Netherlands Journal of Critical Care

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1 Volume 17 - No 3 - July 2013 Bi-monthly journal of the Dutch Society of Intensive Care Review Energy expenditure in different patient populations on intensive care C.M. Mooij, C.J. Beurskens, N.P. Juffermans Case report Extravasation injury by norepinephrine G. van der Wal, J.C. Janssen, P.E. Spronk Book review Pediatric Anesthesia, Intensive Care and Pain: Standardization in Clinical Practice A.P. Bos

2 Cancidas (caspofungin, MSD) Breed toepasbaar bij Invasieve candidiasis Invasieve aspergillose * Empirische antifungale therapie Antifungale therapie zonder compromis Voor volwassenen én kinderen Voor neutropenen én niet-neutropenen Goed verdragen 1 Eenvoudige dosering Als add-on DBC volledig vergoed 2 11 jaar klinische ervaring 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: , Bijlage 5 Beleidsregel BR/CU-2076 Raadpleeg de volledige productinformatie alvorens CANCIDAS voor te schrijven M Merck Sharp & Dohme BV, Postbus 581, 2003 PC Haarlem, Tel , AINF Evidence. Experience. Confidence.

3 13_A_042 Wordt los aangeleverd

4 Ecalta Als medicatieveiligheid telt Geen klinisch relevante geneesmiddelen interacties 1-5 Geen dosisaanpassing in verband met gewicht, lever- en nierfunctiestoornissen 1-5 Zie voor referenties en productkenmerken elders in deze uitgave Doeltreffend en gemakkelijk 1-5 Doeltreffend en gemakkelijk ECL.21.1

5 Executive editorial board A.B.J. Groeneveld, editor in chief Mw. drs. I. van Stijn, managing editor J. Box, language editor COPYRIGHT ISSN: NVIC p/a Domus Medica P.O. Box 2124, 3500 GC Utrecht T.: +31-(0) NVIC. All rights reserved. Except as outlined below, no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher. Permission may be sought directly from NVIC. Derivative works Subscribers may reproduce tables of contents or prepare lists of articles including abstracts for internal circulation within their institutions. Permission of the publisher is required for resale or distribution outside the institution. Permission of the publisher is also required for all other derivative works, including compilations and translations. Electronic storage Permission of the publisher is required to store or use electronically any material contained in this journal, including any article or part of an article. Subscriptions An annual subscription to The Netherlands Journal of Critical Care consists of 6 issues. Issues within Europe are sent by standard mail and outside Europe by air delivery. Cancellations should be made, in writing, at least two months before the end of the year. The annual subscription fee for the Netherlands is v 170, for Europe v 285, for the rest of the world v 380. Subscriptions are accepted on a prepaid basis only and are entered on a calendar year basis. Please make your cheque payable to Van Zuiden Communications B.V., PO Box 2122, 2400 CC Alphen aan den Rijn, the Netherlands or you can transfer the fee to ING Bank, account number , Castellumstraat 1, Alphen aan den Rijn, the Netherlands, swift-code: ING BNL 2A. Do not forget to mention the complete address for delivery of the Journal. Claims Claims for missing issues should be made within two months of the date of dispatch. Missing issues will be mailed without charge. Issues claimed beyond the two-month limit must be prepaid at back copy rates. CONTENTS REVIEWS 3 Energy expenditure in different patient populations on intensive care: One size does not fit all C.M. Mooij, C.J. Beurskens, N.P. Juffermans 9 A restrictive transfusion policy in the paediatric intensive care unit: safe and effective L. de Vetten, M.C.J. Kneyber, R.Y.J. Tamminga CASE REPORTS 15 Extravasation injury by norepinephrine: a case report and description of treatment options G. van der Wal, J.C. Janssen, P.E. Spronk 18 Intravenous lipid emulsion in the treatment of verapamil intoxication M.A.J. Assink, P.E. Spronk,, H.J.M. van Kan,, A. Braber COMMENTARY 22 Statins for sepsis? D. Pretorius, P. Pickers BOOK REVIEW 23 Pediatric Anesthesia, Intensive Care and Pain: Standardization in Clinical Practice A.P. Bos CONFERENCES 24 Conference agenda 26 Editorial board 26 International advisory board 27 Information for authors Advertising-exploitation/business contacts For orders, reprints and advertising, please contact Van Zuiden Communications B.V. Van Zuiden Communications B.V. PO Box CC Alphen aan den Rijn The Netherlands Tel.: +31 (0) Internet: is indexed in: EMBASE EMCare Scopus 1

6 Accepted June 2013 REVIEW Energy expenditure in different patient populations on intensive care: One size does not fit all C. M. Mooij, C.J. Beurskens, N.P. Juffermans Laboratory of Experimental Intensive Care and Anaesthesiology and the Department of Intensive Care, Academic Medical Center, University of Amsterdam, the Netherlands Correspondence C. Beurskens Keywords - Energy expenditure, oxygen consumption, calorimetry, Intensive Care Unit Abstract Objective: Adequate nutrition has an impact on outcome in critically ill patients. This descriptive literature search investigates whether there are differences in energy expenditure (EE) between specific subgroups of critically ill patients, including patients with sepsis, trauma, burns and cerebrovascular accidents. Also, we summarised specific factors which may influence EE, such as the use of sedation, body temperature and severity of illness. Design: A descriptive review of studies which have measured EE or oxygen consumption with indirect calorimetry in critically ill patients. Studies were retrieved by a systematic search of the Medline database, using search terms referring to the measurement (energy expenditure), the patient population in general (critically ill patients), and to the four specific subgroups (sepsis, trauma, burns, stroke). Results: EE in patients with sepsis, trauma and burns was increased (sepsis %; trauma %; burns %; stroke 149% for men and 120% for women) compared with reference values of EE in healthy individuals. Burn patients had the highest EE levels. There was no difference in EE between sepsis and trauma patients. Patients with a cerebrovascular accident had the lowest EE. Half of these patients had an EE that did not exceed EE levels in healthy adults. Use of sedation lowered EE whereas fever increased EE. Uncertainty persists whether treatment of stroke patients with hypothermia decreases EE. According to most studies, higher disease severity scores are associated with higher EE, but one study found that severity of illness is negatively correlated with EE in sepsis. Conclusions: Data for this review were limited, precluding definite conclusions. However, it is clear EE differs among critically ill patient populations. The use of a one size fits all formula to estimate caloric need in the critically ill may not be appropriate in the design of studies on caloric need nor in patient care. Introduction In critically ill patients, meeting caloric demand by adequate nutrition is related to better outcome. 1 Therefore, adequately responding to the nutritional demands of patients admitted to the intensive care unit (ICU) should be a daily goal in patient care. However, the optimal amount of calories that should be prescribed to critically ill patients has been a matter of debate. 1 It is thought that the consumption of calories, termed energy expenditure (EE), is increased in critically ill patients compared with the general hospital population, due to high metabolic demands during various inflammatory conditions. 2 A disbalance between high demands and limited energy supply may contribute to organ failure and adverse outcome in ICU patients. 3,4 In this view, underfeeding could be detrimental. An alternative hypothesis relating to the optimal amount of calories holds that this hypermetabolic state might be harmful and that hypocaloric nutrition reduces hypermetabolism, 5 thereby improving outcome. 6 In both strategies, measuring or estimating energy demands of patients are crucial in determining the optimal amount of feeding. The EE can be measured in several ways, including indirect calorimetry. Alternatively, the Harris-Benedict equation is used, which calculates the amount of calories needed in ICU patients and estimates an individual s basal metabolic rate, multiplied by an activity factor. 7 A shortcoming of this formula is the controversy about what exactly this activity factor should be Also, the formula does not distinguish between specific ICU patient populations. Comparing caloric targets based on the calculated caloric need with use of this formula 6,11 may therefore lead to inadequate conclusions in ICU patients. Given the relation between caloric supply and outcome, it seems paramount to be aware of possible EE differences between different subgroups. This paper summarises data from all available studies which have directly measured EE in four specific subgroups of ICU patients: sepsis, trauma, burns and cerebrovascular accident (CVA). 3

7 Energy expenditure in different patient populations on intensive care: One size does not fit all Methods The Medline database was used to identify medical subject s headings (MeSH) and select search terms. In addition to MeSH terms, free text words were used. Search terms referred to the measurement: energy expenditure (calorimetry, indirect [MeSH]; energy metabolism [MeSH]; energy metabolism; energy expenditure; indirect calorimetry), to the patient population in general: critically ill patients (critical illness [MeSH]; intensive care unit [MeSH]; critical care [MeSH]; intensive care [MeSH]; critical care; intensive care unit; critical illness; ICU patients) and to the four specific subgroups: (septic shock [MeSH]; bacteremia [MeSH]; sepsis [MeSH]; sepsis; pyemia; septicemia; blood poisoning; severe sepsis; bacteremia; septic shock); (wounds and injuries [MeSH]; trauma; wounds and injuries; severe trauma); (burn, chemical [MeSH]; burn [MeSH]; burn; chemical burns; electric burns; burn wounds); (brain ischemia [MeSH]; cerebral infarction[mesh]; subarachnoid hemorrhage [MeSH]; intracranial hemorrhage [MeSH]; stroke [MeSH]; stroke; cerebrovascular apoplexy; CVA; cerebrovascular accident; brain infarction; cerebral ischemia; intracranial hemorrhage; subarachnoid hemorrhage; SAH). Search results were limited to adults. Studies were selected when data on EE (kcal/day) or oxygen consumption (VO₂) (ml/(min.m²)) were provided. If not otherwise mentioned, measured EE refers to resting EE. When EE or VO₂ of individual patients were given, mean and SD were calculated. Kilojoules were converted by using the equation 1 kcal = 4184 kj. When only EE/ kg body weight was given, EE was calculated by multiplying by the mean body weight of the patient group. In that case, no SD could be calculated. To facilitate comparisons of metabolism between groups, all measurements of EE in the subgroups of critically ill patients were compared with a reference value of EE or VO 2 as measured in healthy adult men and women 12 and expressed as a percentage of that reference value. If the male/female (M/F) proportion of a study group was given, EE was corrected for the M/F ratio, by multiplying the number of male patients with the reference value of a healthy male and the number of female patients with the reference value of a healthy female, divided by the total number of patients. If no M/F ratio was given, an M/F ratio of 3/1 was used, because this ratio corresponded best with the M/F ratios in the studies of EE in sepsis, trauma and burns groups where this ratio was given. The normal VO 2 range is ml/(min.m²). The effect of several clinical conditions was investigated, including body temperature, use of sedation and disease severity. Severity of illness was estimated using either the Acute Physiology and Chronic Health Evaluation (APACHE) II or III score, 24,25 Injury Severity Score (ISS) 26,27 or the percentage of body surface area (%BSA) that was burned for burn patients only. Results The Medline search yielded 361 studies. Of these, 338 were not suitable because data on measured EE or VO₂ were not given for the specific patient subgroups under study, leaving 23 studies with data on EE or VO₂ in patients with sepsis (n=10), sepsis and trauma (n=3), trauma (n=3), trauma and burns (n=1), burns (n=3) and CVA (n=3). In total, EE measurements in 448 patients were included. Comparison of EE and/or VO₂ between different patient groups In patients suffering from sepsis (table 1), all studies except one 13 found an increase in measured EE with values ranging Table 1. Caloric demand in critically ill patients with sepsis References Number of patients Male/F EE (kcal/ day) % of reference EE VO₂ (ml/(min.m²)) Frankenfield et al / ± % - Koea et al / ± % - Rusavy et al Unknown 2116 (No SD) 127% - Liggett et al. 9 * 18 Unknown 1982 ± % - Clark et al Unknown 1950 ± % - Kiiski et al / ± % - Uehara et al / ± % - Basile-Filho et al / ± % - Schaffartzik et al Unknown ± 30 Fernandes et al / ± / ± 30.5 Hanique et al / ± 19 Natalini et al Unknown ± 35 Zauner et al / ±26 from % compared with the reference value. Three out of the six VO₂ measurements were high, but within the normal range. The other VO₂ measurements slightly exceeded the normal range. In the trauma group (table 2), all studies reported high EE measurements, ranging from % compared with the reference value. Of the VO₂ measurements, one study reported values within the normal range (153.6 ml/(min.m²), 14 other studies reported VO 2 values higher than 160 ml/(min.m²). In the patient population suffering from burns (table 3), EE measurements ranged from % of the reference values. Two studies reporting VO₂ measurements exceeded the normal range, with values of 131 and 209% compared with the upper limit of the normal range of oxygen consumption of 160 ml/(min.m²). 15,16 In stroke patients (table 4), increased levels of EE of 149% of the reference value for men and 120% for women were found in one study. 17 However, the two other studies 18,19 found no increased EE levels compared with the reference value. In this patient group, no VO₂ measurements were available. Clinical conditions influencing EE The use of sedative medication generally lowers EE. 20,21 However, one study showed a positive correlation between sedative dose and EE. 22 Different types of sedative medication did not result in differences in EE levels when measurements were corrected for body temperature. 21 An increase in EE caused by fever was found in sedated head-injured patients 21 and in septic patients. 23 Conversely, induced hypothermia to 33 C resulted in a significantly lower EE in stroke patients. 18 However, not all studies report such a decrease, as Badjatia et al. found no significant differences in EE between the hypothermic ( C) and the normothermic ( C) stroke patients. 17 In this study, shivering as a result of treatment with hypothermia was clearly shown to increase EE. 17 The severity of illness may influence EE. EE was related to either the APACHE II or III for sepsis, 24,25 ISS for trauma 26,27 or %BSA for burn patients (table 5). Not all studies mentioned severity scores. In general, however, patients with higher severity scores were more hypermetabolic, which was most distinct in patients with burns. 8,16 An association between severity of illness and EE was also noted in septic trauma patients. 22 One study, however, reported a negative correlation between APACHE III scores and resting EE in sepsis. 23 Discussion EE measurements were highest in burn patients, with all studies reporting substantially higher values than reference Table 2. Caloric demand in critically ill patients with trauma References Number of patients M/F EE (kcal/ day) % of reference EE VO₂ (ml/(min.m²)) Frankenfield et al / ± % - Bruder et al / ± % 203 ± 55 Stucky et al Unknown 2263 ± % - Kiiski et al / ± % - Uehara et al / ± % - Raurich et al. 10 * Total: / ± % / ± % - Huschak et al / ± / ± 30.4 Total % Data are mean ± SD; M/F = proportion male/ female; *In Raurich et al., 40 EE measurements are reported for 26 patients in total. One group of measurements was compared with 20 surgical patients, the other to 20 medical patients. Table 3. Caloric demand in critically ill patients with burns References Number of patients M/F EE (kcal/ day) % of reference EE VO₂ (ml/(min.m²)) Gore et al Unknown % 209 ± 27 Khorram-Sefat et al / ± % - Royall et al / ± % 335 ± 80 Stucky et al Unknown 2284 ± % - Total % Data are mean ± SD; M/F = proportion male/ female; *In Liggett et al., EE was measured using a pulmonary artery catheter. Total % Data are mean ± SD; M/F = proportion male/ female. 4 5

8 Energy expenditure in different patient populations on intensive care: One size does not fit all Table 4. Caloric demand in critically ill patients with cerebrovascular accident References Number of patients M/F EE (kcal/ day) % of reference EE Badjatia et al / Male 2647 ± % Female 1622 ± % Bardutzky et al. 18 * 10 4/ % Bardutzky et al. 19 * 34 20/ % Total % Data are mean ± SD; M/F = proportion male/ female; *In Bardutzky et al., total EE is given instead of resting EE. Table 5. Energy expenditure and the illness severity scores in different patient populations References % of reference EE Sepsis patients APACHE II score Clark et al Uehara et al Basile-Filho et al ± 7.2 Trauma patients Injury severity score Frankenfield et al ± 9 Bruder et al ± 9 Stucky et al ± Kiiski et al ± 20 Uehara et al Burn patients Injury severity score Stucky et al ± Burn patients % of BSA burned Gore et al ± 9.8 Khorram-Sefat et al ± 20 Royall et al ± 18.8 Stucky et al ± Data are given in mean ± SD. EE values. Also, EE values of burn patients were higher than EE values in most studies describing sepsis or trauma patients. A probable explanation is that burned patients are highly hypermetabolic and catabolic. 28 In both the sepsis and trauma patient populations we found increased EE values compared with the EE levels in healthy adults. Patients suffering from sepsis do not have consistently higher EE values than trauma patients. As expected, EE measurements in the CVA group were lowest, with two out of three studies (50% of the patient population) not reporting increased EE compared with healthy adults. 18,19 This may be due to the fact that in these patients an inflammatory state is not as apparent as in sepsis, trauma or burn patients. Taken together, there are profound differences in EE between specific patient populations, with burn patients having the highest EE values. A large variation was also observed within subgroups of patients, as well as a large variety between different studies. The use of sedation was generally found to decrease EE in critically ill patients, without apparent differences between types of sedative medication. 20,21 As expected, fever increases the levels of EE. 21,23 The use of induced hypothermia seems to decrease EE. 18 One study found no significant difference in EE between normothermia and hypothermia, which was attributed by the authors to the heterogeneity of the patient population. 17 The positive correlation between body temperature and EE can be explained by thermogenesis. Of note, we found that EE was positively correlated to the severity of illness in the majority of the reviewed studies, suggesting that within a specific clinical condition, also disease severity should be taken into account when estimating the caloric need. However, it should be considered that variation was large. 8,16,22 Given the differences in EE between patient populations as well as the variance within patient groups, we feel it would be best to measure the EE in each individual patient when assessing the amount of nutrition. When predictive equations are used instead of indirect calorimetry, factors can be added correcting for the patient s type of lesion and for clinical conditions such as the use of sedation, severity of illness and body temperature. However, various recommendations on estimating EE in patients have been made. According to some, predicting the individual EE by using an equation is not possible, because of the variation in EE in critically ill patients and the quantity of factors influencing EE. 10 Therefore, it was proposed to use the same predictive equations for all patients without adding factors. On the other hand, others hold that factors attributing to differences in energy expenditure between critically ill patients should be better understood to allow more accurate estimation of the caloric needs of individual patients. 21 In burned patients, it was recommended to use equations that do not give higher predictions of EE than times basal EE to avoid overfeeding. 8 Taken together, there is no consensus on what the correcting factors should be. The summary of our findings points towards a patient-tailored approach, taking into account the clinical condition as well as disease severity. Besides patient care, our findings may also have implications for future research. In studies comparing the impact of hyper- versus hypo-caloric nutrition on outcome, it should be considered that EE differs between patient populations. The use of predictive equations in such studies is inappropriate in predicting the actual EE and thus the caloric demand of individual patients. However, some of these studies claim a relation between predictive equations and outcome. 6,11 When the less than goal and near goal amount of calories is based on those predictions and is related to outcome, results may be confounded. Therefore, indirect calorimetry seems the best way to estimate the nutrition status of a patient and provide tailored care to possibly improve outcome. There are several limitations to this review. The amount of data on measured EE or VO₂ is limited. Thereby, patient numbers are small. The most important limitation is that statistical analysis of the data was limited as individual patient data were not available, rendering this study a descriptive review. Also, the ratio between male and female was not always given. Most collected measurements were performed during the first week. Thereby, variations in EE during the course of illness were not detected. 23 As individual energy expenditure can fluctuate significantly from day to day, 22 this may influence the reliability of the comparison of EE measurements in the current study. However, EE is largely stable in the course of the first week. 18,19,23 As we did not perform consecutive measurements, conclusions of this study only pertain to the first week following admission. Another limitation is that several factors such as age, body weight, types of nutrition, presence of shock, administration of medications such as insulin or inotropics and the use of mechanical ventilation were not considered. Patients and circumstances were quite heterogeneous and EE measurements were not corrected for that. However, we corrected for sex, which importantly determines EE. 7 There is a great need for collecting more data to improve the limited knowledge, before adapting this in daily ICU care. Future research should ideally include the influence of mechanical ventilation and inotropic drugs on EE values. Nonetheless, this study attempts to give an indication of differences in EE between four distinct groups of patients. Despite the limitations of this study, results may have implications for estimating energy expenditure in clinical practice and for research goals. Conclusion Energy expenditure differs between and within patient populations. The use of sedatives, body temperature and severity of illness have an impact on EE values. The use of the same formula to calculate caloric need for each patient may not be appropriate. References 1. Stapleton, RD, Jones N, Heyland DK. Feeding critically ill patients: what is the optimal amount of energy? Crit Care Med. 2007;35(Suppl 9):S Tappy, L, Chiolero R. Substrate utilization in sepsis and multiple organ failure. Crit Care Med. 2007;35(9 Suppl):S Villet S, Chiolero RL, Bollmann MD, et al. Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr. 2005;24: Rubinson L, Diette GB, Song X, et al. Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit. Crit Care Med. 2004;32: Patino JF, de Pimiento SE, Vergara A, et al. Hypocaloric support in the critically ill. World J Surg. 1999;23: Krishnan JA, Parce PB, Martinez A, et al. Caloric intake in medical ICU patients: consistency of care with guidelines and relationship to clinical outcomes. Chest. 2003;124: Harris JA, Benedict FG. A biometric study of basal metabolism in man. Carnegie Institution of Washington publication, Washington, Carnegie Institution of Washington 1919;no. 279: Khorram-Sefat R, Behrendt W, Heiden A, et al. Long-term measurements of energy expenditure in severe burn injury. World J Surg. 1999;23: Liggett SB, Renfro AD. Energy expenditures of mechanically ventilated nonsurgical patients. Chest. 1990;98: Raurich JM, Ibanez J, Marse P, et al. Resting energy expenditure during mechanical ventilation and its relationship with the type of lesion. JPEN J Parenter Enteral Nutr. 2007;31: Arabi YM, Haddad SH, Tamim HM, et al. Near-target caloric intake in critically ill medical-surgical patients is associated with adverse outcomes. JPEN J Parenter Enteral Nutr : Mifflin MD, St Jeor ST, Hill LA, et al. A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr. 1990;51: Basile-Filho A, Auxiliadora Martins M, Marson F, et al. An easy way to estimate energy expenditure from hemodynamic data in septic patients. Acta Cir Bras. 2008;23(Suppl 1): Huschak G, Zur Nieden K, Hoell T, et al. Olive oil based nutrition in multiple trauma patients:a pilot study. Intensive Care Med. 2005;31: Gore DC, Ferrando A, Barnett J, et al. Influence of glucose kinetics on plasma lactate concentration and energy expenditure in severely burned patients. J Trauma. 2000;49: Royall D, Fairholm L, Peters WJ, et al. Continuous measurement of energy expenditure in ventilated burn patients: an analysis. Crit Care Med. 1994;22: Badjatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the Bedside Shivering Assessment Scale. Stroke. 2008;39: Bardutzky J, Georgiadis D, Kollmar R, et al. Energy expenditure in ischemic stroke patients treated with moderate hypothermia. Intensive Care Med. 2004;30: Bardutzky J, Georgiadis D, Kollmar R, et al. Energy demand in patients with stroke who are sedated and receiving mechanical ventilation. J Neurosurg. 2004;100: Terao Y, Miura K, Saito M, et al. Quantitative analysis of the relationship between sedation and resting energy expenditure in postoperative patients. Crit Care Med. 2003;31:

9 Accepted June Bruder N, Raynal M, Pellissier D, et al. Influence of body temperature, with or without sedation, on energy expenditure in severe head-injured patients. Crit Care Med. 1998;26: Frankenfield DC, Wiles CE, Bagley S, et al. Relationships between resting and total energy expenditure in injured and septic patients. Crit Care Med. 1994;22: Zauner C, Schuster BI, Schneeweiss B. Similar metabolic responses to standardized total parenteral nutrition of septic and nonseptic critically ill patients. Am J Clin Nutr. 2001;74: Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13: Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100: Copes WS, Champion HR, Sacco WJ, et al. The Injury Severity Score revisited. J Trauma. 1988;28: Baker SP, O Neill B, Haddon W, et al. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974;14: Cunningham JJ, Hegarty MT, Meara PA, et al. Measured and predicted calorie requirements of adults during recovery from severe burn trauma. Am J Clin Nutr. 1989;49: Koea JB, Wolfe RR, Shaw JH. Total energy expenditure during total parenteral nutrition: ambulatory patients at home versus patients with sepsis in surgical intensive care. Surgery. 1995;118: NVIC CURSUS LUCHTWEGMANAGEMENT OP DE INTENSIVE CARE 2013 maandagavond 25 november en dinsdag 26 november 2013 Skills center OSG te Houten 30. Rusavy Z, Sramek V, Lacigova S, et al. Influence of insulin on glucose metabolism and energy expenditure in septic patients. Crit Care. 2004;8:R Clark MA, Plank LD, Connolly AB, et al. Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis--a randomized, clinical trial. Crit Care Med. 1998;26: Kiiski R, Takala J. Hypermetabolism and efficiency of CO2 removal in acute respiratory failure. Chest. 1994;105: Uehara M, Plank LD, Hill GL. Components of energy expenditure in patients with severe sepsis and major trauma: a basis for clinical care. Crit Care Med. 1999;27: Schaffartzik W, Sanft C, Schaefer JH, et al. Different dosages of dobutamine in septic shock patients: determining oxygen consumption with a metabolic monitor integrated in a ventilator. Intensive Care Med. 2000;26: Fernandes CJ Jr, Akamine N, De Marco FV, et al. Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. Crit Care. 2001;5: Hanique G, Dugernier T, Laterre PF, et al. Significance of pathologic oxygen supply dependency in critically ill patients: comparison between measured and calculated methods. Intensive Care Med. 1994;20: Natalini G, Schivalocchi V, Rosano A, et al. Norepinephrine and metaraminol in septic shock: a comparison of the hemodynamic effects. Intensive Care Med. 2005;31: Stucky CC, Moncure M, Hise M, et al. How accurate are resting energy expenditure prediction equations in obese trauma and burn patients? JPEN J Parenter Enteral Nutr. 2008;32: VERKORTE PRODUCTINFORMATIE CANCIDAS 50 mg poeder voor concentraat voor oplossing voor intraveneuze infusie. CANCIDAS 70 mg poeder voor concentraat voor oplossing voor intraveneuze infusie. Samenstelling CANCIDAS 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 of kinderen. Behandeling van invasieve aspergillose bij volwassen patiënten of 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-indicaties Overgevoeligheid 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. Bijwerkingen Volwassen patiënten Flebitis 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. Kinderen Het 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-marketingervaring Sinds de introductie van het product zijn de volgende bijwerkingen gemeld: leverfunctiestoornis, zwelling en perifeer oedeem, hypercalciëmie. Farmacotherapeutische groep Antimycotica voor systemisch gebruik, ATC-code: J 02 AX 04 Afleverstatus UR Verpakking CANCIDAS 50 mg is beschikbaar in een verpakking met 1 injectieflacon. CANCIDAS 70 mg is beschikbaar in een verpakking met 1 injectieflacon. Vergoeding CANCIDAS wordt volledig vergoed. Raadpleeg de volledige productinformatie (SPC) voor meer informatie over CANCIDAS. Merck Sharp & Dohme BV Waarderweg BN Haarlem Tel.: Mei 2012 (SmPC datum 19 juli 2012) REVIEW A restrictive transfusion policy in the paediatric intensive care unit: safe and effective L. de Vetten 1, M.C.J. Kneyber 2, R.Y.J. Tamminga 3 Departments of 1 Paediatrics, 2 Paediatric Intensive Care and 3 Haematology and Oncology 3, the Beatrix Children s Hospital, University Medical Centre of Groningen, the Netherlands Correspondence L. de Vetten Keywords Transfusion, red blood cell, paediatric intensive care unit Abstract Background: Red blood cell transfusions are frequently used in the paediatric intensive care unit (PICU) with a primary goal of increasing oxygen delivery to the tissues. There are several disorders in which a high haemoglobin level is suggested to improve outcome, including sepsis and cardiac disease. Nevertheless, red blood cell transfusions are associated with a higher morbidity and mortality rate in critically ill children and adults. In our article, we will give a narrative review of the existing literature on a restrictive transfusion policy in the PICU. Methods: A literature search was done using the terms red blood cell transfusion or erythrocyte transfusion and pediatrics or child in the Cochrane, Sumsearch, Trip and PubMed medical databases. Review of literature: The TRIPICU study offers the largest number of patients in whom a restrictive transfusion policy was concluded to be as safe and effective as a liberal transfusion policy. Several sub-studies were extracted from the TRIPICU database, focusing on specific groups of patients, e.g. sepsis patients, patients with non-cyanotic heart disease who underwent cardiac surgery and patients who underwent general surgery. One additional study focused on cyanotic heart disease, using higher haemoglobin levels than the studies named before. In all sub-categories a restrictive transfusion policy was found to be safe and effective. Conclusion: We conclude that it is safe to work with a haemoglobin threshold of 4.3 mmol/l for children admitted to the PICU with burns, sepsis or after general and cardiac surgery, and 5.6 mmol/l for patients with cyanotic heart disease. Introduction Up to 50% of the critically ill children admitted to the paediatric intensive care unit (PICU), receive one or more red blood cell (RBC) transfusions. After a stay of more than seven days in the PICU, this amount increases up to 75%. 1,2,3 Red blood cell transfusions can cause serious side effects. 1,4,5 Nevertheless, no international consensus exists on a haemoglobin threshold for administering RBC transfusions to critically ill children. 6 Previous research has shown that there are quite some differences between doctors usage of RBC transfusions, and that the volume given is often not adapted to the degree of anaemia. 6,7 A clear guideline on the usage of RBC transfusions at the PICU is desirable. Little information is known on the subject of a restrictive transfusion policy in critically ill children. In September 2011 the renewed Dutch consensus on Blood Transfusions was published. 8 This extensive guideline includes information about the patient population admitted to the PICU. The consensus concludes that a restrictive transfusion policy is safe for patients in the PICU based on literature published until the year We want to support and emphasise this statement by offering a narrative review on the subject of a restrictive transfusion policy in the PICU. We will also describe more recent literature, making a more specific usage of RBC transfusions possible. Methods The Cochrane, Sumsearch, Trip and PubMed medical databases were used during the literature search. We used the following terms in searching the databases red blood cell transfusion or erythrocyte transfusion and pediatrics or child. We then confined the results to articles comparing a restrictive and liberal transfusion policy. We excluded literature on neonates, premature neonates and children admitted elsewhere than the PICU. We focused on randomised clinical trials for our review and used citations from associated articles. Background Anaemia is defined as a haemoglobin (Hb) level in the blood that is lower than two standard deviations below the median of the age-dependant reference. Anaemia is common in children admitted to a PICU. At admission, already 33% of these children 8 9

10 A restrictive transfusion policy in the paediatric intensive care unit: safe and effective have anaemia and after 48 hours, another 18% have developed anaemia. 1 The pathogenesis of anaemia in critically ill children is multi-factorial, including poor nutritional state, changes in iron metabolism, lowered erythropoietin production and response, blood loss and frequent blood tests in the PICU. 4 Physiological changes Hb is of importance for the delivery of oxygen (DO2) to tissues and thereby maintaining an adequate organ function. At low serum Hb levels, less oxygen can be transported to the tissues. The tissues will extract proportionally more oxygen from the blood resulting in an increased concentration of deoxyhaemoglobin in the red blood cells. This process stimulates the production of 2,3-diphosphoglycerate (2,3-DPG). 2,3-DPG ensures a shift of the oxygen-dissociation curve, making it easier for the tissues to extract oxygen from the blood. Other compensating mechanisms to ensure an adequate DO2 are a redistribution of blood flow and an increase in cardiac output. 1 High haemoglobin target level Based on pathophysiological changes, it seems reasonable to strive for a high Hb level to ensure adequate tissue oxygenation in at least two categories of PICU patients. The first category consists of septic patients. During sepsis, endotoxins, tumour necrosis factor-alpha and nitrogen-oxygen molecules are released, causing mitochondrial depression and thereby an increased oxygen demand of the tissues. Yet, the oxygen supply is limited through decreased myocardial function and maldistribution of blood flow in the microcirculation results. The second category consists of patients who have undergone cardiac surgery. A compromised respiratory and cardiac condition results in limited oxygenation of the blood. The percentage of unsaturated blood is even higher in patients with a mixed circulation. Decreased contractility of the myocardium and/or arrhythmia can contribute to a decreased cardiac output. For both categories of patients it seems that a higher Hb level is able to compensate for the restricted oxygen delivery to the tissues. Effects of RBC transfusions The primary goal of RBC transfusions is to preserve organ function by ensuring an adequate oxygen supply. Yet, for the individual patient, it is unknown at which haemoglobin threshold the oxygen supply to the tissues becomes critical. Also, RBC transfusions seem to have a limited effect on improvement in the oxygen supply to the tissues. 1 Three mechanisms can explain this limited effect. First, the storage of red blood cells leads to a depletion of 2,3-DPG in a couple of days. We explained earlier that 2,3-DPG is necessary for the compensatory shift of the oxygen dissociation curve. Second, adenosine triphosphate (ATP) is depleted from stored blood. A shortage of ATP can lead to deformation of the membrane and thereby destruction of red blood cells. Finally, a small amount of free Hb in stored blood binds to endogenously produced nitric oxide (NO). NO can lead to vasoconstriction of the microcirculation, restricting the oxygen delivery to the tissues. 1,2 Adverse effects of RBC transfusions Different studies in adults as well as children show that RBC transfusions are associated with a longer duration of hospital stay and a higher morbidity and mortality. RBC transfusions are associated with a longer duration of ventilatory need, an increased usage of vasoactive medication and longer duration of stay in the PICU, independent of severity of illness. 1,4,5,9 For some adverse effects of RBC transfusions, a clear causal mechanism is known. For example, cardiac decompensation can be the result of volume load in critically ill patients. Disturbances in electrolytes and/or coagulation originate from the dissimilarity in composition of stored blood products compared with fresh blood. The mechanisms causing non-haemolytic fever and transfusion related-immunomodulation are less clear. It has been postulated that the leukocytes and cytokines that are released from the blood product cause an inflammatory cascade. 1,10 This immunomodulation is associated with an increased risk for nosocomial infections and multi-organ failure. 1,2,4 Nevertheless, two recent studies have shown that leukocyte-depleted RBC transfusions are also associated with nosocomial infections. 2,4 Because of this controversy with respect to leukocyte depletion, more research is desired. In addition, a longer storage time of blood products seems to be associated with a worse outcome, but this has not been confirmed universally. 2,10,11 Until more research is done, it seems recommendable to use fresh leukocyte-depleted RBC transfusions when treating critically ill children. In the Netherlands this is already standard practice. Restrictive transfusion strategy Several articles have been published on a restrictive transfusion strategy in critically ill adults and children. In the year 1999, the TRICC study (Transfusion Requirements in Critical Care) 13 compared a traditional transfusion policy (liberal strategy: Hb threshold of 10 g/dl or 6.2 mmol/l) with a restrictive transfusion strategy (Hb threshold of 7 g/dl or 4.3 mmol/l) in adults. According to this multicentre, prospective, Table 1. Patient characteristics per study* Group Number of patients Age (years) randomised trial, a restrictive strategy is as effective and safer than the traditional policy. The TRICC motivated different researchers to evaluate the transfusion policy in critically ill children. We will now describe the published literature on restrictive transfusion strategies in children. From each study, patient characteristics, transfusion information and outcome parameters are assembled in table 1, table 2 and table 3, respectively. First indications, 2007 The first study on a restrictive transfusion strategy in children concerned a population of burn patients. In a retrospective review two groups of patients were compared who were treated in a burns centre for children in the period of The first group (traditional group, n=146) received a RBC transfusion at a Hb threshold of 10 g/d (6.2 mmol/l). In the second group (restrictive group, n=127) this Hb threshold was lowered to 7 g/dl (4.3 mmol/l). No differences were found in outcome parameters such as duration of stay, duration of ventilation, amount of surgery needed and mortality. The restrictive transfusion strategy did lead to a great decrease in Sex (% M) PRISM score # Ventilation (%) Hb at start of the study 0 (mmol/l) Palmieri 14 Liberal ± 0.4 2:1 5.9 ± 0.03 Restrictive ± :1 5.4 ± 0.04 Two historical cohorts of burn patients P value NS <0.001 Lacroix 3 Liberal ± ± ± 0.6 (TRIPICU) Restrictive ± ± ± 0.6 Randomised PICU patients P value NS NS NS NS NS Karam 12 Liberal ± ± ± 0.6 (Sub-TRIPICU) Restrictive ± ± ± 0.6 Randomised sepsis patients P value NS NS NS NS NS Willems 15 Liberal ± ± ± 0.6 (Sub-TRIPICU) Restrictive ± ± ± 0.5 Randomised non-cyanotic heart disease P value NS NS NS NS NS Cholette 16 Liberal ± ± 0.7 (post-surgery) Restrictive ± ± 0.8 (post-surgery) Randomised cyanotic heart disease patients P value NS NS NS Roulette 17 Liberal ± ± ± 0.6 (Sub-TRIPICU) Restrictive ± ± ± 0.7 Randomised surgery patients P value NS NS NS NS NS * Plus minus values are means ± SD. Total percentage can differ from 100% because of rounding. # Scores of the Pediatric Risk of Mortality (PRISM) range from 0 to 76, with higher scores indicating a higher risk of death. Score taken at the moment of randomisation. Before randomisation. 0 At the moment of randomisation. NS = not significant

11 A restrictive transfusion policy in the paediatric intensive care unit: safe and effective Table 2. Transfusion information per study* Group Threshold Hb before transfusion (mmol/l) Amount of patients receiving RBC transfusion (%) Amount of units of RBCs per transfused patient Total amount of transfused units of RBCs Length of storage of RBCs (days) Palmieri 14 Liberal ± ± 0.2 Restrictive ± ± 0.3 P value NS <0.001 <0.001 <0.001 Table 3. Outcomes per study * Group New/ progressive multi-organ dysfunction syndrome (%) Mortality (%) Nosocomial infections (%) Reactions to RBC transfusion (%) Length of ventilation (days) Palmieri 14 Liberal ± 2.3 Restrictive ± 1.5 P value NS NS Length of stay at the PICU (days) Lacroix 3 Liberal ± ± 10.5 (TRIPICU) Restrictive ± ± 10.3 P value <0.001 NS <0.001 NS Karam 12 Liberal ± ± 8.6 (Sub-TRIPICU) Restrictive ± ± 8.3 P value <0.01 NS <0.01 NS Willems 15 Liberal ± ± 10.9 (Sub-TRIPICU) Restrictive ± ± 9.3 P value <0.001 NS <0.001 NS Cholette 16 Liberal Restrictive P value <0.01 NS <0.01 Rouette 17 Liberal ± 9.2 (Sub-TRIPICU) Restrictive ± 11.4 P value <0.01 NS <0.01 NS * Plus minus values are means ± SD. Total percentage can differ from 100% because of rounding. NS = not significant. Lacroix 3 Liberal ± ± 7.4 (TRIPICU) Restrictive ± ± 7.9 P value NS NS NS NS NS NS Karam 12 Liberal ± ± 6.2 (Sub-TRIPICU) Restrictive ± ± 6.3 P value NS NS NS NS Willems 15 Liberal ± 4.6 (Sub-TRIPICU) Restrictive ± 3.1 P value NS NS NS NS NS Cholette 16 Liberal (0.2-9) 5.4 ± 3.3 Restrictive (0.2-26) 6.6 ± 6.4 P value NS NS NS Rouette 17 Liberal ± ± 10.2 (Sub-TRIPICU) Restrictive ± ± 6.6 P value NS NS NS NS 0.03 the amount of RBC transfusions resulting in cost saving. An important point of concern is the time frame of the study. The traditional group was treated in the period , while the restrictive group was treated in the period Changes in the general treatment of burn patients could very well have influenced the outcome of this study. TRIPICU study After the TRICC study, a comparable research was designed for critically ill children in The TRIPICU study (Transfusion Requirements in the Pediatric Intensive Care Unit) included more than 600 stable but critically ill children who were admitted to the PICU. 3 Patients were considered stable if the mean systemic arterial pressure was not less than 2 SD below the normal mean for age and if cardiovascular treatments had not been increased for at least two hours. The patients were randomised in a liberal transfusion group (Hb threshold 9.5 g/dl or 5.9 mmol/l) and a restrictive transfusion group (Hb threshold 7.0 g/dl or 4.3 mmol/l). RBCs were transfused within 12 hours after the threshold value had been reached and were always leukocyte depleted. The results showed no differences in primary outcomes of mortality and multiple organ dysfunction syndrome (MODS). Regarding the side effects and thus safety of RBC transfusions, no differences were found between the two groups. The authors conclude that for stable critically ill children in the PICU a haemoglobin threshold of 4.3 mmol/l can be used. An important remark is that the TRIPICU study did not include children with cyanotic heart disease. Sepsis patients The TRIPICU study included a group of 137 critically ill children with stabilised sepsis. 12 The patients were analysed after randomisation in a liberal and a restrictive transfusion group (table 2). In the restrictive group, 39 of 68 patients received a blood transfusion, compared with 68 of 69 patients in the liberal group. No differences were found in mortality, MODS and length of hospital stay (table 3). Cardiac surgery patients From the TRIPICU study, another subgroup of post-cardiac surgery patients was analysed, using the same Hb threshold as described above. 15 In the restrictive transfusion group, twice as much MODS was found than in the liberal group but because of the small number of patients this was not statistically significant. No difference was found in mortality or in the secondary outcomes of length of hospital stay and length of ventilation. As described before, an important restriction is the exclusion of patients with cyanotic heart disease. * Plus minus values are means ± SD. Total percentage can differ from 100% because of rounding. NS = not significant. A second, smaller study on RBC transfusions in children after cardiac surgery was published in In this study, 60 patients who underwent a cavopulmonary connection were randomised in a restrictive and a liberal transfusion group, receiving leukocyte-depleted RBC transfusions. These patients all suffered from cyanotic heart disease. Therefore, higher Hb thresholds were used, 9.0 g/dl (5.6 mmol/l) and 13.0 g/dl (8.1 mmol/l) for the restrictive and the liberal group, respectively. No differences were found in the outcomes of oxygen saturation, mortality, length of stay on the PICU and length of ventilation. Side effects, for example nosocomial infections, were not described in this study. General surgery patients A third subcategory of the TRIPICU study includes a group of 124 children who underwent general surgery. 17 This group was also randomised in a liberal transfusion group (Hb threshold 9.5 g/d or 5.9 mmol/l) and a restrictive transfusion group (Hb threshold 7 g/dl or 4.3 mmol/l). In the restrictive group, 30 of 60 patients received an RBC transfusion, compared with 62 of 64 patients in the liberal group. No differences were found in mortality and MODS. A difference in length of hospital stay was found in favour of the restrictive transfusion policy. Conclusion The literature described above clearly indicates that a restrictive transfusion policy is effective in the treatment of stable critically ill children admitted to the PICU. From the number of adverse effects of RBC transfusions, including nosocomial infections, duration of ventilatory support and occurrence of MODS, it can be concluded that a restrictive policy is as safe as a liberal policy. We therefore support the CBO consensus with the addition that a restrictive transfusion policy can also be used in specified groups of patients, such as sepsis patients and general and cardiac surgery patients. It must be noted that in the subcategory of cardiac surgery patients, more MODS was found in the restrictive group. This finding was not found to be significant, yet a greater number of patients should be included to further investigate this finding. The studies described above advise to use a haemoglobin threshold of 4.3 mmol/l in PICU 12 13

12 Accepted June 2013 patients, decreasing the exposure to RBC transfusions and their possible side effects. For patients with cyanotic heart disease, a haemoglobin threshold of 5.6 mmol/l can be used. Multicentre studies with greater numbers of patients are recommended to confirm these statements. References 1. Istaphanous GK, Wheeler DS, Lisco SJ, Shander A. Red blood cell transfusion in critically ill children: a narrative review. Pediatr Crit Care Med. 2011;12: Kneyber MCJ. Red blood cell transfusion in paediatric critical care. Clin Lab. 2011;57: Lacroix J, Hébert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356: Bateman ST, Lacroix J, Boven K, et al. Anemia, blood loss, and blood transfusions in North American children in the intensive care unit. Am J Respir Crit Care Med. 2008;178: Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plötz FB. Red blood cell transfusion in critically ill children is independently associated with increased mortality. Intensive Care Med. 2007;33: Laverdière C, Gauvin F, Hébert PC, et al. Survey on transfusion practices of pediatric intensivists. Pediatr Crit Care Med. 2002;3: Nahum E, Ben-Ari J, Schonfeld T. Blood transfusion policy among European pediatric intensive care physicians. J Intensive Care Med. 2004;19: 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) , fax: +31(0) 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 MYC CBO richtlijn Bloedtransfusies, 2011, 9. Murphy GJ, Angelini GD. Indications for blood transfusion in cardiac surgery. Ann Thorac Surg. 2006;82: Vamvakas EC. Deleterious clinical effects of transfusion immunomodulation:proven beyond a reasonable doubt. Transfusion. 2006;46: Gauvin F, Spinella PC, Lacroix J, et al. Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients. Transfusion. 2010;50; Karam O, Tucci M, Ducruet T, Hume HA, Lacroix J, Gauvin F. Red blood cell transfusion thresholds in pediatric patients with sepsis. Pediatr Crit Care Med. 2011;12: Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340: Palmieri TL, Lee T, O Mara MS, et al. Effects of a restrictive blood transfusion policy on outcomes in children with burn injury. J Burn Care Res. 2007;28: Willems A, Harrington K, Lacroix J, Biarent D, Joffe AR, Wensley D, et al. Comparison of two red-cell transfusion strategies after pediatric cardiac surgery:a subgroup analysis. Crit Care Med. 2010;38: Cholette JM, Rubenstein JS, Alfieris GM, Powers KS, Eaton M, Lemer NB. Children with single-ventricle physiology do not benefit from higher hemoglobin levels post cavopulmonary connection:results of a prospective, randomized, controlled trial of a restrictive versus liberal red-cell transfusion strategy. Pediatr Crit Care Med. 2011;12: Rouette J, Trottier H, Ducruet T, Beaunoyer M, Lacroix J, Tucci M. Red blood cell transfusion threshold in postsurgical pediatric intensive care patients:a randomized controlled trial. Ann Surg. 2010;251: CASE REPORT Extravasation injury by norepinephrine: a case report and description of treatment options G. van der Wal, J.C. Janssen, P.E. Spronk Department of Intensive Care Medicine, Gelre Hospitals Apeldoorn, the Netherlands Correspondence G. van der Wal Keywords - Extravasation injury, norepinephrine, skin necrosis Abstract In this case report we describe a patient with extravasation injury with norepinephrine given through a peripheral catheter in an emergency setting, awaiting placement of a central venous catheter. Delayed recognition and management of extravasation injury may result in serious consequences. It is important to be familiar with the treatment options to prevent further damage. We describe local treatment using the flush-out technique with good results. Introduction Extravasation of medication given by the intravenous route occurs when the medication given accidently flows out of the blood vessel into the surrounding tissue. Recognition of extravasation injury can be difficult but is important because skin necrosis can be prevented with immediate treatment in some cases. We describe a patient with extravasation injury following norepinephrine infusion through a peripheral catheter and outline treatment options of extravasation injury. Case report A 65-year-old woman was admitted to the ICU with respiratory failure because of exacerbation of her chronic obstructive pulmonary disease. Despite non-invasive ventilation, intubation and mechanical ventilation was needed. After intubation, a subclavian central venous catheter was inserted, but placement was aborted because it was complicated by a tension pneumothorax with haemodynamic deterioration. Volume resuscitation was started and a thoracic drain was inserted immediately. Because of severe hypotension while placing the thoracic drain, norepinephrine was started for haemodynamic support through a peripheral intravenous catheter. The haemodynamic situation in the patient stabilised immediately after placement of the thoracic drain. The nurse noticed that the skin was pale and cold around the puncture of the peripheral catheter located in her left underarm, suggesting subcutaneous extravasation of norepinephrine (infusion of 0.1 mg (0.5 ml) in max. 15 minutes) ( figure 1a). The norepinephrine infusion was promptly stopped and transferred to the central catheter, which had been inserted in the meantime. No fluids could be aspirated from the peripheral catheter and the line was removed. The extravasation injury was treated by the subcutaneous flush-out technique described by Gault. 7 Little incisions were made around the affected area, the subcutaneous tissues were made permeable by blunt cannulation and physiological saline was irrigated through the subcutaneous tissue flowing out of the other incisions. Follow-up after irrigation (figure 1b) showed improvement of the local skin perfusion. Five days later (figure 2a) and after four months ( figure 2b) good healing was seen and skin necrosis had been prevented. After two days she was extubated. She recovered well and was discharged from the hospital 16 days after ICU admission. Discussion Extravasation injury results from a combination of factors including 1) solution osmolality (e.g. potassium chloride, sodium bicarbonate, calcium, glucose (>10%), hypertonic saline and total parenteral nutrition), 2) local tissue toxicity (cytotoxic agents), 3) vasoconstrictor properties (epinephrine, norepinephrine), 4) infusion pressure (radiographic contrast media) and 5) regional anatomical peculiarity (thin skin or places with little soft-tissue coverage). 1-6 Extravasation injury should be recognised as soon as possible to prevent further damage. Norepinephrine is a vasopressor (alpha adrenergic agonist) commonly used in haemodynamically unstable patients in the intensive care unit (ICU). Other aforementioned medications are also widely used in the ICU and they are in general administered through a central venous catheter for rapid dilution and to prevent the risk of extravasation injury. 1,2,5-8 Extravasation with norepinephrine may cause severe local tissue ischaemia mediated by vasoconstriction, which can 14 15

13 Extravasation injury by norepinephrine: a case report and description of treatment options result in severe skin necrosis. Ischaemic necrosis can also occur when the peripheral catheter is in place without extravasation, because of local stasis and concentration of the drug in case of low blood flow. 8 The extent of damage is dependent on the dilution, volume, time of infusion and the localisation of the peripheral catheter. 3,7 The severity of injury immediately after extravasation is not always predictable and frequently underestimated. 4,5 An early warning sign might be pain at the site of infusion, local swelling or a change of skin colour. However, most ICU patients are unable to localise, as in our case, because of their decreased level of consciousness. 5 Delayed recognition and management or mismanagement may therefore have serious consequences from scarring, damage to the underlying tendons and nerves, contracture, marked soft skin tissue loss requiring skin grafting to amputation and permanent disability. 1,5,7 No randomised controlled trials exist about the management of extravasation injuries. Consequently, treatment strategy is mostly based on empiric research. 1,3,7 In case of extravasation injury the medication should be discontinued quickly and the injury should be treated without any delay. Before removing the catheter, aspiration through the catheter may remove some blood and extravasate. The extremity should be elevated and immobilised. Mild extravasations can be observed and do not need further treatment. When more severe, intervention seems to improve outcome and can prevent further damage. 1,3-7 Gault used saline flush-out and/or local liposuction within 24 hours after extravasation before skin necrosis occurs with favourable results. Of 44 cases, 88.5% healed with no soft tissue loss. 7 When the patient is awake 1% lidocaine is injected subcutaneously. Infiltration with hyaluronidase (1500 Units) can increase Figure 1. (a) Extravasation injury and (b) directly after wash out A B permeability of the connective tissue by enzymatic breakdown of hyaluronic acid. Small stab incisions are made around the extravasation area and a large amount (500 ml) of physiological saline solution is flushed with a blunt tipped catheter through the subcutaneous tissue flowing out of the other incisions. This should be repeated through the other incisions. Care should be taken that the fluids do not accumulate and a sterile procedure should be used. The incisions are allowed to close spontaneously. 7 If saline flush-out and hyaluronidase are insufficient, liposuction under local or general anaesthesia can be used to aspirate the extravasated material and subcutaneous fat. 3,4,6-8 Administration of a vasodilator such as phentolamine 5-10 mg (an alpha adrenergic antagonist) is also recommended in case of extravasation injury with vasopressors which give local vasodilatation and hyperaemia. 2,8 In more severe cases with blistering and necrosis, the treatment should be surgical: debridement, eventually followed by skin grafting or flap reconstruction. It is not exactly known which patients will have serious damage after extravasation and who needs aggressive treatment, 7 but when necrosis develops it is too late to save the skin. In our case it was sufficient to use the saline flush-out technique with good result. We made the subcutis permeable with a blunt instrument because hyaluronidase was not available at the time of the injury. In conclusion, extravasation injury with norepinephrine may result in serious skin necrosis when not recognised rapidly and treated correctly. The best way of treating an extravasation injury is to prevent it. This case underlines the importance of giving high-risk medications through a central venous catheter. When, like in our case, these medications need to Figure 2. (a) Extravasation injury after 5 days and (b) 4 months later A B be given as an emergency through a peripheral catheter, the puncture site should be monitored closely. Although evidence for treatment is limited, it is good to be familiar with the treatment possibilities that are described to be able to prevent further damage. References 1. Hannon MG, Lee SK. Extravasation Injuries. J Hand Surg. 2011;36A: Kim SM, Aikat S, Bailey A. Well recognised but still overlooked: norepinephrine extravasation. BMJ Case Reports. 2012; /bcr Takx-Kohlen BCMJ, Hooff JP van. De behandeling van extravasatie van geneesmiddelen. Ned Tijdschr Geneeskd. 1996;140(8): Blecourt RA de, Bloem JJAM. De behandeling van extravasatie van intravenous toegediende middelen. Ned Tijdschr Geneeskd. 1996;140(8): Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg. 2002;48: Kumar RJ, Pegg SP, Kimble RM. Management of extravasation injuries. ANZ J Surg. 2001;71: Gault DT. Extravasation Injuries. Br J Plast Surg. 1993;46: Oglesby JE, Baugh JH. Tissue necrosis due to norepinephrine. Am J Surg. 1968;115(3): nvic traumatologie en acute geneeskunde 2013 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 ( ). 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): *. 2. Glöckner et all, Treatment of invasive candidiasis with echinochandines. Mycoses 2009 pag Ecalta Sept 2011 Summary of Product Characteristics Taxe April 2012, WMG-geneesmiddelen Z-Indez, 13e jaargang nr Stichting Werkgroep Antibioticabeleid (SWAB), Optimaliseren van het antibioticabeleid in Nederland XII, SWABrichtlijnen voor de behandeling van invasieve schimmelinfecties,september Joseph J.M et all; Anidulafungin: a drug evaluation of a new echinocandin; Expert opinion Informa health care 2008; *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. donderdag 19 september 2013 vrijdag 20 september 2013 ReeHorst, Ede 12.ECL PFI_Ecalta_1BTekst.indd /4/13 11:01 AM

14 Accepted June 2013 Intravenous lipid emulsion in the treatment of verapamil intoxication CASE REPORT Intravenous lipid emulsion in the treatment of verapamil intoxication M.A.J. Assink 1, P.E. Spronk 1, H.J.M. van Kan 2, A. Braber 1 Departments of 1 Intensive Care and 2 Clinical Pharmacy, Gelre Hospitals, Apeldoorn, the Netherlands Correspondence A. Braber Keywords - Verapamil intoxication, calcium channel blockers, intralipid, 4-aminopyridine Abstract Calcium channel blockers are commonly used in a variety of cardiovascular diseases. Their extensive clinical use concurs with an increase in the incidence of deliberate and accidental poisonings. Intoxication with non-dihydropyridine calcium channel blockers is currently treated with supportive therapies, since no antidote is available. When conventional therapies fail to achieve haemodynamic stability, alternative approaches should be considered. In this case report we describe the effect of continuous renal replacement therapy and intravenous lipid emulsion in the treatment of severe verapamil intoxication. High-volume continuous venovenous haemofiltration did not have a substantial effect on verapamil clearance. However, after intravenous administration of lipid emulsion the haemodynamics stabilised, which suggests that this intervention is beneficial after life-threatening verapamil intoxication, although the exact underlying mechanism remains to be elucidated. Introduction The incidence of cardiovascular disease, especially hypertension and congestive heart failure, is increasing. Calcium channel blockers are commonly used in a variety of cardiovascular diseases, including angina pectoris, supraventricular tachycardias and hypertension, and in noncardiac conditions such as migraine and Raynaud s phenomenon. Their extensive clinical use concurs with an increase in the incidence of deliberate and accidental poisonings. 1 Overdosage of the non-dihydropyridine calcium channel blocker verapamil causes a variety of symptoms including cardiogenic shock, arrhythmias, conductance disturbances, vasodilatation, central nervous system depression, pulmonary oedema and paralytic ileus (table 1). 2 Treatment of intoxication with calcium channel blockers is controversial. 3-5 Generally, accepted treatment options are prevention of absorption by giving active charcoal, and supportive care including calcium suppletion, glucagon and insulin infusion. 6 Recently, high-dose lipid solutions have been advocated in these intoxications. In this case report we describe the use of intravenous lipid emulsion in a severe verapamil intoxication and discuss the potential benefit of this intervention to improve outcome. Case description A 68-year-old man was brought to the emergency room one hour after a suicide attempt by ingestion of 6700 mg of verapamil, of which 6300 mg (94%) in extended-release capsules. Four weeks previously he was diagnosed with AV-nodal re-entry tachycardia for which verapamil was prescribed. On evaluation we saw a drowsy man. His blood pressure was 80/50 mmhg, pulse rate 70 beats/min in sinus rhythm, and respiratory rate 19 breaths/min with oxygen saturation 98% while breathing 5 litres O 2. Examination of heart, lungs, abdomen and extremities was unremarkable. Laboratory tests on arrival showed normal serum potassium and glucose levels, and an increased level of lactate. Gastric lavage did not show traces of the consumed medication. Supportive treatment was started, including volume resuscitation and administration of low-dose norepinephrine. Absorption prevention was attempted by colon lavage. Despite this treatment, the patient deteriorated and developed Table 1. Symptoms caused by verapamil intoxication Clinical features Altered mental status, dizziness, seizures Respiratory depression Nausea, vomiting, abdominal pain Physical examination Hypotension, bradycardia, cardiogenic shock Paralytic ileus Jugular venous distension Pulmonary crackles Diagnostic clues Electrocardiogram: conduction abnormalities of the SA/AV nodes, idioventricular arrhythmias Laboratory results: hyperglycaemia, metabolic acidosis, elevated transaminase values Chest X-ray: pulmonary oedema Figure 1. Vasocative medication and blood pressure during treatment Ml/hr Intralipid infusion Vasopression and blood pressure Elapsed time (hours) MAP (mm Hg) Norepinephrine dose (0.2 mg/ml) deep vasoplegic shock within a few hours after admission to the ICU. High doses of inotropes and vasopressors, and respiratory support were necessary (figure 1). Transthoracic echocardiography, while substantial amounts of inotropes were administered, showed relatively normal contractility of the right and left ventricle without valve pathology. Eight hours later, an external pacemaker was introduced because of severe bradycardia, followed by ventricular fibrillation requiring resuscitation by defibrillation and basic life support for one hour. High-volume continuous venovenous haemofiltration (HVCVVH; substitution fluid rate 9.4 litre/h) was started because of severe metabolic acidosis due to vasoplegic shock (lactate 11 mmol/l). Twelve hours after intake of verapamil, intravenous lipid emulsion 20% (Intralipid ) was administered, starting with a bolus of 1.5 ml/kg, followed by 0.25 ml/kg/ min for one hour. A few hours after starting HVCVVH and administration of the lipid emulsion, less vasopressors were required to stabilise the patient (figure 1). Verapamil and norverapamil concentrations were measured in the serum and by ultrafiltration (figure 2, table 2). There was not a substantial amount of verapamil or norverapamil ultrafiltrated, resulting in a low sieving coefficient. Three days after ingestion, the vasoplegic shock had resolved. Due to the development of acute kidney failure, intermittent haemodialysis was necessary. Six months later, the patient had fully recovered without renal replacement therapy. Discussion Verapamil is a non-dihydropyridine L-type calcium-channel blocker, acting on myocardial muscle, the conduction system Figure 2. Total verapamil and norverapamil concentration in serum over time. High-volume continuous venovenous haemofiltration started at a rate of 9.4 l/h; after 12 hours the filtration rate changed to 3 l/h Serum (ug/l) Verapamil and Norverapamil in serum Intralipid infusion Elapsed time (hours) Start HCVVHH Start Intralipid Serum Verapamil Serum Norverapamil Table 2. Concentrations of verapamil (V) and norverapamil (NV) in serum and ultrafiltrate (UF) and the resulting sieving coefficients (Si) during continuous venovenous haemofiltration Time (h) Serum V (μg/l) Serum NV (μg/l) UF V (μg/l) UF NV (μg/l) and vascular smooth muscle. Verapamil antagonises calcium channels and inhibits calcium influx into myocardial and vascular tissue. The negative inotropic and chronotropic effects of verapamil result in bradycardia, decreased cardiac output, vasodilatation of smooth muscle and cardiovascular collapse (table 1). 6 Only 13-65% of a normal verapamil dose reaches the systemic circulation after absorption in the gastrointestinal tract due to an extensive first-pass effect in the liver, via multiple cytochrome P450 (CYP) isoenzymes. These enzymes, Si V Si NV

15 Intravenous lipid emulsion in the treatment of verapamil intoxication responsible for hepatic metabolism, may become saturated in cases of overdose. This will decrease the effect of first-pass metabolism, allowing increased quantities of active drug to reach the systemic circulation, thus prolonging the half-life of the calcium-channel blocker. 2 The plasma half-life of verapamil is 2-8 hours but can increase to hours after ingestion of large amounts of verapamil or slow-release preparations. The primary metabolite of verapamil is norverapamil, which has 20% of the pharmacological activity of verapamil. 5,7 In plasma, both verapamil and norverapamil are highly protein bound and have large volumes of distribution. Metabolites of verapamil are mainly (70%) excreted in the urine, while faecal elimination accounts for 9-16% of the excreted dose. 8 Treatment of verapamil intoxication consists of several supportive interventions, since no antidote is available for calcium channel blockers. Gastric and bowel lavage may be considered in any patient with potentially life-threatening ingestion to prevent absorption. This can be futile since an overdose of verapamil can cause paralytic ileus. 9 Intravenous calcium is given to treat cardiac symptoms from mild to moderate intoxications, in order to raise the extracellular calcium concentration gradient, although it does not significantly affect peripheral vascular resistance or heart rate. 2,5 Glucagon and phosphodiesterase inhibitors may also be considered because they have a potent inotropic effect by increasing formation of intracellular cyclic adenosine monophosphate (camp) in myocardial cells. 5,10 Because hyperglycaemia is reported with verapamil intoxication, insulin should be given to reach normoglycaemia and promote more efficient cardiac metabolism. 11,12 Besides the aforementioned treatment modalities, other strategies may be considered, such as levosimendan, which acts as a calcium sensitiser. 13 In cats, 4-aminopyridine effectively reversed the toxic effects of verapamil, 14 but no human case reports are available. The application of plasmapheresis, as a method of detoxification in several intoxications, is rapidly increasing. 15 In patients who have ingested substances that are highly lipid bound, plasmapheresis is more effective than haemodialysis because in plasmapheresis clearance is achieved through the longer total blood-filter time compared with intermittent haemodialysis. 16 Plasmapheresis resulted in cardiovascular stability in three cases with severe verapamil intoxication; unfortunately verapamil and norverapamil levels were not measured in the ultrafiltrate, only in serum. 17,18 In our case, we started HVCVVH in an attempt to correct metabolic disturbance due to severe metabolic acidosis. The low sieving coefficient of verapamil and norverapamil, calculated using verapamil and norverapamil concentrations in serum and ultrafiltrate, supported the hypothesis that HVCCVH is not effective in removing verapamil and the active metabolite norverapamil (table 2). Serum verapamil concentration shows a bimodal course: after ingestion first an increase, a few hours later a decrease followed by an increase of serum concentration (figure 2). Hypothetically the extended-release modality and clustering of verapamil capsules due to paralysis of the gastrointestinal tract could explain this bimodal course. More recently, lipid emulsion, described in several animal and human case reports, seems to be beneficial in the treatment of verapamil intoxication. 4 The product we used (Intralipid ) is an intravenous emulsion composed of triglycerides and a phospholipid emulsifier. The currently favoured mechanism for lipid emulsion in verapamil intoxication is the formation of a lipid sink An expanded intravascular lipid phase will sequester lipophilic toxins, thereby reducing the active free serum verapamil concentration and its toxic effect. Alternative mechanisms are based on the assumption that lipid emulsion improves adenosine triphosphate (ATP) synthesis in the cardiomyocyte, thereby improving contractility of the intoxicated heart. 19 Lipid emulsion infusion might also directly increase intra-cardiomyocyte calcium levels and lead to a direct positive inotropic effect. 19,20,22,23 Infusion of lipid emulsion in rats intoxicated with verapamil resulted in prolonged survival after administration of double doses of verapamil, as compared with the control group. 3 In another animal model, in which dogs were intoxicated with verapamil, lipid emulsion increased blood pressure and survival rate. 23 The use of lipid emulsion in humans intoxicated with verapamil remains doubtful. A recent review mentioned five cases of verapamil intoxication and use of lipid emulsion. 24 In these cases, administration of lipids seemed to be beneficial. After infusion of lipid emulsion, inotropes could be tapered, 25,26 and haemodynamic parameters stabilised. 26 Intravenous lipid emulsion could be beneficial in intoxications with other lipid-soluble agents as well as verapamil. An Australian review article describes data of human case reports suggesting a possible benefit of intralipid in potentially life-threatening cardiotoxicity from bupivacaine, mepivacaine, ropivacaine, haloperidol, tricyclic antidepressants, lipophilic beta blockers and calcium channel blockers. 19 Other human and animal studies subscribe this. 4,24 The section on cardiac arrest associated with toxic ingestions of the American Heart Association guidelines mentions the use of lipid emulsion as possibly beneficial in the treatment of beta-blocker overdose, when other standard therapies are not effective. Lipid emulsion is not mentioned in the treatment of intoxication with calcium-channel blockers. 27 In our case, it was administered 12 hours after arrival on the ICU. A few hours after administration of lipid emulsion, the norepinephrine dose could be tapered (figure 1). A positive response to lipid emulsion seems likely. Although circulating levels of verapamil and norverapamil were already decreasing prior to the start of the intralipids, there was an obvious direct correlation between stabilising haemodynamic parameters and the infusion of lipid emulsion ( figure 1). The lipid sink theory only applies to the 10% of unbound verapamil, so beneficial effects could also be caused due to unmeasurable effects, e.g. the intracellular or receptor-mediated effects. In theory, the use of lipid emulsion after intoxication with calcium channel blockers should be properly evaluated against standard therapy to evaluate the effect, side effects and potential interactions. However, since this intoxication is rare, additional case reports are necessary to support the inclusion of intravenous lipid emulsion in treatment guidelines. Nevertheless, publication bias should be taken into account. In conclusion, intoxication with calcium channel blockers such as verapamil should be managed with conventional therapies. When these therapies are insufficient to reach haemodynamic stability, alternative therapies are indicated. High-volume continuous venovenous haemofiltration did not show a substantial effect on verapamil and norverapamil clearance, resulting in a low sieving coefficient. Administration of intravenous lipid emulsion may be beneficial and it may be considered as treatment for life-threatening intoxication with verapamil. References 1. Bronstein AC, Spyker DA, Cantilena LR, Green JL, Rumack BH, Dart RC annual report of the american association of poison control centers national poison data system (NPDS): 28th annual report. Clin Toxicology. 2011;49: Arroyo AM, Kao LW. Calcium channel blocker toxicity. Pediatr Emer Care. 2009;25(8): Tebbutt S, Harvey M, Nicholson T, Tox D, Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med. 2006;13: Jamaty C, Bailey B, Larocque A, Notebaert E, Sanogo K, Chauny J. Lipid emulsion in the treatment of acute poisoning: A systematic review of human and animal studies. Clin Toxicology. 2010;48: Ashraf M, Chaudhary K, Nelson J, Thompson W. Massive overdose of sustained-release verapamil: A case report and review of literature. Am J Med Sci. 1995;310(6): Salhanick SD, Shannon MW. Management of calcium channel antagonist overdose. Drug Saf. 2003;26(2): Wanroy JL, de Weerdt O, Joore JCA, van der Hoven B, van de Wiel A. Overdosis van een geneesmiddel met vertraagde afgifte. Ned Tijdschr Geneeskd. 1996;140(1): Micromedex healthcare series. Micromedex Healthcare Series Web site. Accessed october/29, Schultz H, Vernon B. Intestinal pseudo-obstruction related to using verapamil. West J Med. 1989;151: Quispel R, Baur HJCM. Tentamen suicidii door diltiazem met gereguleerde afgifte. Ned Tijdschr Geneeskd. 2001;145(19): Kline JA, Raymond RM, Leonova ED, Williams TC, Watts JA. Insulin improves heart function and metabolism during non-ischemic<br />cardiogenic shock in awake canines. Cardiovasc Res. 1996;34: Levine M, Boyer EW, Pozner CN, Geib A, Thomson T, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med. 2007;35(9): Osthoff M, Bernsmeier C, Marsch SC, Hunziker PR. Levosimendan as treatment option in severe verapamil intoxication: A case report and review of the literature. Case Med Rep. 2010;2010: Agoston S, Maestrone E, van Hezik EJ, Ket JM, Houwertjes MC, Uges DRA. Effective treatment of verapamil intoxication wit 4-aminopyridine in the cat. J Clin Invest. 1984;73: Nenov VD, Marinov P, Sabeva J, Nenov DS. Current applications of plasmapheresis in clinical toxicology. Nephrol Dial Transplant. 2003;18:v Bayliss G. Dialysis in the poisoned patient. Hemodial Int. 2010;14: Kolcz J, Pietrzyk J, Januszewska K, Procelewska M, Mrocek T, Malec E. Extracorporeal life support in severe propranolol and verapamil intoxication. J Intensive Care Med. 2007;22(6): Kuhlmann U, Schoenemann H, Muller T, Keuchel M, Lange H. Plasmapheresis in life-threatening verapamil intoxication. Artif Cells Blood Sub Immobil Biotechnol. 2000;28: Cave G, Harvey M, Graudins A. Review article: Intravenous lipid emulsion as antidote: A summary of published human experience. Emerg Med Australasia. 2011;23: Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma, Rescusc and Emerg Med. 2010;18: Manavi M. Lipid infusion as a treatment for local anesthetic toxicity: A literature review. AANA Journal. 2010;78(1): ter Horst M, Tjiang GCH, Luitwieler RL, van Velzen C, Stolker RJ, de Quelrij M. Tegengif voor intoxicatie door lokale anesthetica. Ned Tijdschr Geneeskd. 2010;154(A1302). 23. Bania T, Chu J, Perez E, Su M, Hahn I. Hemodynamics effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium and saline. Acad Emerg Med. 2007;14: Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: A systematic review. Acad Emerg Med. 2009;16: Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation. 2009;80: Montiel V, Gougnard T, Hantson P. Diltiazem poisoning treated with hyperinsulinemic euglycemia therapy and intravenous lipid emulsion. Eur J Emerg Med. 2011;18: Hoek TL, Morrison LJ, Shuster M, et al American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. part 12: Cardiac arrest in special situations. AHA Guidelines

16 C OMMEN T A R Y B OO K R EV I E W Statins for sepsis? Pediatric Anesthesia, Intensive Care and Pain: Standardization in Clinical Practice D. Pretorius, P. Pickkers Department of Intensive Care Medicine, Radboud University Nijmegen, Medical Centre, Nijmegen, The Netherlands Statins inhibit the enzyme HMG-CoA reductase and thereby exert their well-known effect on cholesterol metabolism. In addition, statins may also exert anti-inflammatory, immune-modulating, and antioxidant effects, known as pleiotropic effects. The mechanism of action by which statins modulate the inflammatory pathways is complex and involves increased gene expression of NFκB, lowered expression of P-selectin influencing leukocyte-endothelium interaction, attenuation of up-regulation of Toll-like receptors and subsequent cytokine production, less platelet aggregation and less expression of tissue factor, less inos expression and augmented extracellular adenosine formation.1,2 These effects raise the question if statins may play a role in the treatment of sepsis patients. Several animal sepsis models have shown improved outcome with statin pre-treatment. It was also demonstrated that mice treated with statins six hours after a septic insult had improved outcome, although not as good as with statin pre-treatment. 3,4 In addition, there have been several observational studies that showed an association between statin treatment and improved outcome in humans. The largest of these observational studies was a cohort study from a Canadian administration database, with almost 70,000 patients.5 There are two problems with these studies: First, their observational nature makes them prone to bias (for example, patients from a higher socioeconomic background are more likely to use statins and have a more beneficial prognosis compared with patients from a lower socioeconomic background) and second, the patients were already on chronic statin treatment and therefore no conclusions can be drawn on the acute effects of statins in sepsis patients. Over the past few years, several small, single-centre acute intervention studies were conducted. The ASEPSIS trial had fewer conversions from sepsis to severe sepsis in the atorvastatin group,6 and in the HARP study,7 the simvastatin group suffered less non-pulmonary organ dysfunction. However, these studies were too small to be able to detect effects on hard endpoints. In April of this year, Kruger and co-workers published the first large, multicentre randomised trial that looked at the effect of a statin (atorvastatin) on intensive care patients with severe sepsis.8 Patients already on statin therapy were also 22 N e th j cr it c ar e vo lume 17 n o 3 july 2013 randomised, which meant that half of chronic statin users had to stop their statins. Patients had to be randomised within 48 hours of the start of their sepsis, and statins were continued for 14 days. The primary endpoint was the effect on interleukin-6 levels, as a measure of the immune response. Secondary endpoints were C-reactive protein concentrations, sequential organ failure assessment scores, intensive care unit (ICU) and hospital length of stay, and ICU, hospital, 28-day and 90-day mortality. The investigators found no differences between the intervention (n=123) and control (n=127) group in the course of interleukin (IL)-6 levels. The patients on chronic statin therapy had lower IL-6 concentrations, regardless of whether they were subsequently randomised to the statin or control group. There were no differences in the secondary endpoints between the two groups. In subgroup analyses, the patients on chronic statin therapy, who were randomised to the intervention group (so who continued statin therapy), had a lower 28-day mortality. As the survival benefit was only found in patients who were already on statins, while their IL-6 was similar to prior statin users who were randomised to placebo, these results suggest that the value of IL-6 as a marker of the statin effect is limited. In conclusion, this study suggests that initiation of statin therapy within 48 hours of the start of the SIRS response and treatment continued up to day 14 is not beneficial in sepsis patients. However, if a patient is already on statin therapy, the study suggests that when sepsis develops, continuation of statin therapy might be beneficial for the patient. Preclinical pharmacodynamic experiments with HMG-CoA reductase blockers suggested that it could be the sepsis-wonder drug. Animal and observational studies also looked promising; however, once again, from evidence obtained in randomised prospective studies, the role of statins in sepsis appears to be limited. Larger multicentre prospective trials would be needed to demonstrate possible beneficial clinical effects and mortality advantages with the use of statins in septic patients. For now, continuation of statin therapy in a patient with sepsis could be recommended. Marinella Astuto (Editor) Springer-Verlag Italia, pages ISBN e-isbn (ebook) This book gives an overview of current standards of anaesthesia and intensive care in neonates and children. It is an easy-to-use compilation of several relevant aspects in the acute care of neonates, infants and children. The literature is easily accessible so it is written in a convenient way to provide an update on the various subjects. Some chapters are constructed around conclusions and others around future perspectives. An identical approach might have been a more logical choice. On the one hand, this book gives an impression of several key points in paediatric intensive care, anaesthesia and analgesia. On the other hand, the actual choice for the various topics seems to be rather arbitrary, whereas each subject has its own concern and relevance. The first part of the book is devoted to intensive care and this section summarises different aspects of this field. It is hard to understand why scoring systems to assess severity of illness are being combined with, for instance, HFO ventilation, non-invasive ventilation and long-term home ventilation. From this perspective, it does not contribute to standardisation of care. This seems to me one of the major drawbacks of this book. The same holds true for the section on anaesthesia and perioperative medicine. This is a combination of subjects on safety and regional anaesthesia. But why is there a chapter on single lung ventilation? So, if you are familiar with paediatric anaesthesia, intensive care and pain, it provides a nice update. However, if you are in training as a paediatric intensivist or a paediatric anaesthetist, you might look for a book that provides you with a more complete overview of the field and that takes the approach by age group. This book brings you an overview of relevant key points in the Italian intensive care community. A.P. Bos References References: see page 25. N e th j cr it c ar e vo lume 17 n o 3 july

17 C ON F E R EN C E S August 12 October SSAI 2013 Congress - Focusing on the Brain ASA 2013: American Society of Anesthesiologists Annual Meeting Turku, Finland San Francisco, USA December 4-7 March Topics in Intensive Care CRRT 2014 the 19th International Conference CongresHotel De Werelt, Lunteren, the Netherlands Acute Kidney Injury: Controversies, Challenges and Solutions dvances in Critical Care San Diego, California December 28 August-1 September October EuroEcho-Imaging th Congress of the World Federation of Societies of Intensive and Critical Care Medicine The 38th Annual ANZICS/ACCCN Intensive Care Annual Scientific Meeting Durban, South Africa Hobart, Tasmania, Australia Istanbul, Turkey welcome.aspx 2-3 September 6-9 November International Symposium on Critical Bleeding 9th WINFOCUS WORLD CONGRESS on Ultrasound in Emergency & Critical Care 9-13 January 3-7 April SCCM 43rd Annual Critical Care Congress Continuous Renal Replacement Therapies 2014 Hong Kong, China Moscone Center San Francisco, California, USA San Diego, California, USA November January ATS 2014 International Conference Glasgow NVIC Echografiecursus 42e Congrès International de la SRLF CNIT, Paris-La Défense San Diego, California, USA September November Traumadagen Actualités en Réanimation:Réanimation, Surveillance continue et Urgences Graves Molkes Palace, Copenhagen 4-7 September 32nd Annual European Society of Regional Anaesthesia Congress (ESRA 2013) 2-3 October NVIC Echografiecursus 3-4 October 7th Belgian Heart Rhythm Meeting Brussels, Belgium N e th j cr it c ar e vo lume 17 n o 3 july March 34th International Symposium on Intensive Care and Emergency Medicine Brussels Meeting Center (Square) May June X Pan-American Iberic Congress of Intensive and Critical Care Medicine Madrid, Spain Lyon, France November Infectiedagen References Statins for sepsis? (p. 22) November NVIC Cursus Luchtwegmanagement 5. Hackam D, Mamdani M, Li P, et al. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analyses. Lancet. 2006;367: Patel J, Snaith C, Thickett D, et al. Randomised double-blind placebo-controlled trial of 40mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS trial) Critical Care. 2012;16:R Gao F, Linhartova L, Johnston A, et al. Statins and sepsis. BJA. 2008;100: Terblance M, Almog Y, Rosenson R, et al. Statins: panacea for sepsis? Lancet Infect Dis. 2006;6: Merx M, Liehn E, Janssens U, et al. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circ. 2004;109: Craig T, Duffy M, Shyamsundar M, et al. A randomised clinical trial of hydroxymethylglutaryl-coemzyme A reductase inhibition of acute lung injury (the HARP study). Am J Respir Crit Care Med. 2011;183: Merx M, Liehn E, Graf J, et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005;112: Kruger P, Bailey M, Bellomo R, et al. A multicentre randomised trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013;187: N e th j cr it c ar e vo lume 17 n o 3 july

18 Editorial Board of the Information for authors A.B. Johan Groeneveld, Editor in Chief Erasmus Medical Center Rotterdam PO Box CA Rotterdam Jan Bakker, Section Editor Hemodynamics Erasmus Medical Center Rotterdam PO Box CA Rotterdam Alexander Bindels, Section Editor Endocrinology Dept. of Internal Medicine Catharina Hospital Michelangelolaan EJ Eindhoven Bert Bos, Section Editor Pediatrics Department of Pediatrics Academic Medical Center University of Amsterdam Meibergdreef AZ Amsterdam Frank Bosch, Section Editor Imaging Dept. of Internal Medicine Rijnstate Hospital PO Box TA Arnhem International Advisory Board Charles Gomersall Dept. of Anaesthesia and Intensive Care The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong, China Frank van Haren A/ Professor, Australian National University Medical School Department of Intensive Care Medicine The Canberra Hospital PO Box 11, Woden, ACT 2606 Canberra, Australia Charles Hinds Professor of Intensive Care Medicine St. Bartholomew s Hospital West Smithfield, London, UK Wolfgang Buhre, Section Editor Anesthesiology Dept. of Anesthesiology University Medical Center Utrecht PO Box GA Utrecht Hans van der Hoeven, Section Editor Mechanical Ventilation Radboud University Nijmegen Medical Centre PO Box HB Nijmegen Can Ince, Section Editor Physiology Dept. of Physiology Academic Medical Center University of Amsterdam Meibergdreef AZ Amsterdam Evert de Jonge, Section Editor Scoring and quality assessment Leiden University Medical Center P.O. Box RC Leiden Nicole Juffermans Section Editor Hemostasis and Thrombosis Dept. of Intensive Care Academic Medical Center University of Amsterdam Meibergdreef AZ Amsterdam Patrick Honoré Heads of Clinics Director of Critical Care Nephrology Platform ICU department Universitair Ziekenhuis Brussel, VUB University Brussels, Belgium Alun Hughes Professor of Clinical Pharmacology Imperial College London South Kensington Campus London, UK Manu Malbrain Dept. of Intensive Care Unit Hospital Netwerk Antwerp Campus Stuivenberg Antwerp, Belgium Heleen Oudemans-van Straaten, Section Editor Nephrology VU University Medical Center PO Box MB Amsterdam Peter Pickkers, Section Editor Sepsis and inflammation Radboud University Nijmegen Medical Centre PO Box HB Nijmegen Arjen Slooter, Section Editor General Dept. of Intensive Care University Medical Center Utrecht PO Box GA Utrecht Peter Spronk, Section Editor General Gelre Hospital, location Lukas PO Box DS Apeldoorn Jaap Tulleken, Section Editor General University Medical Center Groningen PO Box RB Groningen Paul Marik Associate Professor Dept. of Medicine and Medical Intensive Care Unit University of Massachusetts St. Vincent s Hospital, USA Greg Martin Dept. of Medicine Division of Pulmonary, Allergy and Critical Care Emory University School of Medicine Atlanta, USA Ravindra Mehta Professor of Clinical Medicine Associate Chair for Clinical Research Department of Medicine UCSD Medical Centre 8342, 200 W Arbor Drive San Diego, USA Anton van Kaam, Section Editor Neonatology Dept. of Neonatal Intensive Care Emma Children s Hospital, Academic Medical Center University of Amsterdam Meibergdreef AZ Amsterdam Jozef Kesecioglu, Section Editor Pulmonology Dept. Of Intensive Care Medicine University Medical Center Utrecht PO Box GA Utrecht Michael Kuiper, Section Editor Neurology Medical Center Leeuwarden PO Box BR Leeuwarden Maarten Nijsten, Section Editor Surgery University Medical Center Groningen PO Box RB Groningen Xavier Monnet Service de réanimation médicale Centre Hospitalier Universitaire de Bicêtre France Jean-Charles Preiser Dept. Intensive Care CHU Liege Domaine Universitaire Liege, Belgium Yasser Sakr Dept. of Anaesthesiology and Intensive Care Friedrich-Schiller University Hospital Jena, Germany Hannah Wunsch Dept. of Anaesthesia New York Presbyterian Columbia New York, USA The (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 abstracts All 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 objectives State 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. Design Describe 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 results Summarize here accurately, although concisely, summarize how you will proceed in learning the answer to the objective. Also provide the main outcomes of the study. Conclusions The conclusions and their applications (clinical or otherwise) should be clearly stated, limiting interpretation to the domain of the review. Original articles/reviews Articles 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 Reports The 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 Images A 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 information The original manuscript and two copies (or electronic file) are to be submitted to the editor in chief at the NVIC office by (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. Layout Paragraphs 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. Tables Tables are to be numbered independently of the figures with Arabic numbers, with headings and kept separate from the text. Figures Figures 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. References Only 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: Books (-sections): Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent J L (eds). Clinical trials for the treatment of sepsis. (Update in intensive care and emergency medicine, volume 19). Berlin Heidelberg New York, Springer, 1995, pp 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 Copyright Copyright 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. 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

19 How to submit Submit manuscript directly to: Editorial office Proofs The corresponding author will receive proofs by . Corrected proofs must be returned within 48 hours of receipt. Production process Decisions 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 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-mathematical 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 28

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