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1 Netherlands Journal Netherlands Journal o f cc r i t i c al l Cc ar re e Volume 10, No. 1 February 2006 bi-monthly official journal of the dutch society of intensive care ( nvic) In this issue from the editor The review process 2 A.B.J. Groeneveld clinical image Sternal dehiscence 3 W.J. Engelbrecht review Lung volume recruitment in chronic respiratory failure: new strategy with old tools 8 E.J.A.Westermann, M.J. Kampelmacher case report Sodium disorders in neurocritical care patients: 14 diagnostic and therapeutic dilemma s M. Petjak, K.H. Polderman, A.R.J. Girbes Structured abstracts 19 NVICatern verenigingsnieuws Onvoldoende nascholing kan effect hebben op herregistratie 32 R.A.L. de Waal, J. Damen De Commissie Richtlijnontwikkeling van de NVIC: 34 overzicht over 2005 en plannen voor 2006 J. Damen, H.J. van Leeuwen Richtlijn: Het voorkomen van bacteriële longontsteking en sterfte tijdens beademing 38 J. H. Rommes, P.E. Spronk, P.H.J. van der Voort, H.K.F. van Saene, D.F. Zandstra Nederlandse Vereniging voor Intensive Care (NVIC) V O L U M E 1 0

2 TOTAL is all about: PERFORMANCE SPEED STRENGTH ENDURANCE Voor productinformatie zie elders in dit blad

3 Colofon Executive editorial board AB Johan Groeneveld, Editor in Chief Arthur RH van Zanten, Managing Editor Kees H Polderman, Internet Editor Peter HJ van der Voort, Correspondence Editor Publisher NETHERLANDS JOURNAL OF CRITICAL CARE issn: nvic Stationsweg 73C 6711 PL Ede (Gld) Telephone: Fax: KvK Utrecht V Production Interactie, Ede Design v i l l a y, The Hague Layout Unit-1, The Hague Printing ASB Drukwerkbegeleiding, Badhoevedorp Advertising-exploitation/ Business contacts Eldering Studio BV Thomas Eldering Communication and media-specialists Zijlweg BA Overveen Telephone: Fax: Internet address Neth J Crit Care: Dutch IC society: Bankaccount ABN AMRO Ede IBAN NL 55ABNA BIC ABNANL 2 A NVIC membership and subscriptions One year NVIC-membership costs 165 (for registered intensivist) or 110(otherwise). These costs include a subscrition for the Neth J Crit Care. Separate issues are available for 27,50 excluding 6% VAT. Prices subject to change without notice. Further information can be obtained by telephone at or by fax at Netherlands Journal o f c r i t i c a l c a r e Vol. 10, No. 1, February 2006 From the editor The review process 2 A.B.J. Groeneveld Clinical image Sternal dehiscence 3 W.J. Engelbrecht Information for authors 7 Scientific manuscripts, reviews, reports, opinions and guidelines Lung volume recruitment in chronic respiratory failure: new strategy with old tools 8 E.J.A.Westermann, M.J. Kampelmacher Sodium disorders in neurocritical care patients: 14 diagnostic and therapeutic dilemma s M. Petjak, K.H. Polderman, A.R.J. Girbes Structured abstracts 19 NVICatern Verenigingsnieuws 23 Agenda 23 Onvoldoende nascholing kan effect hebben op herregistratie 32 R.A.L. de Waal, J. Damen De Commissie Richtlijnontwikkeling van de NVIC: 34 overzicht over 2005 en plannen voor 2006 J. Damen, H.J. van Leeuwen Richtlijn: Het voorkomen van bacteriële longontsteking en sterfte tijdens beademing 38 J. H. Rommes, P.E. Spronk, P.H.J. van der Voort, H.K.F. van Saene, D.F. Zandstra Inschrijvingsformulier 55 Copyright 2006 nvic All information contained in this issue is the property of the NVIC. Reproduction in any kind is prohibited without prior written permission by the NVIC. 1

4 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. F R O M T H E E D I T O R The review process In this issue of the Neth J Crit Care, we would like to emphasize the independent review process for our journal. Indeed, papers are externally peer-reviewed by at least one external reviewer outside the editorial board and we would like to expand the number of reviewers per paper, since this will improve the quality. Moreover, we will try to shorten the time associated with the peer-review process, aiming at a maximum time interval of 3 months between submission and publication, in line with trends for international journals. Obviously, this can only be achieved by dedicated section editors and reviewers and we would like to take the opportunity to thank the following reviewers who devoted the precious time in reviewing for the NJCC. The quality of the journal critically depends on the quality of the reviews. Finally, editorial dreams include a web-based online system for submission, reviewing and editing. Johan Groeneveld Reviewers 2005 Dr PE Spronk Prof dr J Damen Dr DF Zandstra Prof dr PCM van den Berg Prof dr JG van der Hoeven Dr JMM Verwiel Prof dr GJ Scheffer Drs ARH van Zanten Dr KH Polderman Dr MJ Schultz Dr MA Kuiper Dr A van Kaam Dr TS van der Werf Dr R Braams Dr J Kesecioglu Dr M de Hoog Dr PHJ van der Voort Dr AJ van Boven Dr JE Tulleken Dr JA Hazelzet Dr P Pickkers Dr E de Jonge Dr JM Binnenkade Dr MA Boermeester Dr PHM Egbers Dr HJ van Leeuwen Dr OHH Beenen Dr HM Oudemans-van Straaten Dr MJIJ Albers Dr GD Vos 2

5 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received December 2005; accepted in December 2005 C L I N I C A L I M A G E Sternal dehiscence W.J. Engelbrecht Department of Intensive Care, VU Medical Centre Amsterdam, The Netherlands Figure 1. Chest X-ray with of out of line positioning of sternal wires, suggestive of sternal dehiscence. A 66-year old female was admitted to our Intensive Care Unit after cardiac surgery. She had undergone mitral valve reconstruction because of progressive congestive cardiomyopathy, caused by mitral valve insufficiency. She had a history of morbid obesity; 2 months before surgery, atrial fibrillation was converted to sinus rhythm by electroconversion. At the end of surgery, there was a total heart block, followed by a rapid atrial rhythm for which electrocardioversion was performed. External pacemaker wires were placed on the epicardium. The postoperative recovery was complicated by an airway infection. Because of persisting pacemaker dependency, an internal pacemaker was placed fourteen days after the valve operation. Eight days later (22 days after surgery), we did not succeed in weaning the patient from the ventilator. The patient was very anxious each time she woke up. For this, treatment with anxiolytics was started. Another possible cause for the difficult weaning process was pulmonary oedema, and the patient was treated by continuous infusions of furosemide. In the days following this treatment regimen some progression was made but one week later, we had to conclude that weaning was stilll unsuccessful. To exclude a cardiac cause a pulmonary artery catheter was placed. Measurements showed a normal cardiac index and no signs of cardiac dysfunction. Three days later, a dehiscent sternum was palpated by physical examination. The cardiac surgeon performed a refixation operation of the sternum. There were no signs of infection present. Ten days after this operation, the patient was successfully weaned from the ventilator and extubated. Fifteen days later, the patient could be discharged from the hospital. After the discovery of the dehiscent sternum on physical examination we re-evaluated the daily performed chest X-ray s of the patient together with the radiologist. The chest x-ray on the day of discovery is shown as figure 1. On re-evaluation of previous chest x-ray s, the sternal dehiscence could be visualized from the fourteenth day after surgery on, and it had been present for more than fourteen days until recognition. Sternal wound complications including infection and dehiscence are serious, with a prevalence of 0.3-5% and a mortality rate between 14 and 47%, after cardiac surgery [1, 2]. Pre-operative risk factors for sternal dehiscence are chronic obstructive airway disease, diabetes mellitus, obesity and smoking. Perioperative risk factors are a prolonged bypass time, off-midline sternotomy, osteoporosis, use of internal thoracic arteries or excessive use of bonewax in combination with electro-coagulation. The most important postoperative risk factors are blood transfusion, rethoracotomy, prolonged duration of mechanical ventilation, placement of a tracheostoma and prolonged length of stay in the intensive care unit. The diagnosis of sternal dehiscence is relatively simple. Physical examination with inspection of the sternal wound, palpation of the sternum and auscultation for rubs during palpation is easily done and highly sensitive. One should also look for signs of infection: fever, a raises the white blood cell count or C-reactive protein, in case mediastinitis is suspected. On a plain chest X-ray, some typical signs can make a dehiscence likely. One should look for broken sternal wires, changes in the position of the wires, especially when comparing the position of the wires to one another. One should also look for signs of dehiscence (a dark bandage in the middle of the stenum) and signs of fractures or pseudarthrosis. For a thorough investigation one should compare the chest X-ray with an X-ray that is made shortly after surgery [3]. When a mediastinitis is suspected, a CT scan can reveal infiltrates, abscesses and a more thorough visualization of bony structures. In our patient we missed the diagnosis of sternal dehiscence on physical examination and on routine daily chest x-ray examinations for numerous days. This prolonged the course of postoperative recovery in the ICU. Correspondence W.J. Engelbrecht References 1. Losanoff JE, Richman BW, Jones JW. Disruption and infection of median sternotomy: a comprehensive review. Eur J Cardio-thor Surg 2002;21: Douville EC, Asaph JW, Dworkin RJ, Handy JR Jr, Canepa CS, Grunkemeier GL et al. Sternal Preservation: A Better Way to Treat Most Sternal Wound Complications After Cardiac Surgery. Ann Thorac Surg 2004;78: Boiselle PM, Mansilla AV. A Closer Look at the Midsternal Stripe Sign. AJR 2002;178:

6 Hoewel Thomas een inwendige port-a-cath heeft tengevolge van zijn taaislijmziekte, is hij net zo ondeugend als andere kleine jongetjes. Om het risico op infectie te verminderen wordt de catheter gefixeerd met IV3000. Hierdoor kan Thomas rustig doorgaan met zijn zeer belangrijke bezigheid van het te water laten van zijn nieuwe schip. Smith & Nephew B.V. Postbus AM Hoofddorp T Handelsmerk van Smith & Nephew

7 Editorial Board of the Netherlands Journal of Critical Care A.B. Johan Groeneveld, Editor in Chief Dept. of Intensive Care Medicine VU University Medical Center PO box MB Amsterdam Arthur van Zanten, Managing Editor Dept. of Intensive Care Medicine Gelderse Vallei Hospital PO box HN Ede Kees Polderman, Internet Editor/ Section Editor Dept. of Intensive Care Medicine VU University Medical Center PO box MB Amsterdam Peter van der Voort, Correspondence Editor Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box BR Leeuwarden Jan Bakker, Section Editor Dept. of Intensive Care Medicine Erasmus Medical Center Rotterdam PO Box CA Rotterdam Johan Damen, Section Editor Dept. of Cardiothoracic Anesthesiology and Intensive Care Medicine Isala Klinieken, location Weezenlanden Groot Weezenland 20/ GM Zwolle Armand Girbes, Section Editor Dept. of Intensive Care Medicine VU University Medical Center PO box MB Amsterdam Jan Hazelzet, Section Editor Pediatric Intensive Care Unit; Sophia Children s Hospital; Erasmus Medical Center Rotterdam PO Box CB Rotterdam Hans van der Hoeven, Section Editor Dept. of Intensive Care Medicine UMC St. Radboud PO Box HB Nijmegen Evert de Jonge, Section Editor Dept. of Intensive Care Medicine Academic Medical Center, University of Amsterdam Mail stop G3-206 Meibergdreef AZ Amsterdam Heleen Oudemans-van Straaten, Section Editor Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box HM Amsterdam Peter Pickkers, Section Editor Dept. of Intensive Care Medicine UMC St. Radboud PO Box HB Nijmegen Dick Tibboel, Section Editor Pediatric Intensive Care Unit; Sophia Children s Hospital; Erasmus Medical Center Rotterdam PO Box CB Rotterdam Paul van den Berg Dept. of Intensive Care Medicine Leids University Medical Center PO Box RC Leiden Alexander Bindels Dept. of Internal Medicine Catharina Hospital Michelangelolaan EJ Eindhoven Reinier Braams Dept. of Intensive Care Medicine University Medical Center Utrecht PO Box GA Utrecht Can Ince Dept. of Physiology Academic Medical Center, University of Amsterdam Meibergdreef AZ Amsterdam Anton van Kaam Dept. of Neonatal Intensive Care Emma Children s Hospital Academic Medical Centre University of Amsterdam, Meibergdreef AZ Amsterdam Jozef Kesecioglu Division of Perioperative Medicine and Emergency Care, Cardiothoracic and Neurosurgical Intensive Care University Medical Center Utrecht Mail stop E03-511; PO Box GA Utrecht Michael Kuiper Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box BR Leeuwarden Andrew Maas Dept. of Neurosurgery Erasmus Medical Center Rotterdam PO Box CB Rotterdam Manu Malbrain Dept. of Intensive Care Medicine Academic Hospital Stuivenberg Lange Beeldekenstraat 267 B-2060 Antwerpen, Belgium Gerrit-Jan Scheffer Dept. of Anaesthesiology UMC St. Radboud PO Box HB Nijmegen Marcus Schultz Dept. of Intensive Care Medicine Academic Medical Center, University of Amsterdam Mail stop G3-206 Meibergdreef AZ Amsterdam Peter Spronk Dept. of Intensive Care Medicine Gelre Hospital, location Lukas PO Box DS Apeldoorn Tjip van der Werf Intensive and Respiratory Care Unit Dept. of Internal Medicine Groningen University Hospital PO Box RB Groningen Durk Zandstra Dept. of Intensive Care Medicine Onze Lieve Vrouwe Gasthuis PO Box HM Amsterdam 5

8 Laat de humane cel ongemoeid Cell Membrane Fungal Cell Wall ß(1,3)-D-glucan Cell Membrane Fungal Cell Wall CANCIDAS Precursors to ß(1,3)-D-glucan Normal Cell-Wall Synthesis Precursors to ß(1,3)-D-glucan Synthesis Inhibited by CANCIDAS Invasieve candidiasis? C. albicans C. rugosa C. glabrata C. parapsilosis C. tropicalis C. krusei C. guilliermondii C. lipolytica C. dubliniensis C. kefyr C. lusitaniae A. flavus A. fumigatus A. terreus A. niger A. nidulans CANDIDA ALBICANS CANDIDA NON-ALBICANS ASPERGILLUS 0205 CAN04NL86J Duarte P.N.: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 347: , David W. Denning: Echinocandin antifungal drugs. The Lancet 362: , 2003 Raadpleeg alvorens het product voor te schrijven de volledige productinformatie. CANCIDAS is een geregistreerd handelsmerk van Merck & Co., Inc., Whitehouse Station, NJ, USA M Postbus 581, 2003 PC Haarlem, Telefoon , Bewezen effectiviteit 1 Gunstig veiligheidsprofiel 2

9 Information for authors The Netherlands Journal of Critical Care (Neth J Crit Care) is the official journal of the Dutch Society of Intensive Care ( Nederlandse Vereniging voor Intensive Care-NVIC ). Reports of research related to any aspect of the field of intensive care, whether laboratory, clinical, or epidemiological, will be considered for publication in Neth J Crit Care. All manuscripts will be subject to an independent reviewing process managed by the executive board. Major Articles. Major articles report the results of original investigations that have been brought to an acceptable degree of completion. They should contain a maximum of 4,000 words and 50 references. Manuscript should be clear in outline (with subheadings) for maximum clarity. There is no fixed limit to the number of figures and tables; However, duplication of data from the text of the manuscript should be avoided. The first page of the manuscript should include: The title of the article, the names of all authors, footnotes to the title, complete address of all authors with identification of the corresponding author, and running title (for page heading). The text should contain the following sections: an Abstract, Introduction, Materials and Methods, Results, Discussion and Conclusion. An abstract should not exceed 250 words. In addition, writers are encouraged to write one or more short key-messages. For major articles the abstract should be divided into the following sections: Objective - Setting and Patients Interventions - Measurements and Main Results - Conclusions. (Systemic) reviews. Review articles are usually submitted after prior consultation with the editors, and are subject to the peer review process. They should contain a maximum of 4,000 words and 50 references. Systemic reviews should be focused: state the question to be addressed, the methods by which potential materials (original articles, published and unpublished abstracts, etc) have been selected, and the methods through which they are subsequently appraised. The text should contain an Abstract, Introduction, Search Results, Discussion and Conclusion section. An abstract should not exceed 250 words. For reviews it should be divided into the following sections: Objective - Search strategy Summary of findings - Conclusions. Editorials. Editorials may deal with any aspect of intensive care medicine. They are generally invited, but occasionally unsolicited editorials may be considered. Clinical notes, images in intensive care medicine, and case reports Clinical notes should describe a specific intensive care medicine-related entity; images in intensive care medicine are photographic pictures in intensive care medicine, noteworthy for their scientific, emotional and/or challenging content; case reports are short presentations on cases that merit special attention. Clinical notes, images in intensive care medicine, and case reports should include an abstract and must be limited to no more than 2000 words of text, a maximum of two inserts (tables or figures), and 15 references. In addition, writers are encouraged to write one or more short key-messages Letters. Only correspondence submitted in reference to a previous publication in NJCC will be considered. Letters should be submitted within 8 weeks of publication of the paper to which it refers. Please prepare the letter in manuscript format, including a title page. Letters are limited to a maximum of 500 words of text, one table or figure, and a maximum of 5 references. Guidelines. Guidelines, which are produced by the NVIC guideline committee ( commissie richtlijnontwikkeling ) will be published in our Journal. Guidelines are usually preceded by a review on the topic of the guideline; these reviews should be in English, and are subject to the peer review process. Guidelines themselves will be published in both English and Dutch. General information. Manuscripts should be submitted by (as attachments) to: The manuscript should be accompanied by a cover letter stating the following: the complete mailing address, address, telephone number and fax number of the corresponding author. Receipt of the manuscript will be acknowledged by within 14 days. If this should not be the case, authors are requested to check with the editor. Please submit your manuscript as a Word- Perfect or Microsoft Word text-file. The language of the journal is English. Authors who are not fluent in the Englsih language should have their manuscript checked by a native English speaker. Tables. Tables should be numbered independently of the figures, with Arabic numerals, with headings, and kept separate from the text. Figures. Figures should also be numbered using Arabic numerals, and kept separate from the text. Legends should be provided on a separate sheet. Schematic line drawings are preferred. Figures previously published elsewhere will generally not be considered for publication, except for review articles, provided written permission from the original authors has been obtained and the source is clearly indicated. Colour figures are encouraged. Short, clear legends make additional description in the text unnecessary. The preferred location for figures and tables may be marked in the margins of the manuscript sheets. During the final lay-out process these remarks will be taken into account. References. Only articles cited in the text should be listed. These should be arranged in order of appearance in the text [ ] and numbered sequentially. Only the reference number should appear in the text. The maximum number of listed authors is six; if there are more than six authors please list the first six and add et al. Article in journals: Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344: Books or book-sections: Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent JL (eds) Clinical trials for the treatment of sepsis. (Update in intensive care and emergency medicine, volume 19). Berlin Heidelberg New York, Springer 1995: pp Proofs. The corresponding author will receive proofs by as a pdf-file (Adobe -Acrobat - file). Corrected proofs must be returned by fax within 48 hours of receipt. Production process. Decisions of the editors are final. All materials accepted for publication are subject to editing. The original manuscript will be discarded one month after publication unless the author requests the return of these original materials. The Neth J Crit Care reserves the right to edit manuscripts to conform to the journal style, and to improve clarity, precision of expression, and grammar. Authors may review these changes at the proof stage, but should limit any alterations in the proofs to correction of errors and clarification of misleading statements. 7

10 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received June 2005; accepted in revised form January 2006 Lung volume recruitment in chronic respiratory failure: new strategy with old tools E.J.A.Westermann, M.J. Kampelmacher Centre for Home Mechanical Ventilation, Division of Internal Medicine and Dermatology, University Center Utrecht, Utrecht, The Netherlands Abstract. Lung volume recruitment is achieved by insufflation of the lungs with the largest volume they can hold. It enables airway patency and supports removal of airway secretions. The different techniques are mechanical insufflation with resuscitator bag, volume ventilator or cough mimicking device, as well as voluntary inhalation during glossopharyngeal breathing. They can be performed invasively and noninvasively. The former are nowadays more frequently practised in the ICU as part of a ventilatory strategy. The latter require cooperation and are also known as air or breath stacking. Although lung volume recruitment techniques for acute lung injury can improve oxygenation and compliance, they have yet to demonstrate an improvement in outcome of intensive care treatment. In chronic respiratory failure noninvasive manoeuvres have unfortunately been forgotten by most of us, since we have grown accustomed to mainly invasive techniques for the removal of airway secretions. Retrospective studies suggest time has come to reconsider what is already known for many years and to start using lung volume recruitment techniques with noninvasive removal of airway secretions on a broader scale, especially in cooperative patients with muscle weakness and chest wall stiffness. They may, in fact, prevent pulmonary morbidity, hospital admissions and tracheotomies. Another inheritance of the past is that randomized controlled studies in this field are almost non-existent. Despite the favourable experiences elsewhere, such studies will be needed before techniques and devices to support lung volume recruitment may be used more generally in intensive care of these patients. The acknowledgement of intensivists to use lung volume recruitment more generally may necessitate a change in the usual approach of respiratory failure. With the appropriate level of alertness and team effort, secondary complications of long term mechanical ventilation will be prevented. Introduction Lung volume recruitment (LVR) is a dynamic physiologic process that, at least in the healthy lung, refers to the reopening of previously collapsed alveolar units. Normally this is achieved by inspiratory force during stretching, yawning and sighing [1]. In the absence of voluntary movement or adequate inspirational force, they can be mimicked by special manoeuvres such as air stacking, glossopharyngeal breathing and mechanical insufflation. The common purpose of these techniques is to deliver the largest volume of air the lungs can hold. Thus, bronchial secretions are mobilised and alveolar collapse is resolved. When deep insufflations are followed by spontaneous coughing, manually assisted coughing (MaAC) or mechanically assisted coughing (MeAC), they can help remove airway secretions and thus maintain airway patency. LVR techniques may be performed invasively as well as noninvasively via translaryngeal tubes or tracheostomy cannulae, respectively, oral or oronasal interfaces. Clearly, to perform these techniques effectively, cooperation of the patient is needed. On the other hand, insufflation techniques can be performed in the critically ill by using manual resuscitator bags, sophisticated mechanical ventilators or by mechanical insufflation devices. Since more than a decade invasive LVR has been advocated to maintain oxygenation, carbon dioxide removal and compliance in diseased lungs of the critically ill on mechanical ventilation [2]. In these patients alveolar collapse, flooding and consolidation occur together and require a different recruitment approach, which has been described elsewhere [2-6]. It is, however not yet clear how these actions may influence ICU-outcome in terms of unit survival and length Correspondence: of stay [6], but local opinion is optimistic. Although briefly beneficial for ventilation, oxygenation and compliance, LVR is at present not yet practised uniformly as part of a lung-protective mechanical ventilation strategy and ventilation modes incorporating sighs have nowadays largely been abandoned. Instead, the open lung concept has been introduced in computer driven tools for ventilatory strategies. Nevertheless, it is clinically important to distinguish between different LVR strategies, especially in lung injured ICU-patients with significant muscle weakness and to assure that the correct technique is used in the appropriate clinical circumstance and at the appropriate time. Then what could be the place of LVR in the management of respiratory failure? It is clear that LVR may resolve alveolar collapse and loosen airway secretions, but in itself is not appropriate to remove them. The latter is crucial to achieve the most important goal of mechanical ventilation and to facilitate its discontinuation process. In critical care medicine we have before long focused only on invasive methods for clearance of airway secretions. We must, however, admit that bronchial suctioning procedures and bronchoscopies are only partially effective at best for this purpose. Furthermore, in our experience, respiratory power failure in the critically ill is regularly approached expectantly, unless life-threatening hypoxia supervenes. Apart from mechanical ventilatory support few additional measures are usually taken to improve evacuation of airway secretions. There are, however, some more to consider. We must ask ourselves whether or not the accustomed treatment strategy itself might be an important surplus factor in determining the length of mechanical ventilation, its discontinuation and the length of unit stay. To address these issues it is necessary to evaluate the extent of conventional therapy, E.J.A. Westermann 8

11 the pathophysiology of respiratory power failure and to discuss other procedures, which may also be beneficially applied in the ICU. Conventional measures for respiratory failure The objectives of treating respiratory failure in the ICU are primarily to improve gas exchange, diminish work of breathing (WOB), prevent secondary complications and to shorten length of unit stay. The latter is determined by the time spent by reversal of disease processes and the duration of discontinuing ventilation. Additionally, it is vital to maintain airway patency. This is mainly achieved by invasive techniques, such as bronchial suctioning and bronchoscopies, but also by postural drainage. Prone positioning as a ventilatory strategy can sometimes be considered as the high point of postural drainage, especially when the increased requirement for bronchial suctioning immediately afterwards is observed. Furthermore, airway patency is supported by bronchodilators, mucolytic agents and aerosolized antibiotics [7]. Techniques to mobilise secretions are usually not suitable to remove them, such as chest physiotherapy, manual percussion [8,9] and noninvasive intrapulmonary percussive ventilation [10]. MaAC and MeAC to remove airway secretions are seldomly practised in the ICU: the former as a matter of fact seem rather useless to perform in uncooperative intubated or cannulated individuals and the latter has in the past simply never been given any consideration. Although, on the one hand it is as yet uncertain if assisted coughing can be safely undertaken regarding the still unclear risks of creating or maintaining biotrauma [11], on the other, mechanical insufflation with a manual resuscitator can assist in improving oxygenation and mobilising secretions prior to bronchial suctioning. Its application invariably ceases as soon as patients are judged well enough to be extubated or decannulated, after which one usually assumes that the patient can sigh and cough effectively without assistance. This assumption is hardly ever proved: it is not customary to measure vital capacity (VC) or even peak cough flow (PCF) in the ICU except prior to invasive airway management during imminent respiratory failure. When secretions cannot be evacuated, reintubation is often necessary and unit stay may be prolonged. Invasive ventilation and invasive mucus clearance techniques will remain the preferred approach for most critically ill patients with acute or acute on chronic respiratory failure, especially when combined with multisystem dysfunction. Recently, however, noninvasive ventilation for solitary acute respiratory failure has been started more often, with clearly defined benefits for selected patients and the ICU. Of note, patients on noninvasive ventilation must be able to cough or rely on noninvasive methods for secretion removal. Otherwise, noninvasive ventilation will soon become ineffective after which we will have to resort to invasive treatment modalities. Who may benefit from LVR in the ICU? Probably, a larger number of patients than has previously been appreciated may benefit from LVR and noninvasive mucus clearance techniques. Those with acute or acute on chronic respiratory failure with multiple system involvement can only become possible candidates after resolution of the acute disease, rendering them clinically stable and cooperative, but still respiratory dependent and obviously not yet able to completely discontinue mechanical ventilation [12,13]. The second category of patients with stable acute on chronic respiratory failure, who are cooperative and willing to comply with treatment are candidates for noninvasive mechanical ventilation and therefore, if their PCF is inadequate, also for LVR and noninvasive secretion management techniques. Thirdly, there is a growing and ageing population with chronic respiratory insufficiency on home mechanical ventilation, which usually has to depend on local ICU facilities when admitted to a hospital acutely or electively and for other than respiratory reasons. As yet it is doubtful whether LVR can achieve its goals in these patients. Finally, there is a group of clinically stable patients with a progressively restricted respiratory reserve who may become respiratory insufficient in the near future. The main goal of their follow-up is prevention of acute on chronic respiratory failure, ICU admission and to start noninvasive chronic mechanical ventilation electively [14-17]. Whereas in the past their ventilatory deterioration was passively followed, earlier experience and recent insights have learned that active involvement in LVR may improve their general condition and PCF, postpone chronic mechanical ventilation and probably avoid tracheotomies. In retrospect, this expectant approach has been successfully challenged for many years and under varying clinical circumstances. Some rehabilitation centres in the United States and Canada have managed over 800 continuously ventilator dependent individuals with LVR and coughing techniques, some for over 50 years, without tracheostomy [18-21]. Still, it seems difficult to change the generally employed conventional insights and to try something different, probably because we prefer to adhere to reliable techniques, which we have grown accustomed to in the past [22-24]. Pathophysiology-the reasons to try something else. Normal respiration at varying metabolic demands is characterized by the maintenance of airway patency, normocapnia and normoxia. To achieve the first, adequate airway reflexes and coughing strength are essential. Ventilatory pump failure is the final common pathway in acute as well as chronic respiratory insufficiency. The main physiologic derangements are caused by respiratory muscle weakness and muscle contraction insufficiency. Both compromise ventilatory reserve and the ability to cough effectively. Respiratory muscle weakness is often accompanied by muscle atrophy, fibrosis and shortening, which ultimately result in an increased elastance and contractures. This stiffens the chest wall and by limiting inspiratory and expiratory pressures, gradually decreases VC. When VC approximates tidal volume, a WOB comparable to that of maximal minute ventilation occurs, which energetically can at best be sustained by contracting a pattern of rapid shallow breathing (RSB) [25-27]. Then, expiratory force must be generated to increase expiratory flow at the expense of additional WOB. Moreover, an increased pulmonary elastance has been shown to be present in muscle weakness even before hypercapnia can be registered. This increased elastance, measured as the elastic load of the lungs per unit of maximal inspiratory muscle strength, was the strongest predictor of the variance in PCO 2 [28]. The most common cause of an increased elastance in neuromuscular disease is microatelectasis or chest wall abnormalities or a combination of these [29-31]. Microatelectasis can result from prolonged motionless positioning during sleep, sedation or anesthesia, pharmacological muscle relaxation, mechanical ventilation with high FiO 2, destruction of surfactant, clogging of small airways by retained bronchial secretions and failure to take periodic deep breaths. It is hypothesised that RSB is the consequence of the 9

12 disturbed balance between elastic load and muscle strength. On the other hand, RSB causes microatelectasis, which closes the vicious circle. Muscle weakness impairs the three phases of coughing and thus causes decreased PCF s as well as alarming symptoms of asphyxiation and oxygen desaturation. Especially impaired coughing poses an increased risk of pulmonary morbidity, acute on chronic respiratory failure and mortality in patients with neuromuscular disease [20]. Together, muscular weakness and decreased compliance are responsible for the development of alveolar hypoventilation and impaired coughing. Evidently, during increased metabolic demands or when airway resistance is raised following retention of bronchial secretions or respiratory tract infections (RTIs) compensatory mechanisms will be overwhelmed. This will result in respiratory acidosis, shortly thereafter followed by death. Since muscle weakness commonly occurs in critically ill patients without primary neuromuscular disease, especially in those with a prolonged ICU length of stay [32-34], it can be anticipated that loss of respiratory compliance, risk of aspiration and retention of bronchial secretions may negatively influence the process of discontinuing artificial ventilation. It therefore seems rational for treatment to support inspiratory as well as expiratory muscle strength and to address ineffective coughing [35]. Old tools to improve mucus clearance revisited To reverse or better still, to prevent the ventilatory derangements accompanied by RSB, several noninvasive LVR techniques, using deep insufflations should be applied regularly every day. In addition, noninvasive ventilation should be started as needed. These noninvasive methods date from the polio epidemics [36]. The direct clinical goal of these measures is to increase intrathoracic volume, stretch expiratory chest wall muscles to increase their preload, increase lung recoil and mobilise secretions. When followed by voluntary coughing, PCF is enhanced, and it should be further improved by MaAC [37]. The long term goals are the improvement of chest wall and pulmonary compliance, to diminish air leakage during noninvasive mechanical ventilation, facilitate noninvasive ventilation by mouthpiece, prevent pneumonia s and hospital admissions and the need for intubation and tracheostomy. In an adult, a PCF exceeding 160 l/min (2.7 l/sec) is minimally required to clear the airways of secretions. A minimal assisted PCF of 270 l/min (4.5 l/sec) is required to prevent complications of pneumonia, as during chest infections, these PCFs usually drop below 160 l/min [38,39]. Deep insufflations can be provided for by air or breath stacking with a resuscitator bag, respectively, a volume controlled mechanical ventilator. Secondly, deep inhalations can be provided for by glossopharyngeal breathing (GPB) and lastly by mechanical insufflation-exsufflation (MI-E) with a mechanical air compressor also known as cough-assist, using just the insufflation phase. Table 1. Classification of diseases as to their level of respiratory compromise Respiratory centres Idiopathic central hypoventilation Congenital central hypoventilation syndrome (CCHS, «Ondines curse») Arnold-Chiari malformation Central sleep apnea syndrome Brainstem lesions e.g. infarction, hemorrhage, infectious disease or tumour Spinal cord and peripheral nervous system Upper cervical spinal cord injury Syringomyelia Motor neuron diseases (following poliomyelitis, amyotrophic lateral sclerosis) Juvenile progressive spinal muscular atrophy Hereditary motor and sensory neuropathy Guillain-Barré syndrome Bilateral phrenic nerve paralysis Critical illness polyneuromyopathy Neuromuscular junction Myasthenia gravis Lambert-Eaton syndrome Respiratory muscles Muscular dystrophies (type Duchenne, Becker) Congenital myopathies (nemalin-myopathy) Mitochondrial myopathies Hereditary disorders of muscular metabolism (Pompe disease) Myotonias (myotonic dystrophy) Electrolyte disorders (hypophosphataemia, hypomagnesiaemia) Chest wall Scoliosis (congenital or acquired; e.g. after poliomyelitis or neuromuscular disease) Chest wall distortion secondary to neuromuscular disease. 1. Air stacking, or lung and chest wall range-of-motion maintenance. Prerequisites for effective air stacking are a cooperative and motivated patient with intact bulbar function and a dedicated care giver with a high level of endurance. Tachypnea hampers the procedure. Slow successive insufflations are delivered by resuscitator bag through a mouthpiece or an oronasal mask, which is gently applied to the face to prevent the escaping of air during bagging. On squeezing the resuscitator bag, the patient is asked to inhale. The patient should not exhale between consecutive insufflations. When maximal insufflation is achieved (maximal insufflation capacity, MIC), judged by a maximal chest expansion, the patient is asked to keep his breath for a moment allowing the care giver to position his hands over the patients lower chest and abdomen. Then, patient and care giver should combine efforts in a coordinated MaAC, thus producing an assisted PCF. The patient on mouthpiece volume controlled mechanical ventilation can use his ventilator to receive deep insufflations independently. Depending on tidal volume settings he can receive and stack several breaths in succession, provided the pressure limiting alarm is disabled or maximized. If PCF remains below 160 l/min, deep secretions are insufficiently cleared [40] and MI-E should be considered as the most effective alternative. Despite progressive neuromuscular weakness, the MIC of the majority of patients can improve with training, even if VC diminishes. This can result in increased effectiveness of coughing. MIC is a function of oropharyngeal and laryngeal muscle strength and in part of pulmonary compliance. When MIC does not rise above VC, regardless of its magnitude, severe bulbar muscle weakness should be suspected [41]. Air stacking by 21 neuromuscular patients resulted in a MIC that tripled VC while PCF following MIC almost doubled, increasing even further after an abdominal thrust [42]. Some of these results were confirmed by a recent pilot study on the effectiveness of air stacking in improving unassisted PCF in 28 neuromuscular patients. An increase in coughing strength was experienced by 45% of patients. Motivation and endurance of patients as well as care providers seemed essential, as only 28% of patients complied with the thrice daily prescription of performing these LVR manoeuvres [43]. Probably, better results may be expected if patient motivation is improved. Maintenance therapy 10

13 with LVR is prescribed minimally three times daily. After gaining experience with this method, the patient may be able to use it more frequently or as needed to improve coughing during upper RTI, thereby preventing mucus retention in the distal airways. Sometimes frequencies of 6 times hourly are necessary for several days. Without a dedicated care provider it is usually impossible to avoid intubation and invasive mucus clearance techniques [38]. It is generally accepted that tracheostomally ventilated patients cannot stack breaths. Instead, they should regularly receive deep insufflations by resuscitator bags (which are limited by the squeezed volume and air leaks around the cannula) or by a mechanical in-exsufflator during the insufflation phase. 2. Glossopharyngeal breathing (GPB) or frog breathing. In this breathing technique muscles of the oral cavity (lips, mouth, tongue), pharyngeal and laryngeal structures work together to quickly take several mouthfuls and throatfuls of air and move these in rapid succession in the direction of the upper airway in a pump-like action. Every breath consists of 10 to 15 cycles or strokes ( gulps ) which last about 0.6 second each. Thus a normal sized breath can be accumulated in the lungs. It was first observed in patients surviving from poliomyelitis in the 50s who appeared to be swallowing air [44]. Later it became clear that they were actually breathing, resembling that of a frog. The technique can be used by ventilator assisted individuals to increase ventilator-free time, to stack air for LVR, stretching the chest wall and to increase coughing strength. Prerequisites for learning this technique are an intact bulbar function, more or less normal respiratory system compliance and instructors with patience. Having a tracheostomy cannula was thought to render this method ineffective. This point of view, however, has recently been refuted by a case report on a quadriplegic patient after cervical spinal cord tumour resection [45]. McKim and coworkers published comprehensive presentations with informative instructions and videos on the internet among which a tracheotomized patient using GPB to stack air following a deep spontaneous inhalation [21]. GPB is important in noninvasive management of neuromuscular weakness with preserved bulbar function e.g. cervical spinal cord injury, provided that hemodynamic stability and cooperation are preserved. Case reports show that translaryngeal intubation and tracheostomy can be prevented and totally avoided if noninvasive ventilation is initiated early together with the instruction in LVR techniques [46]. The gain for ICU departments is a substantially decreased length of stay as well as cost containment [15]. Approximately 10% of high level cervical spinal cord injuries may benefit from early noninvasive methods. In such cases the usual practice of early tracheotomy procedures warrants reconsideration in order to achieve these benefits. 3. Mechanical insufflation-exsufflation (MI-E) This technique, adding negative pressure generation to already existing cough-mimicking devices, was used noninvasively in 1953 to produce an artificial cough in COPD patients with complaints of excessive bronchial secretions. Exsufflation devices, used in iron lung dependent poliomyelitis patients in the early 50s precluded the need for bronchoscopies for mucus clearance. Contemporary mechanical in-exsufflators permit manual and automatic cycling between insufflation and exsufflation phases and setting of insufflation and exsufflation times and cycle pauses during automatic operation. In- and exsufflation pressures and insufflation flows can be set as necessary. The tubing of the device can be connected to an oronasal interface but also to a tracheostomy cannula. For treatment to be effective, pressure gradients between in- and exsufflation of approximately 80 mm Hg should be reached [47]. However, also much lower in-exsufflation pressure ranges can produce a considerable increase in PCF [48]. During manual operation an in-exsufflation cycle should last no longer than seven seconds to avoid hypoventilation during treatment, which may be a cause of its failure [49]. Furthermore, for MeAC, abdominal thrusts are to be given during the exsufflation phase to optimally increase PCF. The cooperative patient is asked to also cough during exsufflation. A treatment consists of five cycles of MI-E and to avoid hyperventilation, treatment is interrupted for seconds, during which normal breathing or mechanical ventilation can be resumed. Five such consecutive treatments comprise a session. The number of sessions needed depend on the clinical situation. To receive deep insufflations (without exsufflation) as a maintenance LVR therapy, three sessions a day are customary, however during treatment of RTI, sessions should continue until no further secretions are produced or pulse oximetry saturation exceeds 94% on a FiO 2 of To achieve these goals, during RTIs, treatments as frequently as every 10 to 60 minutes may be indicated, which put a substantial strain on the stamina of care providers and ICU nursing staff [49]. The unfamiliarity with such an intensity of MI-E causes treatment to fail and then one usually has to resort to invasive mucus clearance techniques Treatment with MI-E has been successful in clearing secretions in neuromuscular patients without breathing capability, in patients with asthma, bronchiectasis and emphysema, in facilitating extubation postsurgically in the post-anesthesia care unit, and in resolving pulmonary lobar collapse. Also intubation for acute respiratory failure caused by RTIs could be avoided by the technique [50]. Evidence from randomised controlled trials however, is scarce. It has been argued that it is even unethical to perform such studies, especially because the effectiveness of LVR therapy in these patients has become clear since so many years [42,51-53]. The effectiveness of MI-E to increase PCF was compared prospectively with other cough strength increasing methods in 22 selected neuromuscular patients versus 19 healthy controls [48]. LVR techniques were not used, except for pressure limited ventilator breaths prior to coughing. PCF increased by 128 L/min following MI-E, using substantially lower pressure settings than recommended. MI-E was well accepted by all patients, adults as well as children and resulted in a greater increase in PCF than all other cough augmenting methods, even in the normal controls. Recently MI-E has been applied as primary treatment for RTI in 11 neuromuscular patients compared with 16 historical controls [54]. Chest physiotherapy was administered in all of them. Intubation rates were reduced to 18% versus 63% among controls. Bronchoscopies had to be performed equally often as in controls (45% vs. 38%). MI-E was complicated by gastric distention in one patient, probably provoked by aspiration and bronchspasm, which required intubation. MI-E was only partly successful because of inadequate treatment and instruction [49]. Practical considerations Noninvasive LVR techniques can be advised for patients with restrictive respiratory disorders without significant pulmonary disease 11

14 when VC drops below 50% of predicted or when VC in the adult diminishes below 1.5 liter, at which point effective coughing becomes impaired. Alternatively, a PCF equal to or smaller than 270 L/min should prompt to start LVR techniques. PCF can be measured during coughing through a simple disposable peak flow meter (Respironics, Inc, Cedar Grove, NJ). In children, LVR methods are advised when their P Emax drops below 60 cm H 2 O [53] and when they are old enough to understand the procedure. If recurrent RTIs jeopardise respiration, noninvasive ventilation should be contemplated together with LVR methods for mucus clearance. In the ICU invasive LVR techniques may be considered with caution shortly before patients are eligible for discontinuation of invasive ventilation in order to facilitate and expedite the discontinuation process, extubation or decannulation. Invasive ventilation may be replaced by noninvasive ventilation, provided that noninvasive mucus clearance techniques are used. Measuring VC, PCF, MIC and PCF after MIC may identify patients, who can continue to be managed noninvasively. The workload of the ICU nursing staff may increase, but on the other hand, effective use of noninvasive mucus clearance techniques should obviate the need for bronchial suctioning and bronchoscopies. Studies to compare the effectiveness of LVR and mucus clearance techniques with conventional treatment of respiratory failure using length of invasive ventilation, length of discontinuation of ventilation, length of unit stay and cost of treatment as suggested end points should be initiated only after the safety of these techniques in avoiding volu-, baro- or biotrauma is ascertained and commitment with these methods and level of alertness of ICU staff are optimised. Although caution for adverse events is necessary in patients at risk, barotrauma or pneumothorax have not occurred [53]. Minor inconveniences include esophageal insufflation and gastric distention, which can be easily resolved. Noninvasive LVR techniques may be associated with serious complications only if a one-way valve is simultaneously used [55]. When MI-E is applied for acute pulmonary infectious disease complicating muscle weakness, occlusion of central airways by copious purulent and tenacious secretions can be a serious hazard, threatening survival [56]. In the Netherlands MI-E devices are nowadays advised for clinical use only. In conclusion, the claim of individuals with neuromuscular weakness on ICU resources can be expected to increase in the near future. Weakened muscles as well as a decreased pulmonary compliance are responsible for symptoms of respiratory failure. Whereas the first usually is resistent to therapy, possible treatment of the latter is often overlooked, unless or until artificial airways are present. Although noninvasive ventilation is nowadays an established treatment, noninvasive techniques for LVR are only seldomly applied. Using noninvasive ventilation together with noninvasive LVR and mucus clearance techniques seem to be essential in achieving surplus benefits in individual patients. Success or failure of LVR methods in achieving the preventive benefits may heavily depend on cooperation and motivation of selected individuals as well as on dedication and endurance of nursing staff and other care providers. Before we consider to use these noninvasive methods after earlier extubation or, preferably, to pursue them preventively before intubation, randomized controlled trials should be designed to determine their effectiveness and risks. Only then can LVR techniques be included in the treatment strategy more frequently and may we prevent secondary morbidity of imminent chronic respiratory failure. In addition, intensivists may then use these techniques to also unburden their already overcrowded ICU facilities. References 1. Ferris BG, Pollard DS. Effect of deep breathing and quiet breathing on pulmonary compliance in man. J Clin Invest 1960;39: Lachmann B. Open the lung and keep the lung open. Intensive Care Med 1992;18: Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J med 1998;338: The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342: Rouby JJ, Lu Q, Goldstein I. 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16 Copyright 2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received November 2005; accepted in revised form January 2006 Sodium disorders in neurocritical care patients: diagnostic and therapeutic dilemma s M. Petjak, 1,2 K.H. Polderman, 1 A.R.J. Girbes. 1 1 Department of Intensive Care, VU Medical Center, Amsterdam, 2 Department of Intensive Care, Groene Hart Hospital, Gouda, The Netherlands. Abstract. This article describes the histories of three patients who developed severe electrolyte disorders following elective neurosurgical procedures or traumatic brain injury with the emphasis on disorders of salt and water homeostasis. The literature on the subject of electrolyte disorders, especially in disorders of salt and water homeostasis in neurocritical patients, is also reviewed. These case histories provide some insight into the complexity of electrolyte disorders in critically ill patients with neurological injuries, and illustrate the difficulties in the diagnostic work-up of these patients. They also highlight the crucial role of desmopressin administration when central diabetes insipidus is suspected. Introduction Electrolyte disorders, especially disorders pertaining to salt and water homeostasis, occur frequently in patients with neurological illnesses such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH) or a brain tumour [1,2]. Hyponatraemia is often considered to be the most common electrolyte disorder in the neurological intensive care setting [2-4].The main mechanisms responsible for most of the non-iatrogenic cases of hyponatraemia in patients with neurological or neurosurgical disease are the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) and the so-called cerebral salt wasting syndrome (CWS) [3-7]. On the other hand, central diabetes insipidus (CDI) which can lead to severe hypernatraemia is frequently observed following neurosurgical interventions [8,9]. Disorders in sodium homeostasis, as well as other electrolyte disorders, have been linked to adverse outcome and increased mortality both in the intensive care unit [10-12] and general ward [13,14]. The impact of electrolyte disorders may be greater in patients with neurological injuries, as the injured brain may be more susceptible to the deleterious effects of electrolyte disorders such as hypo- or hypernatraemia [10]. The signs and symptoms of hypo- and hypernatraemia include progressive headache, nausea, confusion, disorientation, coma and seizures [15]. Other electrolyte disorders such as hypomagnesaemia and hypophosphataemia can induce hypertension, coronary vasoconstriction, disturbances in heart rhythm, and muscle weakness including weakness of respiratory muscles, leading to weaning problems and an increased rate of respiratory infections [16-18]. The latter electrolyte disorders can be caused by a combination of increased urinary excretion and intracellular shift [1]. Various studies performed by our group and by others have shown that the rate of severe electrolyte disorders (especially hypomagnesaemia, hypophosphataemia, and hypokalaemia) in patients with severe head injury and subarachnoid haemorrhage (SAH) is surprisingly high [1,19-21]. Apart from the abovementioned mechanisms that are related to the primary neurological injury itself, this may be explained by the fact that various treatments commonly used in the ICU can increase the risk and severity of electrolyte disorders [1]. Thus electrolyte disorders in critically ill patients may be, and often are, in part iatrogenic. Correspondence: M. Petjak Similar issues apply to disorders of sodium and water balance. Patients with neurological injuries and polyuresis and/or disorders in sodium metabolism are often treated with the synthetic arginine vasopressin analog desmopressin [22]; however, this can lead to (severe) hyponatraemia [23-25]. The aim of this article is to illustrate this problem using the case histories of three patients with neurological injuries (traumatic or following neurosurgical intervention), who developed severe disorders of salt and water homeostasis as well as other electrolyte disorders during their ICU admission. Case histories Patient no. 1 was a 58-year old woman who underwent a neurosurgical intervention to remove a cystic macroadenoma of the pituitary gland that was causing subacute visual impairment. Peri- and postoperative substitution of thyroid hormone and steroids was indicated due to secondary hypothyroidism and secondary adrenal failure. During endoscopic transsphenoidal surgery, it proved impossible to remove the tumour entirely. Apart from this, the procedure was uncomplicated, and the initial post-operative neurological examination revealed no abnormalities. The patient was admitted to the high-care unit of our hospital. Her Glasgow Coma Score (GCS) at that time was 15 points. Twelve hours postoperatively the patients urinary production increased to >500ml/hr. Urine examination showed a specific gravity of Desmopressin (dose: 4 µg) was administered intravenously. Six hours later the patient became disoriented and dysarthric (expressive aphasia). On neurological examination an intentional tremor of her arms was noted. There were no signs of paresis or paralysis. Blood pressure was 170/100mmHg, with a heart rate of 64 beats/min. A CT scan of the brain showed no signs of infarction or bleeding. Urinary production still exceeded 500 ml/hr. Meanwhile, laboratory tests showed (severely) decreased blood concentrations of sodium (Na + ), magnesium (Mg 2+ ), potassium (K + ) and chloride (Cl - ) (see Table 1). Serum sodium level had dropped to 121 mmol/l (pre-operative level 140 mmol/l); the urinary concentration of Na + was 167 mmol/l. Specific gravity of the urine was The patients medication at that moment was as follows: nadroparine 2850 IE subcutaneously once daily, desmopressin 2 µg as required, naproxen 250mg TID and inhalation therapy with ipratropiumbromide/salbutamol. 14

17 Table I (Patient no 1) Event ICU admission End of ICU stay Na+ (mmol/ l) K+ (mmol/ l) Mg2+ (mmol/ l) Ca2+ (mmol/ l) Phosphate (mmol/ l) Cl- (mmol/ l) Urine Na+ (mmol/ l) 167 The initial treatment consisted of hypertonic saline (1000 ml/24 hrs of 2.9% saline intravenously) and steroids (hydrocortisone 50 mg TID) as well as supplementation of Mg 2+, K + and phosphate. However, the patients neurological condition quickly deteriorated, with decreased EMV score (E4 M5 V2) followed by a generalized tonic-clonic epileptic seizure accompanied by vomiting. The patient was transferred from the high care to the intensive care unit for respiratory and neurological monitoring. Laboratory results on ICU admission are summarized in Table I. Intubation was not necessary and her neurological condition improved quickly. She could be transferred back to the high care unit 36 hours after ICU admission. Treatment at this time consisted of fluid-restriction (2 litres/24hrs comprising 1000 ml NaCl 0.9%, 250 ml NaCl 2.9% and 750 ml orally). The dose of steroids was tapered slowly. The further course was uneventful and the patient was able to leave our hospital soon thereafter. Patient number 2 was a 26-year old man who was admitted to our ICU following a motorcycle accident with severe multiple injuries, including severe head injury. The injuries included a right crural fracture, multiple facial fractures and a fracture of the skull base including the sphenoid bone. The CT scan of the brain showed some traumatic subarachnoidal bleeding in the left hemisphere, as well as some mild cerebral contusion areas in the right frontal area (Figure 1). In addition, the CT scan also showed some midline shift to the left, a slight compression of the ventricles and a pneumencephalon. As prescribed by our hospital protocol the patient had been intubated in the emergency room (ER) because the EMV score was <8. On admission to our ICU, the patients GCS had increased to 10 points (E4 M6 Vt). The laboratory results on admission were as follows: Na mmol/l, K mmol/l, and blood-osmolality 342 mosmol/kg (other electrolytes not measured). Shortly after admission his diuresis increased to >500ml per hour. Four micrograms of desmopressin were administered intravenously. Urinary output subsequently decreased to ml per hour. In the following days additional doses of desmopressin (4 µg iv) were given every 24 hours, based on (varying) urinary output of 500ml per hour or more. Desmopressin was discontinued on day 5 after hospital admission. During the preceding period, fluid balances had been positive and urinary output had stabilized around 80 ml per hour. From day 7 the serum Na + concentration started to decrease, with values of 133, 130 and 127 mmol/l measured on days 7, 8 and 9, respectively. Treatment consisted of administration of NaCl 2.9%. On day 14 serum Na + concentrations had normalized. On day 18, the patient was discharged from the ICU. Patient no. 3 was a 30-year old man with a medical history of non-seminoma testis requiring surgery 8 years before admission. Since then he had been in complete remission. Three weeks before Table II (Patient no 2) Day 6 Day 7 Day 8 Day 9 Day 10 Na+ (mmol/ l) K+ (mmol/ l) Mg2+ (mmol/ l) 0.76 Posm (mosmol/ kg) Phosphate (mmol/ 0.92 l) Cl- (mmol/ l) 107 UNa+ (mmol/ l) Uosm (mosmol/ kg) admission to our hospital, a growth hormone producing macroadenoma of the pituitary gland was diagnosed elsewhere. The symptoms included longstanding fatigue as well as subtle changes of character and physionomy. During the last days before admission there had been clinical signs of increased intracranial pressure, including headache, nausea, vomiting and finally decreased conscience and incontinence of urine. Diagnostic imaging (MRI) showed a tumour in the region of the pituitary gland with obstructive hydrocephalus. Initial treatment consisted of placement of a ventriculoperitoneal drain (VPD) to lower intracranial pressure. Subsequently an external liquor drain (ELD) was inserted because of VPD dysfunction. Endonasal sphenoidectomy with biopsy was performed, revealing growth-hormone producing macroadenoma of the pituitary. Subsequently the patient was transferred to our hospital for transsphenoidal tumor debulking. During surgery, a large tumour was resected. Twelve hours after surgery, the patients urine production increased to 500ml/hr. Laboratory results showed a serum Na + concentration of 151 mmol/ l, a plasma osmolality of 309 mosmol/ kg and a urinary osmolality of 101 mosmol/ kg suggestive of a severe concentrating defect. The most likely diagnosis at this point was a central diabetes insipidus (CDI). The patient was treated empirically with a single dose of desmopressin (2 µg). Subsequently, the polyuria subsided and serum sodium levels returned to normal. The urine specific gravity remained above Three weeks after surgery the patient was able to leave the hospital. His home medication comprised desmopressin as well as hydrocortisone and growth hormone substitution. Six months after neurosurgery the patient was doing reasonably well. A second tumour debulking surgical procedure is scheduled in the near future. Discussion Disorders of salt and water homeostasis occur frequently in the intensive care population, especially in the neurocritical care setting. There are numerous causes of hyponatraemia requiring different clinical management [1]. Often, different causes of hyponatraemia may be present simultaneously in neurocritical patients. Outside the ICU setting hypernatraemia is found mainly in elderly patients, adult patients with an impaired mental status and in very young infants. The reason for this is that these are patients most likely to have an impairment of thirst sensation and/or restricted access to water. Most ICU patients by definition do not have access to free water, and in the general ICU population hypernatraemia is most often caused by excessive treatment with diuretics and/or hyperchloraemia caused by massive infusion of crystalloids. As for diabetes insipidus, e.g. in neurocritical care patients, hypernatraemia will normally not occur because, under controlled circumstances, the increase in urinary fluid loss will be readily compensated by 15

18 Figure 1. CT scan of the brain of patient 2, showing some traumatic subarachnoidal bleeding in the left hemisphere and a few mild cerebral contusion areas in the right frontal area. Figure 2. Diagnostic imaging (MRI) of patient 3, showing a tumour in the region of the pituitary gland with obstructive hydrocephalus. administration of desmopressin and/or fluid administration. Many physicians will readily assume that polyuria following a neurosurgical procedure is highly likely to be caused by diabetes insipidus. However, this may overestimate the actual incidence of this disorder, and it should be realized that polyuria following neurosurgery is often due to other causes [26]. These may include excretion of excess fluid administered during surgery, or osmotic diuresis caused by concomitant treatments aimed at minimizing cerebral oedema. This problem is illustrated by the case history of our first patient, who underwent a trans-sphenoidal endoscopic tumour extirpation procedure and developed high urinary output shortly thereafter. An initial diagnosis of diabetes insipidus was established based on this case history and the high urinary volume with relatively low specific urinary gravity. Additional blood- and urinary analysis (osmolality, urinary sodium excretion) to confirm this diagnosis were not performed, and desmopressin was administered empirically. The ensuing marked hyponatraemia with decreased consciousness followed by seizures could very well have been the result of desmopressin administration. Hyponatraemia and seizures following intravenous administration of desmopressin acetate have been previously described in paediatric patients [23]. Williford et al. [24] performed a review of the literature and found 11 children and 2 adults in whom intranasal desmopressin administration had led to hyponatraemia; all these patients experienced seizures and/or altered mental status. Desmopressin usage as a potential cause of hyponatraemia may be overlooked especially when a patient is using the drug chronically, for example as a treatment for nocturia [25]. Around 8% of these patients may develop hyponatraemia [25]. Co-medication of our patient consisted of the non-steroidal anti-inflammatory drug (NSAID) naproxen. NSAIDs can increase the effects of ADH by reducing renal prostaglandin synthesis; prostaglandins play a key role in mediating the effects of ADH through a number of different mechanisms [27-31]. However, these mechanisms cannot fully explain all of the electrolyte disorders (hyponatraemia, hypomagnesaemia, hypophosphataemia and hypokalaemia) seen in our first patient. We therefore presume that these were caused by a combination of desmopressin administration (accounting for the severe hyponatraemia) and electrolyte loss caused by the earlier administration of osmotic diuretics. The second patient was admitted to our intensive care unit following severe traumatic head injury. Especially at admission and during the first 24 hours of his ICU stay, we observed moderate to severe hypokalaemia, hypomagnesaemia and hypophosphataemia. Severe electrolyte depletion at admission caused by a combination of intracellular shift and increased urinary excretion has been reported previously [1]. Although no toxicology screening was performed, the high plasma osmolality at admission (342 mosmol/ kg) with an estimated osmol gap of 48.6 mosmol/kg suggest that alcohol ingestion (through ethanol-induced inhibition of ADH secretion) may have contributed to the initially high urinary output. The persistently high urine osmolality (both before and after administration of desmopressin) suggest that CDI probably also played a role. Why the hyponatraemia developed after day 7 is unclear. Potential causes for hyponatraemia such as hypothyroidism, adrenal insufficiency or pseudohyponatraemia had been excluded. One potential explanation could be the development of a late anti-diuretic phase within a so-called tri-phasic response [26,32,33], as first described by Hollinshead et al. [32], who were able to induce this phenomenon with experimental injuries to the hypothalamus and/ or hypophyseal stalk. The tri-phasic response comprises an anti-diuretic phase between two distinct polyuric phases, caused by the slow release of stores of hormone from the injured posterior pituitary gland [26,32]. Another frequently occurring condition associated with hyponatraemia is cerebral salt wasting (CSW). The exact causes of this syndrome have not been fully elucidated. One possible explanation is an increase in the release of natriuretic peptides from hormoneproducing neurons in the brain that are activated by central nervous system dysfunction [34]. A diagnosis of CSW is established by exclusion; it requires the presence of an intra-cerebral lesion, a negative balance for Na +, K + and Cl and a decrease in the effective volume 16

19 of extra-cellular fluid (ECF) [35-37]. However, various animal studies have shown that infusion of large volumes of saline can lead to a significant negative Na + and Cl balance, through down-regulation of renal Na + absorption [38]. This implies that saline infusion could be a frequent, and often overlooked, cause of (excessive) urinary Na + and Cl -excretion. Singh et al. [36] have suggested that genuine CSW may actually be quite rare, and that a substantial part of CSW patients described in the literature may in fact be patients with side effects of so-called triple-h therapy (hypertension, hypervolaemia and haemodilution). The problems encountered in our second patient clearly illustrate the many different potential causes of polyuria and hyponatremia, and the potential interactions between these causes. These complex situations present a challenge to the attending physician [39]. The case history of our third patient illustrates that hypernatraemia in diabetes insipidus can develop even under controlled conditions. Diabetes insipidus is characterized by the complete or partial failure of ADH secretion (CDI) or of a renal response to ADH (NDI). As a result, renal water reabsorption decreases, and production of dilute urine varying from 3 to 20 litres/24 hours ensues. The majority of patients maintain water balance with a near normal plasma Na + concentration because their thirst mechanism remains intact [40]. However, under certain circumstances such as the postoperative state, this mechanism may be disturbed. The numerous potential causes of CDI can be subdivided into a number of subcategories including post-neurosurgery, head trauma, hypoxic or ischaemic encephalopathy, neoplasia, and various others/ miscellanous (e.g. histiocytosis X) [41]. In case of diabetes insipidus following neurosurgical procedures the incidence is particularly high after surgery for craniopharyngioma, regardless of the technique (transcranial or transsphenoidal). A recently published large retrospective study by Nemergut et al. [42] reported that patients with intra-operative CSF leak and a diagnosis of craniopharyngioma or Rathke cleft cyst (RCC) had an increased risk of transient or even persistent CDI. Establishing a diagnosis of diabetes insipidus can be difficult, since the patient s volume status influences the degree of polyuria in CDI and NDI. Therefore, a decrease in effective circulating volume can limit the urinary volume and therefore mask the presence of CDI [43]. The same is true of cortisol deficiency; a decrease in cardiac output, systemic blood pressure and renal blood flow combined with an increase in the release of ADH caused by cortisol deficiency can lead to a decrease in urinary output which in turn can mask the presence of diabetes insipidus [44]. The underlying CDI can be unmasked (and polyuria will ensue) when cortisol replacement is given [45]. Regarding the problem of polyuria in hospitalized patients in general, a distinction should be made between loss of free water and loss of solutes, respectively. A Uosm below 250 mosmol/ kg generally indicates the presence of water diuresis, and in most cases a fluid restriction test will be required to distinguish diabetes insipidus from increased water intake (including excessive intravenous administration of fluids). On the other hand isosmotic or hyperosmotic urine (Uosm 300 mosmol/ kg) is generally indicative of solute or osmotic diuresis, caused by administration of large amounts of saline, use of hypertonic enteral feed with high protein content, or resolution of a urinary tract obstruction followed by a polyuric phase. Nevertheless, partial CDI or NDI can also result in a similar Uosm. In cases where the diagnosis is uncertain measuring urinary levels of Na +, glucose and urea can be used to identify the major solute that is being excreted. In conclusion, disorders in sodium homeostasis in neurocritical patients may be complex, and often have multiple causes. Diagnostic tools are available to detect the causes that are clinically most relevant, although the interpretation of these tests can sometimes be difficult. Factors complicating the interpretation of diagnostic tests include the use of drugs that influence electrolyte metabolism, the presence of multiple causes of electrolyte disorders, and the presence of co-morbidities such as renal failure. Empiric treatment with desmopressin in patients with polyuria should be avoided in most cases, as is illustrated by the history of our first patient. The risk of side effects of desmopressin can be increased by renal electrolyte losses and various co-medications; this should be kept in mind when desmopressin treatment is considered [1,46]. An accurate assessment of the patients volume status is of crucial importance in all patients with severe electrolyte disorders, especially disorders of sodium levels, to better understand the underlying pathophysiological processes and to accurately predict the response to (empiric) References 1. Polderman KH, Bloemers FW, Peerdeman SM, Girbes AR. Hypomagnesemia and hypophosphatemia at admission in patients with severe head injury. Crit Care Med 2000;28: Cole CD, Gottfried ON, Liu JK, Couldwell WT. Hyponatremia in the neurosurgical patient: diagnosis and management. Neurosurg Focus 2004;15;16:E9. 3. Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill neurological patients. Neurologist 2003;9: Coenraad MJ, Meinders AE, Taal JC, Bolk JH. Hyponatremia in intracranial disorders. Neth J Med 2001;58: Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery 1996; 38: Betjes MG, Koopmans RP. [Hyponatremia in acute intracranial disorders: cerebral salt wasting] Ned Tijdschr Geneeskd 2000;144: Harrigan MR. Cerebral salt wasting syndrome. Crit Care Clin 2001;17: Honegger J, Buchfelder M, Fahlbusch R. Surgical treatment of craniopharyngiomas: endocrinological results. J Neurosurg 1999;90: Smith D, Finucane F, Phillips J, Baylis PH, Finucane J, Tormey W et al. Abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma. Clin Endocrinol (Oxf) 2004;61: Polderman KH, Schreuder WO, Strack van Schijndel RJ, Thijs LG. Hypernatremia in the intensive care unit: an indicator of quality of care? Crit Care Med 1999; 27: Vachharajani TJ, Zaman F, Abreo KD. Hyponatremia in critically ill patients. J Intensive Care Med 2003;18: Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med 2003;31: Arinzon Z, Feldman J, Peisakh A, Zuta A, Berner Y. Water and sodium disturbances predict prognosis of acute disease in long term cared frail elderly. Arch Gerontol Geriatr 2005;40: Al-Zahraa Omar F, Al Bunyan M. Severe hyponatremia as poor prognostic factor in childhood neurologic diseases. J Neurol Sci 1997;51: Arieff AI. Central nervous system manifestations of disordered sodium metabolism. Clin Endocrinol Metab 1984;13: Nadler JL, Rude RK. Disorders of magnesium metabolism. Endocrinol Metab Clin North Am 1995;24: Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet 1998; 352: Aubier M, Murciano D, Lecocguic Y, Viires N, Jacquens Y, Squara P et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985;313: Van den Bergh WM, Algra A, van der Sprenkel JW, Tulleken CA, Rinkel GJ. Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery 2003;52: Gadisseux P, Sica DA, Ward JD, Becker DP. Severe hypophosphatemia after head injury. Neurosurgery 1985;17: Fukui S, Katoh H, Tsuzuki N, Ishihara S, Otani N, Ooigawa H et al. Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage. Crit Care 2003;7:R7-R12. 17

20 22. Richardson DW, Robinson AG. Desmopressin. Ann Intern Med. 1985;103: Shepherd LL, Hutchinson RJ, Worden EK, Koopmann CF, Coran A. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989;114: Williford SL, Bernstein SA. Intranasal desmopressininduced hyponatremia. Pharmacotherapy 1996;16: van den Born BJ, Hart W, Koopmans RP [Clinical reasoning and decision making in practice: a 30-year old man with unexplained coma.] Ned Tijdschr Geneeskd 2005;149: Dutch 26. Seckl JR, Dunger DB. Postoperative diabetes insipidus. BMJ 1989;298: Bonvalet JP, Pradelles P, Farman N. Segmental synthesis and actions of prostaglandins along the nephron. Am J Physiol 1987;253:F Kirschenbaum MA, Lowe AG, Trizna W, Fine LG. Regulation of vasopressin action by prostaglandins. Evidence for prostaglandin synthesis in the rabbit cortical collecting tubule. J Clin Invest 1982;70: Breyer MD, Jacobson HR, Hebert RL. Cellular mechanisms of prostaglandin E2 and vasopressin interactions in the collecting duct. Kidney Int 1990; 38: Yared A, Kon V, Ichikawa I. Mechanism of preservation of glomerular perfusion and filtration during acute extracellular fluid volume depletion. Importance of intrarenal vasopressin-prostaglandin interaction for protecting kidneys from constrictor action of vasopressin. J Clin Invest 1985;75 : Ecelbarger CA, Murase T, Tian Y, Nielsen S, Knepper MA, Verbalis JG. Regulation of renal salt and water transporters during vasopressin escape. Prog Brain Res 2002;139: Hollinshead WH. The Interphase of Diabetes insipidus. Mayo Clin Proc 1964; 39: Lindsay RS, Seckl JR, Padfield PL. The triple-phase respons problems of water balance after pituitary surgery. Postgrad Med J 1995;71: Tanneau RA, Pennec YL, Jouquan J, Le Menn G. Cerebral salt wasting in elderly persons. Ann Intern Med 1987;107: Carlotti AP, Bohn D, Rutka JT, Singh S, Berry WA, Sharman A et al. A method to estimate urinary electrolyte excretion in patients at risk for developing cerebral salt wasting. J Neurosurg 2001;95: Singh S, Bohn D, Carlotti AP, Cusimano M, Rutka JT, Halperin ML. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med 2002;30: Chung HM, Kluge R, Schrier RW. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 1987;83: Zhang Y, Mircheff AK, Hensley CB, Magyar CE, Warnock DG, Chambrey R et al. Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis. Am J Physiol 1996;270:F1004-F Laredo S, Yuen K, Sonnenberg B Coexistence of central diabetes insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and treatment. J Am Soc Nephrol 1996;7: Rose BD. Physiologic approach to acid base and electrolyte disorders: hyperosmolal states hypernatremia: diabetes insipidus. In: Rose BD (ed) Clinical physiology of acid-base and electrolyte disorders, ed 4. New York: McGraw-Hill, 1994; Rose BD. Physiologic approach to acid base and electrolyte disorders: hyperosmolal states hypernatremia: Table 24-2: etiology of central diabetes insipidus. In: Rose BD (ed) Clinical physiology of acid-base and electrolyte disorders, ed 4. New York: McGraw-Hill, 1994; Nemergut EC, Zuo Z, Jane JA Jr, Laws ER Jr. Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg. 2005;103: Valtin HV, Edwards BR. GFR and the concentration of urine in the absence of vasopressin: Berliner-Davidson re-explored. Kidney Int 1987;31: Linas SL, Berl T, Robertson GL, Aisenbrey GA, Schrier RW, Anderson RJ. Role of vasopressin in impaired water excretion of glucocorticoid deficiency. Kidney Int 1980;18: Martin MM. Coexisting anterior pituitary and neurohypophyseal insufficiency. Arch Int Med 1969;123: Rose BD. Renal physiology: effects of hormones on renal function: Table 6-4: Renal actions of the prostaglandins and possible complications with nonsteroidal anti-inflammtory drugs. In: Rose BD (ed) Clinical physiology of acid-base and electrolyte disorders, ed 4. New York: McGraw-Hill, 1994;

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