 (0.36-0.54) 0.24 (0.17-0.33) 0.88 86 85

4 3.2e-06 P7-o1 relative alpha 0.10 (0.08-0.14) 0.26 (0.19-0.33) 0.87 81 90

5 3.5e-06 P3-P4 slow Fast ratio 4.0 (2.5-5.2) 1.0 (0.6-1.7) 0.87 77 89


7 6.1e-06 P7-P8 relative alpha 0.11 (0.09-0.16) 0.31 (0.19-0.39 0.86 81 95

8 7.9e-06 P7-P4 slow Fast ratio 4.0 (2.9-5.6) 1.1 (0.7-2.2) 0.86 77 88



*All p-values were smaller than 5.6*10-4. Therefore, all combinations in this table showed a statistically significantly difference between delirium and non-delirium. Abbreviations: AUC = Area Under the Curve; IQR = Inter Quartile Range; Relative alpha = Relative power in the alpha frequency band; Relative delta = Relative power in the delta frequency band; Sens = Sensitivity; Slow Fast ratio = Ratio between the sum of the relative power in the delta and theta frequency band and the sum of the relative power in the alpha and beta frequency band ; Spec = Specificity.

Table 1. listing the 10combinations of eeg derivation and eeg characteristic that showed the lowest p-value in discriminating delirium from non-delirium for registration with eyes closed

Eyes closedRank p-value* Derivation Characteristic Delirium, median (IQR) Non-delirium, median (IQR) AUC Sens (%) Spec (%)1 1.8e-12 F8-Pz relative delta 0.59 (0.47-0.71) 0.20 (0.17-0.26) 0.99 100 96

2 3.7e-12 F8-P3 relative delta 0.59 (0.46-0.69) 0.19 (0.15-0.26) 0.99 96 96

3 1.1e-11 F8-o2 relative delta 0.60 (0.49-0.73) 0.23 (0.18-0.30) 0.99 96 96

4 1.5e-11 Fp2-o1 relative delta 0.66 (0.60-0.75) 0.27 (0.23-0.36) 0.99 96 95

5 1.7e-11 F8-F4 relative delta 0.60 (0.43-0.70) 0.20 (0.17-0.26) 0.98 96 92

6 2.2e-11 F8-o1 relative delta 0.62 (0.48-0.72) 0.22 (0.17-0.26) 0.99 96 95

7 2.4e-11 F8-cz relative delta 0.57 (0.46-0.67) 0.26 (0.20-0.33 0.98 91 96

8 2.4e-11 F8-c3 relative delta 0.57 (0.49-0.67) 0.21 (0.17-0.30) 0.98 91 92

9 2.9e-11 Fp2-Pz relative delta 0.64 (0.53-0.72) 0.28 (0.22-0.36) 0.99 100 95

10 3.0e-11 cz-o1 relative delta 0.50 (0.37-0.57) 0.17 (0.10-0.25) 0.96 92 88

*All p-values were smaller than 4.0*10-5.Therefore, all combinations in this table showed a statistically significantly difference between delirium and non-delirium. Abbreviations: AUC = Area Under the Curve of the receiver operating curve; IQR = Inter Quartile Range; Relative delta = Relative power in the delta frequency band; Sens = Sensitivity; Spec = Specificity.



p=0.21), gender (n=14 (54%) males versus n=16 (57%) males; p=0.81),

bypass time (median (interquartile range) 129 (95-158) versus 108 (77-

168); p=0.07) and euroscore (median (interquartile range) 7 (6-9) versus

7 (5-8); p=0.17).

Table 1 lists the 10combinations of eeg derivations and eeg charac-

teristics with the lowest p-value for the eyes closed condition, while

table 2 lists these 10 combinations for the eyes open condition. When

comparing the eyes-closed with eyes-open condition, the p-value

for the best derivation and characteristic for eyes-closed was smaller

than for eyes-open. With eyes closed, the optimal combination of elec-

trode derivation and eeg characteristic was F8-Pz and relative delta

power (p=1.8*10-12, table 1). Also neighboring electrodes of both F8

(for example Fp2) and Pz (for example P3) in combination with relative

delta power were in the top five of smallest p-values.

Conclusion: delirium can be easily distinguished from non-delirium

with only two electrodes. The largest difference (i.e. the lowest p-value)

was observed in eeg epochs with eyes closed. In this condition, the

optimal eeg characteristic and electrode derivation was relative delta

power in F8 (frontal, lateral) to Pz (midline, parietal).

References1. van eijk mm, van den boogaard m, van marum rJ, et al.routine use of the

confusion assessment method for the intensive care unit: A multicenter study. Am J respir crit care med. 2011;184:340-4.

2. van der kooi AW, leijten Fss, van der Wekken rJ, et al.What are the oppor-tunities for eeg-based monitoring of delirium in the Icu. J neuropsychiatry clin neurosci. 2012;24:472-7

3.

Quality of life of critically ill patients six months and five years after discharge from Intensive Care

T.N. Adonis, G. Kroeze, S. Rijkenberg, H. Endeman

Department of Intensive Care,Onze Lieve Vrouwe Gasthuis,Amsterdam, The Netherlands

Background: In recent years there has been growing interest in the

quality of life of critically ill patients after discharge of the intensive care

unit (Icu). long term Icu-therapy can result in medical, physical and

psychological problems afterwards. Aim of this observational trans-

versal study was to assess the health related quality of life (HrQl) of

critically ill patients six months and five years after Icu discharge and

to identify patients at risk for decreased HrQl.

Methods: All patients treated in the Icu more than 72 hours last 5

years were eligible for inclusion in this study. Patients who were dis-

charged six months and five years before start of this study were

included. After inclusion, patients were tracked by using the hospital

information system. If a patient was recorded to be alive, they were

asked to participate and to fill out the rAnd-36 questionnaire. As a

reference group, a gender-and-age matched population (n=1742) was

used. The HrQl scores between the two groups and the reference

group were analyzed by means of the one-sample t-test. results of the

independent variables influencing the HrQl of patients were statisti-

cally analyzed with use of multiple linear regression. A p value of <0.05

was regarded as statistically significant.

Results: The ‘six-months’ cohort contained 114 patients. of these 114

patients 69 (61%) were still alive, 59 were able to participate the study

of which 36 (61%) completed the questionnaire. The ‘five-year’ cohort

consisted of 370 patients; 157 (42%) of them were still alive, 119 were

able to participate of whom 75 (63%) completed the questionnaire.

results of the HrQl measured by the rAnd-36 for the ‘six-month cohort’

are given in table 1, together with the results of the control population.

As shown, the HrQl-subcategories physical functioning, social function-

ing, emotional role limitations, physical role limitation, mental health and

vitality were all statistically significant lower than the reference group.

The results of the HrQl analysis of the ‘five-year’ cohort are also shown

in table 1. The subcategories physical functioning, social function-

ing, physical role limitation and vitality were all significant lower than

the reference group. According to multiple regression analysis, age,

gender, bmI, length of Icu-stay and co-morbidity significantly corre-

lated with a lower HrQl of the subcategory physical functioning in

critically ill patients after Icu discharge.

Conclusion: critically ill patients being treated in Icu for more than

72 hours consider their HrQl significantly lower than the reference

group. This counts for both patients six months after Icu discharge

as patients 5 years after Icu discharge, though on some of the sub-

categories HrQl is improving. The long-term experienced the HrQl-

subcategory physical functioning is influenced by patient characteris-

tics – age, gender, bmI and co-morbidity – and length of stay in the Icu.

References1. schenk P, Warszawska J, Fuhrmann v, et al. Health-related quality of life of

long-term survivors of intensive care: changes after intensive care treat-ment. experience of an Austrian intensive care unit. Wien klin Wochenschr. 2012;124:624-32.

2. granja c, Amaro A, dias c, et al. outcome of Icu survivors: a comprehensive review. The role of patient-reported outcome studies. Acta Anaesthesiol scand. 2012;56:1092-103.

Table 1. HrQl results of the ‘6 month cohort’ and the ‘5 year cohort’ together with the HrQl of the the gender-and-age matched population

months after ICU discharge

Norm-population

hrQL subcategory Mean±SD Mean± SD P value

Physical functioning 51.7±30.3 83.0±22.8 .000

social functioning 63.5±29.2 84.0±22.4 .000

Physical role limitations 39.7±41.8 76.4±36.3 .000

emotional role limitations 55.2±45.3 82.3±32.9 .002

mental health 69.2±21.0 76.8±17.4 .037

5 years after ICU discharge

Norm-population

hrQL subcategory Mean±SD Mean±SD P value

Physical functioning 62.1±27.4 83.0±22.8 .000

social functioning 73.8±26.0 84.0±22.4 .001

Physical role limitations 53.5±44.0 76.4±36.3 .000

vitality 57.7±20.5 68.6±19.3 .000

vitality 53.3±21.7 68.8±19.3 .000




4.

Influenza A and B virus infection 2012-2013; incidence, characteristics and outcome in critically ill patients in

two Dutch intensive care unitsD. Jansen1,2, R. van den Berg2, G. Bosman2, P. Vos1, J.A.H. van Oers1

1Intensive Care Unit, St Elisabeth Hospital, Tilburg, The Netherlands, 2Intensive Care Unit, Tweesteden Hospital, Tilburg, The Netherlands

Background: With 18 weeks (17th of december 2012 – 21st of April 2013),

this season’s flu epidemic was by far the longest in the past 20 years.1

Its peak incidence was 160 new influenza-like diseases per 100,000

inhabitants weekly.1 In the whole country, intensive care units (Icus)

were highly occupied with patients with flu symptoms. The aim of this

study is to describe the incidence of influenza-related Icu admission,

demographic characteristics, clinical features and outcome of laborato-

ry-confirmed influenza A or b infection in critically ill patients admitted

to our Icus during the winter of 2012-2013.

Methods: A retrospective, observational multicenter cohort study was

conducted in two dutch Icus: a 30-bed mixed medical/(neuro)surgical

Icu of st. elisabeth hospital and a 12-bed mixed medical/surgical Icu

of Tweesteden hospital. All critically ill patients (≥ 16 years) with con-

firmed influenza A or b virus infection that were admitted between

december 2012 and April 2013 were studied. data of demographics,

clinical features and treatment were collected. Primary outcome was

mortality; secondary outcomes included length of stay in the Icu and

hospital and disease severity. The non-parametric mann-Whitney u

test was performed to compare the characteristics between survivors

and non-survivors in both Icus. A p-value <0.05 was considered statis-

tically significant.

Results: In 148 Icu patients polymerase chain-reaction (Pcr) analyses

for Influenza A and b were performed; 19 of them were positive for

Influenza A and 16 for Influenza b. demographic characteristics,

clinical features and outcome are presented in table 1. A positive

culture occurred in 22.9% of the respiratory cultures and in 17.1% of the

blood cultures with Staphylococcus aureus respectively Streptococcus

pyogenes as most common pathogens. differences between survivors

and non-survivors are shown in table 2.

Conclusion: The Influenza epidemic during the winter of 2012-2013

lasted longer than those during previous years and more patients

were affected. Icu admission was associated with an age above 65, the

presence of coPd and/or a bacterial superinfection. mean Icu mor-

tality was 28.6%, as predicted by APAcHe II and PsI score. There were

no significant differences between survivors and non-survivors with

respect to disease severity, comorbidities and duration of ventilation.

References1. www.nivel.nl/griep.

Table 2. survivors versus non-survivors

Survivors (n=25)

Non-survivors (n=10)

P-value

gender, male/female 14/11 6/4 0.84

Age, median [IQR] 68.0 [54-79] 71.5 [62-78.8] 0.76

coPd, no. (%) 15 (60.0) 5 (50.0) 0.61

bacterial superinfection, no. (%)

Respiratory culture positive 6 (24.0) 2 (20.0) 0.80

Blood culture positive 4 (16.0) 2 (20.0) 0.80

mechanical ventilation, no. (%)

Non-invasive 18 (72.0) 7 (70.0) 0.91

Invasive 15 (60.0) 7 (70.0) 0.59

Pao2/Fio2 at admission, median [IQR]

192 (76-254] 244 [150-300]

0.18

duration of ventilation (hours), median [IQR]

62 [42-206] 45 [20-53] 0.18

disease severity, median [IQR]

Apache II score 18 [16-23] 24.5 [18-34.8]] 0.08

PSI score* 132 [108-147.75]

# #

CURB-65 score* 1.5 [1.0-2.0] # #

* In ´Community acquired pneumonia´ (CAP) patients. # n=1

Table 1. Patient characteristics

EZ (n=23) TSZ (n=12) ALL (n=35)gender, male/female 17/6 3/9 20/15

Age, median [IQR] 76 [64.5-82] 59 [53.5-69.8] 68 [59-79]

current tobacco use, no. (%) 2 (8.7) 3 (25.0) 5 (14.3)

coPd, no. (%) 14 (60.9) 6 (50.0) 20 (57.10)

reason of Icu admission, no. (%)

Pneumonia (viral/bacterial) 7 (30.5) 4 (33.3) 11 (31.4)

Emphysema/bronchitis 6 (26.1) 5 (41.7) 11 (31.4)

Sepsis/shock 4 (17.4) 3 (25.0) 7 (20.0)

Others 6 (26.0) (0.0) 6 (17.2)

use of antibiotics at home, no. (%)

3 (13.0) (0.0) 3 (8.6)

clinical symptoms, no (%)

Cough 11 (47.8) 8 (66.7) 19 (54.3)

Dyspnea 22 (95.7) 12 (100.0) 34 (97.1)

clinical findings

Temperature (⁰C), mean ± SD 37.1 ± 1.0 37.1 ± 1.3 37.1 ± 1.1

Respiratory rate (/min), mean ± SD 24 ± 7 30 ± 9 26 ± 8

laboratory findings, median [IQR]

Leukocytes 10.9 [7.7-16.9] 11.4 [6.2-19.7] 10.9 [7.7-17.5]

CRP 52 [41-140] 105 [59-176] 88 [44-176]

bacterial superinfection, no. (%)

Respiratory culture positive 4 (17.4) 4 (33.3) 8 (22.9)

Blood culture positive 4 (17.4) 2 (16.7) 6 (17.1)

mechanical ventilation, no. (%)

Non-invasive 16 (69.6) 9 (75.0) 25 (71.4)

Invasive 14 (60.9) 8 (66.7) 22 (62.9)

Pao2/Fio2 at admission, median [IQR]

219 [143-225] 150 [46-287] 219 [83-285]

duration of ventilation (hours), median [IQR]

50 [24-102] 67 [28-206] 55 [24-155]

disease severity, median [IQR]

Apache II score 17 [15.5-23.5] 23 [18.5-25.5] 20 [16-24]

PSI score* 133.0 [108-143.5]

132.0 [122.75-141.5]

133.0 [108-143.5]

CURB-65 score* 2.0 [1.5-2.0] 1.0 [1.0-1.75] 2.0 [1.0-2.0]

length of Icu stay (days), median [IQR]

4.18 [1.71-8.88]

4.26 [2.49-10.12]

4.18 [1.76-9.32]

length of hospital stay (days), median [IQR]

12.57 [7.65-18.03]

10.46 [4.94-27.89]

12.57 [5.40-20.71]

mortality in Icu, no. (%) 8 (34.8) 2 (16.7) 10 (28.6)

* In ´Community acquired pneumonia´ (CAP) patients



5.

Hyperoxemia is not associated with increased in-hospital mortality

in critically ill patients L.W. de Boo, A.E. van den Berg, R. Baak, P. Melief, I.A. Meynaar

Department of Intensive Care Medicine, Haga Hospital, The Hague, The Netherlands

Background: several studies have demonstrated an association

between increased in-hospital mortality and hyperoxemia in critically ill

patients.1,2 The aim of this study was to test the hypothesis that hyperox-

emia is independently associated with increased in-hospital mortality.

Methods: For this retrospective observational study, we included all con-

secutive patients admitted to the Hospital Icu (a combined medical and

surgical tertiary Intensive care unit, 16 beds) between January 2010 and

december 2012. Patient characteristics and outcome are routinely col-

lected. We also collected the highest Pao2 values in the first 24 hours after

Icu admission. For the purpose of analysis we divided these Pao2 values

in hyperoxemia (defined as Pao2 >13.31 kPa), hypoxemia (Pao2 <9.29 kPa)

and normoxemia (Pao2 9.3-13.3 kPa). The primary outcome was in-hospi-

tal mortality.

Results: during the study period we admitted 4158 individual patients to

the Icu. Patients characteristics are shown in table 1. univariate analysis

shows that hyperoxemia during the first 24 hours of Icu treatment was

associated with increased in-hospital mortality (table 2). However on mul-

tivariate analysis, after correction for illness severity (APAcHe Iv score),

hyperoxemia was not an independent predictor of in-hospital mortality.

on the contrary and as to be expected hypoxemia was an independent

risk factor for in-hospital mortality even after correction for illness severity

(table 3). similar results were seen were groups were divided differently.

Conclusion: In conclusion hyperoxemia was not an independent

predictor of in-hospital mortality after correction for illness severity

(APAcHe Iv score). This contradict the results found in previously

studies. on the contrary, and as to be expected, hypoxia was an inde-

pendent risk factor for mortality even after correction for illness severity.

Table 2. Highest Pao2 values in data from the first 24 hours after Icu admission and in-hospital mortality

Highest PaO2 first 24 hrs

In-hospital mortality

Relative risk (95% CI)

p

normoxemia (9.3-13.3 kPa) 67/796 (8.4%) reference = 1 <0.001

Hypoxemia (<9.29 kPa) 17/30 (56.7%) 6.73 (4.57-9.92)

Hyperoxemia (>13.3 kPa) 359/2662 (13.5%) 1.60 (1.25-2.05)

Table 3. multivariate analysis of predictors of in-hospital mortality

Wald p OR (95% CI)Apache Iv score 681 <0.001 1.056 (1.052-1.060)

Highest Pao2 first 24 hrs 27 <0.001

Hypoxemia (ref = normoxemia) 25 <0.001 13.6 (4.9-38.0)

Hyperoxemia (ref = normoxemia) 0 0.988 1.0 (0.7-1.4)

References1. martin d, grocott m. oxygen therapy in critical illness: Precise control of

arterial oxygenation and permissive hypoxemia. crit care med. 2013;41:423-32.

2. de Jonge e, Peelen l, keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ven-tilated intensive care unit patients. crit care. 2008;12:r156.

6.

Critical care pain observation tool: a single center observational study

E. Berger, M. Anderson, R. Birjmohun, N. Kusadasi

Intensive Care Unit, Vlietland Hospital, Schiedam, The Netherlands

Introduction: currently the numeric rating scale (nrs) is used by

nurses to determine whether and to what extent the patient expe-

riences pain. However, this is only applicable for patients who are

approachable. mirror conversations with former Icu-patients of our

hospital showed that almost half of them has had suffered more or less

pain during their stay. sedated and ventilated patients can usually not

express their pain verbally. The only way for these patients to express

pain is non-verbal, by their behaviour. The intensive care team needs

to pick up on these signals. A measuring instrument based on behav-

iour as a result of pain can be a tool to detect pain and to achieve the

best possible patient care. The literature describes different scales to

measure pain. The critical-care Pain observation Tool (cPoT) seems to

be most appropriate for use at the Icu. various studies show different

Table 1. characteristics of patients admitted to the Icu (n=4158)

All patients(n=4158)

Hospital survivors(n=3651)

Hospital non-survivors(n=507)

p

Age, years 65.1 (13.9) 64.5 (13.9) 69.3 (13.7) <0.001

APAcHe Iv score 64.4 (30.7) 57.84 (22.8) 114.7 (36.7) <0.001

APAcHe Iv expected mortality

0.03 (0.01-0.18)

0.03 (0.01-0.10)

0.75 (0.36-0.91)

<0.001

lowest Pao2 first 24 hrs, kPa 11.0 (3.3) 11.1 (3.1) 10.3 (4.6) <0.001

Highest Pao2 first 24 hrs, kPa 19.8 (9.3) 19.1 (8.0) 24.9 (14.7) <0.001

Admission type

medical 1106 770 (69.6%) 336 (30.4%) <0.001

Planned surgery 2625 2559 (97.5%)

66 (2.5%)

emergency surgery 427 322 (75.4%) 105 (24.6%)

diagnostic category

cardiac surgery 2650 2584 (97.5%)

66 (2.5%) <0.001

sepsis 215 135 (62.8%) 80 (37.2%)

overdose 106 104 (98.1%) 2 (1.9%)

cPr 298 145 (48.7%) 153 (51.3%)

other 889 683 (76.8%)

206 (23.2%)

length of stay Icu, days 0.9 (0.7-1.9) 0.9 (0.7-1.5) 2.1 (0.8-5.2) <0.001

length of stay Hospital, days

8.2 (6.2-14.5)

8.3 (6.3-14.7)

5.2 (2.0-13.5)

<0.001

Data are presented as mean (SD), median (IQR) or number (%) as appropriate. Abbreviations: APACHE = acute physiology and chronic health evaluation; hrs = hours; PaO2 = partial pressure of oxygen in arterial blood; CPR = cardiopulmonary resuscitation; ICU = intensive care unit.A total of 4082 patients fulfilled APACHE IV inclusion criteria.




results with a varying correlation from moderate to very strong, regard-

ing the unambiguous use of the cPoT by various reviewers.

Aim of the study: To demonstrate whether the cPoT-score simultane-

ously taken by a pain and a Icu nurse and an intensivist is comparable,

whether the instrument is reliable and applicable in daily practice of the

Icu, and whether this pain management can easily be implemented.

Study design: A single center observational study.

Methods: A cPoT score was performed at 30 intubated patients at

rest by three reviewers independently of each other. The cPoT has

four categories with behavioural characteristics. These indicators are

facial expression, body movements, compliance with the ventilator

(intubated patients) or vocalization (extubated patients) and muscle

tension. each category has a score of 0-2. A total score of more than

one point at rest means that the reviewer gives the patient the nursing

diagnosis ‘pain’. sPss 20 was used for the data analysis. The correla-

tion was calculated by spearman’s rank correlation (a nonparametric

measure of statistical dependence between two variables).

Results: 30 patient were enrolled. only four patients were able to

perform the nrs. Three of them were consistent with the cPoT score. The

total cPoT scores ranged from zero to two points. This yielded the follow-

ing data (table 1). A coefficient of 0.73 means a strong correlation between

the pain consultant and the Icu nurse. A coefficient of 0.59 / 0.62 means a

moderate correlation between the intensivist and the both nurses.

Table 1. spearman’s rank correlation between the reviewers

Pain nurse ICU-nurse IntensivistPain nurse 0.73 0.62

Icu-nurse 0.73 - 0.59

Intensivist 0.62 0.59 -

Correlation is significant (1-sided) at 0.05.

Conclusion: In order to avoid fluctuations in pain management in our

hospital we were curious about the differences between reviewers.

From this study it can be concluded that there is a strong positive cor-

relation in the use of the cPoT between the pain-consultant and the

Ic-nurse. both have a moderate correlation with the intensivist. These

results show that the cPoT is acceptable and useful in practice and can

easily be implemented.

7.

A systematic review of risk factors for delirium in the intensive care unit

I.J. Zaal1, J.W. Devlin2, A.J.C. Slooter1

1Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands, 2School of Pharmacy, Northeastern University, Boston,

United States

Background: clear delineation of variables that predispose or precip-

itate delirium in the intensive care unit (Icu) is important when for-

mulating prevention strategies and in statistical model building in

etiologic research. We systematically reviewed studies evaluating ≥ 1

variable as a potential risk factor for Icu delirium.

Methods: Five electronic databases were searched from 2000 to

February 2013 for studies that at least daily evaluated critically ill adults,

not undergoing cardiac surgery, for delirium with a validated assess-

ment method, and used either multivariate analysis or randomization

to evaluate variables as potential risk factors for delirium occurrence

(ProsPero #crd42013004886). In duplicate, data was abstracted

and quality was scored using sIgn checklists [i.e. high (HQ), accept-

able (AQ), unacceptable]. The presence of substantial inter-study het-

erogeneity prevented statistical pooling and consequently, reported

variables were quantitatively evaluated using 3 criteria: number of

studies evaluating the variable, the quality of each of these studies,

and whether the direction of association was consistent (i.e., across ≥

75% of the studies). The strength of evidence was defined as: strong

(consistent findings in ≥ 2 HQ studies), moderate (consistent findings in

1 HQ study and ≥ 1 AQ studies), weak (1 HQ study or consistent findings

in ≥ 3 AQ studies) or inconclusive (inconsistent findings or consistent

findings in ≤ 2 AQ studies).

Results: Among the 25 [observational (n=21); randomized (n=4)] studies

included, 64% were of high quality and 90 different variables were eval-

uated. risk factors for delirium at Icu admission deemed strong were

age, hypertension, dementia, pre-Icu emergency surgery or trauma,

APAcHe II score and sepsis. In the first 24-48 hours of Icu admission met-

abolic acidosis, iatrogenic coma and the use of mechanical ventilation,

morphine or epidural analgesia are risk factors with strong evidence

in the literature. risk factors classified as moderate were nicotine con-

sumption, alcohol consumption, moderate cognitive impairment, admis-

sion with infection or respiratory insufficiency and medical (rather than

surgical) admission. All other variables, including several laboratory or

environmental parameters, were either weak or inconclusive.

Conclusion: Among 90 variables hypothesized to increase the risk for

delirium occurrence in the Icu, only 18 have either a strong or moderate

level of evidence in the literature to support their role as risk factors.

8.

The association between benzodiazepine use and delirium in the ICU: a prospective cohort study

I.J. Zaal1, J. Devlin2, A. van der Kooi1, P.K. Klouwenberg1, M. Hazelbag3, D. Ong1, R. Groenwold3, A. Slooter1

1Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands, 2School of Pharmacy, Northeastern University, Boston, United

States, 3Julius Centre for Health Sciences & Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands

Background: Prior Icu studies reporting benzodiazepine (bZ)

exposure to be a risk factor for delirium have failed to include impor-

tant confounders and to differentiate bZ intermittent administration

(either oral or Iv) from bZ continuous Iv infusion. This study aims to

further clarify this proposed association.



Methods: This ongoing, prospective, cohort study included consec-

utive adults, admitted to a 32-bed mixed Icu ≥ 24 hour over a 2 year

period without a baseline neurological condition, whom were evalu-

ated at least twice daily for coma (rAss ≤ -4) and delirium. All delirium

assessments were completed using a validated protocol (IsIcem 2011:

P335) that included cAm-Icu assessments by both research physicians

and the bedside nurse and a review of the patient record. A multinomial

logistic regression model was used to quantify the odds of a daily transi-

tion to delirium and accounted for 5 different outcomes (coma, delirium,

neither of these, death and Icu discharge), both fixed confounders esti-

mated at Icu admission (n=7) and time-varying confounders which

were defined per day (n=10), daily bZ use in mg (adjusted to midazolam

equivalents), bZ administration method (i.e. none, intermittent admin-

istration only or continuous Iv infusion including bolus administrations)

and the 3 daily mental states (i.e. coma, delirium or neither of these).

Results: Among 866 patients evaluated [age (60 ± 16 yrs), mechanical

ventilated (94%), medical admission (50%), APAcHe Iv (76 ± 29)], 50%

had delirium on 24% of their total (n=8338) Icu days. bZs were admin-

istered to 78% of patients on 49% of these patients’ Icu days. Among

comatose patients the relative risk ratio for being delirious the follow-

ing day versus being neither comatose nor delirious the following day

for every mg increase in bZ administered was 1.15 (1.00-1.31, p=0.02)

for intermittent administration and 0.93 (0.87-1.00, p=0.02) for continu-

ous Iv infusion. The administration of bZ to patients with neither coma

nor delirium was not associated with delirium the following day with

relative risk ratio of 1.0 (0.98-1.02, p=0.50) for intermittent administra-

tion and 1.0 (0.99-1.01, p=0.44) for continuous Iv infusion.

Conclusions: bZ use appears not to be a risk factor for transition-

ing to delirium in patients who are awake and non-delirious. Among

comatose patients, the effect of bZ use on a transition to delirium is less

clear, and may depend on whether bZ are administered intermittently

or by continuous Iv infusion.

9.

Intoxicated ICU patients: death after hospital discharge

R. Brandenburg1, S. Brinkman2,3, N.F. de Keizer2,3, J. Meulenbelt1,4,5, D.W. de Lange1,3,4

1Department of Intensive Care and Emergency Medicine, University Medical Center Utrecht, The Netherlands, 2Department of Medical Informatics, Academic Medical Centre, University of Amsterdam, The Netherlands, 3National Intensive

Care Evaluation (NICE) Foundation, Amsterdam, The Netherlands, 4Dutch National Poison Information Center (NPIC), University Medical Center Utrecht, The

Netherlands, 5Institute for Risk Assessment Sciences (IRAS), University of Utrecht, The Netherlands

Background: For a physician, a patient with acute intoxication can be

difficult to evaluate and allocate. This is mostly because an intoxication

could give a broad range of symptoms (from harmless to life-threaten-

ing), that may change quickly. If a physician considers Icu admission,

the decision to admit a patient is often based on assumptions about

the short term survival. However, we feel that long-term outcome

should also be taken into account. Indeed, little is achieved when a

patient dies soon after hospital discharge.1

The aim of this study is to use APAcHe Iv intoxication subgroups to

assess and compare (case-mix adjusted) in-hospital and long-term

mortality of Icu patients admitted with acute intoxication.

Methods: design: cohort of Icu admissions from a national Icu-

registry (nIce) linked to records from an insurance-claims database.

setting: 81 Icus (85% of all dutch Icus).

Patients: 7331 admissions between January 1st 2008 and october 1st 2011.

Measurements: kaplan-meier curves were used to compare the unad-

justed mortality of the total intoxicated population and for specific

intoxication subgroups based on the APAcHe Iv reasons for admis-

sion: (a) alcohol(s), (b) analgesics, (c) antidepressants, (d) street drugs,

(e) sedatives, (f) poisoning (carbon monoxide, arsenic or cyanide),

(g) other toxins and (h) combinations. The case-mix adjusted mor-

tality was assessed by the odds ratio (or) adjusted for age, gender,

severity of illness, intubation status, recurrent intoxication, and several

co-morbidities.

Results: The Icu mortality was 1.2%, the in-hospital mortality was

2.1%. The mortality 1, 3, 6, 12 and 24 months after Icu admission was

2.8%, 4.1%, 5.2%, 6.5% and 9.3% respectively. street drugs had the

highest mortality two years after Icu admission (12.3%); a combination

of different intoxications had the lowest mortality two years after Icu

admission (6.3%).

The adjusted observed mortality showed that intoxications with

street drugs and “other toxins” have a significant higher mortality 1

month after Icu admission, oradj= 1.63 and oradj=1.73 respectively.

Intoxications with alcohol or antidepressants have a significant lower

mortality 1 month after Icu admission (oradj = 0.50 and oradj =0.46

respectively). These differences weren’t found in the adjusted mortality

3 months upward of Icu admission.

Conclusion: The difference between the in-hospital mortality and the

mortality after two years is substantial. The first 3 months after Icu

admission there is a difference in mortality between the subgroups;

not thereafter.

References1. brinkman s, bakhshi-raiez F, Abu-Hanna A, et al. determinants of mortality

After Hospital discharge in Icu Patients: literature review and dutch cohort study. crit care med. 2013;41:1237-51.

10.

Mortality of patients readmitted to the ICUA.E. van den Berg, R. Baak, P. Melief, I. Meynaar

ICU, Haga Hospital, The Hague, The Netherlands

Introduction: We studied our Icu database to see whether patients

who require readmission to the Icu during the same hospital admission

have a worse prognosis as compared to patient who are not readmitted.

Patients and Methods: We included all patients admitted to the Icu of

the Haga Hospital between January 1st, 2010, and december 31st, 2012,




in the study. The Icu is a level 3, intensivist-led, 16-bed mixed medical

surgical unit. All specialties including cardiothoracic and neurosurgery

are available in our hospital. We extracted all relevant patient data

including APAcHe Iv score, expected mortality and hospital mortality

from our database. The study endpoint was hospital mortality.

Results: during the study period a total of 4,492 patients were

admitted to the Icu, 4,280 of whom were admitted only once while

212 patients were admitted more than once during the same hospital

admission (table 1).

From table 1 we learn that hospital mortality is twice as high in patients

readmitted to the Icu as compared to patients with only one Icu

admission (25.5% versus 12.0%). This might be explained by the fact

that patients readmitted to the Icu were sicker at the first Icu admis-

sion (mean APAcHe Iv score 75.5 versus 63.4, mean expected hospital

mortality 28.3 versus 16.2%). To correct for illness severity on admission

we performed logistic regression analysis (table 2).

Table 2 shows that readmission to the Icu is an independent risk factor

for hospital mortality.

Conclusion: In patients readmitted to the Icu, hospital mortality is

about twice as high as compared to patients who were not readmitted,

even after correction for illness severity on admission.

Table 1. Patient characteristics.

Patients with 1 ICU admission

Patients with more than 1 ICU admission

Total p

4280 (95.3%)

212 (4.7%) 4492 (100%)

Age 67 (57-75) 66 (55-74) 67 (57-75) ns

score APAcHe Iv * 63.4 (30.8) 75.5 (28.7) 64 (30.9) p<0.001 (1)

APAcHe Iv exp. mort 16.2% (26.5) 28.3% (29.1) 16.8% (26.7) p<0.001 (2)

Ic los (1st admission) 0.9 (0.7-1.8) 1.8 (0.9-4.8) 0.9 (0.7-1.9) p<0.001 (2)

Hospital los 8.1 (6.1-13.3) 25.6 (15.3-43.8) 8.2 (6.2-14.9) p<0.001 (2)

HosP morT 512 = 12.0% 54 = 25.5% 566 = 12.6% p<0.001 (3)

smr (APAcHe Iv) 0.67 0.91 0.69

*APACHE IV inclusion criteria are fulfilled in 4369 patients. Data are presented as mean (SD), as median (IQR) or as number (%) and compared using (1) t test, (2) MannWhitney-U test, (3) Chi-square-test as appropriate.

Table 2. logistic regression analysis for hospital mortality

Risk factor Wald p ORApache Iv score (per point) 733 <0.001 1.055 (1.051-1.059)

readmission 21 <0.001 2.55 (1.71-3.81)

11.

Neurally adjusted ventilation in patients with acute respiratory distress

syndrome: ahead with caution!J. Doorduin1, C.A. Sinderby2,4, J. Beck3,4, J.G. van der Hoeven1,

L.M.A. Heunks1

1Department of Critical Care Medicine, Radboudumc, The Netherlands, 2Department of Medicine, Division of Critical Care Medicine, The Netherlands,

3Department of Pediatrics, St. Michael’s Hospital, University of Toronto, Canada, 4Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s

Hospital, University of Toronto, Canada

Background: In patients with acute respiratory distress syndrome

(Ards) the use of assisted instead of controlled ventilation is subject

of debate. Although, assisted ventilation improves gas exchange

of the lungs and prevents respiratory muscle weakness it is not free

of risks, such as the lack of control of tidal volume (vt). Indeed, early

administration of a neuromuscular blocking agent, improves survival

in patients with severe Ards. It was reasoned that muscle paralysis

might results in less lung injury through elimination of patient-venti-

lator asynchrony, thereby allowing better control of volumes and pres-

sures. neurally adjusted ventilatory assist (nAvA) is a ventilator mode

that uses the electrical activity of the diaphragm to cycle the ventilator

and to adapt the level of support. nAvA provides better patient-venti-

lator interaction compared to conventional modes and might there-

fore be more suitable in Ards patients. Alternatively, nAvA provides

proportional assist, tidal volume and lung distending pressure may be

higher than recommended in Ards patients. The aim of the present

study is to compare vt and transpulmonary pressure (Ptp) during nAvA

and conventional modes in patients with Ards. In addition, we studied

patient-ventilator interaction in these patients.

Methods: Ten adult patients with moderate Ards were included in this

physiological study. After obtaining informed consent, patients were

instrumented with a multi-electrode nasogastric tube with an esopha-

geal balloon. consequently, patients were ventilated in a randomized

order in pressure control (Pc), pressure support (Ps) and nAvA for 30

minutes each. during this period, airway pressure (Paw), esophageal

pressure (Pes), flow and electrical activity of diaphragm (eAdi) were

recorded. Ptp was calculated as Paw – Pes. Patient-ventilator interac-

tion was analyzed using a computer algorithm.

Results: Although peak Paw tended to be higher with nAvA, mean

Paw and Ptp are lower with nAvA in comparison to Pc and Ps (p<0.05,

figure 1). median tidal volume was not different between groups (figure

2A). However, the coefficient of variation of vt is higher with nAvA in

comparison to the other modes (p<0.05; figure 2B). In addition, the per-

centage of delivered breaths exceeding a patient’s average vt with

more than 2 ml/kg is higher (p<0.05) with nAvA (4.1 [IQr 1.3-14.5]%)

than with Ps (0.0 [IQr 0.0-2.2]%) and Pc (0.3 [IQr 0.0-2.0]%). Patient-

ventilator interaction, given by the neurosync index, is best with nAvA

(6.5 [IQr 5.5-10.5]) followed by Ps (13.1 [IQr 10.5-29.9]) and Pc (28.9 [IQr

12.8-54.5]) (p<0.0001).

Conclusion: In conclusion, these preliminary results demonstrate that

in patients with moderate Ards, nAvA is feasible and results in lower

mean transpulmonary pressures and equal tidal volumes compared

to conventional modes. Furthermore, the physiological variability

of breathing is better preserved with nAvA, leading to an improved

patient-ventilator interaction. However, due to this higher breath-by-

breath variability care should be taken in ventilating patients with

nAvA who have a high respiratory drive.



Figure 1. Airway (Paw) and transpulmonary pressures (Ptp) for different ventilation modes. red bars represent peak pressures and blue bars mean pressures during inspiration. median and interquartile range. *p<0.05

Figure 2. Tidal volume (vt) and coefficient of variation (cv) of vt for different ventilation modes. median and interquartile range. *p<0.05

12.

Surveillance cultures in intensive care units: a study on current practice

providing future perspectivesJ.B.J. Scholte1, W.N.K.A. Van Mook1, C.F.M. Linssen, H.A. van Dessel3,

D.C.J.J. Bergmans1, P.H.M. Savelkoul3, P.M.H.J. Roekaerts1

1Department of Intensive Care Medicine, Maastricht UMC+, The Netherlands, 2Department of –Microbiology, Atrium Medical Center, Heerlen, 3Department of

Microbiology, Maastricht UMC, The Netherlands

Background: evidence for obtaining surveillance cultures (sc) in inten-

sive care units (Icus) is scarce. This study explored sc implementation,

underlying motives for obtaining sc and the clinical decision making

process based on sc results.

Methods: A questionnaire was distributed to Heads of department

(Hod) and microbiologists of all Intensive care departments in the

netherlands.

Results: response rates were high, as presented in figure 1. sc were

routinely obtained according to 55/75 (73%) and 33/38 (87%) of Hod

and microbiologists, respectively. sc were more often obtained in

higher level Icus.1 most frequently, sc were obtained twice weekly

and sampled from trachea (74-87%), pharynx (74-88%), and rectum

(68-84%). major reasons to obtain sc included perceived optimiza-

tion of treatment of the individual patient (58% and 73%), preven-

tion of multiple drug resistant (mdr) micro-organisms (28% and 35%),

and resistance monitoring (27%). on suspicion of infection of a yet

unknown source, micro-organisms identified by sc were generally

targeted, while in absence of signs of infection, these micro-organisms

were not targeted. A third of Hod target micro-organisms identified by

sc in absence of signs of infection at the sampled site. microbiologist

were more reluctant to target these micro-organisms.

Conclusion: sc implementation is common practice in dutch Icus and

sc are presumed to optimize individual patients’ treatment by target-

ing micro-organisms identified by sc when infection is suspected and

origin unknown. consensus is lacking on how to deal with sc when

the focus of infection is not at the sampled site and therefore sc may

sometimes create more upheaval than intelligibility.

References1. nederlandse vereniging voor Anesthesiologie: organisatie en werkwijze

op intensive care-afdelingen voor volwassenen in nederland. In utrecht: http://nvic.nl; 2006:1-35.

Figure 1. Flow chart and primary outcome measure of the survey (the nationwide extend of sc implementation in Icus), classified according to level of Icu.1

13.

Effect of oxygen status on inflammatory parameters in humans

H.D. Kiers1,2, G.J. Scheffer2, J.G. van der Hoeven1, P. Pickkers1, M. Kox1,2 1Department of Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands,

2Department of Anesthesiology, Radboudumc, Nijmegen, The Netherlands

Background: The optimization of oxygen delivery is a cornerstone

of critical care medicine. In vitro and animal studies have shown that

oxygen status (i.e. hypoxia or hyperoxia) directly influences the inflam-

matory response. Hypoxia exerts pro-inflammatory effects, suppos-




edly mediated by the transcription factor hypoxia inducible factor 1α

(HIF1α). on the other hand, hyperoxia is related to immune suppres-

sion, possibly through increasing oxidative stress. As such, permis-

sive hypoxia or hyperoxia could be a cheap, non-pharmacological,

non-invasive treatment modality to modulate the immune response in

inflammatory conditions such as sepsis. However, human data on the

effects of oxygen status on the inflammatory response are scarce. The

aim of this study was to investigate the effects of systemic hypoxia and

hyperoxia on inflammatory parameters in healthy subjects.

Methods: 20 healthy, non-smoking, male volunteers, aged 18-35

years were randomized to either hypoxia or hyperoxia. All subjects

were admitted to the research department of the Icu for 9 hours. After

baseline measurements, subjects were exposed to 3,5 hours of hypoxia

(Fio2 titrated to a peripheral saturation of 80 to 85%) or hyperoxia (Fio2 of

100%) in an air tight respiratory helmet followed by 5,5 hours of exposure

to room air without the helmet in place. blood was obtained at various

time points throughout the day as well as the next morning. Parameters

obtained were basic hemodynamic and ventilator parameters, symptoms,

blood gas analysis, leukocyte differentiation, circulating cytokines, ex vivo

stimulation of leukocytes with lipopolysaccharide (lPs), HIF1α expression

in neutrophils, monocytes and lymphocytes, and neutrophilic oxidative

burst as measured by intracellular reactive oxygen species.

Results: Hypoxia (sao2 81.4(+- 0.29)%) was induced using an average

Fio2 of 12.1 (+-1.0)%. Hyperoxia (Fio2 100%) resulted in an average Pao2

of 54.9 +- 7.516 kPa. Hypoxic subjects exhibited a significant decrease in

Paco2 and respiratory rate compared to hyperoxic subjects, and a sig-

nificant increase in heart rate (figure 1). Hypoxia resulted in headache in

3 out of 10 subjects. Furthermore, hypoxic subjects displayed a signif-

icant increase in circulating neutrophils (figure 2), while no changes in

other leukocyte subpopulations were observed. Hypoxia or hyperoxia

did not induce detectable levels of circulating cytokines, and no effects

cytokine production by leukocytes ex vivo stimulated with lPs were

observed. There was large interindividual difference in leukocyte HIF1α

expression in both hypoxic and hyperoxic subjects with no apparent

effects of both treatments. Furthermore, hypoxia and hyperoxia did

not influence neutrophilic oxidative burst.

Conclusion: exposure of 3.5 hours to mild hypoxia or hyperoxia does

not lead to cytokine production, nor does it change the capacity of leu-

kocytes to produce inflammatory cytokines upon ex vivo stimulation.

The extent and duration of hypoxia and hyperoxia used in this study

appears not to result in induction of HIF1α or increased reactive oxygen

production, respectively.

Figure 2. neutrophil count during and after 3.5 hours of hypoxia and hyperoxia. The oxygen status adjustment period is marked in grey. P-values calculated using two-way AnovA (interaction term)

14.

Innate immune response-mediated late increase in SuPAR in multi-trauma patients K. Timmermans1,2, M. Kox1,2, M. Vaneker1, G.J. Scheffer1, P. Pickkers2

1Department of Anesthesiology, Radboudumc, Nijmegen, The Netherlands, 2Department of Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands

Background: The soluble form of urokinase-type plasminogen activa-

tor (suPAr) has been identified as a marker for immune activation and

is demonstrated to accurately predict outcome in patients with sepsis

or infectious diseases. In multi-trauma patients also a considerable

immunological response occurs that is related to multiple organ failure

Figure 1. respiratory and hemodynamic parameters during 3.5 hours of hypoxia and hyperoxia. The oxygen status adjustment period is marked in grey. P-values calculated using two-way AnovA (interaction term)



and patient outcome. We investigated the kinetics of suPAr, correla-

tion with the immune response and outcome in multi-trauma patients.

Methods: blood was obtained from adult multi-trauma patients

(n=63) on arrival at the emergency room (er) of the radboud

university nijmegen medical centre and days 1, 3, 5, 7, 10 and 14 fol-

lowing trauma. Plasma concentrations of TnF-α, Il-6, Il-10, IFn-γ, Il-8

and mcP-1 were determined by luminex, and suPAr concentrations

using elIsA. clinical data were collected from electronic patient files.

concentrations, areas under the curve (Auc) and regression coeffi-

cients were statistically analyzed. spearman correlation coefficients

were calculated and differences between survival/non-survival groups

were analyzed using unpaired student T-tests.

Results: suPAr values at admission to the er were higher in non-sur-

vivors compared to survivors (n=16, mean ± sem 4.1 ± 0.6 ng/ml versus

n=40, 3.0 ± 0.2 ng/ml, p=0.03). suPAr levels increased in time (figure

1, kruskal-Wallis, p<0.0001). An increase of suPAr did not predict or

precede death, though. suPAr Auc from er to day 5 tended to corre-

late with injury severity score (r=0.5, p=0.07). Plasma cytokines in the

er did not correlate with suPAr measured at the same time (e.g. TnF-α

r=0.2, p=0.37, Il-10 r=-0.02, p=0.91), while cytokine concentrations at

the er did correlate with suPAr levels at days 3 (TnF-α r=0.6, p<0.01,

Il-10 r=0.5, p=0.02) and 5 (TnF-α: r=0.7, p<0.01).

Conclusion: Plasma concentrations of suPAr measured at admission

to the er are associated with overall survival of multi-trauma patients.

Furthermore, suPAr concentrations increased during hospital admis-

sion, with most pronounced increases found in patients that suffered

more serious injury and related to the innate immune response deter-

mined in the er. These results indicate that suPAr is a innate immune

response-induced late mediator in multi-trauma patients.

Figure 1. suPAr increase in time (median, box 25-75% and whisker min-max)

15.

Intestinal Fatty Acid Binding Protein (i-FABP), a possible new marker for

intestinal damage in trauma patientsK. Timmermans1,2, O. Sir3, M. Kox1,2, M. Vaneker1, G.J. Scheffer1, P.

Pickkers2 1Department of Anesthesiology, Radboudumc, Nijmegen, The Netherlands,

2Department of Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands 3Department of Emergency Medicine, Radboudumc, Nijmegen, The Netherlands

Background: Intestinal damage is difficult to determine in multiple

trauma patients. Apart from the trauma itself, hemodynamic instabil-

ity may contribute to intestinal damage. Intestinal Fatty Acid binding

Protein (i-FAbP) is exclusively expressed by enterocytes. It is released

following enterocyte damage and established to be a good marker

for intestinal ischaemia. The aim of this study was to assess intestinal

damage using the biomarker i-FAbP in trauma patients during the first

days of their hospital admission.

Methods: We studied adult multitrauma patients (n=92) admitted to

the radboudumc. blood was obtained at the trauma scene by the heli-

copter emergency medical services (Hems), at arrival at the emergency

room (er), and at days 1, 3, 5, 7, 10, and 14 after trauma. Plasma concen-

trations of i-FAbP were determined by elIsA. clinical data, e.g. Injury

severity score (Iss), simplified Acute Physiology score (sAPs) II score,

mean Arterial blood Pressure (mAP) and hemoglobin (Hb) values were

collected from electronic patient files.

Results: Plasma i-FAbP concentrations were highest immediately fol-

lowing trauma at time points Hems and er. From day 3 onwards, i-FAbP

levels were lower compared with time points Hems and er (figure 1).

I-FAbP values at the er were correlated with Iss (r=0.32, P<0.01) and

patients suffering from abdominal trauma demonstrated higher I-FAbP

concentrations in comparison to patients with other types of trauma

(p<0.01, figure 2). Also the sAPs II score, calculated at day 1, significantly

correlated with the i-FAbP concentration on the same day (r=0.35,

p=0.03).

Finally, patients presenting with a low mAP (<70 mmHg) at the er,

demonstrated higher er plasma i-FAbP concentrations in comparison

with patients with a normal (70-99 mmHg) or high (>100 mmHg) mAP

(p<0.01, figure 3A). The same pattern was observed for patients with a

low Hb (<80% of reference value) in comparison with patients with a

normal Hb (p<0.01, figure 3B).

Conclusions: Plasma i-FAbP is highest within minutes to hours after

trauma and related to the severity and abdominal involvement of the

trauma. Hemodynamic instability, determined by low mAP and Hb

levels, are also associated with higher levels of marker i-FAbP, likely

related to secondary ischaemia-induced intestinal damage. I-FAbP

could serve as an early marker for direct trauma-related and secondary

ischemic intestinal damage in trauma patients.




Figure 1. I-FAbP levels over time

Figure 2. I-FAbP levels in abdominal/non-abdominal trauma

Figure 3. I-FAbP levels and hemodynamic indicators

16.

Comparison of wrist actigraphy and video-based actigraphy for

delirium detection in ICUsM. van den Boogaard1, E.M. van der Heide2

1Radboudumc, Department of Intensive Care, Nijmegen, The Netherlands, 2Philips Research, Department of Patient Care Solutions, Eindhoven, The Netherlands

Background: delirium in Icu-patients is mostly assessed by the

cAm-Icu and Icdsc at least twice daily. With its fluctuating course

delirium is still easily missed. Hence, there is need for an objective,

(semi-) automated, continuous measurement method.

disturbed motor activity pattern (dmAP), a frequent manifested

feature in delirious patients, could be interesting for delirium detec-

tion. measurement of dmAP to detect delirium is reported in a few

studies, all making use of on-body accelerometer-based techniques.

However, these techniques measures movements of one part of the

body, missing movements of the rest of body. video-based actigra-

phy monitoring has the advantage that altered motions of the whole

body can be observed without extra on-body sensors. This could be

an interesting method for objective delirium detection. The captured

video will be analyzed for dmAP that could be indicative of delirium.

Advanced image analysis allows for a more detailed analysis of the

context of the movement, going beyond mere activity counts.

objective: To determine if dmAP measured with video-based actigra-

phy are indicative for delirium and can be used for continuous delirium

detection in Icu-patients.

Method: An observational case-control study including delirious

and non-delirious patients. besides video-monitoring (24-hrs a day,

maximum 5 days), a wrist Actiwatch is used measuring activity level of

the arm. Patients are screened using cAm-Icu 3/day, and by a delirium

expert screening.

Results: In total 31 patients, mean age of 67.8 years, were included

of which 21 (67%) were delirious and 10 (33%) were not. Preliminary

results showed that activity levels measured with of video-based actig-

raphy compared with Actiwatch has important advantages to deter-

mine whole body activity level. Furthermore, we were able to identify

from the video-images dmAP possibly related to delirium.

Conclusion: The actiwatch results were in line with earlier results

shown in literature. It confirms that measurement of motoric altera-

tions can be sed for detection of delirium in Icu patients.

our preliminary results show that for measuring dmAP in delirious

patients video-based actigraphy monitoring is superior to wrist-based

accelerometer techniques.

Table 1.

Characteristics (n=30)Age, y (mean, sd) 68.2 ± 11

APAcHe II score (mean, sd) 19 ± 4

PredelIrIc score (mean, sd) 63 ± 24

male, n (%) 19 (63)

sedation, y (%) 16 (53)

medical patients, n (%) 25 (83)

sepsis, n (%) 9 (30)

died, n (%) 7 (23)

delirium, n (%) 21 (70)

delirium days (median, IQr) 2.0 0-4

delirium free-days (median, IQr) 2.0 [0-2.3]



17.

Numbers tell the tale in lung protective mechanical ventilation;

estimating body weight by eye versus calculating predicted body weight

M.L. Gruijters-van den Bos, M. Vriends, E.R. van Slobbe-Bijlsma

Department of Intensive Care Medicine, Tergooi, The Netherlands

Background: low tidal volumes are essential in lung protective

mechanical ventilation and based on predicted body weight. Predicted

body weight (PbW) is calculated using the devine formula, based on

gender and height. In acute situations bodyweight sometimes is esti-

mated by eye. We assessed the hypothesis that estimating by eye

results in higher initiating tidal volumes since everyone overestimates

predicted body weight.

Methods: All patients admitted to the Icu and in need of mechan-

ical ventilation were included during a six month period in 2010-

2011. medical staff (intensivist, resident and nurse) estimated by eye

the body weight of all patients. mechanical ventilation was started.

Hereafter height was measured in centimeters and the predicted body

weight was calculated and mechanical ventilation was adjusted if nec-

essary. Initiating tidal volumes were set to 6ml/kg. sPss was used for

data collection and a mann-Whitney u test was used for statistical

analysis. significance was considered if p<0.05.

Results: A total of 175 patients was included; 105 patients were

excluded because of low height and/or incomplete data collection.

data of 70 patients was analyzed. The entire Icu staff overestimated

bodyweight, with a median difference of 4 kg in the nurse group and 5

kg in the resident and intensivist group (0-24 kg) (p<0.001). There were

no significant differences between intensivists, residents and nurses.

estimating by eye resulted in higher initiating tidal volumes. median

overestimation was 26 ml (0-220 l in nurse-group (p<0.001) and 30 ml

in the resident- (0-270 ml) and intensivist group (0-234 ml) (p= 0.004).

28% of all cases showed overestimation of tidal volume with more than

50 ml.

Conclusion: setting tidal volumes based on estimating bodyweight

by eye resulted in higher initiating tidal volumes as compared to tidal

volumes based on calculated predicted body weight. nurses, residents

and intensivists overestimated body weight.

The initial higher tidal volumes were considered as not harmful

because of low initial settings (vt 6 ml/kg), so lung protective ventila-

tion was still warranted.

In conclusion, in patients in need of mechanical ventilation, body

weight should be calculated and not estimated by eye to ensure lung

protective mechanical ventilation. numbers do tell the tale.

Reference1. The Acute respiratory distress syndrome network. ventilation with lower

tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. neJm. 2000;342:1301-8.

18.

Implementation of a high volume, complex clinical pathway for cardiothoracic surgery

patients in the intensive care unitB.M. van der Kolk1, M. van den Boogaard2, C. Speelman-ter Brugge2,

J.C. Hol2, J.G. van der Hoeven 2, H. van Swieten3, L. Noyez3, P. Pickkers2 1Department of Surgery, Radboudumc, Nijmegen, The Netherlands, 2Department of Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands, 3Department of

Cardiothoracic Surgery, Radboudumc, Nijmegen, The Netherlands

Introduction: clinical pathways (cPs) have been developed for many

high volume – low risk patient groups. However, cPs for high risk (Icu)

patients are rare. In the Icu a cP implicates an “hour-to-hour” care plan.

deviations of the path, so called ‘variances’, are registered and used

for care evaluation afterwards. In this case control study we evaluated

the effects of the implementation of a cP for cardiothoracic surgery

patients in the Icu on several outcome measures.

Methods: The cP implementation period was January 2006 till April

2006. As part of the cP this also includes several nurse driven protocols.

A tailored implementation strategy was used including Icu key-nurses.

Adherence to the cP was retrospectively analyzed for Icu mobiliza-

tion, electrolyte administration, blood pressure regulation and blood

loss associated interventions.. cP data were compared with a control

group admitted one year earlier. cP and non-cP patients were meticu-

lously matched for type of operation, age, gender, APAcHe II score and

euro-score. except for the cP there were no other differences in care

between both periods.

Results: The cP group consisted of 81 Icu patients and the control

group of 162 Icu patients. Time to extubation decreased from median

from 8.5 hrs to 6.5 hrs (p=0.002) after implementation of the cP. The

incidence of temperature drop (>0.3 °c) decreased from 29.1% to

17.5% (p=0.007). The day following surgery all included cP patients

resumed normal nutritional intake and were mobilized on the Icu,

which was one day sooner than in the non-cP group. With the nurse

driven protocol significantly more patients received electrolyte supple-

mentation (97.5%) compared with the medical driven (43.2%) protocol

(p<0.0001). Adherence to the blood pressure regulation protocol

increased to over 90% (p<0.0001) with a nurse driven protocol in the

cP. los-Icu in the cP group 22.5 hrs [20.4-25.2] hours versus 23.8 hrs

[21.6-49.9] in the control group (p=0.02) There was a trend towards less

Icu readmissions in de cP group compared with the non-cP group,

17 (10.5%) versus 3 (3.7%), respectively p=0.06. mortality and los-in

hospital did not significantly change.

Conclusion: The cP implementation for cardiac surgery in the Icu was

successful and resulted in an improvement of protocol adherence and

patient outcome. This is the first study describing a cP for high volume

and high risk Icu patients. This model and the used implementation

strategy can serve as a ‘blue print’ for other categories of high and low

volume Icu patients.




19.

Effects related to ScvO2-guided preoperative optimization in open

transhiatal esophagectomy patientsB.M. van der Kolk1,2, M. van den Boogaard1, J.J. Bonenkamp2,

C.J.H.M. van Laarhoven, J.G. van der Hoeven1, P. Pickkers1 1Department of Intensive Care Medicine, Radboudumc, Nijmegen, The Netherlands,

2Department of Surgery, Radboudumc, Nijmegen, The Netherlands

Introduction: open transhiatal esophagectomy is associated with

considerable short term postoperative morbidity and mortality.

optimizing the circulation pre-operatively may result in improved

wound healing, attenuated risk for anastomic leakage and prevent

infection/sepsis, but may theoretically also lead to more blood loss

during surgery. The effects of preoperative optimization in this specific

group of high risk surgical patients is unknown.

Methods: A group of consecutive pre-operatively optimized patients

was compared with a control group of non-pre-optimized patients

which were admitted two years earlier. Preoperative optimization was

started one day prior to esophagectomy. Patients were admitted to

the intensive care unit (Icu) and received an arterial and jugular line.

A scvo2 <70% was treated with fluids and inotropics according to the

protocol.

Results: 68 patients received pre-operative optimization and 32

patients did not. optimized patients lost significantly less blood

intra-operatively (p=0.01) and needed less blood products (p=0.002)

compared with non optimized patients, while the transfusion trigger

did not change during these years. Postoperative sepsis occurred in

25% of the non optimized patients and 4% of the optimized patients

(p=0.002), anastomotic leakage occurred in 12% of optimized patients

and 25% of non-optimized patients (p=0.08). other postoperative pul-

monary and cardiovascular complications did not differ significantly

between both groups. optimized patients had a significantly shorter

hospital length of stay of median 10 days IQr 9-15 versus median 17 IQr 13-35, p<0.001) and a shorter duration of mechanical ventilation median

4.7 hrs IQr [3.6-6.8] versus 7.7 hrs IQr [3.5-28.2], (p=0.01) compared

with the control group. There was a trend that optimized patients

were less readmitted to the Icu 9 versus 25%, (p=0.06) compared to

the control group. Within the optimized group delta scvo2 increased

median 4% [IQr 0-7] and targeted scvo2 >70% was achieved in 76.6

of the optimized patients. Patients not reaching the target scvo2 were

more likely to have a cardiovascular medical history (p<0.02). not

reaching the svo2 target or a delta scvo2 rise less than 5%, was not

associated with an unfavourable course or outcome.

Conclusion: Pre-operative scvo2 guided optimization of patients

treated with an open transhiatal esophagectomy is associated with a

several beneficial effects. However, there is no straightforward expla-

nation for the observed beneficial effects pre-operative optimization

that are related to achieved or delta increase in scvo2. At this moment,

routine use of scvo2 guided pre-operative optimization cannot be

advised. nevertheless, we cannot rule out that a more sustained

increase in svo2, e.g. in the 6 hrs, preceding surgery, could result in a

further improvement of the prognosis of these patients. However, this

warrants confirmation in a rcT.

20.

Alkaline phosphatase attenuates the inflammatory response in human

proximal tubule epithelial cells: the potential mechanism of action of the observed beneficial effects in septic

patients with acute kidney injury E. Peters1,2, S. Heemskerk1,2, R. Masereeuw2, P. Pickkers1

1Department of Intensive Care Medicine, Nijmegen Institute for Infection, Inflammation and Immunity, Radboudumc, Nijmegen, The Netherlands,

2Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands

Background: sepsis carries a high morbidity and mortality, especially

when complicated by acute kidney injury (AkI). currently, no treatment

is available for sepsis-induced AkI. Two phase-II trials showed that

kidney function improved in critically ill patients with sepsis-induced

AkI after treatment with the enzyme alkaline phosphatase (AP).1,2

The mechanism of this beneficial effect on the kidney is unknown,

but might be related to the dephosphorylation, and thereby detoxi-

fication, of endotoxin (lipopolysaccharide, lPs). We investigated the

anti-inflammatory properties of AP by using a human proximal tubular

cell model.

Methods: conditionally immortalized human proximal tubular epi-

thelial cells (ciPTec) were incubated with lPs (10 µg/ml) or TnF-α (10

ng/ml) to induce an inflammatory response. recombinant human AP

(10 u/ml) was added 2 hours prior to the inflammatory insult and the

cytokine production of TnF-α, Il-6, and Il-8 was studied after 24 hours

by elIsA. supernatant of peripheral blood mononuclear cells (Pbmcs),

prestimulated for 24 hours with or without lPs (1 ng/ml), was added

to the ciPTec to mimic endotoxin-induced renal inflammation. AP was

added 2 hours prior to this insult and Il-6 and Il-8 were measured after

24 hours. data are expressed as mean ± sem (n=5 per group) and the

effect of AP was analyzed by one-way AnovA.

Results: AP pretreatment significantly reduced the lPs induced

cytokine response of TnF-α (reduction 40.4 ± 7.9%, p<0.05), Il-6 (reduc-

tion 47.5 ± 3.1%, p<0.0001) and Il-8 (reduction 39.6±2.4%, p<0.0001)

in ciPTec (figure 1). similar effects of AP were observed in ciPTec stim-

ulated with TnF-α, as the inflammatory response of Il-6 en Il-8 was

significantly reduced by AP (Il-6: 21.0 ± 4.2%, p<0.05; Il-8: 21.6 ± 4.6%,

p<0.05; figure 2). Inactive AP, lacking enzyme activity so it cannot

dephosphorylate molecules, had no effect on both lPs- and TnF-α-

induced cytokine response (figure 1 and 2). The supernatant of Pbmcs,

pre-incubated with lPs, induced the production of Il-6 and Il-8 in the

ciPTec. stimulating the ciPTec directly with 1 µg/ml lPs had no effect,

demonstrating that the inflammatory response is induced by media-



tors present in the Pbmc supernatant. AP treatment could significantly

reduce this response (Il-6: 39.2 ± 9.6% reduced, p<0.05; Il-8: 34.9 ±

6.0%, p<0.05; figure 3).

Conclusion: The dephosphorylating property of AP is responsible for

the reduction of the cytokine response induced by lPs and TnF-α, as

inactive AP had no effect. TnF-α and the inflammatory mediators in the

Pbmc supernatant itself cannot be dephosphorylated by AP, strongly

suggesting that AP targets other molecules as well. A possible target

might be ATP which is released by these cells upon stress conditions

and can be converted by AP into the cytoprotective adenosine. These

findings suggest that the ability of AP to reduce renal inflammation

may account for the observed attenuated acute kidney injury in sepsis

patients.

References1. Pickkers P, Heemskerk s, schouten J, et al. Alkaline phosphatase for treat-

ment of sepsis-induced acute kidney injury: a prospective randomized dou-ble-blind placebo-controlled trial. crit care. 2012;23:16, r14.

2. Heemskerk s, masereeuw r, moesker o, et al. APseP study group. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. crit care med. 2009;37:417-23, e1.

Figure 1. AP significantly reduced the lPs induced cytokine response

Figure 2. AP significantly reduced the TnF-α induced cytokine response




Figure 3. AP significantly reduced the cytokine response induced by the supernatant of lPs-stimulated Pbmcs

21.

Early PREdiction of DELIRium in ICu patients (E-PRE-DELIRIC): Development and

validation of an early delirium prediction model for intensive care patients

A. Wassenaar1, M. van den Boogaard2, T. van Achterberg1, A.J. Slooter3, M.A. Kuiper4, P.H.J. van der Voort5, M.E. Hoogendoorn6,

K.S. Simons7, E. Maseda8, C. Plowright9, C. Jones10, A. Luetz11, P.V. Sackey12, P.G. Jorens13, L.M. Aitken14, F.M.P. van Haren15,

P. Pickkers2, L. Schoonhoven1,16

1Scientific Institute for Quality of Healthcare, Radboudumc, Nijmegen, The Netherlands, 2Department of Intensive Care Medicine, Radboudumc, Nijmegen,

The Netherlands, 3University Medical Centre Utrecht, Department of Intensive Care Medicine, Utrecht, The Netherlands, 4Medical Centre Leeuwarden Department of Intensive Care Medicine Leeuwarden, The Netherlands, 5Onze Lieve Vrouwe

Gasthuis, Department of Intensive Care Medicine Amsterdam, The Netherlands, 6Isala clinic Research Department of Anesthesiology & Intensive Care, Zwolle,

The Netherlands, 7Jeroen Bosch Hospital, Department of Intensive Care Medicine ’s-Hertogenbosch, The Netherlands, 8Hospital Universitario La Paz Department of Intensive Care Medicine Madrid, Spain, 9Medway Maritime Hospital Anaesthetic

department Kent, United Kingdom, 10Whiston Hospital Ward 4E (Critical Care) Prescot, United Kingdom, 11Charité Universitaetsmedizin Berlin Department

of Anesthesiology and Intensive Care Medicine, Berlin, Germany, 12Karolinska University Hospital Solna Department of Anesthesiology, Surgical Services and

Intensive Care Medicine and Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden, 13Antwerp University Hospital, University

of Antwerp Department of Critical Care Medicine, Edegem (Antwerp), Belgium, 14Princess Alexandra Hospital Intensive Care Unit, Brisbane, Australia, 15Canberra

Hospital, department of Intensive Care, Canberra, Australia, 16University of Southampton, Faculty of Health Sciences, Southampton, United Kingdom

Background: delirium often occurs in Intensive care unit (Icu)

patients and is associated with serious short- and long-term conse-

quences. As a consequence, delirium prevention is imperative, espe-

cially in high-risk patients. The recently developed and validated Pre-

delIrIc model reliably predicts delirium after 24 hours in the Icu.1

However, in a relevant number of patients delirium occurs within 24

hours following Icu admission and thus identifying them as high risk

is not possible with the Pre-delIrIc model. Therefore the aim of this

study was to develop and validate an early Prediction of delIrium Ic

(e-Pre-delIrIc) model based on data available at Icu admission.

Methods: An international multicenter prospective cohort study was

carried out in 13 Icus from 7 countries between october 2011 and June

2012. every Icu included all eligible patients aged ≥18 years during a

period of approximately three months. data of 16 putative risk factors

of delirium were collected immediately after Icu admission. The

cAm-Icu was used by well trained Icu nurses to diagnose delirium.

cAm-Icu screening compliance and inter-rater reliability (Irr) were

measured in order to check the quality of these assessments. multiple

logistic regression analysis was used to develop the e-Pre-delIrIc

model on data of the first two-thirds of every participating hospital.

The model was validated on data of the last one-third of every partic-

ipating hospital. We determined discriminative power using the area

under the receiver operating characteristic curve (Auroc) and calcu-

lated the linear predictor for each patient for calibration.

Results: In total 5,352 patients were screened, of which 2,433 patients

were excluded (figure 1). The study cohort consisted of 2,919 patients;

data of 1,966 patients were included in the development database and

data of 953 patients in the validation database. see table 1 for patient

characteristics and delirium incidences. The mean (sd) overall cAm-Icu

compliance was 83 ± 16% and the mean Irr was 0.83. The delirium inci-

dence was 24.6% in the development database and 21.8% in the vali-

dation database. Preliminary Results: the e-Pre-delIrIc model consists

of 7 predictors: age, history of cognitive disturbances, history of sub-

stance abuse, urea level, admission category, urgent admission, and

respiratory failure. The discriminative power (Auroc) of the model is

0.75 (95% cI: 0.73-0.78), with a sensitivity and specificity of 0.66 and

0.73, respectively.

Conclusion: In this study we internationally developed and validated

an early delirium prediction model (e-Pre-delIrIc). using this model

patients’ risk for delirium in the Icu can be predicted immediately

after admission, allowing the start of delirium preventive interventions

immediately after Icu admission.

Reference1. van den boogaard m, Pickkers P, slooter AJ, et al. development and valida-

tion of Pre-delIrIc (Prediction of delIrium in Icu patients) delirium pre-diction model for intensive care patients: observational multicentre study. bmJ (clinical research ed). 2012;344:e420. epub 2012/02/11.



Figure 1. study flow chart

Table 1. Patients characteristics

Variable Development (n=1966)

Validation (n=953)

Age in yearsmedian [IQr, range]

65(53-74, 77)

64(51-73, 76)

male (%) 1168 (59.4) 551 (57.8)

Admission category, n (%)1. surgery2. medical3. Trauma4. neurology/neurosurgery

1021 (51.9)685 (34.8)90 (4.6)170 (8.6)

476 (49.9)339 (35.6)44 (4.6)94 (9.9)

urgent admission, n (%) 1166 (59.3) 571 (59.9)

los-Icu, in daysmedian [IQr, range]

2.0(1-6, 132)

2.0 (1-5, 125)

delirium, n (%) 483 (24.6) 208 (21.8)

22.

Factors of influence on the morbidity and mortality after pancreaticoduodenectomy

R.J.C. van den Broek1, E. Olofsen1, B.A. Bonsing2, L.P.H.J. Aarts1, J. Vuyk1

1Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands, 2Department of Surgery, Leiden University Medical Center, Leiden,

The Netherlands

Background: The perioperative course of patients undergoing pan-

creaticoduodenectomy (Pd) is associated with surgical and anesthetic

challenges reflected in its significant morbidity and 30-day mortal-

ity (3-10%).1 little is known regarding peroperative factors that affect

outcome after Pd. We studied the factors of influence on mortality and

morbidity after Pd.

Methods: With ethics committee approval, perioperative parameters

(amongst others: Possum score, presence of epidural blockade, peri-

operative plasma creatinine concentrations, blood loss, fluid balance,

need for postoperative mechanical ventilation or vasopressive agents,

complications classified according to the clavien-dindo classifica-

tion and the International study group of Pancreatic surgery (IsgPs),

mortality and length of stay) of all patients scheduled for a Pd in the

lumc during 2006-2011 were prospectively collected. univariate and

multivariate logistic regression analysis were performed to determine

the parameters of influence on morbidity and mortality. A model to

improve informedness was developed to allow the prediction of the

incidence of complications.2 Informedness is the probability that an

informed decision is made, rather than a guess.

Results: All 143 patients who underwent Pd were included in the study.

complications (table 1) occurred in 76 (53%) patients, with a mortality of

5.6% during hospital stay. mean length of stay was 14 ± 6 days for patients

without complications and 27 ± 19 days for patients with complications

(p= 0.001). results of univariate regression analysis are presented in table

2. mortality and morbidity were, in part, the result of non-influenceable

parameters, such as AsA physical status, Possum score and the presence

of malignancy. some parameters, however, that are in reach of the clini-

cian, affected outcome. These included epidural analgesia that reduced

the risk to develop pneumonia (5.8% versus. 21.7%, p=0.02), and a positive

fluid balance that increased the incidence of postoperative intra-abdomi-

nal abscesses (p=0.01). Age, gender, bmI, blood loss and length of surgery

as individual parameters did not influence the incidence of postopera-

tive complications or mortality in this population. A predictive model

with the combined parameters: AsA status, gender, presence of oliguria

during surgery, length of surgery, need for postoperative ventilation, fluid

balance and plasma creatinine concentration at 24 h after surgery as sig-

nificant parameters, improved informedness from 0 to 0.24.

Conclusion: epidural blockade and fluid balance are influenceable

perioperative factors that affect outcome after Pd. Perioperative care

physicians should be aware of this and guide patients for Pd accord-

ingly. We developed a model that increases informedness of postop-

erative complications.

References1. greenblatt dY, kelly kJ, rajamanickam v, et al. Preoperative Factors Predict

Perioperative morbidity and mortality After Pancreaticoduodenectomy. Ann.surg.oncol. 2011;18:2126-35.

2. http://en.wikipedia.org/wiki/Accuracy_and_precision.

Table 1. complications as classified according to the clavien-dindo classification and the International study group of Pancreatic surgery (IsgPs) as occurred in 76 out of 143 patients (53%) after pancreaticoduodenectomy

Complication type n %Wound infection 15 10.5

Intrathoracic / intraabdominal infection (abcess) 21 14.7

rebleed 10 7

Fistula 25 17.5

myocardial infarction 3 2.1

cardiac decompensation 0

Pneumonia 12 8.4

Pulmonary embolism 6 4.2

bowel motility disorder 14 9.8

other (atrial fibrillation, diarrhea, hepatic infarction, neuropathy etc.)

33 23




Table 2. P-values of the univariate logistic regression analysis of parameters on mortality and morbidity in patients after pancreaticoduodenectomy. Presented are the p-values of the significant results (p<0.05). All blanks represent non-significant results

ASA

phy

sica

l st

atus

Phys

iolo

gica

l PO

SSU

M s

core

Ope

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ve

POSS

UM

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re

Tota

l PO

SSU

M

scor

e

Epid

ural

an

alge

sia

Pero

pera

tive

bl

ood

loss

Post

oper

ativ

e m

echa

nica

l ve

ntila

tion

Vas

opre

ssiv

e ag

ents

Hig

h flu

id

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nce

afte

r 24

h

Crea

tini

ne le

vel

afte

r 24h

Pres

ence

of

mal

igna

ncy

mortality 0.03 0.05 0.01 0.02

complications 0.02 0.02 0.03

Pneumonia 0.02

myocardial infarction 0.01 0.03

Abscess 0.02 0.02 0.001 0.02 0.02 0.01

Fistula 0.03 0.03

23.

Using ultrasound of the lung to predict fluid responsiveness and estimate volume status

J.M. Schoonejans, S. Rijkenberg, H. Endeman

Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

Background: excessive fluid resuscitation in critically ill patients is

associated with adverse outcome. determining fluid responsiveness

is therefore a pivotal element of intensive care therapy. many methods

of fluid responsiveness have been developed, the majority needing

invasive measurements, such as central venous or arterial catheters.

The same counts for estimation of the volume status of the patient.

ultrasound of the lung is an non-invasive method to diagnose the inter-

stitial syndrome. The interstitial syndrome is associated with excessive

extravascular lung water.1 In this pilot study we analyzed the relation

between parameters of fluid responsiveness, the pulse pressure vari-

ation (PPv) and volume status, the central venous pressure (cvP), and

the interstitial syndrome.

Methods: Patients were included in case of arterial catheter and

central venous catheter (cvc) in place. PPv was measured in venti-

lated and non-ventilated patients, but only if the patients was in sinus

rhythm. values of cvP were only used for further analysis, if the cvc

was in upper diaphragm position. ultrasound of the lung was per-

formed using the adjusted blue protocol.2 lungs were classified A, A/b

or b in which b represents the interstitial syndrome. A second, hydro-

static, classification was made using the zones of West (empty, partially

filled or fully filled lungs) (figure 1).

Results: In 38 patients 82 measurements were done. during 35 ultra-

sound examination an accurate PPv was measured. PPv is highest in

case of an A-profile present (mean 14.0%, sd 8.6%), decreases in an

A/b-profile (mean 9.0%, sd 3.6%) and is lowest in the b-profile (mean

7.8%, sd 5.1%), but differences were not statistical significant. This

trend was not seen using the hydrostatic classification (figure 1). cvP

was measured properly during 37 measurements. The cvP is highest

in the b-profile (median 16.5 mmHg, IQr 4.2 mmHg) and lowest in the

A-profile (median 9 mmHg, IQr 6.4 mmHg); this difference is statisti-

cally significant (p=0.043). The cvP in the A/b profile is lays between

those values (median 12.3 mmHg, IQr 8 mmHg). A similar non-signifi-

cant trend was found using the hydrostatic profiles (figure 2).

Conclusion: This pilot study shows lung ultrasound might be a

reliable non-invasive way to measure the limit of fluid responsiveness

(measured by PPv) and seems to give a estimation of volume status

(measured by cvP). A larger cohort of patients is needed to confirm

these findings.

References1. lichtenstein dA. lung and Interstitial syndrome. Whole body

ultrasonography in the critically Ill springer, Heidelberg, 2010;151-61.

2. lichtenstein dA, meziere gA. relevance of lung ultrasound in the diagnosis of acute respiratory failure: the blue protocol. chest. 2008;134:117-25.

Figure 1. lung profiles using the classification of the blue protocol and on basis of the hydrostatic pressure described by West

Figure 2a-d. cvP in patients with the A, A/b or b-profile (a); difference between A-profile and b-profile is statistically significant (p=0.043). cvP in patients with the hydrostatic profiles empty, partially filled, fully filled and (b). PPv in patients with the A, A/b or b-profile (c) and empty, partially and fully filled lungs



24.

25-OH-vitamin D deficiency is a frequent finding in critically ill patients but is not an independent risk factor for mortalityI.A. Meynaar1,L. Dawson1, Y. Schriel1, J. Verzijl2, F. van der Dijs2

1ICU, Reinier de Graaf Hospital, Delft, The Netherlands, 2Department of Clinical Chemistry, Reinier de Graaf Hospital, Delft, The Netherlands

Introduction: some authors found 25-oH-vitamin d to be an inde-

pendent risk factor for mortality (venkatram, crit care 2011), others

did not (cecchi, minerva Anesthesiol 2012). our aim was to study

the incidence of vitamin d deficiency and to test the hypothesis that

25-oH-vitamin d deficiency is independently associated with increased

mortality in critically ill patients.

Methods: This prospective observational study was done in the 10-bed

mixed Icu of the reinier de graaf Hospital. For all patients admitted

to the Icu between July 1st, 2011 and June 30th, 2013, 25-oH-vitamin d

(ArcHITecT 25-oH vitamin d, Abbott diagnostics europe) was measured

in leftover blood samples from the first 24 hrs of Icu treatment. Patient

characteristics and outcome are collected routinely. study end point was

hospital mortality. The need for informed consent was waived.

Results: 25-oH-vitamin d on Icu admission was available for 955

of 1173 individual patients (81%) admitted during the study period.

Patient characteristics are shown in table 1.


All patients

(n=955)

Survived to hospital discharge(n=824)

Died in hospital

(n=131)

p

Age 65.0 (16.2) 63.8 (16.5) 72.4 (11.9) < 0.001 (1)

Apache Iv score 58.5 (30.7) 52.7 (25.0) 96.1 (37.5) < 0.001 (1)

Apache Iv exp mort 8.5% (2.8-25.1)

6.6% (2.4-18.4)

49.3% (21.9-81.2)

< 0.001 (2)

medical 530 430 (81.1%) 100 (18.9%) <0.001 (3)

Planned surgery 301 291 (96.7%) 10 (3.3%)

emergency surgery 124 103 (83.1%) 21 (16.9%)

Icu los 1.6 (0.8-3.4) 1.5 (0.8-3.1) 2.1 (0.9-5.1) < 0.001 (2)

HosP los 9.3 (5.1-18.7) 9.9 (5.7-18.3) 6.4 (2.1-19.1) 0.003 (2)

25-oH-vit d nmol/l (4) 33.5 (2.0) 34.0 (2.0) 30.5 (2.0) 0.088 (1)

Data presented as mean (SD), median (IQR), number (%) as appropriate. (1) T test, (2) Mann Whitney U test, (3) Chi-square test, (4) after log conversion. 936 patients fulfilled Apache IV inclusion criteria.

When regarding 25-oH-vitamin d levels below 30 nmol/l as deficient,

55+292=347 patients (36.3%) were deficient. some use a cut-off level of

50 nmol/l, this would mean that 55+292+344=691 of our patients were

deficient (72.4%). Table 2 shows that low 25-oH-vitamin d levels are not

associated with increased mortality. We found similar results with uni-

variate logistic regression or when using roc curves (not shown): no

association between 25-oH-vitamin d and hospital mortality. As might

be expected, in multivariate analysis including Apache Iv score as a

measure of illness severity, 25-oH-vitamin d was not an independent

risk factor for mortality, with p<0.001 for APAcHe Iv score and p=0.221

for 25-oH-vitamin d.

Conclusion: In this single centre prospective observational study with

955 patients, depending on the definition of deficiency, one-third to

two-thirds of patients admitted to the Icu were 25-oH-vitamin d defi-

cient. 25-oH-vitamin d however was not an independent risk factor for

hospital mortality.

Table 2. univariate analysis for vitamin d levels and hospital mortality

All patients

(n=955)

Survived to hospital discharge(n=824)

Died in hospital

(n=131)

p

vit d <15 nmol/l 55 47 (85.5%) 8 (14.5%)

ns (3)

vit d 15-29 nmol/l 292 245 (83.9%) 47 (16.1%)

vit d 30-49 nmol/l 344 299 (86.9%) 45 (13.1%)

vit d 50-69 nmol/l 163 140 (85.9%) 23 (14.1%)

vit d ≥70 nmol/l 101 93 (92.1%) 8 (7.9%)

25.

Results of the first 6 months use of dexmedetomidine

C.A.E. Watervoort, N. Embregts, J.A.H. van Oers

Department of Intensive Care Medicine, St Elisabeth Hospital, Tilburg, The Netherlands

Background: dexmedetomidine is a highly selective α2-agonist with

sedative, analgesic and anxiolytic effects. It is known to decrease the

duration of mechanical ventilation compared with midazolam 1 and

to enhance patient comfort at the Icu compared with midazolam and

propofol.1 We started to use dexmedetomidine in december 2012. The

aim of the study is to describe our first experiences.

Methods: We performed a retrospective observational study of all

patients who had been treated with dexmedetomidine between

december 2012 and June 2013 on our 30 bed mixed medical (neuro)

surgical Icu. data of demographics, clinical features, indications to

start, maximum dose and duration of dexmedetomidine, duration

of mechanical ventilation and Icu stay, delirium assessment by the

cAm-Icu and adverse events were collected. differences in quantita-

tive variables were examined using a mann Whitney u test and differ-

ences in categorical variables were examined using a chi-squared test.

A p-value of < 0.05 was considered statistically significant.




Results: In 62 patients dexmedetomidine was started 68 times during

6 months. demographics, clinical features and outcome are presented

in table 1. We identified 3 main groups of indications to start dex-

medetomidine: 1. Patients uncomfortable on non-invasive positive

pressure ventilation (nIPPv) or difficult to wean from invasive ventila-

tion, 2. Patients in delirium and 3. Patients in which dexmedetomidine

was started in an attempt to reduce midazolam and/or propofol and

1 rest group called others. differences between these groups are pre-

sented in table 2. 58 patients were ventilated (6 nIPPv, 35 invasive venti-

lation and 17 both). In the delirium group the cAm-Icu was performed

12 times (10 delirium/2 no delirium) before starting dexmedetomidine

and 7 times (4 delirium / 3 no delirium) after starting dexmedetomi-

dine. x2 1,56 (ns). There were no differences in unplanned extubations

in the different groups.


Total number of patientsNumber of times of dexmedetomidine prescription

6268

male (%) 44 (62%)

Age (mean +/- sd) 56 +/- 17

main reason of admission 30 medical patients (coPd/pneumonia/cHF)16 surgical patients15 neuro(surgical) patients (TbI/sAH)1 others

APAcHe II score (median- interquartile range)

20 (14-24)

mortality number (%) 8 (13%)

number of unplanned extubations (%) 5 (8%)

Table 2. differences between groups

1 2 3 4NIPPV/difficult to wean

Deli-rium

Reduction of midazo-lam/propo fol

Others p-value *

no. of patientsno. dexmed prescriptions

1922

3334

89

23

monotherapy no. (%)

16 (73%) 21 (62%) 0 2 (67%)

maximum dose dexmedmcg/kg/h median (range)

0.4 (0.3-0.5)

0.46 (0.3-0.5)

0.31(0.2-0.4) 0.4 ns

duration of dexmed (hours) median (range)

46 (14-86)

45 (21-78) 47 (23-115) 26 ns

ventilator time(hours) median (range)

90 (34-212)

134 (62-254)

99 (45-313) 414 ns

los in daysmedian (range)

9 (3-15) 7 (4-14) 7 (6-16) 23 ns

Adverse events(hypotension/bradycardia)

3 3 1 0 ns

*p-value differences calculated between group 1,2 and 3 by Mann Whitney U test.

Conclusion: These are our first experiences with a new sedative agent.

We were in a learning phase. We prescribed dexmedetomidine most

frequently in patients uncomfortable on nIPPv or difficult to wean

from invasive ventilation and patients in delirium. There were no signif-

icant differences in the maximum dose and duration of dexmedetomi-

dine and outcome parameters. There were no differences in the small

amount of cAm-Icu performed in the delirium group after starting

dexmedetomidine.

Reference1. Jakob sm, et al. JAmA. 2012;307:1151-60.

26.

Let’s make things better: volumetric capnography to determine dead

space in ARDS patientsJ.L. Nollet1,2, M.P.A.J. Vugts2, L.H. Roesthuis2, J. Doorduin2,

J.G. van der Hoeven2, L.M.A. Heunks2 1Technical Medicine, University of Twente, Enschede, The Netherlands, 2Department

of Critical Care Medicine, Radboudumc, Nijmegen, The Netherlands

Background: bohr’s dead space is the portion of tidal volume not par-

ticipating in gas exchange with pulmonary blood flow. determining

dead space in clinical practice is becoming increasingly important in

critically ill patients with acute respiratory distress syndrome (Ards).

It enables follow-up of treatments, prognostication and it can be used

to optimize ventilator settings. However, dead space calculation is

cumbersome in ventilated patients using current techniques, like the

douglas bag (db) and metabolic monitor (mm).recently, a new non-

invasive technique based on volumetric capnography (vcap) was val-

idated in pigs. The aim of this study is to compare vcap with current

techniques to determine dead space ventilation in Ards patients.

Methods: In a prospective observational study, 15patients with

moderate Ards were recruited. dead space (vd) was calculated with

vcap as fraction of the tidal volume (vT) using the bohr equation: vd/

vT = (PAco2-Peco2)/PAco2, where PAco2 and Peco2 are alveolar and

mixed expired co2 tension, respectively. both variables were calcu-

lated in matlab from a mathematical fit of the volumetric capnogram

(figure 1).In addition, Peco2 was determined by collecting expired air

using a db and via indirect calorimetry with a mm. consequently, dead

space was calculated using the bohr-enghoff modification (arterial co2

tension (Paco2) instead of PAco2). Paco2 was obtained from an arterial

blood gas sampled at the same time of collecting expired air.

Results: In table 1, dead space, Peco2, Paco2 and PAco2 measured with

the db, mm and vcap are shown. There was alow agreement in dead

space between db and vcap (mean bias (± sd): 33 ± 12%) and a high

agreement between db and mm (mean bias: 2.3 ± 8.9%).dead space

determined with vcap (mean: 53 ± 7.9%) was lower compared to dead

space determined with the db (mean: 73 ± 7.1%, p<0.0001) and mm

(mean: 72 ± 8.2%,p<0.0001).There was a higher agreement in Peco2

between db and vcap (mean bias: -2.0 ± 15%), compared to db and mm

(mean bias: -4.9 ± 23%).Paco2 was higher compared to PAco2 (mean:

6.94 ± 1.68kPa versus 3.90 ± 0.80kPa, p<0.0001).



Conclusion: The douglas bag and metabolic monitor both overes-

timate dead space ventilation. both methods usePaco2 to estimate

PAco2, which however, is inappropriate as Paco2 is also affected by

pulmonary shunting in patients on controlled mechanical ventilation.

The agreement in Peco2 between the douglas bag and volumetric cap-

nography is higher compared to the agreement between the douglas

bag and the metabolic monitor. In conclusion, volumetric capnography

measures true bohr’s dead space, is less prone to measurement errors,

noninvasive and therefore the recommended method to determine

dead space in Ards patients.

Figure 1. volumetric capnogram. A volumetric capnogram consists of three phases: phase I, the portion of the tidal volume (vT) free of co2; phase II, the portion of the tidal volume which represents co2 coming from lung units with different rates of ventilation and perfusion; phase III, the portion of the tidal volume representing pure alveolar gas. PAco2 and Peco2 are the alveolar and mixed expired co2 tension, respectively

Table 1. results for dead space ventilation (vd/vT), mixed expired co2 tension (Peco2) and arterial and alveolar co2 tension (Paco2 and PAco2, respectively) determined with the douglas bag, metabolic monitor and volumetric capnography (mean ± sd)

Douglas bag Metabolic monitor

Volumetric capnography

v d/v T (%) 73 ±7.1 72 ±8.2 53 ±7.9

Peco2 (kPa) 1.77 ± 0.31 1.92 ± 0.60 1.83 ± 0.44

Paco2 (kPa) 6.94 ± 1.68 6.94 ± 1.68 -

PAco2 (kPa) - - 3.90 ± 0.80

27.

Respiratory muscle recruitment during mechanical ventilation:

effects of ventilator settingsL.H. Roesthuis1, J. Doorduin1, L.M.A. Heunks1

Department of Critical Care Medicine, Radboudumc, Nijmegen, The Netherlands

Background: mechanical ventilation offers essential ventilatory

support to patients with acute respiratory failure. one of the goals of

mechanical ventilation is to unload the respiratory muscles, while the

respiratory system can recover. nevertheless, selected patients recruit

their accessory respiratory muscles during mechanical ventilation,

which could be sign of inadequate unloading. Probably, this is unfa-

vourable because accessory respiratory muscles are not suited for pro-

longed ventilation. An observational study showed that it is feasible to

monitor accessory respiratory muscle recruitment on an intensive care

unit by using surface electromyography. monitoring the accessory res-

piratory muscles might be useful for optimizing ventilator support and

patient comfort. The aim of the current study is to evaluate the effects

of ventilator settings on accessory respiratory muscle recruitment in

mechanically ventilated patients.

Methods: Ten mechanically ventilated patients were recruited from

the intensive care unit. muscle activity from the alaenasi, genioglos-

sus, scalene, sternocleidomastoid and parasternal intercostals was

measured using surface electromyography. diaphragm electromyogra-

phy was measured using esophageal electrodes. First, pressure support

level was reduced every 5 minutes with 3 cm H2o, starting from 15 cm

H2o till a pressure support level of 0 cm H2o.second,pressure trigger

sensitivities of -2.5% and -15% of the maximal inspiratory pressure were

applied. electromyography was expressed as the root mean square

value. during inspiration, several parameters were calculated for the

last two minutes of each study step. In addition, recruitment order

and onset times of activity of the accessory respiratory muscles with

respect to the diaphragm were determined.

Results: diaphragm activity increased with 45 (28-67)%(n=10),while

reducing pressure support levels to 0 cm H2o. In addition, parasternal

intercostal activity increased with 35 (16-70)% (n=8), scalene activity

with 40 (22-57)% (n=10), sternocleidomastoid activity with 44 (23-70)%

(n=10), genioglossus activity with 61 (7-74)% (n=6) and alaenasi activity

with49 (23-72)% (n=8).For the diaphragm significant differences in

muscle activity were obtained between most of the pressure support

levels that were compared. For the accessory respiratory muscles signif-

icance was reached between the highest two and the lowest pressure

support levels (scalene and alaenasi),15 cm H2o and 3 cm H2o (ster-

nocleidomastoid) and 12 cm H2o and 3 cm H2o (sternocleidomastoid

and genioglossus). low pressure trigger sensitivity did not increase res-

piratory muscle recruitment significantly. recruitment order and onset

times of the accessory respiratory muscles did not change with differ-

ent ventilator settings. note that upper airway muscles were recruited

first and that lower airway muscles had later onset times (figure 1).

Conclusion: Accessory respiratory muscle activity tends to increase in

response to reduced pressure support levels. These findings suggest

that monitoring accessory respiratory muscle recruitment by surface

electromyography could be used as a complementary tool to assess

inspiratory drive in mechanically ventilated patients. It has the poten-

tial to be an easy, non-invasive method to optimize ventilator support.




Figure 1. relative onset times with respect to the diaphragm (=100%). respiratory muscles with an earlier or later onset time than the diaphragm have a relative onset time greater or less than 100%, respectively.

28.

Hemodynamic management: an international survey among pediatric

intensive care physiciansL. Frijns, J. Lemson

Radboudumc, Nijmegen, The Netherlands

Background: Hemodynamic monitoring (Hm) is an indispensable part

of managing critically ill children and needs to be part of a strategy to

provide an improvement in outcome. We conducted a survey to assess

the use of various Hm modalities by pediatric intensive care physicians,

as well as the use of a protocol for hemodynamic management.

Methods: A web-based survey was sent to 400 clinicians in PIcus

(pediatric intensive care units) in 29 countries.

Results: 83 clinicians in as many PIcus in 15 countries responded. Heart

rate, blood pressure and lactate were considered the most important

parameters of 21 clinical, biochemical or Hm derived variables (figure

1). central venous oximetry (scvo2) and lactate were considered impor-

tant by respectively 71% and 79% of respondents (percentage attribut-

ing a value >7 on a 0-10 scale).

57% of respondents indicate their PIcu does not have or does not

commonly use a protocol for hemodynamic management. 55% of

respondents indicate to sometime or frequently use any form of

cardiac output (co) monitoring (figure 2).

Conclusions: 1. scvo2 and lactate are valued parameters, but despite

international campaigns1 promoting an end goal directed approach to

hemodynamic management using these parameters, the use of such pro-

tocols is poor. 2. co monitoring is not widely used by the respondents.

Figure 1. Average of values attributed to parameters when assessing the hemodynamic status of a child in PIcu

Figure 2. use of co monitoring as indicated by respondents (n=83)

29.

Attributable mortality of delirium in critically ill patients

P. Klein Klouwenberg1, A. Slooter1, C. Spitoni2, D. Ong1, M. Bonten1, I. Zaal1, O. Cremer1

1University Medical Center Utrecht, Utrecht, The Netherlands, 2Utrecht University, Utrecht, The Netherlands

Background: Previous studies have reported that delirium increases

the risk of death in critically ill patients, but these studies did not adjust

for discharge as a competing risk. The true mortality caused by delirium

in intensive care unit (Icu) patients therefore remains unknown.



Hypothesis: new-onset delirium is associated with significant attribut-

able mortality in critically ill patients.

Methods: over an 18-month period, we prospectively evaluated

all adults who were admitted to a 32-bed mixed Icu for at least 24

hours. Patients with an acute neurological condition at baseline were

excluded. Patients were screened for delirium twice daily. delirium

assessments were performed using a validated protocol that included

a confusion Assessment method for the Icu (cAm-Icu) assessment by

both a trained observer and the bedside nurse, as well as a review of

the patient record (IsIcem 2011: P335). Time-dependent, multivaria-

ble cox regression analysis was used to estimate the direct effect of

delirium on outcome by calculating the cause-specific hazard ratios

(csHr) for both Icu discharge and death. To evaluate the overall effect

of delirium on death, while taking into account the competing event

of Icu discharge, a subdistribution hazard ratio (sHr) was calculated.

This sHr provides a summary measure of all separate cause-specific

hazards. All analyses were adjusted for age, gender, history of alcohol

abuse, APAcHe Iv score, and admission type.

Results: Among 748 patients evaluated,366 (49%)subjects developed

at least one episode of delirium in the Icu with a median duration

of 3 (IQr 2-6) days. overall, delirium was present on 29% of Icu days

(n=6720 days of observation). median age was 63 (IQr 51-73) years,

66% were male, 45% were medical admissions, 3% had a history of

alcohol abuse, and median APAcHe Iv score was 78 (IQr 59-95).crude

mortality in patients with delirium was 15% (56/366) compared to 5%

(18/382) in patients without delirium (p<0.001). In the cause-specific

analysis, however, delirium had no direct effect on the risk of death

(csHr 0.70 (95% cI 0.36-1.35)). In contrast, delirium did result in a lower

daily probability of being discharged from the Icu (csHr 0.60 (0.50-

0.73)). Patients with delirium were therefore exposed much longer to

a daily risk of death, resulting in overall increased Icu mortality (sHr

2.61 (1.48-4.61)).

Conclusions: To our knowledge, this is the first study to estimate

delirium-associated Icu mortality using a competing risk analysis.

our findings suggest that the increased risk of death in the Icu due to

delirium is merely the result of prolonged Icu stay rather than a direct

effect of delirium on mortality.

30.

Significant change in the practice of chest radiography in Dutch intensive care units

M. Tolsma2, T.A. Rijpstra1, M.J. Schulz3, N.J.M. van der Meer1,4

1Amphia Hospital, Department of Intensive Care, Breda and Oosterhout, The Netherlands, 2Department of Intensive Care, University Medical Center,

Utrecht, The Netherlands, 3Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands, 4Tias Nimbas Business School, Tilburg University,

Tilburg, The Netherlands

Background: chest radiographs (cxrs) are obtained frequently

in intensive care unit (Icu) patients. The diagnostic and therapeutic

efficacy of routine cxrs are now known to be low, but the discussion

regarding specific indications for cxrs in critically ill patients and the

safety of abandoning routine cxrs is still going on. We performed a

new survey under dutch intensivists on the current practice of chest

radiography in their departments.

Methods: A web-based questionnaire was sent to the medical director

of all adult Icus in the netherlands, containing questions regarding

Icu characteristics, Icu patients, daily cxr strategies, indications for

routine cxrs and the practice of radiologic evaluation.

Results: of the 83 Icus that were contacted, 69 (83%) responded to the

survey. only 7% of Icus still perform daily routine cxrs for all patients

while 65% of Icus say never to perform cxrs on a routine basis. A daily

meeting with a radiologist is established in the majority of Icus and is

judged to be important or even essential. The therapeutic efficacy of

routine cxrs was assumed by intensivists to be lower than 10% or to be

between 10% and 20%. The efficacy of on-demand cxrs was assumed

to be between 10% and 60%. There is consensus between intensiv-

ists to perform a routine cxr after endotrachial intubation, chest tube

placement or central venous catheterization.

Conclusion: The strategy of daily routine cxrs for critically ill patients

has developed from a common practice in 2006 to a rare practice

nowadays. Intensivists still assume the value of routine cxrs to be

higher than the efficacy that is reported in the literature. This might

be due to the clinical value of negative findings which has not been

studied before.

References1. graat me, Hendrikse kA, spronk Pe, et al. chest radiography practice in

critically ill patients: a postal survey in the netherlands. bmc med Imaging. 2006;18;6:8.

2. ganapathy A, Adhikari nk, spiegelman J, scales dc. routine chest x-rays in intensive care units: a systematic review and meta-analysis. crit care. 2012;12;16:r68. doi: 10.1186/cc11321.

31.

Stating clear indications for chest radiographs after cardiac surgery increases

their efficacy and safely reduces costsM. Tolsma2, W. Hasselaar1, T.A. Rijpstra1, P.M.J. Rosseel1, T. Scohy1,

M. Bentala3, H.A.J. Dijkstra4, N.J.M. van der Meer1

1Department of Intensive Care, Amphia Hospital, Breda, The Netherlands, 2Department of Intensive Care, University Medical Center, Utrecht, The Netherlands, 3Department of CardioThoracic Surgery, Amphia Hospital, Breda, The Netherlands,

4Department of Radiology, Amphia Hospital, Breda, The Netherlands

Introduction: chest radiographs (cxrs) in the intensive care unit (Icu)

are frequently obtained routinely for postoperative cardiosurgical

patients despite the fact that the diagnostic and therapeutic efficacy

of these cxrs is now known to be low. routine cxrs may only be ben-

eficial for certain indications and the discussion regarding these indi-

cations and the safety of abandoning routine cxrs is still continuing.

We investigated the efficacy and safety of cxrs performed on specified

indications only, directly after cardiac surgery.

Methods: We prospectively included all patients who underwent

major cardiac surgery in the year 2012. A direct postoperative cxr




was performed only routinely for certain specified indications. An

on-demand cxr could be obtained during the postoperative period

according to other specified indications. For all patients who did not

have a cxr taken before the morning of the first postoperative day, a

control cxr was performed then. All cxr findings were noted includ-

ing whether or not they led to an intervention. diagnostic and thera-

peutic efficacy values were calculated.

Results: A total of 1351 patients were included who mainly underwent

coronary artery bypass grafting (cAbg), valve surgery or a combina-

tion of both. 18% of patients underwent minimally invasive cardiac

surgery. The diagnostic efficacy for major abnormalities was clearly

higher for the postoperative and on-demand cxrs performed on indi-

cation, when compared to the next morning routine cxr (6,7% and

6.9% versus 2.9%) (p=0.002). The therapeutic efficacy was also clearly

higher for the postoperative and on-demand cxrs (2.9% and 4.1%),

while the need for intervention after the morning control cxr was now

reduced to be minimally (0.6%) (p=0.002).

Conclusion: stating clear indications for cxrs following cardiac

surgery increases the efficacy of these cxrs and safely reduces the

total number of cxrs.

References1. ganapathy A, Adhikari nk, spiegelman J, scales dc. routine chest x-rays

in intensive care units: a systematic review and meta-analysis. crit care. 2012;12;16:r68.

2. Tolsma m, kröner A, van den Hombergh cl, et al. The clinical value of routine chest radiographs in the first 24 hours after cardiac surgery. Anesth Analg. 2011;112:139-42.

32.

Prospective single centre cohort study into quality of life in Dutch intensive care unit subgroups, one year after

admission, using EuroQol-6DI.W. Soliman, D.W. de Lange, L.M. Peelen, O.L. Cremer, A.J.C. Slooter,

W. Pasma, J. Kesecioglu, D. van Dijk

Department of Intensive Care Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands

Background: The ultimate goal of Intensive care unit (Icu) admission

is to provide long-term survival with the highest possible quality of

life (Qol). We investigated mortality and Qol in a large single centre

cohort, one year after Icu admission. We aimed to identify subgroups

of patients who may be at risk for poor long term outcomes.

Methods: From July 2009 to may 2012 we included 5934 consecu-

tive adult patients admitted to a mixed population Icu. There were

no exclusion criteria. one-year survival status was determined using

the dutch municipal population register. subsequently, all survivors

received the euroQol eQ-6d-3l™ questionnaire. The primary outcome

was overall Qol index in surviving patients at one year follow-up, and

was compared to overall Qol index of an age and gender-matched

control population. secondary outcome was the incidence of poor Icu

outcome defined as either death or low Qol (euroQol index <0.4) at

one-year follow-up.

Results: A total of 5139/5934 patients (86.6%) survived until hospital

discharge, while 4535/5934 (76.4%) patients survived to one-year fol-

low-up. The euroQol questionnaire was sent to 4377/4535 (96.5%) sur-

vivors and returned by 3003/4377 (68.6%). The mean Qol in surviving

patients was 0.79 (standard deviation [sd] 0.23), versus 0.86 (sd 0.04)

in the control population (p<0.001).

of patients with metastasized malignancy, 73/162 (45.1%) survived,

with a mean Qol index of 0.77 (sd 0.21). of patients with chronic renal

failure 156/287 (54.4%) survived, with a mean Qol index of 0.65 (sd

0.28). of patients admitted with sepsis 317/558 (57.0%) survived, with a

mean Qol index of 0.70 (sd 0.27).

Poor Icu outcome was found in 1646/5934 (27.7%) patients. Again, the

subgroups worst off were those with metastasized malignancy (91/162;

56.2% poor Icu outcome), chronic renal failure patients (149/287;

51.9%) and those admitted for sepsis (267/558; 48.0%).

Conclusions: Qol one year after Icu admission was significantly lower

than in an age and gender matched control population. marked vari-

ations were found across subgroups. The highest risk of mortality or a

low Qol at one-year follow-up was found in patients with metastasized

malignancy, chronic renal failure, and sepsis.



A.B. Johan Groeneveld, Editor in ChiefDept. of Intensive Care Medicine Erasmus Medical Center RotterdamPO Box 20403000 CA Rotterdam

Jan Bakker, Section EditorHemodynamicsDept. of Intensive Care MedicineErasmus Medical Center RotterdamPO Box 20403000 CA Rotterdam

Alexander Bindels, Section Editor Endocrinology Dept. of Internal Medicine Catharina HospitalMichelangelolaan 25623 EJ Eindhoven

Bert Bos, Section EditorPediatricsDepartment of Pediatrics Academic Medical Center University of Amsterdam Meibergdreef 91105 AZ Amsterdam

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

Charles GomersallDept. of Anaesthesia and Intensive CareThe Chinese University of Hong Kong, Prince of Wales HospitalHong Kong, China

Frank van HarenA/ Professor, Australian National University Medical School Department of Intensive Care MedicineThe Canberra HospitalPO Box 11, Woden, ACT 2606Canberra, Australia

Charles HindsProfessor of Intensive Care MedicineSt. Bartholomew’s Hospital West Smithfield, London, UK

Wolfgang Buhre, Section EditorAnesthesiologyDept. of AnesthesiologyMaastricht UMC+P. Debyelaan 256229 HZ Maastricht

Hans van der Hoeven, Section Editor Mechanical Ventilation Dept. of Intensive Care MedicineRadboud University Nijmegen Medical CentrePO Box 91016500 HB Nijmegen

Can Ince, Section EditorPhysiologyDept. of Physiology Academic Medical Center University of AmsterdamMeibergdreef 91105 AZ Amsterdam

Evert de Jonge, Section Editor Scoring and quality assessment Dept. of Intensive Care MedicineLeiden University Medical CenterP.O. Box 96002300 RC Leiden

Nicole JuffermansSection Editor Hemostasis and ThrombosisDept. of Intensive Care Academic Medical Center University of Amsterdam Meibergdreef 91105 AZ Amsterdam

Patrick HonoréHeads of ClinicsDirector of Critical Care Nephrology PlatformICU departmentUniversitair Ziekenhuis Brussel,VUB UniversityBrussels, Belgium

Alun Hughes Professor of Clinical PharmacologyImperial College LondonSouth Kensington CampusLondon, UK

Manu Malbrain Dept. of Intensive Care UnitHospital Netwerk AntwerpCampus StuivenbergAntwerp, Belgium

Heleen Oudemans-van Straaten, Section Editor NephrologyDept. of Intensive Care MedicineVU University Medical CenterPO Box 70571007 MB Amsterdam

Peter Pickkers, Section EditorSepsis and inflammationDept. of Intensive Care MedicineRadboud University Nijmegen Medical CentrePO Box 91016500 HB Nijmegen

Arjen Slooter, Section EditorGeneralDept. of Intensive Care University Medical Center Utrecht PO Box 855003508 GA Utrecht

Peter Spronk, Section EditorGeneralDept. of Intensive Care MedicineGelre Hospital, location LukasPO Box 90147300 DS Apeldoorn

Jaap Tulleken, Section EditorGeneralDept. of Intensive Care Medicine University Medical Center GroningenPO Box 300019700 RB Groningen

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

Greg MartinDept. of MedicineDivision of Pulmonary, Allergy and Critical CareEmory University School of Medicine Atlanta, USA

Ravindra MehtaProfessor of Clinical MedicineAssociate Chair for Clinical Research Department of MedicineUCSD Medical Centre8342, 200 W Arbor DriveSan Diego, USA

Anton van Kaam, Section EditorNeonatologyDept. of Neonatal Intensive CareEmma Children’s Hospital, Academic Medical CenterUniversity of AmsterdamMeibergdreef 91105 AZ Amsterdam

Jozef Kesecioglu, Section EditorPulmonologyDept. Of Intensive Care MedicineUniversity Medical Center Utrecht PO Box 855003508 GA Utrecht

Michael Kuiper, Section EditorNeurologyDept. of Intensive Care Medicine Medical Center LeeuwardenPO Box 8888901 BR Leeuwarden

Maarten Nijsten, Section EditorSurgeryDept. of Intensive Care MedicineUniversity Medical Center GroningenPO Box 30 0019700 RB Groningen

Peter van der Voort, Correspondence editorDept. of Intensive Care MedicineOnze Lieve Vrouwe GasthuisPO Box 955001090 HM Amsterdam

Xavier MonnetService de réanimation médicaleCentre Hospitalier Universitaire de BicêtreFrance

Jean-Charles PreiserDept. Intensive Care CHU Liege – Domaine UniversitaireLiege, Belgium

Yasser SakrDept. of Anaesthesiology and Intensive CareFriedrich-Schiller University HospitalJena, Germany

Hannah WunschDept. of AnaesthesiaNew York Presbyterian ColumbiaNew York, USA

Editorial Board of the Netherlands Journal of Critical Care

International Advisory Board



The Netherlands Journal of Critical Care (Neth J Crit Care) is the official journal of the Netherlands Society of Intensive Care (Nederlandse Vereniging voor Intensive Care-NVIC). The journal has a circulation of about 1,750 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 Neth J Crit Care. This includes original articles, reviews, case reports, clinical images, book review, structured abstracts of papers from the literature, notes, correspondence etc. All manuscripts pass through an independent review process managed by the editorial board.The journal is indexed by Embase, Emcare and Scopus. A Medline annotation is in prepara tion. The following manuscript types apply.

Structured abstractsAll manuscripts should be submitted with structured abstracts as described below. No information should be reported in the abstract that does not appear in the text of the manuscript.Manuscripts should include an abstracts of no more than 300 words using the following headings: Background and objectives, Design, Methods and results and Conclusions. For the sake of brevity, parts of the abstract may be written as phrases rather than complete sentences.Background and objectivesState the precise primary objective of the review. Indicate whether the review emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention and include information about the specific population, intervention, exposure, and tests or outcomes that are being reviewed. DesignDescribe the design of the study indicating, as appropriate, use of randomization, blinding, gold standards for diagnosis test and temporal direction (retrospective or prospective).Methods and resultsSummarize here accurately, although concisely, summarize how you will proceed in learning the answer to the objective. Also provide the main outcomes of the study.ConclusionsThe conclusions and their applications (clinical or otherwise) should be clearly stated, limiting interpretation to the domain of the review.

Original articles/reviewsArticles should describe original investigations that have been brought to an acceptable degree of completion. Articles should not exceed 3000 words. The editorial board also welcomes review papers which should also not exceed 3000 words.The manuscript should be clear in outline (with subheadings) for maximum clarity. Only a limited number of figures (coloured figures are encouraged without extra charge) and tables may be included; double presentations in the form of figures and tables should be avoided. The text should follow the IMRAD format and contain an abstract, introduction, materials and methods, results, discussion section and references. The abstract should not exceed 250 words and should be structured. Authors should provide a minimum of three keywords, a running title, and list not more than 30 references for original articles and 70 references for review articles.

Case ReportsThe text of a case reports should also include an abstract, introduction, case report/case history, discussion section, legends for figures and references. The abstract should not exceed 250 words and may be unstructured. The journal kindly requests authors to provide a minimum of three keywords and to list not more than 30 references.

Clinical ImagesA clinical image should contain one or two pictures and a short case history, and should preferably not be referenced. The legend to

the image 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. The journal kindly requests authors to provide a minimum of three keywords.

General informationThe original manuscript and two copies (or electronic file) are to be submitted to the editor in chief at the NVIC office by e-mail (see below). The manuscript must be accompanied by a cover letter stating the following: the complete mailing address, e mail address, telephone number and fax number of the corresponding author, and if it is a re submission, the previous Neth J Crit Care number and year. Receipt of the manuscript will be acknowledged in writing within 14 days. If this is not the case, authors are requested to check. The language of the journal is British English. Authors who are unsure of proper English usage will have their manuscript checked by someone proficient in the English language.

LayoutParagraphs starting immediately under headings and subheadings should begin at the left margin. Subsequent paragraphs should be indented. All text should be double spaced, on one side of the paper and with a wide margin. The manuscript pages, including references and legends, must be sequentially numbered throughout.

TablesTables are to be numbered independently of the figures with Arabic numbers, with headings and kept separate from the text.

FiguresFigures must also be numbered with Arabic numbers and kept separate from the text. Legends must be given on a separate sheet. Schematic line drawings are preferred. Figures already published elsewhere cannot usually be included, except in survey articles. Colour figures can be published. Short, clear legends make additional description in the text unnecessary. The desired placement of figures and tables can be marked in the margins of the manuscript sheets. Figures should be provided in electronic format TIFF or better.

ReferencesOnly articles cited in the text are to be listed. They are to be arranged in order of appearance in the text …. and numbered consecutively. Only the reference number should appear in the text. Include all author names (unless there are seven or more, in which case abbreviate to three and, add ‘et al.’), and page numbers.Article in journals: Calandra T, Cometta A. Anti biotic therapy for gram negative bacteremia. Infect Dis Clin North Am 1991;5:817-34Books (-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 167-190. 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

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. Authors must disclose any potential financial or ethical conflicts of interest regarding the contents of the submission. Any relevant papers that may be considered as duplicating in part the current submission should be reported.

Information for authors



How to submitSubmit manuscript directly to: Editorial office e-mail: [email protected]

ProofsThe corresponding author will receive proofs by e-mail. Corrected proofs must be returned within 48 hours of receipt.

Production processDecisions of the editors are final. All material accepted for publication is subject to copyediting. The original manuscript will be discarded one month after publication unless the publisher is requested to return the originals to the author 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 proof to correcting errors and to clarifying misleading statements.For guidelines on the NJCC’s house style see website

General guidelines on house style• The title of 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.• Generally, abbreviations should not be used in the title (see Table of

standard abbreviations) for exceptions).• The corresponding author need only provide their e-mail address

on the title page.• Please provide a minimum of three keywords and a running title.• In addresses write The Netherlands. In running text, the

Netherlands.• The abstract should be written in the structured format (with the

exception of case reports).• Unstructured abstracts should take the form of a single paragraph.• The abstract should be bold typeface Times New Roman, size 12.• Headings must be in bold.• Non-standard abbreviations (see Table of standard abbreviations)

should always be explained and their use kept to a minimum.• Please use British English spelling, except in titles of institutions

that have chosen to use US spelling, e.g. Academic Medical Center, Amsterdam.

• The journal uses British English spelling, e.g. aetiology, oestradiol, anaemia, haemorrhage, oesophagus, practice (noun), practise (verb), fetus. This should be used consistently. Use z-spellings, e.g. minimize, organization (Oxford spelling).

• Do not use exclamation marks except in direct quotes from other sources.

• No full stops in initials,abbreviations and academic titles.• Reference numbers go after commas and full stops, before

semicolons and colons.• Quotation marks – please use double, not single, inverted commas

for reported speech Full stops go inside quotation marks.• Genus names should be in italics, e.g. Staphylo coccus 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 a capital letter, e.g. see Table 2.

Guidelines on writing style for Dutch-speaking authors• Following English language convention prof. dr. should be written

as Professor.• The gender of an author is not specifically reported. Do not use Ms

or Mrs in front of Professor or Doctor.• Spell check your article before submission using UK English

(references keep original spelling).• Abbreviating names. Use initials only J Smit not Joh Smit.

• Avoid “he” as a general pronoun. Make nouns and pronouns plural, use “they”. If this is not possible then use “he or she”.

• Drugs should be referred to by their English language non-proprietary names, e.g. not fosfomycin but phosphomycin.

• Brackets. In English, information in brackets is not crucial to the meaning of the sentence and may be omitted without detracting from its meaning. The Dutch convention of using brackets to contain information crucial to the sentence should not be applied, e.g. (immuno) histology should be written as immunohistology and histology, (un) sterile gloves as sterile or unsterile gloves.

• Apostrophe. In English the apostrophe is used to indicate possession or omission, e.g. the patient’s notes, not to form a plural, e.g. ECG’s should be ECGs.

• “False friends.” Please be aware that although some words sound like they have the same meaning they do not, e.g. adequaat is not always synonymous with adequate (adequate = toereikend), e.g. “Bij 98% werd technisch adequate wervelmorfometrie verricht” becomes “In 98% spinal morphometry was technically successful.” “Klachten” may not universally be translated as “complaints”; please use “signs and/or symptoms” where appropriate.

• ± is a mathematical symbol and should not be used in a non-math-ematical context to mean approximately or about.

• Generally, organizations and groups of people take single verbs, e.g. the team has researched.

Table of abbreviations

AIds acquired immunodeficiency syndrome

AlI acute lung injury

Ards adult respiratory distress syndrome

APAcHe acute phyisology and chronic health evaluation

bIPAP biphasic positive airways pressure

ccu coronary care unit

coPd chronic obstructive pulmonary disease

cPAP continuous positive airway pressure

cT computerized or computed tomography

ecg electrocardiogram

ecmo extracorporeal membrane oxygenation

eeg electroencephalogram

elIsA enzyme-linked immunosorbent assay

eTco2 end-tidal carbon dioxide

Hdu high dependency unit

HIv human immunodeficiency virus

Ic intensive care

Icu intensive care unit

Im intramuscular

Inr international normalized ratio

IPPv intermittent positive pressure ventilation

Iv intravenous

mAP mean arterial pressure

mods multiorgan dysfunction syndrome

mrI magnetic resonance imaging

PAcu post anaesthesia care unit

PeeP postive end expiratory pressure

PeT positron emission tomography

sArs severe adult respiratory syndrome

sIrs systemic inflammatory response syndrome

soFA sequential or gan failure assessment

sPecT single-photon emission ct

TIA transient ischemic attack

TrAlI transfusion-related acute lung injury

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