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Volume 17 - No 1 - February 2013 Netherlands Journal of Critical Care Bi-monthly journal of the Dutch Society of Intensive Care Editorial Review Case report Pericardial effusion: to drain or not to drain? W.K. Lagrand, J.A.P. van der Sloot The SSEP on the ICU: current applications and pitfalls M.C. Cloostermans, J. Horn, M.J.A.M. van Putten Gastric dilatation and perforation due to binge eating J.A.M. Heijneman, R. Tahmassian, T. Karsten, E.R. van der Vorm, I.A. Meynaar Netherlands Journal of Critical Care Netherlands Journal of Critical Care E x e c u ti v e e dit o r i a l b o a r d A.B.J. Groeneveld, editor in chief J. Box, language editor C O P YR I G H T inhoud ED I TOR IAL Netherlands Journal of Critical Care ISSN: 1569-3511 NVIC p/a Domus Medica P.O. Box 2124, 3500 GC Utrecht T.: +31-(0)30-6868761 3 © 2013 NVIC. All rights reserved. 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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 67.87.10.872, 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. The SSEP on the ICU: current applications and pitfalls M.C. Cloostermans, J. Horn, M.J.A.M. van Putten D e r i v ati v e w o r k s 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. Pericardial effusion: to drain or not to drain? W.K. Lagrand, J.A.P. van der Sloot C ASE RE P OR T S 18 Gastric dilatation and perforation due to binge eating: a case report J.A.M. Heijneman, R. Tahmassian, T. Karsten, E.R. van der Vorm, I.A. Meynaar 21 Trichoderma: an unusual bystander in invasive pulmonary aspergillosis K. Ariese, L. Hulshoff, R. Jansen, P.H.J. van der Voort 25 Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis S. van der Sar-van der Brugge, H. van Ravenswaay Claasen, L. Dawson 30 A rare cause of cardiac failure following transthoracic oesophagectomy D.A. Wicherts, S. Hendriks, W.L.E.M. Hesp, J.A.B. van der Hoeven, H.H. Ponssen 33 Elevated liver enzymes and renal failure, with a surprising outcome. Two similar cases A.E. Boendermaker, D. Boumans, R.A.A. van Zanten, H. Idzerda, H. van de Hout, Th.F. Veneman 37 Editorial board 37 International advisory board 39 Information for authors Netherlands Journal of Critical Care is indexed in: EMBASEEMCareScopus N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 1 Netherlands Journal of Critical Care Accepted January 2013 E D I T OR I AL Pericardial effusion: to drain or not to drain? W.K. Lagrand1, J.A.P. van der Sloot Department of Intensive Care Adults, room C3-430, Academic Medical Center, Amsterdam, The Netherlands 1 Correspondence W.K. Lagrand – e-mail: [email protected] Key words - Hepatic and renal dysfunction, pericardial effusion, cardiac tamponade In this issue of the Netherlands Journal of Critical Care, Boendermaker et al. describe two cases of hepatic and renal dysfunction caused by neoplastic pericardial effusion and resulting in cardiac tamponade1. The incidence of hepatic and renal dysfunction in critically ill patients is high and can have various causes. Because pericardial effusion, of oncologic origin, is not the most likely cause of these organ dysfunctions, critical care clinicians often omit considering cardiac tamponade as the underlying cause. In most cases of pericardial effusion, the condition is found more or less by surprise. Once found, the question arises whether the pericardial effusion is symptomatic (i.e. cardiac tamponade) or asymptomatic (i.e. an innocent bystander without therapeutic consequences). The cases described by Boendermaker et al. nicely illustrate the clinical and therapeutic considerations and place of pericardial effusion and/or tamponade in the differential diagnosis of hepatic and renal dysfunction. The etiology of pericardial effusion is quite diverse: it may be caused by infection (bacterial, viral, fungal, mycobacteria, protozoal), inflammation (auto-immune diseases), myocardial infarction (Dressler syndrome), cardiac surgery, trauma or chemical e.g. uraemia. Pericardial effusion resulting from a malignant process, such as neoplastic pericardial effusion, may occur directly (from the malignant process itself) or as a consequence of therapy e.g. radiotherapy, chemotherapy, necessary to treat the tumour2,3. The signs and symptoms of cardiac effusion may manifest gradually, ranging from overt tamponade to no clinical signs at all. Besides this, most symptoms of cardiac tamponade are nonspecific, like anorexia, cough, hypotension, tachycardia, dyspnoea, tachypnoea and sometimes circulatory collapse. Also, like the cases presented by Boendermaker et al., patients may present with the complications of cardiac tamponade due to reduced organ perfusion resulting in hepatic and renal failure. In cases of pericardial effusion, physical examination may also reveal specific and nonspecific findings. Besides tachycardia, heart sounds may be attenuated, due to the isolating effects of the pericardial fluid. Clinically significant tamponade usually results in hypotension or shock. (i.e. Beck’s triad: hypotension, tachycardia and muffled heart tones). Jugular venous distention is usually present but may be absent in cases of hypovolemia. A key finding in cases of cardiac tamponade is pulsus paradoxus (PP)2,4,5. PP, however, is not pathognomonic for tamponade. It may also be present in cases of massive pulmonary embolism, profound haemorrhagic shock, and obstructive pulmonary diseases. PP is defined as a decline of 10 mmHg or more in systolic arterial blood pressure after inspiration during normal breathing. It may be palpable, but sometimes arterial catheterisation is needed to identify PP. It has to be emphasized that cardiac tamponade is a clinical diagnosis. Additional investigations, however, may support the diagnosis of tamponade. Electrocardiography (ECG) may reveal signs of pericardial effusion: micro voltages, electrical alternans (as a sign of a swinging heart), PR-segment depression, ST-T segment alterations such as elevation and/or depression. These ECG findings are also not specific but may fit in with the diagnosis of pericardial effusion. Chest radiography may depict an enlarged cardiac silhouette with a tent-like shape. The cardiac silhouette, however, may also remain normal despite a large amount of pericardial effusion. Echocardiography is the principal tool for making the diagnosis pericardial effusion. Echocardiographic signs of cardiac tamponade include collapse of the right atrium and/or right ventricle. Left atrial collapse occurs in approximately 25% of patients and is highly specific for tamponade. Doppler echocardiography may show respiratory variations in transvalvular blood flow. This would be an indication that signs of PP can be demonstrated by Doppler echocardiography. By subcostal echocardiographic examination the inferior vena cava (IVC) can be visualized. In cases of tamponade, the IVC is usually dilated, with little or no collapse after inspiration during normal breathing. CT-scanning, MRI and right and left heart catheterisation may be considered but are generally not needed in the evaluation of pericardial effusion, unless it is necessary to search for underlying diseases such as malignancies2. So, what do we learn from the cases presented by Boendermaker et al.? First, pericardial effusion and tamponade should be considered in patients with hepatic and renal dysfunction that has been caused by diminished hemodynamics, thereby compromising the function N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 3 Netherlands Journal of Critical Care of multiple organs including the kidneys and liver. Pericardial effusion in itself does not always result in cardiac tamponade: when it develops slowly, large amounts of pericardial fluid (> 2000 mL) may not result in tamponade, whereas small amounts of pericardial fluid (< 100 mL), accumulating in a very short time, may cause severe obstructive cardiogenic shock4,5. Neoplastic pericardial effusion usually develops slowly with gradual clinical deterioration over time due to inflow obstruction; this may eventually result in cardiac tamponade, as described in the presented cases. Second, cardiac tamponade remains a clinical diagnosis. Echocardiography is essential to assess the existence of pericardial effusion and to find clues for the severity of inflow obstruction. It is to be emphasized, however, that even when there are negative signs of cardiac tamponade by echocardiography, a cardiac tamponade may be present. Clinical signs of cardiac tamponade, in the presence of pericardial effusion, are to be diagnosed as cardiac tamponade unless proven otherwise. Removal of the pericardial fluid either by pericardiocentesis or surgery, should not be postponed in cases of clinically manifest tamponade with negative echocardiographic signs of inflow obstruction. In all patients who are hemodynamically unstable, pericardial drainage has to be considered when there is a pericardial effusion6. References 1. Boendermaker AE, Boumans D, van Zanten RAA, Idzerda H, van de Hout H, Veneman ThF. Elevated liver enzymes and renal failure, with a surprising outcome. Two similar cases. Neth J Crit Care 2012;2013;17:33-6. 2. LeWinter MM, Kabbani S. Pericardial diseases. In: Braunwald E, Zipes DP, Libby, eds. Heart disease: a textbook of cardiovascular medicine. 7th ed. Vol. 2. Philadelphia: W.B. Saunders, 2005:1757-80. 3. Refaat MM, Katz WE. Neoplastic pericardial effusion. Clin Cardiol 2011;34:593-598 4. Spodick DH. Acute cardiac tamponade. N Engl J Med 2003;349:684-90. 5. Reddy PS, Curtiss EI, O’Toole JD, Shaver JA. Cardiac tamponade: hemodynamic observations in man. Circulation 1978;58:265 6. Ariyarajah V, Spodick DH. Cardiac tamponade revisited: a postmortem look at cautionary case. Tex Heart Inst J 2007; 34:347-51. 4 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Netherlands Journal of Critical Care Accepted January 2013 REV I E W The SSEP on the ICU: current applications and pitfalls M.C. Cloostermans1,2, J. Horn3, M.J.A.M. van Putten1,2 Clinical Neurophysiology, MIRA – Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands 1 2 Departments of Clinical Neurophysiology and Neurology, Medisch Spectrum Twente, Enschede, The Netherlands 3 Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Correspondence J. Horn – e-mail: [email protected] Key words - Somatosensory evoked potentials, prognostication, post-anoxic coma, traumatic brain injury, subarachnoid haemorrhage Abstract Clinical neurological evaluation of patients in the intensive care unit (ICU) is often limited. Registration of the somatosensory evoked potential (SSEP) can assist in the neurological evaluation in these patients. In this paper, we discuss the principles, applications and limitations of the SSEPs in the ICU with a focus on prognostication in comatose patients. Registration of the SSEP is a very reliable and reproducible method, if it is performed and interpreted correctly. A bilateral absent cortical SSEP response is a reliable predictor for poor neurological outcome in patients with a post-anoxic coma, but not in patients with traumatic brain injury or subarachnoid haemorrhage. During SSEP recordings, great care should be taken in improving the signal to noise ratio. Since the interpreting clinician is often not present during the actual SSEP registration itself, the role of the lab technician is crucial in obtaining reliable SSEP results. If the noise level is too high, the peripheral responses are abnormal, or the response is not reproducible in a second set of stimuli, interpretation of the SSEP cannot be done reliably. Introduction Neurological evaluation of patients in the intensive care unit (ICU) is often limited, and clinical neurophysiology has provided several techniques to assist in the evaluation of the central and peripheral nervous system in these conditions. Techniques include the electroencephalogram (EEG), brainstem auditory evoked potentials (BAEP) and the somatosensory evoked potential (SSEP). In this paper, we discuss the principles, applications and limitations of the SSEP. SSEPs are used in a variety of clinical settings, including the evaluation of coma, neuromonitoring in the operating theatre, and the evaluation of traumatic spinal cord injury. Here, we focus on the use of the SSEP registration in the prognostication of comatose patients in the ICU. SSEP: Principles The somatosensory evoked potential is a small (< 10-50 µV) electrical signal, that can be recorded noninvasively from the skull, after giving a set of electrical stimuli to one of the peripheral nerves. Measurement of the SSEP evaluates the complete pathway from the peripheral sensory nervous system to the sensory cortex, which runs via the dorsal column lemniscal pathway via the spinal cord, brainstem and thalamus1,2. The dorsal column-lemniscal pathway consists of four neuronal populations. The cell bodies of the first-order neurons are situated in the dorsal root ganglia, the trigeminal ganglion, the midbrain trigeminal nucleus, and the vagal ganglion nodosum. The second-order neuron lies in the dorsal column nuclei (the cuneate nucleus and the gracile nucleus). Axons of these second neurons cross the midline and project to the ventroposterior nuclei of the thalamus (third-order neuron). From there the pathway projects into the network of somatosensory cortex areas (fourth-order neurons), which include primary and secondary somatosensory cortex, posterior parietal cortex, posterior and mid-insula, and mid-cingulate cortex1. Figure 1 shows the anatomical connections evaluated by the median nerve SSEP. SSEPs are usually evoked by bipolar transcutaneous electrical stimulation applied on the skin over the selected nerve, and registered with disk-electrodes along the tract. For example, in SSEP recordings of the median nerve registration electrodes can be placed at the elbow, Erb’s point, cervical, parietal and frontal cortex. The cortical response can only be interpreted reliably, when the peripheral responses are present. In the nomenclature of SSEP waveforms, N or P followed by an integer (e.g. N20) are used to indicate the polarity and the nominal post-stimulus latency (in ms) of the recorded wave in the healthy population1. The earliest cortical potential is the N20, which is generated in the primary somatosensory cortex, where thalamocortical cells make synaptic connections with the superficial and deep pyramidal cell layers3,4. In comparison to the later cortical responses, the N20 is the most robust, and is the latest waveform to disappear during increasing levels of encephalopathy. Furthermore, the N20 is relatively independent to the level of sedation1. As the N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 5 Netherlands Journal of Critical Care later cortical waveforms (P45, N60 and P/N100) are less reliable and more susceptible to changes by sedation, the N20 is used in all prognostic clinical routines. The N20 SSEP in Prognostication Postanoxic Coma Bilateral absence of short latency (N20) SSEP response has been identified as the most powerful predictor of poor outcome in patients who are unconscious after circulatory arrest1. In patients not treated with hypothermia, bilateral absence of cortical N20 responses 24 hours or more after the ischemic event is a reliable predictor for a poor neurological outcome5,6,7. A systematic review of Robinson showed a false positive rate (FPR) of 0%6, while a meta analyse of Wijdicks et al. found a 0.7% false positive rate for bilateral absent N20 responses in those patients7. In patients treated with therapeutic hypothermia, absence of the N20 also indicates a poor prognosis. In two large prospective studies, including 228 patients, the median nerve SSEP was found to be a reliable tool to predict a poor outcome after rewarming with an FPR of 0%8,9. However, a retrospective study of Leithner in 122 available SSEPs revealed one patient treated with therapeutic hypothermia after cardiac arrest with bilateral absent N20 responses at day 3 with good neurological outcome10. This SSEP was measured on day 3 under sedation with midazolam and fentanyl in a patient with alcoholic polyneuropathy. Despite this single case, pooled analysis of these three recent studies8,9,10 on cardiac arrest patients after hypothermia still give very low FPRs of 0.9%, indicating that bilateral absence of the N20 should still be viewed as a reliable predictor for poor outcome in patients treated with hypothermia. Figure 1. The anatomical connections evaluated by the median nerve SSEP Postcentral gyrus Thalamus Cuneate nucleus Lower brainstem Median nerve 6 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Spinal cord Recent studies show that already during the period of hypothermia the SSEP is a reliable tool to predict a poor outcome9,11,12,13. A pooled analysis of these four prospective studies (424 patients), shows an FPR of 1.5% with a sensitivity of 28%. The FPR of 1.5% results from three patients with good neurological outcome and bilateral absent N20 responses during hypothermia, who were reported in the study of Bouwes et al9. However, in a post hoc assessment of these SSEP registrations it was concluded that these three SSEP recordings were undeterminable because there was too much noise in the registration9. Correction of these results led to an FPR of 0%. Unfortunately, preservation of the N20 does not imply a favourable outcome in patients after cardiac arrest. In fact, only a small proportion of patients with a poor outcome after resuscitation have negative SSEP responses resulting in a low sensitivity. This low sensitivity of the SSEP is also reflected in the large variability of EEG patterns that can be observed in patients with a preserved N20, including status epilepticus or even electro-cerebral silence4. As pyramidal cell synaptic function is mainly reflected by the EEG, while SSEP mainly evaluates the thalamocortical synaptic function, a possible explanation is selective hypoxic damage to the cortical pyramidal cells’ synaptic function, with preserved thalamocortical synapses4. Traumatic Brain Injury In patients with severe traumatic brain injury (TBI), the results available on the reliability of SSEP to predict outcome have been contradictive. Sleigh et al. showed in a prospective blinded cohort study including 105 patients that the median nerve SSEP is a reliable predictor for poor neurological outcome, with a 43% sensitivity and no false positives14. In contrast, in several other studies TBI patients were described with initially bilateral absent N20 responses who regained consciousness and had only minor disabilities1,15,16. These results show that absence of cortical SSEP responses is not a reliable predictor in TBI patients. The most likely explanation is that in head trauma, a transient N20 disappearance may be consecutive to focal midbrain dysfunction due to oedema1. Therefore, SSEPs should never be used as a single test in TBI patients, but integrated with other neurophysiologic tools and clinical examination to improve the predictive value1,14,15. In TBI patients it is especially important to rule out traumatic lesions of the peripheral nerves, nerve roots or spinal cord when using clinical neurophysiologic tests. Clinical examination of the peripheral nerves can be difficult in patients with a diminished consciousness. Subarachnoid haemorrhage In patients with subarachnoid haemorrhage, neither median or tibial nerve SSEP, flash-visual evoked potential, BAEP nor central conduction time of the median nerve SSEP can be used as a valid predictor for outcome. The patient’s initial clinical grading still provides the only satisfying predictor, independent of the patient’s clinical course17. Sepsis In patients with severe sepsis and septic shock, prolonged cortical SSEP peak latencies occur in 84% of the patients. These prolonged Netherlands Journal of Critical Care The SSEP on the ICU: current applications and pitfalls latencies can be used to diagnose septic encephalopathy and its severity is associated with the severity of illness18. In these patients SSEP cannot be used to determine prognosis. Pitfalls and limitations of SSEPs at the ICU Noise The most severe limitation of the SSEP is the moderate interobserver agreement, which is extensively described in a study of Zandbergen et al.19. In their study, SSEPs of 56 consecutive patients with anoxic– ischaemic coma were interpreted independently by 5 experienced clinical neurophysiologists. The interobserver agreement for SSEPs in anoxic–ischaemic coma was only moderate (kappa 0.52, 95% CI 0.20–0.65). The main source of disagreement was related to the noise levels. For recordings with a noise level of 0.25 µV or more, mean kappa was 0.34 (fair agreement); for recordings with a noise level below 0.25 µV mean kappa was 0.74, which is a substantial agreement19. Efforts should be made to improve the registration and diminish noise as much as possible. Zandbergen et al. recommend that the peak-to-peak amplitude of noise of the cortical and cervical leads should be lower than 0.25 µV after averaging, especially in the frequency of the SSEPs themselves (20-500 Hz)19. Giving muscle relaxants can often improve the quality of the SSEP in patients with too much muscle activity; an example is given in figure 2. Furthermore, disturbing electrical ICU equipment should be turned off if possible. Also, giving more stimuli (up to 1000 or more) and increasing the stimulus intensity could improve the signal-to-noise ratio19. Since the interpreting clinician is often not present during the actual SSEP registration itself, the role of the lab technician is crucial in obtaining reliable SSEP results. As the quality of the SSEP recording depends on the skills of the technician, it is important that they are well trained and sufficiently familiar with SSEP registrations in the ICU. In those situations where significant artifacts appear to be present, the referring physician should be informed. Furthermore, it is always the role of the interpreting clinician to check the quality and signal-to-noise ratio of the SSEP registration, and to decide whether the SSEP registration is reliable enough for clinical decision making. Interpretation Criteria Despite the noise level, also other criteria for reliable results can be given. An N20 peak on one side can only be considered as present if it fulfils all the following criteria: • It should have an appropriate latency (i.e. at least 4.5 ms longer than the corresponding N13 peak in normal-stature adults)19. • It should be present on the contralateral side, and there should be a clear difference with the recording from the side ipsilateral to the stimulus19. Therefore it is recommended to record not only the contralateral sensory cortex after stimulation, but also co-register the ipsilateral side. This prevents misinterpretation of the N18, which has its origin in the brainstem, as a N20 potential. • Any potentials found should be reproducible in a second set of stimuli1,19. Bilateral absence of N20 peaks requires the presence of normal potentials over Erb’s point and the neck (N13) to ensure that the impulses have arrived in the central nervous system1,19. Disturbing factors and sedation Cortical responses are not influenced by moderate sedation or metabolic disturbances, factors that often hamper clinical neurological examination in the ICU. However, intoxication or metabolic disturbances and other explanations for absent SSEP potentials, for example a high cervical lesion, should be ruled out. The N20 is relatively independent to the level of sedation, and remains present even at a sedation level that is sufficient to induce an isoelectric EEG1,19. Propofol produces minimal to less than 10% suppression of the SSEP amplitude20-23. Also midazolam and opioids have only moderate effect on the SSEP amplitude and latency20-23. Furthermore, remifentanyl can supress the cortical SSEP components by 20-80%, when given in a high dose (0.8 mg/kg/min) as used during neuromonitoring in the operation room20. On the other hand, in a small percentage of cases it may be even useful to Figure 2. Example of the effect of Esmeron on a SSEP after stimulation of the right n. medianus in a patient after resuscitation. The evoked potential is measured cortical (CP3), cervical (Cerv), at Erb’s point and at the elbow (Elb) Before administration of muscle relaxants 10 ms CP3 2.5 µV After administration of muscle relaxants CP3 2.5 µV Cerv 10 µV Cerv 10 µV Erb 10 µV Erb 10 µV Elb 10 µV Elb 10 µV 10 ms N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 7 Netherlands Journal of Critical Care give sedation in low dose to improve the quality of the SSEP. This is especially the case in patients with generalized periodic discharges, which in some situations can be supressed after administration of propofol. These periodic discharges often have large amplitudes in comparison to the evoked potential and can disturb the cortical response. An illustration of a positive effect of propofol on the quality of the SSEP recording is given in figure 3. Discussion Prognostication of comatose patients in the ICU using clinical examination is often difficult and neurophysiological assessment may assist in clinical decision making. The SSEP is a relatively simple, inexpensive, and non-invasive method to evaluate functional damage to the complete sensory pathway from the peripheral nervous system, dorsal column of the spinal cord, lemniscal pathways in the brainstem, with eventual arrival at the somatosensory cortex. The SSEP can be used in the prediction of the neurological outcome in comatose patients with different aetiologies. However, it is only sufficiently reliable in predicting poor neurological outcome in patients with a post-anoxic coma, although the sensitivity for predicting a poor outcome is relatively low. For the prediction of a favourable neurological outcome the SSEP cannot be used. Other neurophysiologic tools, such as continuous EEG13 and the mismatch negativity and P300 responses24,25 may provide additional or even improved information in these cases. In TBI patients, SSEPs can assist in the prognosis, but should never be considered in isolation but integrated with other neurophysiologic tools and clinical examination. In patients with subarachnoid haemorrhage or sepsis the SSEP has no prognostic value. Since the SSEP is usually recorded for prognostication, absent cortical responses almost always lead to withdrawal of intensive care treatment, the clinician interpreting the results of the SSEP recording has to be 100% certain. Decisions to withdraw treatment are irreversible and therefore the N20 SSEPs should be considered as ‘not bilaterally absent’ in cases of doubt. In conclusion, the SSEP is a very reliable and reproducible method, if it is performed and interpreted correctly. A bilateral absent N20 response is a reliable predictor for poor neurological outcome in patients with a postanoxic coma. In postanoxic patients treated with hypothermia, the SSEP can reliable be measured after rewarming and probably also during the period of hypothermia. In other comatose patients, such as TBI patients or patients with a subarachnoid haemorrhage, the SSEP measurement is not reliable enough for the prognosis of poor outcome to use as a single parameter in clinical decision making. During SSEP measurements great care should be taken in improving the signal to noise ratio. If the noise level is too high, the peripheral responses are abnormal, or the response is not reproducible in a second set of stimuli, interpretation of the SSEP cannot be done reliably and the SSEP should be measured again in a later stage. References 1. Cruccu G, Aminoff MJ, Curio G, et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol 2008;119:1705-1719 2. Morgalla MH, Bauer J, Ritz R, Tatagiba M. Coma. The prognostic value of evoked potentials in patients after traumatic brain injury. Anaesthesist 2006;55:760-768 In German. 3. Allison T, McCarthy G, Wood CC, Jones SJ. Potentials evoked in human and monkey cerebral cortex by stimulation of the median nerve a review of scalp and intracranial recordings. Brain 1991;114:2465–503 4. van Putten MJAM. The N20 in post-anoxic coma: Are you listening? Clin Neurophsyiol 2012;123;1460-4 5. Zandbergen EG, de Haan RJ, Stoutenbeek CP, et al. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998;352:1808-1812 6. Robinson LR, Micklesen PJ, Tirschwell DL, Lew HL. Predictive value of somatosensory evoked potentials for awakening from coma. Crit care med 2003;31:960-967 7. Wijdicks EFM, Hijdra A, Young GB, Bassetti CL Wiebe A. Practice parameter: Prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67;203-210 8. Rossetti AO, Oddo M, Logroscino G, Kaplan PW. Prognostication after cardiac arrest and hypothermia: A prospective study. Ann Neurology 2010;67:301-307 9. Bouwes A, Binnenkade JM, Kuiper MA et al. Prognosis of coma after therapeutic hypothermia: A prospective cohort study. Ann Neurology 2012;71:206-212 10. Leithner C, Ploner CJ, Hasper D, Storm. Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest? Neurology 2010;74:965-969 Figure 3. Example of the effect of Esmeron and Propofol on a SSEP after stimulation of the right n. medianus in a patient after resuscitation. The evoked potential is measured cortical (CP3), cervical (Cerv), at Erb’s point and at the elbow (Elb). Before administration of propofol the EEG showed generalized periodic discharges, while after the administration of propofol the EEG showed diffuse delta activity Before administration of propofol 10 ms 8 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 CP3 2.5 µV After administration of propofol CP3 2.5 µV Cerv 10 µV Cerv 10 µV Erb 10 µV Erb 10 µV Elb 10 µV Elb 10 µV 10 ms Netherlands Journal of Critical Care The SSEP on the ICU: current applications and pitfalls 11. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med 2005;33:1736-1740 12. Bouwes A, Binnekade JM, Zandstra DF, et al. Somatosensory evoked potentials during mild hypothermia after cardiopulmonary resuscitation. Neurol 2009;73:1457-1461 13. Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJAM. Continuous EEG monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: A prospective cohort study. Crit Care Med 2012;40;12867-2875 14. Sleigh JW, Havill JH, Frith R, Kersel D, Marsh N, Ulyatt D. Somatosensory evoked potentials in severe traumatic brain injury: a blinded study. J Neurosurg 1999;91:577-580 15. Lew HL, Dikmen S, Slimp J, et al. Use of somatosensory-evoked potentials and cognitive event-related potentials in predicting outcomes of patients with severe traumatic brain injury. Am J Phys Med Rehabil 2003;82:53-61 16. Carter BG, Butt W. Are somatosensory evoked potentials the best predictor of outcome after severe brain injury? A systematic review. Intensive Care Med 2005;31:765-775 17. Wachter D, Christophis P, Stein M, Oertel MF. Use of multimodal electrophysiological monitoring to predict outcome after subarachnoid hemorrhage? A prospective series. J Neurosurg Sci 2011;55:179-187 18. Zauner C, Gendo A, Kramer L, et al. Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med 2002;30:1136-1139 19. Zandbergen EGJ, Hijdra A, de Haan RJ, et al. Interobserver variation in the interpretation of SSEPs in anoxic-ischaemic coma. Clin Neurophysiol 2006;117:1529-1535 20. Asouhidou I, Katsaridis V, Vaidis G, et al. Somatosensory Evoked Potentials suppression due to remifentanil during spinal operations; a prospective clinical study. Scoliosis 2010;5:8 21. Langeron O, Vivien B, Paqueron X, et al. Effects of propofol, propofol–nitrous oxide and midazolam on cortical somatosensory evoked potentials during sufentanil anaesthesia for major spinal surgery. Br J Anaesth 1999;82:340-345 22. Laureau E, Marciniak B, Hébrard A, Herbaux B, Guieu JD. Comparative study of propofol and midazolam effects on somatosensory evoked potentials during surgical treatment of scoliosis. Neurosurgery 1999;45:69-74 23. Taniguchi M, Nadstawek J, Pechstein U, Schramm J. Total intravenous anesthesia for improvement of intraoperative monitoring of somatosensory evoked potentials during aneurysm surgery. Neurosurgery 1992;31:891-897 24. Fischer C, Luauté J, Némoz C, Morlet D, Kirkorian G, Mauguiere F. Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med 2006; 34: 1520-1524 25. Fischer C, Dailler F, Morlet D. Novelty P3 elicited by the subject’s own name in comatose patients, Clin Neurophysiology 2008; 119: 2224-2230. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 9 Netherlands Journal of Critical Care Accepted January 2013 G U I D EL I NE Recommendations for the timing and dosing of CRRT in critically ill patients with AKI H.M. Oudemans-van Straaten1, C.S.C. Bouman2, M. Schetz3, A.B.J. Groeneveld4, A.C. de Pont2, A.M. van Alphen5, H. de Geus6, W. Boer7 1 Department of Intensive Care, VU University Medical Center, Amsterdam, 2 Academic Medical Center, Amsterdam, 3 Universitary Hospital Leuven, Belgium, 4 Erasmus Medical Center, Rotterdam, 5 Department of Nephrology, Maasstad Hospital, Rotterdam, 6 Erasmus Medical Center, Rotterdam, 7 Hospital Oost Limburg, Genk, Belgium Correspondence H.M. Oudemans-van Straaten – e:-mail: [email protected] Key words Continuous renal replacement therapy, hemofiltration, hemodialysis, acute kidney injury, guideline, fluid balance Introduction This guideline is part of the guideline for renal replacement therapy (RRT) in intensive care (IC) patients and concerns recommendations for the timing and dosing of continuous renal replacement therapy (CRRT) in IC patients with acute kidney injury (AKI). Below we present a summary of the guideline. The full version and a summary of appraised studies is presented on http://www.nvic.nl/. Intermittent hemodialysis is an alternative option for stable IC patients. However, the considerations that need to be made for the choice between continuous or intermittent treatment are beyond the scope of this guideline. Considerations regarding the timing of initiation Early initiation can improve metabolic homeostasis, volume balance and body temperature and thereby contribute to the stabilization of the circulation and improve clinical outcome. In contrast, early initiation may unnecessarily expose the patient to possible adverse effects associated with the treatment should renal function recover soon. Late initiation may contribute to worsening of the patient’s condition as a result of metabolic disturbances, fluid accumulation and circulating uremic toxins. The following aspects should be considered when timing CRRT: • The etiology and short-term reversibility of the acute renal insufficiency. With persistent need of high dose vasopressors and continued exposure to other risks of AKI, renal function will likely not recover soon. • Urinary output in the context of the patient’s fluid balance and fluid needs. • The severity and consequences of the fluid overload for the individual patient (e.g. gas exchange, tissue perfusion and cellular oxygen delivery). • The severity of the metabolic disturbance and associated harm for the patient (e.g. consequences of acidosis and uremic toxicity on circulation, respiratory distress, inspiratory pressures, oxidant stress). 10 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 • The trend of renal function (a decreasing-upward or downward slope of the serum creatinine curve in time indicates improvement of function). • Metabolic consequences of fluid removal. In contrast to the use of diuretics, ultrafiltration during CRRT allows the iso-osmotic removal of large amounts of fluids without inducing inevitable diuretic related disturbances of acid base and electrolyte balance. • Costs and adverse effects. CRRT is a complex and expensive extracorporeal treatment with inevitable blood activation, needing catheter insertion and anticoagulation, and there are associated risks of bleeding, thrombosis and metabolic derangements. Considerations regarding the dose The dose of CRRT corresponds to effluent flow (dialysate+filtrate volume for continuous hemodialysis or hemodiafiltration, CVVHD(F), or filtrate volume for continuous hemofiltration, CVVH), expressed per time and kilograms of body weight) (ml/kg/h). The large randomized studies used the body weight before ICU admission1 or at randomization2. It should be noted that the dose of CRRT (25-45 ml/kg/h) is always less than normal renal function (120 ml/min). Dose should minimally be adequate to remove uremic toxins and metabolic acidosis3. The production of uremic toxins and metabolic acids is likely to be higher in hypermetabolic patients with sepsis, while the loss of beneficial substances, such as water soluble vitamins and drugs is also higher when CRRT dose is high. Furthermore, delivered dose is always lower than prescribed dose. The so-called filter down-time is due to a delay in the exchange of bags, stagnation of flow due to access or circuit clotting, discontinuation of treatment due to interventions, investigations or the circuit change. Prescribed dose should be corrected for down-time, which is often 20-25%. In case of predilution, dose should further be corrected for the dilution of blood in the filter. Correction factor is (blood flow +ultrafiltrate flow)/blood flow. Based on the available randomized controlled trials, there is currently no proof that a CRRT dose of 35 ml/kg/h, as was Netherlands Journal of Critical Care Recommendations for the timing and dosing of CRRT in critically ill patients with AKI recommended in the previous guideline, provides a better patient survival than a dose of 20-25 ml/kg/h. The benefit of a higher dose (35-45 ml/kg/h) as found in previous single center clinical trials1,2 was not confirmed in the two recent large multicenter trials3,4. Furthermore, previous non-randomized clinical and animal studies suggested a benefit of early high volume hemofiltration in patients with severe septic shock on stabilization of the circulation5. However, a recent meta-analysis including randomized controlled trials and subgroups from randomized controlled trials could not show any benefit of CRRT versus no CRRT or a higher dose of CRRT in patients with severe sepsis or septic shock on survival, hemodynamics, pulmonary gas exchange, multiple organ dysfunction syndrome or length of stay6. The effect of CRRT on survival was not modified by CRRT dose. Finally, preliminary results of the multicenter IVOIRE study (http://www.clinicaltrials.gov), which compared hemofiltration doses of 35 ml/kg/h to 70 ml/kg/h in patients with septic shock, AKI, and multiple organ failure, do not show a survival benefit of the higher dose (personal communication). Therefore, the best available evidence does not support the routine use of high-volume CRRT in patients with severe sepsis or septic shock. However, CRRT is recommended in patients with AKI and metabolic derangement or diuretic-resistant fluid overload, and dose should be sufficient for the control of acidosis. Appraisal of the literature and grading of the recommendations We appraised the literature according to the guidelines of the NVIC (A-D), but decided to grade the recommendations (1-2) in agreement with the KDIGO Guidelines (http://www.kdigo.org/ ), which are derived from the GRADE classification4, used in the sepsis guidelines. KDIGO is an acronym for Kidney Disease Improving Global Outcomes, an initiative of the National Kidney Foundation. In the KDIGO system there is room for giving a strong recommendation on clinical grounds while the level of evidence is low. We finally based the grade of recommendation on the level of evidence in the literature, the physiological effects and the risks and costs of the treatment (see table 1). Recommendations 1. The timing of initiation of CRRT Absolute indications We recommend initiating CRRT immediately in patients with life-threatening AKI-related symptoms of fluid, electrolyte and acid-base balance (1C). Relative indications We suggest starting CRRT if, despite optimization of the circulation and other supporting interventions, the patient has AKI and • persistent AKI-related metabolic derangements and/or • severe diuretic-resistant fluid overload if and when uremic complications and organ damage are expected to develop (2C). Table 1. Grading of guideline recommendations Grade of Implications recommendation Policy Level 1 ‘‘We recommend’’ Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure. Level 2 ‘‘We suggest’’ Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with his or her values and preferences. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. No grade Used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. Consider starting CRRT in a patient with AKI and AKI-related metabolic derangements • before the patient is being exposed to new risk factors for AKI to improve his metabolic and fluid status and optimize his condition (no grading). Do not apply RRT if • AKI is mild (mild metabolic derangements) and probably transitory (2D); • treatment is expected to be futile (no grading). 2. The dose of CRRT We recommend delivering an effluent (filtrate+dialysate) dose of at least 20-25 ml/kg/h for CRRT in AKI. (IA) We recommend compensating for a decrease of dose due to • filter down-time; • predilution. We recommend assessing the actual delivered dose and adjust prescription to reach target. (1B) CRRT dose can be increased individually to correct severe metabolic derangements more rapidly (no grading). References 1. Ronco C, Belomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. EDTNA ERCA J 2002, Suppl 2: 7-12. 2. Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, Martin PY: Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 2006, 70: 1312-1317. 3. Palevsky PM, Zhang JH, O’Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008, 359: 7-20. 4. Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C, Su S: Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009, 361: 1627-1638. 5. Bouman CS, Oudemans-van Straaten HM, Schultz MJ, Vroom MB: Hemofiltration in sepsis and systemic inflammatory response syndrome: the role of dosing and timing. J Crit Care 2007, 22: 1-12. 6. Latour-Perez J, Palencia-Herrejon E, Gomez-Tellot V, Baeza-Roman A, Garcia-Garcia MA, Sanchez-Artola B: Intensity of continuous renal replacement therapies in patients with severe sepsis and septic shock: a systematic review and meta-analysis. Anaesth Intensive Care 2011, 39: 373-383. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 11 Netherlands Journal of Critical Care Accepted January 2013 review The pharmacologic treatment of alcohol withdrawal syndrome in the ICU D.P.F. van Nunen, D.H.T. Tjan Department of Intensive Care, Gelderse Vallei Hospital Ede, The Netherlands Correspondence DHT Tjan – e-mail: [email protected] Keywords - Alcohol withdrawal syndrome, delirium tremens, withdrawal seizures, benzodiazepines, anticonvulsants, gamma-hydroxybutyrate, α2-agonists, antipsychotics Abstract Alcohol withdrawal syndrome (AWS) presents a significant problem among new admissions to the intensive care unit. In patients with a history of alcohol abuse, AWS manifests itself with symptoms of autonomic hyperactivity, tremors, hallucinations, agitation, anxiety, and seizures. Progression of AWS, called delirium tremens (DT), is associated with increased mortality. Traditionally, AWS is treated with benzodiazepines which have a well-established record for reducing symptoms of withdrawal and provide adequate control of both seizures and DT. However, the side-effects of benzodiazepines have prompted the introduction of alternative agents. Anticonvulsants and gamma-hydroxybutyrate do suppress symptoms of AWS, but their effectiveness in the prevention of seizures and DT is doubtful. Ethanol results in less sedation than benzodiazepines, although the evidence for its role in AWS remains limited. Alpha-2 agonists are potent against symptoms of noradrenergic overdrive and are suitable as adjuvants to benzodiazepines. Antipsychotics have no demonstrable effectiveness in AWS and may even be harmful. Introduction The incidence of alcohol dependence and associated disorders is high amongst ICU patients. Although there are no epidemiological data for the Netherlands, in the United States between 10% and 33% of patients admitted to the ICU suffer from alcohol dependence1. According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) alcohol dependence is formally defined as a maladaptive pattern of alcohol use resulting in clinical impairment or stress as manifested by the development of tolerance and withdrawal, unsuccessful efforts to abstain, consumption of ever greater quantities and the involvement of a considerable amount of time that limits other activities2. Symptoms of alcohol withdrawal may occur in up to 91% of alcohol-dependent patients after acute abstinence3,4. The syndrome of alcoholic withdrawal consists of signs and symptoms (see table 12) developing in alcohol-dependent individuals within 6 to 48 hours after their last intake of alcohol or reduction in intake5,6. Although these 12 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 symptoms are usually mild, 5-10% of alcohol-dependent patients7 develop a severe dysautonomic and encephalopathic state known as ‘delirium tremens’ (DT) after 48-72 hours of abstinence8,9. In this progression of alcohol withdrawal syndrome (AWS) the autonomic disarray is further exacerbated and the patient’s cognition and level of consciousness can change within a short period of time. DT is associated with a mortality rate of 5% which is attributable to complications of its clinical symptomatology like coronary spasms, arrhythmias and myocardial infarction8. The natural course of AWS is a gradual lessening of symptoms 72 hours after its onset9,10. However, given the high mortality and morbidity, early treatment of AWS is warranted. Since the first clinical descriptions of the syndrome in the nineteenth century, many pharmacologic and therapeutic treatments have been published in medical journals11. Reviews of this body of literature are few and inconsistent. The objective of this review is to examine the evidence supporting the popular pharmacologic treatment options for AWS. The subsequent discussion is based on a systematic search of the electronic literature database MEDLINE (PubMed). For each Table 1. DSM-IV-TR Alcohol withdrawal – diagnostic criteria2 A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged B. Two (or more) of the following, developing within several hours to a few days after Criterion A - Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100) - Increased hand tremor - Insomnia - Nausea or vomiting - Transient visual, tactile, or auditory hallucinations or illusions - Psychomotor agitation - Anxiety - Grand mal seizures C. Clinically significant distress or impairment in social, occupational, or other important areas of functioning D. The symptoms are not due to a general medical condition and are not better accounted for another mental disorder Netherlands Journal of Critical Care The pharmacologic treatment of alcohol withdrawal syndrome in the ICU pharmacologic agent a search query was composed of synonyms for the respective agent in combination with ‘alcoholwithdrawal’, ‘AWS’, ‘delirium tremens’ and ‘DT’. The search results were filtered for relevant meta- analyses, trials, cohort studies and case series. Previous reviews describing a segment of the literature were also consulted. The resulting review is structured as follows. First, the pathophysiology of alcohol dependency and withdrawal is elucidated. Second, the method of diagnosing AWS is discussed. Third, the evidence supporting the popular pharmacotherapies is presented. The fourth and final section summarizes and concludes. Pathophysiology Alcohol or ethanol influences multiple stages of the neurotransmission cascade in the central nervous system. Genetic, pharmacological and electrophysiological studies have demonstrated that alcohol modifies synaptic transmission by altering neuronal excitability through an interaction with ligand and voltage-gated ion channels. The sedative effects of alcohol are principally thought to be the result of its interference with two neurotransmission systems. At low concentrations (< 100 mg/dl) alcohol enhances transmission of gamma-aminobutyric acid (GABA), by promoting chloride conductance through the GABAA-receptor. At higher concentrations (> 250 mg/dl) alcohol works directly on the GABAA-receptor and causes a prolonged opening of its chloride channel that is independent of the neurotransmitter GABA. This second mechanism makes alcohol toxic in overdose. A prolonged opening of the chloride channel causes excessive influx of chloride into neurons of the respiratory system resulting in respiratory depression10,12. Continued exposure to alcohol leads to tolerance with downregulation of GABAA-receptors. Besides reinforcing the inhibitory effects of GABA, alcohol tempers excitatory neurotransmission mediated by glutamate. This neurotransmitter binds N-methyl-D-aspartate (NMDA)-receptors resulting in a calcium influx depolarizing the neuron. One of the results of NMDA stimulation is an enhancement of signal transmission between neurons called long-term potentiation which underlies learning and the development of memory. Alcohol serves as a blocker of the NMDA-receptors inhibiting this process and contributing to amnesia and depression of cerebral function. Over time the brain’s reaction is to increase the number of NMDA-receptors which allow normal functioning in the presence of alcohol, the formation of tolerance10,12. In AWS, GABA neurotransmission is decreased while glutamatergic neurotransmission is increased resulting in a state of heightened excitability. Furthermore, the increased sympathetic activity is due to an overstimulation of noradrenergic neurons following increased glutamate function and the loss of noradrenergic autoinhibition12. The hallucinations experienced during withdrawal are caused by an enhanced dopaminergic transmission following disinhibition of dopaminergic neurons through reduced GABAergic activity10. Research has shown that the increased susceptibility to seizures seen in patients is likely to have its origin in the deep layers of the superior colliculus where NMDA-receptor mediated excitation is no longer chronically suppressed by alcohol13. Diagnosis AWS should be considered as a diagnosis of exclusion. If the patient’s history and physical findings prompt clinical suspicion then alternative etiologies must be ruled out, such as infection (meningitis), head trauma (intracerebral hemorrhage), epilepsy, electrolyte or metabolic disturbances, hepatic failure, intoxication or withdrawal from other substances. The formal diagnostic criteria are listed in table 1. The clinical spectrum varies from uncomplicated withdrawal syndrome with patients having a clear sensorium with signs of autonomic hyperactivity and increased sympathetic stimulation. Worsening of the symptoms can result in hallucinations and progression to DT with or without seizures. When the history on alcohol consumption is unavailable or unreliable, biomarkers such as gammaglutamyl transferase (GGT) and carbohydrate-deficient transferrin (CDT) may provide clues for chronic alcohol overuse with combined sensitivities of 81-90% and specificities of 63-95%14. Ethanol levels on admission have no predictive value for AWS15. After the diagnosis of AWS hs been made, the severity of symptoms can be quantified by the Clinical Institute Withdrawal Assessment Scale for Alcohol (CIWA-Ar)16,19. Treatment Without therapy the symptoms of alcohol withdrawal are expected to reach their peak 72 hours after the last ingestion of alcohol and generally resolve within four days after this moment9,12. In most cases the symptoms are relatively mild and no pharmacotherapeutic management is required. However, in manifest AWS treatment is indicated to avoid DT or seizures. The pharmacotherapeutic management of AWS entails the substitution of a long-acting agent for alcohol and subsequently to taper its dosage over time17. Historically, many different classes of drugs have been tried in the management of AWS. This section provides an overview of the primary pharmacologic agents. The discussion of supportive measures is beyond the scope of this article. Benzodiazepines Benzodiazepines have been the mainstay of pharmacotherapeutic treatment of AWS and the prevention of secondary seizures since 196918. Benzodiazepines produce their effect by increasing the affinity of GABAA-receptors for the neurotransmitter GABA. This results in a greater influx of calcium into the neuron which inhibits neurotransmission. In this way benzodiazepines serve as a direct substitute for the GABA-modulating effects of alcohol7. The evidence supporting the use of benzodiazepines in AWS is relatively solid with three good quality meta-analyses independently concluding benzodiazepines to be the preferred treatment. Mayo-Smith19 conducted a meta-analysis of six prospective, placebocontrolled trials from the 1960s to 1980s involving three N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 13 Netherlands Journal of Critical Care different benzodiazepines and concluded that benzodiazepines are more effective than placebo in reducing the occurrence of DT (risk reduction of 4.9 cases of delirium per 100 patients, P=0.04) and in seizure prophylaxis (risk reduction of 7.7 seizures per 100 patients treated, P<0.001). A second meta-analysis was authored by Holbrook et al.20 and included three randomized, placebo-controlled trials from the 1980s with a total of 112 patients and three benzodiazepines21-23. Benzodiazepines were superior to placebo in reducing the signs and symptoms of AWS as measured with the CIWA-Ar score two days after the initiation of therapy (OR 3.28, 95% CI 1.30-8.28). The authors also analyzed eight other randomized, placebo- controlled trials in which benzodiazepines were compared with alternative control drugs. The heterogeneity of the studies prevented pooling but there was no manifest superiority of any alternative agent over benzodiazepines. Benzodiazepines were not appreciably safer when compared with a dopamine-agonist, an anticonvulsant and a tri-cyclic antidepressant (OR 0.67, 95% CI 0.34-1.32). In a more recent meta-analysis, Amato et al.24 included three randomized, placebo- controlled trials from the 1970s and 1980s with a total of 324 patients in which benzodiazepines were compared with placebo18,21,23. Their analysis showed that benzodiazepines perform significantly better in seizure prophylaxis with a relative risk of 0.16 (95% CI 0.04-0.69). When compared with alternative drugs, benzodiazepines demonstrate a non-significant tendency to deliver better seizure and delirium control, fewer adverse effects and a lower dropout rate24. The class of benzodiazepines comprises several drugs with varying properties concerning speed of onset, half-life and route of metabolism. Trials comparing different benzodiazepines have failed to produce evidence in favour of the distinct superiority of one benzodiazepine over any other in the treatment of AWS19,20,24. There are, nonetheless, several considerations which may guide the choice of benzodiazepine. The longer-acting drugs in this class may provide a smoother course of withdrawal and even be more effective in seizure control. In a meta-analysis of three prospective, controlled trials, a non-significant trend was found towards improved seizure control with longer- acting agents (6.7 fewer cases of seizures per 100 patients, P=0.07)19,25-27. Another issue influencing the choice of benzodiazepine is the safety in patients with cirrhotic and other liver diseases. Both diazepam and chlordiazepoxide have a complex metabolism in the liver with active metabolites prolonging the half-lives of both drugs. Decreased liver function enhances and lengthens their sedative effects. In contrast, the shorter acting lorazepam has a simpler metabolism, is less influenced by cirrhosis of the liver and has only inactive metabolites. Consequently, the behaviour of lorazepam is more predictable in patients with hepatic dysfunction. Another potential risk with diazepam is the fact that it is more lipophilic than lorazepam and chlordiazepoxide. This characteristic results in a rapid onset of action because of a swift distribution into the brain. Yet it also causes a rapid redistribution to peripheral fat which may quickly reverse this effect. Given that peripheral fat becomes saturated at an uncertain pace, this 14 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 effect may lead to oversedation when high doses of diazepam are administered6. Anticonvulsants The sedative side-effects of benzodiazepines and their potential for addiction prompted a search for alternative agents in the treatment of AWS. The beneficial effects of anticonvulsants in the prevention of epileptic seizures resulted in trials examining their use in AWS. The best evidence is available for carbamazepine, an anticonvulsant whose mechanism of action in AWS may be explained by its GABAergic activity28 and blockade of NMDA-receptors29. A recent review by Barrons & Roberts30 identified three randomized double blinded trials31-33 in which carbamazepine was compared to a benzodiazepine. In each trial carbamazepine and the benzodiazepine proved equally effective at reducing symptoms of alcohol withdrawal. Moreover, in two trials31,33 carbamazepine demonstrated significantly greater reduction of symptoms on days 6-7 after the start of treatment. This result remained present in a meta-analysis of the trials by the Cochrane Collaboration34. A seizure was observed in just one of the studies42. Carbamazepine has also been compared to placebo in a double blinded randomized trial with 105 patients with mild AWS in an outpatient setting. In the group receiving carbamazepine, withdrawal symptoms diminished significantly faster on the second day of treatment with a non-significant tendency continuing on days 4-735. Oxcarbazepine was studied in a single blinded randomized trial in which it demonstrated similar effectiveness to carbamazepine in controlling symptoms of withdrawal36. However, when compared to placebo in a group of patients with severe AWS in a double blinded randomized trial, oxcarbazepine was not superior neither in suppressing symptoms, nor in seizure prevention37. The effectiveness of the GABA-activity enhancing anticonvulsant valproic acid in AWS has been studied in several small trials38. In a double blinded placebo-controlled study of 43 patients with moderate withdrawal symptoms, the group randomized to valproic acid needed significantly less oxazepam for symptom control39. In comparison to benzodiazepines, two trials showed that valproic acid is just as effective in reducing symptoms in patients with mild, uncomplicated AWS40,41. The potential of the antiglutamergic anticonvulsants topiramate and lamotrigine in treating AWS was assessed in a single blinded randomized trial of 127 patients with significant symptoms42. Compared to placebo, both medications were able to significantly reduce withdrawal severity, dysphoric mood and supplementary diazepam administration. However, their performance was no different from that of the control-drug diazepam. Among the older anticonvulsants, phenytoine has not shown to be effective in the treatment of AWS and DT43, while phenobarbital has demonstrated comparable performance to benzodiazepines44 but has an unattractive side-effect profile. In summary, anticonvulsants seem efficacious in the treatment of mild AWS. Nonetheless, their capability for preventing DT or seizures in severe AWS remains unknown. Netherlands Journal of Critical Care The pharmacologic treatment of alcohol withdrawal syndrome in the ICU Ethanol The use of ethanol in the prophylaxis and treatment of AWS has mostly been limited to surgical wards and intensive care units and is controversial45,46. A nation-wide survey in the Netherlands published a decade ago showed that 16% of intensive care units occasionally used ethanol in the context of AWS47. In the surgical specialties, ethanol is perceived to possess several advantages over other agents. First, compared with benzodiazepines ethanol does not readily cause drowsiness which may hamper the evaluation of a patient, for example, in a trauma setting. The lack of drowsiness also allows for rapid mobilization of patients in the postoperative period. Second, in comparison with benzodiazepines ethanol is seen to carry less risk of respiratory depression which facilitates weaning and participation in pulmonary toilet. In non-surgical specialties ethanol is not as popular due to a short duration of action, a narrow margin of safety and possible tissue damage at the infusion site9,48. Research into the employment of ethanol for the treatment of AWS generally consists of small case series with varying quality of methodology46. Two randomized controlled trials have been published. Spies et al.49 randomized 197 alcohol-dependent surgical patients to four prophylactic regimens started on admission to the ICU: 50 patients received intravenous ethanol, 48 flunitrazepam-clonidine, 49 chlormethiazole-haloperidol and 50 patients were given flunitrazepam- haloperidol. No differences were found between the groups with respect to symptoms of AWS as measured by the CIWA-Ar scale, length of stay in the intensive care and major cardiovascular and pulmonary complications. Weinberg et al.48 randomized 49 trauma patients with a history of severe alcohol abuse into two groups on admission to the intensive care unit. 26 patients were administered ethanol (5%, max 200 ml/hour) intravenously while 24 patients received diazepam by intravenous or enteral route (max 20 mg/4 hours). The ethanol group proved to be significantly more difficult to keep in a calm and cooperative state when measured with the Riker Sedation- Agitation Scale. All patients managed to wean from therapy 96 hours after initiation with no appreciable difference between the two groups. Note that in both trials ethanol was given intravenously. The enteric administration of ethanol is not recommended because of its narrow margin of safety and the dependency of its intestinal absorption on the presence and composition of gastric contents, smoking habits, medications (ranitidine, erythromycin) and inter- and intra- individual differences in the gastric emptying rate50. Moreover, the oral administration of ethanol has been reported to expose patients to taste and behavioural clues promoting relapse into past drinking behaviour51. Gamma-hydroxybutyrate (GHB) Gamma-hydroxybutyrate or GHB is a metabolite of GABA, to which it is structurally similar. GHB is naturally present in the human brain and is involved in the regulation of sleep cycles, temperature regulation, cerebral glucose metabolism and blood flow, memory, and emotional control52. Regarding its use in the treatment of AWS, GHB has the interesting characteristic of being a weak agonist of GABAB-receptors and the fact that exogenous GHB is converted to GABA which results in an indirect activation of GABAA-receptors. Consequently, GHB partly mimics the actions of alcohol in the brain and may therefore act as a substitute drug53. Compared with placebo, GHB is effective in the treatment of AWS as demonstrated by the results of a single published trial. Gallimberti et al.54 randomized 23 patients with AWS to placebo or GHB (50 mg/kg) and scored their symptoms on a 30- point scale during seven consecutive hours. At the end of the observation period the withdrawal symptoms in the GHB-group had virtually disappeared while in the placebo group the level of agitation had increased. In two similar trials, GHB has been compared with diazepam51,55. A total of 102 alcohol-dependent patients were randomized to either GHB (50 mg/kg) or diazepam (0.5-0.75 mg/kg) and for periods of up to three weeks their symptoms were measured with the CIWA-Ar scale. In both trials GHB performed at least as well as diazepam in treating AWS. In sub scores of the CIWA-Ar scale, GHB proved to be faster in suppressing symptoms of anxiety and agitation. Concerns for the use of GHB are possible side-effects and its addiction potential. In a review by the Cochrane Collaboration of 13 trials of GHB for the treatment of alcohol related disorders 20% of patients developed transitory vertigo or dizziness at a dose of 50 mg/kg, while 0.6 to 2.5% reported diarrhea, headache, rhinitis or nausea56. No serious adverse events occurred. Craving was only seen in the treatment of alcohol dependence in up to 10% of patients. α2-agonists The symptoms of AWS are partly the product of noradrenergic overdrive. One of the prime receptors for noradrenergic transmission in the brain is the α2-receptor. Normally this receptor inhibits the firing of the presynaptic norepinephrine neuron, but during AWS its sensitivity is impaired which results in augmented noradrenergic transmission. Accordingly, an exogenous high affinity α2-agonist could potentially reinforce noradrenergic auto-inhibition and be of use in the treatment of AWS61. Three small trials57-59 investigated the application of the α2-agonist clonidine in the prophylaxis for withdrawal in alcohol-dependent patients. Compared with either the sedative chlormethiazole, or the benzodiazepine chlordiazepoxide, no significant difference was found in observer rated symptoms of AWS. However, the groups treated with clonidine had significantly lower blood pressure and heart rate. In another trial, Robinson et al. 60 randomized 32 patients with symptoms of acute alcohol withdrawal to clonidine or chlormethiazole. In the clonidine group eight patients dropped out of treatment due to orthostatic hypotension, seizures or hallucinations. These symptoms were not observed in the chlormethiazole group. Adinoff et al. 61 examined the loading doses required to control symptoms of withdrawal in 25 alcohol-dependent males for diazepam, alprazolam, diazepam and placebo. In contrast to both benzodiazepines, clonidine proved to be no more effective than placebo but did decrease systolic blood pressure significantly. Spies et al. reported that lower median doses of flunitrazepam were required to control symptoms of AWS when N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 15 Netherlands Journal of Critical Care this was combined with clonidine rather than haloperidol49. All in all, the above-mentioned research shows that clonidine is effective in the treatment of symptoms of AWS related to noradrenergic overdrive, but does not support clonidine monotherapy for preventing delirium or seizures62. Dexmedetomidine, a derivative of the veterinary sedative and analgesic medetomidine, has eight times the affinity of clonidine for the α2-receptor61. In the context of AWS, a limited number of case reports demonstrate successful employment of dexmedetomidine for controlling symptoms of noradrenergic overdrive, mainly as an adjunct to benzodiazepines63-67. Antipsychotics Although antipsychotic or neuroleptic drugs, especially haloperidol, are routinely employed in the treatment of AWS9 no randomized, placebo-controlled trials have ever been published demonstrating their effectiveness. The evidence is limited to predominantly non-randomized benzodiazepine controlled studies and only for the older category of atypical antipsychotic drugs (phenothiazines, haloperidol). In the context of AWS, no human studies have been conducted with the newer atypical antipsychotics (clozapine, olanzapine, risperidone)68. Mayo-Smith performed a meta-analysis19 of four prospective trials in which phenothiazines (chlorpromazine and promazine) were compared with benzodiazepines (diazepam or chlordiazepoxide) or placebo. Phenothiazines were no more effective than placebo in preventing delirium and less effective than benzodiazepines (6.6 more cases of delirium per 100 patients, P=0.002). Moreover, in comparison with benzodiazepines, treatment with phenothiazines increased the incidence of seizures (+ 11.4 cases per 100 patients, P<0.001). This finding is compatible with the clinical experience that chlorpromazine lowers the threshold for seizures69,70. Haloperidol was compared to chlordiazepoxide in a double blinded randomized trial71 including 49 patients with symptoms of acute withdrawal. After four hours of treatment haloperidol was able to suppress symptoms in 70% of patients, whereas chlordiazepoxide controlled symptoms in just 44% of patients. No statistical analysis was presented. All studies considered there is insufficient evidence to suggest a prime role for antipsychotics in the treatment of AWS. Moreover, the typical antipsychotics are known for their sometimes severe side-effects including the extra-pyramidal syndrome, the neuroleptic malignant syndrome and the possibility of ventricular tachyarrhythmias induced by a prolongation of the QTc interval9. Conclusion In ICU patients, AWS is a major problem associated with significant morbidity and mortality. Treatment is aimed at reducing symptoms of withdrawal and at preventing seizures and the development of DT. Benzodiazepines have proven to be effective for all these objectives and remain the gold standard in treatment. Anticonvulsants and GHB have both demonstrated to diminish symptoms of withdrawal, but their adequacy in preventing seizures and DT is not known. 16 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Ethanol may result in less sedation than benzodiazepines, but good quality evidence supporting its role in AWS is scant. There is no indication for antipsychotics in the treatment of AWS. Finally, α2-agonists could serve as adjuvant agents to benzodiazepines in order to suppress noradrenergic overdrive. References 1. De Wit M, Jones DG, Sessler CN et al. Alcohol-use disorders in the critically ill patient. Chest. 2010 Oct;138(4):994-1003. 2. DSM-IV-TR. Substance-related disorders [Internet]. Arlington: American Psychiatric Publishing; c. 2010 [cited Mar 10 2011]. Available from: http://psychiatryonline.org/ 3. Caetano R, Clark CL, Greenfield TK. Prevalence, trends, and incidence of alcohol withdrawal symptoms: analysis of general population and clinical samples. 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Norberg A, Jones AW, Hahn RG, Gabrielsson JL. Role of variability in explaining ethanol pharmacokinetics: research and forensic applications. Clin Pharmacokinet. 2003;42(1):1-31. 51. DiPaula B, Tommasello A, Solounias B, McDuff D. An evaluation of intravenous ethanol in hospitalized patients. J Subst Abuse Treat. 1998 Sep-Oct;15(5):437-42. 52. Addolorato G, Balducci G, Capristo E, Attilia ML, Taggi F, Gasbarrini G, Ceccanti M. Gamma- hydroxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine. Alcohol Clin Exp Res. 1999 Oct;23(10):1596-604. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 17 Netherlands Journal of Critical Care Accepted January 2013 C ASE RE P OR T Gastric dilatation and perforation due to binge eating: a case report J.A.M. Heijneman1, R. Tahmassian2, T. Karsten3, E.R. van der Vorm4, I.A. Meynaar1 1 Department of Intensive care, Reinier de Graaf Hospital, Delft, The Netherlands 2 Department of Clinical Pharmacy, Reinier de Graaf Hospital, Delft, The Netherlands 3 Department of Surgery, Reinier de Graaf Hospital, Delft, The Netherlands 4 Department of Clinical Microbiology, Reinier de Graaf Hospital, Delft, The Netherlands Correspondence J.A.M. Heijneman – e-mail: [email protected] Keywords - Gastric dilatation, gastric ischemia, binge eating, Candida albicans, fluconazole, caspofungin Abstract We present a case of massive gastric dilatation and necrosis in a patient with psychogenic polyphagia. The patient developed a Candida albicans sepsis due to gastric perforation and was treated with antifungal therapy and multiple surgical interventions. Case A 43-year-old female attended the emergency department with complaints of severe abdominal pain. The pain, mainly localized in the epigastric area, arose after the ingestion of a large amount of food one day prior to admission. The patient was suffering from nausea but was unable to vomit. She was afebrile and did not complain of altered bowel movements. Her medical history reported a lumbar sympathectomy, psychosis and an eating disorder (periods of polyphagia alternated with periods of extreme anorexia). An erect abdominal X-ray ( figure 1) showed a remarkably distended stomach. The patient was admitted to the surgical ward with the suspected diagnosis of gastric distension, possibly caused by delayed gastric emptying provoked by her anti-psychotic drugs, namely Olanzapine and Clomipramine. She was put on ‘nil by mouth’ and was given a nasogastric tube, which immediately drained 2.5 litres of gastric fluid. However, in the next few hours the patient’s condition deteriorated, showing signs of shock with progressive tachypnoea, tachycardia, cold extremities and falling blood pressure. At emergency laparotomy, the ventral side of the stomach was found to be completely necrotic and had perforated from the distal oesophagus to the pylorus. Further, 3.5 litres of gastric fluid and undigested food particles had leaked into the abdominal cavity. Extensive abdominal lavage was performed, followed by resection of the necrotic ventral side with reconstruction of a “tube-like” stomach, using the vital dorsal side of the stomach. After surgery, the patient was admitted to the Intensive Care Unit (ICU), where she was mechanically ventilated and treated in 18 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 accordance with the ICU’s sepsis protocol (inotropes, cefotaxime, metronidazole and a single dose of gentamicin), continuous venovenous hemofiltration and administration of amphotericin, colistin and tobramycin in mouth and stomach (routine selective decontamination of the digestive tract). Although at this stage Figure 1. Abdominal X-ray showing a massively distended stomach Netherlands Journal of Critical Care Gastric dilatation and perforation due to binge eating: a case report there was only slight clinical suspicion of candidemia, fluconazole was added as a precautionary action because of the severity of the sepsis. On the fifth day of admission, abdominal cultures taken at the laparotomy as well as a blood culture showed Candida albicans and fluconazole was replaced by caspofungin. All intravenous and arterial lines were replaced. Fundoscopy of both eyes by an ophthalmologist did not show signs of Candida endophthalmitis. Subsequent blood cultures (9 sets) on different days were negative for C.albicans. Despite the antifungal treatment with caspofungin, the patient’s abdominal fluid remained positive for C.albicans. After seven days of caspofungin monotherapy, fluconazole was again added to the antifungal regimen in order to augment the treatment with higher tissue levels. C.albicans was found in abdominal samples up to 3 weeks after admission. The C.albicans found in the blood and peritoneal fluid was sensitive to fluconazole, tested in the Vitek system (Biomerieux). A total of 16 re-laparotomies were performed in the following five weeks because of recurrent gastrointestinal leakage and inadequate source control. This eventually resulted in a subtotal gastrectomy. Both the oesophagus and the leaking antrum stump were drained by Foley catheters. Also the left hemicolon was resected together with a large part of the small bowel due to ongoing leakage from various fistulas. The patient had a surgical procedure for end colostomy of the transverse colon. Eventually the patient’s Figure 2. Abdominal X-ray showing a massively distended stomach clinical condition stabilized. She was weaned from mechanical ventilation and no longer in need of inotropic agents. All antifungal therapy was stopped after 29 days and cultures remained negative thereafter. After 46 days of ICU-admission the patient was transferred to the surgical ward for further recovery. Eventually, 118 days after admission, the patient was transferred to a university hospital for home parenteral nutrition (TPN) training. After almost one year of TPN, bowel continuity was restored in a ten hour surgical procedure in which, after extensive adhesiolysis, a Roux and Y oesophagojejunostomy was created with reconstruction of the abdominal wall with a Ramirez-plasty. The patient is currently recovering from this surgery. Discussion It is well known that the stomach has rich vascularisation and collateral blood supply. As a result, gastric infarction due to an insufficient perfusion is a rather rare condition and its exact pathophysiology remains unclear. The reported causes of gastric infarction are diverse and include volvulus, acute necrotizing gastritis, intrathoracic herniation, the ingestion of caustic materials, vascular compromise and acute gastric dilatation1. Experimental models have shown that gastric infarction will only appear when both venous and arterial occlusion is present2. In a massively distended stomach, the intragastric pressure can reach over 30cm H2O exceeding the gastric venous pressure, therefore compromising venous drainage of the stomach3. In healthy individuals, satiety mechanisms prevent over-distension of the stomach. However, in patients suffering from eating disorders, these satiety mechanisms are often insufficient or absent. Geliebter et al4 showed that patients with bulimia nervosa have a significantly larger stomach capacity, possibly due to repetitive expansion of the stomach during binge eating. Some studies have found evidence of delayed gastric emptying in bulimic patients, possibly due to smaller gastric contractions in the enlarged stomach5,6,7. These gastrointestinal changes in patients with eating disorders might lead to a higher risk of developing gastric infarction. The incidence of acute gastric dilatation in anorexia and psychogenic polyphagia seems to be higher in females (67%)8. A distended abdomen and the urge to vomit are the most common early signs of gastric distension9. With progression of the gastric distension, continuous abdominal pain and the inability to vomit are the predominant findings. An abdominal X-ray may show gastric dilatation (and, in rare cases of recurrent gastric distension, gastric pneumotosis caused by gas-forming pathogenic bacteria infiltrating the injured stomach wall10). With clinical signs of gastric distension, prompt decompression by nasogastric suctioning should be initiated. When gastric decompression is delayed, progression of the gastric distension may lead to gastric infarction and subsequently gastric perforation. The overall mortality of gastric infarction is 73%11. Mortality can often be attributed to severe sepsis and multi-organ failure as a result of gastric perforation. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 19 Netherlands Journal of Critical Care In our case, necrosis and perforation of the stomach resulted in an ongoing peritonitis and candidemia. Candidemia requires systemic antifungal treatment. Studies show a high mortality rate associated with candidemia, which is highest in those patients who are not treated with an antifungal drug12,13. In a patient who is clinically suspected of candidemia (e.g. presenting with classic skin or eye lesions), preemptive antifungal therapy should be initiated while awaiting the return of blood cultures. Yet most patients have no obvious signs suggesting the presence of candidiasis. In those cases, depending upon the acuity of the patient’s condition, clinicians should consider whether it is appropriate to initiate empiric treatment with an antifungal agent. The 2009 Infectious Diseases Society America (IDSA)14, and the 2008 Dutch SWAB15 treatment guidelines for candidiasis recommend an echinocandin for the treatment of candidemia in patients who are considered to be ‘moderately severe’ or ‘severely’ ill14. Conclusion Massive gastric dilatation caused by psychogenic polyphagia can progress to gastric necrosis and perforation. 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Kiss A, Wiesnagrotzki S, Abatzi T, Meryn S, Huabenstock A, Base W. Upper gastrointestinal endoscopy findings in patients with long-standing bulimia nervosa. Gastrointest Endosc. 1989;35:516-8 6. Anderson L, Shaw JM, McCargar L. Physiological effects of bulimia nervosa on the gastrointestinal tract. Can J Gastroenterol. 1997;11:451-9 7. Kamal N, Chami T, Andersen A, Rosell FA, Schuster MM, Whitehead WE. Delayed gastrointestinal transit times in anorexia nervosa and bulimia nervosa. Gastroenterology 1991;101:1320-4 8. Gomez MA, Blum L, Scotto B, Besson M, Roger R, Alison D. Gastric necrosis from acute dilatation without underlying psychiatric disorder. J Radiol. 2004;85:643-5 9. Werner Harmse ChB, Vicci Smith DA, Aisne Stoker DMRD. Intramural gastric air – gastric pneumatosis or emphysematous gastritis? SA J Radiol. 2007;57-8 10. Billitier AJ, Abrams BJ, Brunetto A. Radiographic imaging modalities for the patient in the emergency department with abdominal complaints. Emerg Med Clin North Am. 1996;14:789-850 11. Kerstein MD, Goldberg B, Panter B, Tilson D, Spiro H. Gastric infarction. Gastroenterology. 1974;67:1238-9 12. Nucci, M, Colombo, AL, Silveira, F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol. 1998;19:846-50 13. Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G. Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality. Clin Infect Dis. 1992;15:414-21 20 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 14. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-35. 15. SWAB-richtlijnen voor de behandeling van invasieve schimmelinfecties. Stichting Werkgroep Antibioticabeleid (SWAB), September 2008. Prof. dr. B.J. Kullberg (voorzitter) et al. 16. Hernandez S, López-Ribot JL, Najvar LK, McCarthy DI, Bocanegra R, Graybill JR. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother. 2004;48:1382-3 17. Pfaller MA, Diekema DJ, Gibbs DL, Newell AV, Meis JS, Gould IM, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance study, 1997 to 2005: an 8.5-year analysis of susceptibilities of Candida species and other yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol. 2007;45:1735-45 Netherlands Journal of Critical Care Accepted January 2013 C ASE RE P OR T Trichoderma: an unusual bystander in invasive pulmonary aspergillosis K. Ariese1, L. Hulshoff1, R. Jansen2, P.H.J. van der Voort3 1 Department of Anaesthesiology and Intensive Care, NKI-AvL, Amsterdam, The Netherlands 2 Department of Microbiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands 3 Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Correspondence K. Ariese-Beldman – e-mail: [email protected] Keywords - Trichoderma, invasive fungal disease, immunocompromised, HIPEC Abstract In this case report we present a 64-year old female patient who was admitted to our intensive care unit (ICU) with an abdominal sepsis six days after a laparotomy and a hyperthermic intraperitoneal chemotherapy (HIPEC)-procedure. During her ICU admission she developed a pneumonia and sepsis. Bronchoalveolar lavage (BAL) was positive for Aspergillus species and an unknown fungus species. Despite maximum treatment for invasive aspergillosis, the patient died after being on the ICU for 29 days. Evaluation of the unknown species in the BAL showed Trichoderma. This case reports focuses on the clinical relevance of finding the Trichoderma species in the BAL. In addition, we provide a literature overview concerning Trichoderma species infections. Introduction Trichoderma species has always been considered as a contaminant in organ site cultures. However, in the recent literature, Trichoderma species has been increasingly reported as etiologic agents in human infections, especially in immunocompromised patients. We describe a case report and discuss recent literature in order to achieve increased awareness of this frequently fatal infection. Case A 64-year old female, with a medical history of hypertension and a right sided hemicolectomy for carcinoma three months prior to admission was admitted to our intensive care unit following a mitomycin-C hyperthermic intraperitoneal chemotherapy (HIPEC) procedure for metastatic carcinoma of the colon. The patient did not receive chemotherapy in the six months before the HIPEC procedure. Six days following the procedure, the patient developed abdominal pain and sepsis. A diagnostic laparotomy was performed which showed a perforation of the small intestine and an extensive faecal peritonitis. The perforation was surgically closed and an abdominal lavage was performed. The patient was hemodynamically unstable and mechanically ventilated at the time of admission to the ICU. Antibiotic treatment was started with amoxicillin, ceftriaxone and metronidazol. In addition, she received selective digestive tract decontamination consisting of amphotericin B, colistin/polymyxin and tobramycin in oral paste and gastric suspension. Blood cultures remained negative except for one anaerobic blood culture, dated just before the re-laparotomy, showing Bacteroides species. The patient’s condition deteriorated and a second look laparotomy was performed on day two of ICU admission. A necrotizing pancreatitis was found, most probably due to low-flow state during sepsis, and antibiotic treatment was changed to meropenem, dosed 500 mg twice daily (adjusted for renal function). On the third day of ICU admission the cultures of the abdominal fluid showed positive for Enterococcus faecium for which vancomycin was added to the meropenem. Seven days after ICU admission the patient stabilized and infection parameters improved. Antibiotic treatment was stopped after 12 and 11 days of meropenem and vancomycin treatment respectively. At day 16 of ICU admission, the patient’s infection parameters deteriorated. After obtaining cultures from the wound, drain fluids, and sputum, meropenem and vancomycin were re-initiated. The cultures were negative except for the tracheal aspirate which showed less than five colonies of Aspergillus fumigatus ( figure 1). Aerosolized amphotericin B was added to the antibiotic regiment as topical treatment, as the positive tracheal aspirates were considered to reflect colonization. Because the patient could not be weaned from mechanical ventilation and continued to have fever between 38 and 39° Celsius, a computer tomogram of the thorax and abdomen was performed on day 22 of ICU stay. It showed increasing pulmonary consolidations in both inferior lobes and the right superior lobe. Multiple sputum cultures grew Aspergillus fumigatus, susceptible for itraconazole (minimal inhibitory concentration [mic] after incubation for 48 hours by E-test and broth microdilution on Sabouraud dextrose agar was 0.75 mg/ml) and amphotericine B (mic 0.38 mg/ml). Because of potential invasive fungal infection, caspofungin was added on day 22 to the antibiotic regimen, initially dosed at 70 mg N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 21 Netherlands Journal of Critical Care Figure 1. Aspergillus Figure 2. Trichoderma daily then reduced to 50 mg daily. Liver function abnormalities precluded the prescription of azoles. At day 27, the chest X-ray showed a cavity in the right middle lobe. The antifungal regime was intensified by adding voriconazole (6 mg/kg twice daily, followed by 4 mg/kg) to the already prescribed caspofungin and a broncho-alveolar lavage (BAL) was performed. The galactomannan test in the BAL was strongly positive (optical density index of 9.3, cut off 0.5 for serum). Galactomannan in serum was not performed. A CT-scan of the thorax performed on day 29 showed progression of consolidations compared with the previous one. These consolidations were highly suspicious for invasive aspergillosis because of extensive cavitation. The patient’s condition worsened and she subsequently died on day 29 in the ICU. Cultures from the tracheal aspirate taken two days before her death revealed the same Aspergillus species and another fungus which was difficult to identify. It was ultimately determined by the Dutch tertiary reference centre for fungal infections (Department of Medical Microbiology Radboud University, Nijmegen) as Trichoderma species ( figure 2), which showed relative susceptibility to voriconazole and anidulafungin. The mic for Trichoderma as were (in mg/ml): itraconazole: >16, fluconazole: >64, amphotericin B: 2.0, 5-flucytosine: >64, voriconazole: 1.0, anidulafungin: 0.25 and posaconazole: >16. An autopsy was performed. The pulmonary slides showed (bilaterally) necrotizing pneumonia with clusters of mould-cords consistent with Aspergillus with vascular invasive growth. Trichoderma could not be detected in the obtained tissue samples. infection. Criteria for IFD have been developed by the EORTC (European Organization for the Research and Treatment of Cancer) for patients with haematological malignancies to standardize clinical and epidemiological research (table 1)1. Despite this they are often applied to such patient groups2, as we did on day 22, facing an immunocompromised patient with increasing pulmonary consolidations on CT and moulds found in multiple sputum cultures. The autopsy results confirmed our diagnosis by showing a necrotising pneumonia with clusters of hyphae conform Aspergillus with invasive growth in vascular structures. In our patient, Trichoderma was found in combination with Aspergillus in the BAL-material. In the tissue samples obtained by autopsy, Trichoderma could not be identified. The relative contribution of Trichoderma in the clinical course is undetermined. Indeed, Trichoderma could just be an unusual bystander in invasive pulmonary Aspergillosis, emphasizing the severe immune-incompetence of our patient. However, the clinician confronted with a culture containing Trichoderma should be aware of this emerging pathogen in immunocompromised patients, as we have described, and should make a therapeutic decision. Previously, Trichoderma species were considered to be contaminants. Trichoderma infections in humans appeared to be rare, but they are increasingly reported as emergent pathogens, probably due to their opportunistic behaviour, but also because of the increasing number of immunocompromised patients nowadays3,4. The first case of an invasive Trichoderma infection was described by Robertson, concerning an accidental intravenous infusion of contaminated fluid5. In the last decades of the past century, the majority of described patients suffered peritonitis as a result of peritoneal dialysis. Mortality was high, with less than fifty percent survival rate. The majority of the non-peritonitis cases contain Discussion The diagnosis of invasive fungal disease (IFD) is challenging, since moulds are ubiquitously present in the environment and detection in a clinical sample does not necessarily represent invasive fungal 22 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Netherlands Journal of Critical Care Trichoderma: an unusual bystander in invasive pulmonary aspergillosis Table 2. IFD criteria by the EORTC Host criteria Clinical criteria (of the respiratory tract) Microbiologic criteria • The presence of 1 of the following 3 signs on CT: • Recent history of neutropenia (0.5x109 - dense, well-circumscribed lesions(s) with or neutrophils/L for >10 days) temporally related to without a halo sign the onset of fungal disease - air-crescent sign • receipt of an allogeneic stem cell transplant -cavity • prolonged use of corticosteroids (excluding or among patients with allergic bronchopulmonary • tracheobronchial ulceration, nodule, aspergillosis) at a mean minimum dose of 0.3 mg/ pseudomembrane, plaque, or eschar seen on kg/day of prednisone equivalent for 13 weeks bronchoscopic analysis • treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-a blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days • inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency) • Direct test (cytology, direct microscopy, or culture) - mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following: • presence of fungal elements indicating a mold • recovery by culture of a mold • indirect tests (detection of antigen or cell-wall constituents): -aspergillosis • galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF - invasive fungal disease other than cryptococcosis and zygomycoses • β-d-glucan detected in serum Proven IFD is defined as recovering a fungal species from a sterile compartment of the body (e.g. positive microscopy or culture from blood, cerebrospinal fluid or sterile tissues). Probable IFD requires the presence of a host factor, a clinical criterion and a microbiological criterion. Possible IFD is established when cases meet the criteria for a host factor and a clinical criterion but for which mycological criteria are absent. opportunistic infections complicating the course of haematological malignancies and solid organ transplantations. Little is recorded about the clinical manifestations of Trichoderma, perhaps because the clinical image seems very un-specific. Symptoms appear predominantly in immunocompromised patients as nodular pulmonary infiltrates, sometimes mimicking invasive aspergillosis 6, localized (ulceronecrotic) cutaneous lesions or disseminated infection, including the central nervous system. In the case of peritonitis (due to infected peritoneal dialysis catheters) the symptoms range from mild (abdominal discomfort) to more severe (bowel obstruction). Sometimes fever is present. None of these symptoms could suggest a fungal rather than a bacterial origin. This makes the definitive diagnosis of Trichoderma difficult. The diagnosis relies on the demonstration of hyphae in tissue sections associated with positive culture results in non-biopsy specimens, obtained from accessible sites, e.g. skin, upper- or lower airways, or urine, sputum cultures, wound swabs etc. Once hyphae have been demonstrated in tissue sections, Trichoderma infection can easily be misdiagnosed as aspergillosis or other hyalohyphomycosis, because the hyphae are morphologically quite similar. Guarro et al. emphasized the complexity of the branching pattern of Trichoderma hyphae in tissue, compared to the other hyalohyphomycosis7. Also the identification of Trichoderma isolates at species level may be difficult by only relying on morphology, sometimes leading to erroneous species identification. Nowadays molecular techniques are used for species identification, since Kuhls et al. identified the human pathogenic Trichoderma isolates by PCR-fingerprinting8. The prognosis for patients with Trichoderma infections is poor. For disseminated infections the mortality is as high as 100%. Favourable outcome of the infection is associated with immunocompetence, catheter or drain removal in cases of peritonitis and surgical debridement of the localized lesion. The major problem with Trichoderma genus is its poor susceptibility to antifungal drugs. The minimal inhibitory concentrations for fluconazole and 5-fluorocytosine are far above the human toxicity level9,10,11,12. Possible susceptibility (i.e. fungal mic for which non-toxic blood levels are achievable) is reported for itraconazole, ketoconazole and miconazole, although for itraconazole and ketoconazole high mic levels have also been reported7. Apparent susceptibility to voriconazole has been described13,14. Recent data indicate that there may be resistance to amphotericin B15,16,17. There is a lack of information about the efficacy of caspofungin, although low mics have been recorded6,18. No clinical trials have been performed directing the treatment of Trichoderma infections. Susceptibility testing is of utmost importance, and preferably antifungal drugs with low mics should be used. There is no evidence for advising a specific antifungal agent in the empirical setting (i.e. before susceptibility testing). The most recent case report uses a combination of an echinocandine (caspofungin) in combination with voriconazole, both more tolerable than amphotericin B, with the aim that Trichoderma will at least be susceptible to one of these antifungals18. Since for other susceptible fungal infections duo therapy is not proven to be superior to monotherapy, we advise switching to monotherapy when results for susceptibility testing become available from the laboratory19,20,21. Conclusion A case of an invasive opportunistic pulmonary infection with Aspergillus and possibly Trichoderma spp. is presented. Awareness of this frequently fatal invasive Trichoderma infection is warranted for critical care physicians. Clinical backgrounds and considerations concerning the diagnosis have been discussed and suggestions for treatment are given in this article. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 23 Netherlands Journal of Critical Care References 1. De Pauw B, Walsh TJ. Donelly JP et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813-21 2. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Critical Care 2006; 10(1):R31 3. De Miguel D, Gómez P, Gonzáles R, et al. Nonfatal pulmonary Trichoderma viride infection in an adult patient with acute myeloid leukemia: report of one case and review of the literature. Diagn Microbiol Infect Dis 2005;53(1):33-7 4. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 2004;10 (Suppl. 1): 48-66 5. Robertson MH. Fungi in fluids- a hazard of intravenous therapy. J Med Microbiol 1970;3:99-102 6. Alanio A, Brethon B, Feuilhade de Chauvin M, et al. Invasive pulmonary infection due to Trichoderma longibrachiatum mimicking invasive Aspergillosis in a neutropenic patient successfully treated with voriconazole combined with caspofungin. Clin Infect Dis 2008;46(10):e116-8 7. Guarro J, Antolin-Ayala MI, Gene J, Gutierrez-Calzada J, Nieves-Diez C, Ortoneda M. Fatal case of Trichoderma harzianum infection in a renal transplant recipient. J Clin Microbiol 1999;37:3751-5 8. Kuhls K, Lieckfeldt E, Borner T, Gueho E. Molecular reidentification of human pathogenic Trichoderma isolates as Trichoderma longibrachiatum and trichoderma citrinoviride. Med Mycol 1999;37:25-33 9. Seguin P, Degeilh B, Grulois I, et al. Successful treatment of a brain abscess due to Trichoderma longibrachiatum after surgical resection. Eur J Clin Microbiol Infect Dis 1995;14(5):445-8 10. Munoz FM, Demmler GJ, Travis WR, Ogden AK, Rossmann SN, Rinaldi MG. Trichoderma longibrachiatum infection in a pediatric patient with aplastic anemia. J Clin Microbiol 1997;35:499-503 11. Furukawa H, Kusne S, Sutton DA, Manez R, Carrau R, Nichols L, Abu-Elmagd K, Skedros D, Todo S, Rinaldi MG. Acute invasive sinusitis due to Trichoderma longibrachiatum in a liver and small bowel transplant recipient. Clin Infect Dis 1998;26:487-9 12. Richter S, Cormican MG, Pfaller MA, Lee CK, Gingrich R, Rinaldi MG, Sutton DA. Fatal disseminated Trichoderma longibrachiatum infection in an adult bone marrow transplant patient: species identification and review of the literature. J Clin Micriobiol 1999;37:1154-60 13. Antal Z, Kredics L, Doczi I, Manczinger L, Kevei F, Nagy E. The pysiological features of opportunistic Trichoderma strains. Acta Microbiol Immunol Hung 2002;49:393 14. Marco F, Pfaller MA, Messer SA, jones RN. Antifungal activity of a new triazole, voriconazole (UK-109,496), compared with three other antifungal agents tested against clinical isolates of filamentous fungi. Med Mycol 1998;36:433-6 15. Ragnaud JM, Marceau C, Roche-Bezian MC, Wone C. Infection péritonéale à Trichoderma koningii sur dialyse continue ambulatoire. Med Mal Infect 1984;14:402-5 16. Tanis BC, van der Pijl H, van Ogtrop ML, Kibbelaar RE, Chang PC. Fatal fungal peritonitis by Trichoderma longibrachiatum complicating peritoneal dialysis. Nephrol Dial Transplant 1995;10(1):114-6 17. Campos-Herrero M, Bordes A, Perera A, Ruiz M, Fernandez A. Trichoderma koningii peritonitis in a patient undergoing peritoneal dialysis. Clin Microbiol Newslett 1996;18:150-2 18. Trabelsi S, Hariga D, Khaled S. First case of Trichoderma longibrachiatum infection in a renal transplant recipiënt in Tunisia and review of the literature. Tunis Med 2010;88(1):52-7 19. Singh N, Limaye AP, Forrest G, Safdar N, Munoz P, Pursell K, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006;81(3):320-6. 20. Kontoyiannis DP, Boktour M, Hanna H, Torres HA, Hachem R, Raad, II. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis. Cancer 2005;103(11):2334-7. 21. Maertens J, Glasmacher A, Herbrecht R et al. Multicenter noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006;107: 2888-97. 24 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Netherlands Journal of Critical Care Accepted January 2013 C ASE RE P OR T Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis S. van der Sar-van der Brugge1, H. van Ravenswaay Claasen2, L. Dawson3 1 Department of Internal Medicine, Reinier de Graaf Hospital Delft, The Netherlands Currently: Department of Pulmonology, Haga Hospital, Den Haag, The Netherlands 2 Department of Pathology, Reinier de Graaf Hospital Delft, The Netherlands 3 Department of Intensive Care, Reinier de Graaf Hospital Delft, The Netherlands Correspondence S. van der Sar-van der Brugge – e-mail: [email protected] Keywords - Drug induced lung injury, bleomycin, interstitial pneumonitis, intensive care unit Abstract Bleomycin is an antineoplastic agent that is known for its potential for fatal lung toxicity. Cell injury occurs through the formation of free radicals. Timely detection of bleomycin-induced pneumonitis (BIP) can be difficult and it is vital to keep a low index of suspicion in patients receiving bleomycin. We describe a patient with Hodgkin’s lymphoma who died of bleomycin-induced lung injury in our intensive care unit. We discuss treatment options and review the literature. Introduction With the knowledge that the prognosis of patients with haematological malignancies in the ICU has been improved in the past decades1, dealing with life-threatening conditions in these patients forms a major challenge for the ICU clinician. Usually, respiratory failure and /or sepsis are the main reasons for ICU admission. Less often we are involved in the treatment of toxicity of chemotherapy in patients cured of haematological malignancy. We report a patient with Hodgkin’s lymphoma who died in our ICU due to a complication of bleomycin-containing chemotherapy. Case description A 74-year old patient was transferred from the haematology-oncology department to our ICU because of respiratory failure. He had been diagnosed with M. Hodgkin stage IVB with cervical, mediastinal and retroperitineal localisations and was treated with six courses of adriamycine, bleomycine, vinblastine and dacarbazine in a 4-weekly schedule. His previous medical history included a myocardial infarction and CABG at the age of 55. For the past 54 years he had smoked one pack of cigarettes per day, and never managed to quit despite counselling. Pulmonary function tests performed before the initiation of chemotherapy showed COPD GOLD stadium II, without reversibility and without complaints (table 1). After the first two rounds of chemotherapy, however, the patient complained of rhinitis, an irritable cough and dyspnoea on exertion. CT thorax at that point showed no intrapulmonary abnormalities, and pulmonary function tests were stable (table 1). Treatment for an upper respiratory tract infection was given, and chemotherapy continued as scheduled. Chest X-ray and pulmonary function tests were repeated after the fourth month of chemotherapy, and again there were only minor changes and as his symptoms had not worsened, chemotherapy continued (table 1). After the sixth ABVD-course, the patient underwent a FDG-PET-scan, and as staff members noticed considerable dyspnoea, he was referred to the haematology-oncology department for admission afterwards. Progressive dyspnoea and cough had developed since his last round of chemotherapy three weeks earlier. On examination the patient was not acutely ill, but mildly distressed with a respiratory rate of 16 breaths per minute, reaching a PaO2 of 8.2 kPa and an oxygen saturation of 92%. The temperature was 37.3 °C. Laboratory analysis showed: ESR 21 mm/hr, C-reactive protein 29 mg/l, haemoglobin 7.5 mmol/l, LDH 544 mmol/l, creatinine 61 mmol/l. The PET-CT thorax revealed diffuse ground glass opacities Table 1. Pulmonary function tests during chemotherapy VC max [L] VC [% of predicted] FEV-1 [L] FEV-1 [% of predicted] TLC-He [L] TLC-He [% of predicted] DLCOc [mmol/ min/kPa] Baseline 3.98 93 2.30 73 6.90 95 5.62 Two months 3.94 92 2.38 76 6.90 94 7.12 Four months 3.56 83 2.02 65 6.91 95 6.34 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 25 Netherlands Journal of Critical Care and thickening of intra- and interlobular septa ( figure 1), but no new localisations of Hodgkin’s lymphoma. Given the subacute onset of dyspnoea after administration of bleomycin, the absence of fever and relatively low inflammation markers, the working diagnosis was bleomycin interstitial pneumonitis rather than pneumonia. However, as the patient was immunocompromised, bacterial (super)infection or an opportunistic infection (especially Pneumocystis jirovecii pneumonia) had to be considered as well. Therefore, treatment with prednisone (100 mg/ day), cefuroxime and high-dose cotrimoxazole was commenced. Administration of oxygen was kept to a minimum, aiming for an oxygen saturation level of 90%. The consulting pulmonologist decided to review the patient shortly after admission in order to schedule a broncho-alveolar lavage for further diagnostic steps. During admission, however, the patient’s clinical condition deteriorated rapidly with major changes in behaviour, and progressive hypoxaemia. On day 2 of hospital admission, the ICU’s rapid response team was called to the haematology-oncology ward to assess the patient. We saw a distressed, restless and at times aggressive patient who responded to verbal stimuli. His airway was clear. With 22 breaths per minute and administration of 2 L O2/min by nose prong, his SpO2 was 80%. On auscultation bilateral crackles were heard. His blood pressure was 135/80 mmHg, with a sinus tachycardia of 110 beats per minute, and a temperature of 37.4°C. Further examination was unremarkable. Blood gas analysis at that point showed: pH 7.46; pCO2 3,7 kPa; bicarbonate 20 mmol/l; base excess -3.6; pO2 4.8; O2saturation 65%. Further lab results were: Haemoglobin 6.5 mmol/l; leucocytes 12.4 *109/l, thrombocytes 132*109/l, CRP 38 mg/l, LDH 570 U/l. A CXR showed bilateral consolidations ( figure 2). We transferred the patient to the ICU where high flow oxygen through nasal cannulae (Optiflow™) was given, aiming for an oxygen saturation of 88-90%. Morphine and sedatives were administered for comfort. Figure 1. CT thorax: Bilateral airspace consolidation and ground glass opacities 26 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Figure 2. Chest X-ray with bibasal consolidations We considered bleomycin interstitial pneumonitis to be the most likely diagnosis, but were also concerned about possible PJP-infection. Alternative diagnoses (atypical pneumonia, acute lung injury due to a different, unknown cause) were considered much less likely. Therefore high-dose prednisolone and cotrimoxazole were continued and to include Pseudomonas aeruginosa coverage, ceftazidim was substituted for cefuroxim. We discussed intubation and mechanical ventilation of the patient in order to perform a broncho-alveolar lavage. But considering the fact that bleomycin toxicity was the most likely diagnosis, given the subacute onset and slowly progressive course coupled with a relatively low CRP, we decided against intubation. Treatment with Optiflow™ had the main advantage of the patient being able to communicate with his relatives. Over the next two days, the patient’s condition was poor but stable. His CRP-level dropped slightly, and consolidations on CXR barely improved. He remained strictly dependent on Optiflow (FiO2 55%, 50L/min), with oxygen saturation levels between 85-94% and had considerable respiratory distress on incidental removal of the Optiflow™ cannulae. Academic institutions were consulted for their opinion regarding the benefit of mechanical ventilation, e.g. extracorporeal membrane oxygenation (ECMO) or other experimental therapies. However, as lung damage was severe, and no short-term improvement was to be expected, they advised continuing the conservative treatment. We informed the patient and his relatives of the prognosis, with a very poor chance of survival in an acceptable condition. They agreed to withhold further active treatment. Patient comfort was ensured by continuous administration of morphine and midazolam. The patient died a few hours after cessation of therapy. Permission for autopsy was obtained, and findings were as follows: Both lungs were heavy and solid, with white-yellow to grey discolorations. Microscopic examination revealed areas of Netherlands Journal of Critical Care Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis congestion and haemorrhage in alveolar septa ( figure 3 and 4) and fibroblast-plugging in alveoli ( figure 5). Macrophages in alveoli were noted as well as a few hyaline membranes. These findings are consistent with diffuse alveolar damage and organizing pneumonia, which are both known patterns of lung reaction to toxic drugs, like bleomycin. Additional PAS and Grocott-stain of the lungs did not reveal any micro-organisms, and culture for Aspergillus was negative. There was mediastinal lymphadenopathy but on microscopy no atypical lymphoid cells were found. Figure 5. Diffuse alveolar damage: Late phase of organizing pattern with intra-alveolar plugs, and dense connective tissue Figure 3. Diffuse alveolar damage: acute and organising pattern. Congestion of alveolar capillaries in the alveolar septal wall (left) and rupture of this wall by young organizing fibrine, fibroblasts and type II pneumocytes (right) In conclusion, there was diffuse alveolar damage and organizing pneumonia, consistent with bleomycin pulmonary toxicity, but no evidence of an opportunistic infection or recurrence of the Hodgkin’s lymphoma. Figure 4. Diffuse alveolar damage: acute and organizing patterns. Erythrocyte extravasation in alveolar spaces (upper left), congestion of erythrocytes in septal capillary (right below) and fibrosis in alveolar septal wall consisting of loose organizing type of connective tissue. Prominent hyperplastic type 2 pneumocytes line the alveolar walls Discussion Drug-induced lung injury is an important cause of respiratory failure, but presentation is usually non-specific. In patients treated with antineoplastic agents, differentiation between drug toxicity and other causes of lung injury like (opportunistic) infection, cardiovascular disease or progression of primary disease can be difficult. Bleomycin is an antineoplastic agent that is known for its potential for fatal lung toxicity2. This toxicity can present in several distinct patterns, including eosinophilic hypersensitivity, organizing pneumonia and bronchiolitis obliterans and interstitial pneumonitis (BIP), which may eventually progress to pulmonary fibrosis2. The incidence of BIP increases with cumulative dose up to 18% in patients who receive a dose of over 360 units of bleomycin3, but it can occur even with doses < 50 units. Fatal toxicity has been reported in 0-3% of all patients receiving bleomycin-containing chemotherapy4,5. Patients surviving the acute phase of BIP, however, usually recover completely with total recovery of all lung function parameters after two years6. The main indications for bleomycin are disseminated germ cell tumours and Hodgkin’s disease. Omission of bleomycin from the standard treatment for germ cell tumours has been shown to decrease the disease free survival4. In patients at high risk for BIP, however, alternative chemotherapeutic regimens can be used. The antineoplastic effect of bleomycin occurs by inducing cell-death through induction of free radicals. Bleomycin binds to Fe(II), which is oxidized to Fe(III), resulting in free radicals formation. These free N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 27 Netherlands Journal of Critical Care radicals cause single- and double-strand breaks in DNA (scission), leading to cell-death. The enzyme bleomycine hydrolase deactivates the drug, but as this enzyme has low activity in the skin and the lungs, these organs are most susceptible to bleomycin toxicity2. Bleomycin causes activation of alveolar macrophages by an unknown mechanism, resulting in release of inflammatory, profibrotic cytokines7. Tumour necrosis factor α, transforming growth factor β and platelet-derived growth factor receptor α are believed to play a role in formation of fibrosis8. Bleomycin interstitial pneumonitis typically (but not exclusively) develops subacutely during treatment, up to six months afterwards2. Symptoms are nonspecific and include dyspnoea on exertion, dry cough, tachypnoea and fever. On examination, bibasilar fine crepitations and hypoxaemia can be noted. Pulmonary function tests (PFTs) are usually obtained before initiation of bleomycin. Subsequent PFTs are usually performed as clinically indicated. Diffusing capacity of the lung for carbon monoxide (DLCO) decreases in most patients on bleomycin, but also decreases in patients receiving non-bleomycin-containing chemotherapy9. Deterioration of vital capacity (VC) or total lung capacity (TLC) also occurs in patients on bleomycin and is more specific for BIP9. Diagnosis is by exclusion. Cultures including viral and PCRs on blood, sputum or broncho-alveolar lavage (BAL) fluid can be done to rule out infection including opportunistic. Usually empiric antibiotic treatment is started pending culture results. BAL-fluid can also be checked for malignant cells. Chest radiographic findings can be normal, but typically bibasilar infiltrates, progressing to diffuse alveolar or interstitial consolidation are found. Rarely, pneumothorax and pneumomediastinum have been reported in BIP10. On high resolution computed tomography (HRCT) abnormalities may be detected earlier than on plain chest radiography. HRCT is useful in characterizing the pattern and distribution of abnormalities. HRCT findings vary with underlying histopathologic pattern (table 2)11. Rarely, organizing pneumonia due to bleomycin presents with subpleural nodules, which should not be mistaken for progression of primary disease. Lung biopsy can be obtained for histopathological examination, but findings may be nonspecific. Histopathologic patterns of bleomycin-induced lung injury include diffuse alveolar damage (DAD), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia (COP) and bronchiolitis obliterans and eosinophilic pneumonia12. DAD, which was also found in our patient, is the most common form but is nonspecific. It is also the most common histopathologic pattern seen in ARDS13. It is characterized by diffuse alveolar septal thickening, patchy or diffuse airspace organization and focal or diffuse hyaline membranes, in the absence of signs of infection (including viral), granulomas and prominent eosinophils or neutrophils14. Risk factors for development of BIP have been identified (table 3)2,15. A previous history of pulmonary disease has not been reported as a risk factor, but the risk of dealing another blow to an already compromised organ seems obvious. 28 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Table 2. High resolution computed tomography manifestations of different histopathological types associated with bleomycin toxicity11 Diffuse alveolar damage Bilateral airspace consolidation and ground glass opacities involving dependent lung regions Alveolar haemorrhage Extensive bilateral ground glass opacities with or without superimposed interlobular linear opacities (‘crazy paving’) Hypersensitivity pneumonitis Bilateral ground glass opacities and/or small poorly defined centrilobular nodules. Air trapping Nonspecific interstitial pneumonia Patchy bilateral or diffuse ground glass opacities with associated reticular opacities. Mainly lower lung zones and subpleural regions involved Cryptogenic organizing pneumonia and bronchiolitis obliterans Ground glass opacities in bilateral random distribution. Airspace consolidation in subpleural or peribronchial distribution. Rarely solitary nodules Eosinophilic pneumonia Airspace consolidation and ground glass opacities in predominantly peripheral distribution, involving middle and upper lung zones Table 3. Risk factors for bleomycine pulmonary toxicity2,15 Age Renal insufficiency Smoking Radiation therapy High fraction of inhaled oxygen Concurrent use op granulocyte colony stimulating factor Concurrent use of cisplatin The role of high FiO2-administration is controversial. The pathogenetic mechanism (with a central role for formation of free radicals) suggests a possibly harmful effect of high FiO2, which has been confirmed by most studies in animals. In humans, this is supported by reports of patients developing acute respiratory failure postoperatively after previous treatment with bleomycin. A major review article in 77 patients who received bleomycin, however, failed to show a correlation between FiO2-restriction and postoperative pulmonary morbidity or survival16. Usual practise is to keep FiO2 as low as possible. In hypoxemic patients, oxygen is supplemented as needed to reach an oxygen saturation of 89-92%. Once BIP has been diagnosed, further bleomycin treatment should be withheld. Patients can be treated with glucocorticoids (for example, prednisone 0.75-1 mg/kg day up to 100 mg/day). There are no controlled studies of glucocorticoids, but observational studies have suggested a beneficial effect5. Response may vary according to histopathological pattern. Further treatment is mainly supportive. Shortly after we lost our patient, an interesting case report was published, describing a patient with life-threatening BIP, who was completely cured with imatinib-mesylate, after steroid treatment failed17. Our patient was at increased risk of bleomycin pulmonary toxicity due to his age, smoking status and COPD. In retrospect, he had already showed symptoms of BIP after the first two rounds of chemotherapy. His symptoms were given clinical attention, but unfortunately the treating physicians were lured into a false sense of Netherlands Journal of Critical Care Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis security by the normal findings on CT-scan and pulmonary function testing and bleomycin-containing chemotherapy was continued. During ICU admission we were faced with the difficult decision regarding intubation or palliative treatment. Though the patient’s chances seemed poor, there would have been a small chance of survival with aggressive management. The patient and his relatives, however, decided against this as they were afraid of prolonged suffering and a poor clinical and functional outcome. Conclusion Bleomycin treatment is often complicated by pulmonary toxicity, which can be severe. Screening tests (like radiographic imaging or pulmonary function tests) are unreliable, making it vital to keep a low index of suspicion especially in patients with risk factors. Withholding further bleomycin from patients with dyspnoea or a non-productive cough should be seriously considered, even in the absence of abnormalities on CT-scans or PFTs. As establishing the diagnosis is mainly by exclusion and patients are also prone to infection whether opportunistic or not, this can be problematic. Once BIP is suspected, treatment with high-dose glucocorticoids should be started. Excess administration of oxygen is to be avoided, but in patients with respiratory failure, adequate tissue oxygenation should be maintained. Initiation of mechanical ventilation requires careful consideration as the effect on BIP is unknown. Treatment with high flow oxygen allows comfort and verbal communication. By admitting this severely hypoxaemic patient to the ICU we were able to gain some valuable time for him through good palliative treatment. 13. Parambil JG, Myers JL, Aubry MC, Ryu JH. Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy. Chest 2007;132:50-7. 14. American Thoracic Society; European Respiratory Society. American Thoracic Society/ European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;16:277-304. 15. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ cell tumours. Ann Oncol 2003;14:91-6. 16. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? J Urol 1998;160:1347-52. 17. Carnevale-Schianca F, Gallo S, Rota-Scalabrini D, et al. Complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with Hodgkin’s lymphoma: hope for severe chemotherapy-induced toxicity? J Clin Oncol 2011;29:e691-3. References 1. Ferrà C, Marcos P, Misis M, et al. Outcome and prognostic factors in patients with hematologic malignancies admitted to the intensive care unit: a single-center experience. Int J Hematol. 2007;85:195-202. 2. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001;120:617-24. 3. De Wit R, Roberts JT, Wilkinson PM, et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001;19:1629-40. 4. Simpson AB, Paul J, Graham J, Kaye SB. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review of patients with germ cell tumours. Br J Cancer 1998;78:1061-6. 5. White DA, Stover DE. Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids. Chest 1984;86:723-8. 6. Van Barneveld PW, Sleijfer DT, van der Mark TW, et al. Natural course of bleomycin-induced pneumonitis. A follow-up study. Am Rev Respir Dis 1987;135:48-51. 7. Denholm EM, Phan SH. Bleomycin binding sites on alveolar macrophages. J Leukoc Biol 1990;48:519-23. 8. Yoshida M, Sakuma J, Hayashi S, et al. A histologically distinctive interstitial pneumonia induced by overexpression of the interleukin 6, transforming growth factor beta 1, or platelet-derived growth factor B gene. Proc Natl Acad Sci U S A. 1995;92:9570-4. 9. Sleijfer S, van der Mark TW, Schraffordt Koops H, Mulder NH. Decrease in pulmonary function during bleomycin-containing combination chemotherapy for testicular cancer: not only a bleomycin effect. Br J Cancer 1995;71:120-3. 10. Keijzer A, Kuenen B. Fatal pulmonary toxicity in testis cancer with bleomycin-containing chemotherapy. J Clin Oncol 2007;25:3543-4. 11. Silva CI, Müller NL. Drug-induced lung diseases: most common reaction patterns and corresponding high-resolution CT manifestations. Semin Ultrasound CT MR 2006, 27:111-6. 12. Godoy MC, Nonaka D, Raphael BG, Vlahos I. Diffuse ground-glass opacities in a patient with Hodgkin lymphoma and progressive respiratory failure. Chest 2008;134:207-12. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 29 Netherlands Journal of Critical Care Accepted January 2013 C ASE RE P OR T A rare cause of cardiac failure following transthoracic oesophagectomy D.A. Wicherts1, S. Hendriks2, W.L.E.M. Hesp1, J.A.B. van der Hoeven1, H.H. Ponssen2 1 Albert Schweitzer Hospital, Department of Surgery, Dordrecht, The Netherlands 2 Albert Schweitzer Hospital, Department of Intensive Care Medicine, Dordrecht, The Netherlands Correspondence D.A. Wicherts – e-mail: [email protected] Keywords - Oesophagectomy, cardiac failure, chylomediastinum, chylothorax Abstract Following elective transthoracic oesophagectomy in a 75-year old female, sudden haemodynamic instability occurred on the second postoperative day, requiring re-intubation and inotropic support. A large mediastinal fluid collection with mechanical compression of the heart was found with computed tomography imaging of the thorax. Restoration of cardiac function was noted following successful surgical fluid drainage. Subsequent ligation of the thoracic duct because of persisting leakage of chylous fluid resulted in final patient recovery. Chyle leakage following oesophagogastrectomy usually results in pleural effusion. However, a chylomediastinum may sometimes occur with potentially significant haemodynamic consequences. Recognition of the thoracic duct at initial surgery with or without prophylactic ligation is crucial for preventing major complications caused by chyle leakage. Introduction During oesophagogastrectomy, injury to the main thoracic duct or its branches often occurs. This is related to the close anatomical proximity of the thoracic duct to the oesophagus. As a consequence, lymphatic fluid may leak into the thoracic cavity, resulting in a so-called chylothorax1. This complication causes significant morbidity, but fortunately is relatively uncommon. The overall incidence is reported to be around 2% to 3%, depending on the type of surgical approach used2. Opening the thoracic cavity during a transthoracic approach logically increases the risk of a chylothorax compared to a transhiatal oesophagogastrectomy. A chylothorax usually presents as a high-volume lymphatic output from a chest tube or an undrained pleural effusion on a chest radiograph. A chylomediastinum (mediastinal chyle collection), however, may have significant haemodynamic consequences due to its close relationship with the heart and major vascular structures. This situation is illustrated in the following case report. Case report A 75-year old female was admitted to our hospital with a biopsy-proven squamous cell carcinoma of the distal oesophagus. 30 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 At preoperative work-up, including endoscopic ultrasound as well as computed tomography (CT) imaging of the thorax and abdomen, it was classified as a cT3N1 tumour. Following standard preoperative chemoradiotherapy, a transthoracic oesophagectomy was performed with a primary anastomosis located in the neck. During surgery, the oesophagus and surrounding lymph nodes were mobilized through a right thoracotomy and incisions in the upper abdomen and neck. The anastomosis was made between the cervical oesophagus and the fundus of the stomach. The initial surgery was uneventful. Drains were situated in the neck, right pleural cavity and upper abdomen. Postoperatively, the patient was admitted to the Intensive Care Unit and was extubated the following day without any problems. On postoperative day (POD) 2, the patient suddenly deteriorated haemodynamically (hypotension, tachycardia and increased central venous pressure [23 mm Hg]), requiring re-intubation and inotropic support. The chest radiograph showed bilateral pleural effusions for which an additional chest tube was placed at the left side, draining a large amount of typical chylous (milky) fluid. Laboratory analysis showed an elevated level of triglycerides (5.3 mmol/L) suggestive for chyle. Fluid cultures were negative. Additionally, conservative treatment with total parenteral nutrition (TPN) was started. However, the patient did not improve. Subsequent CT imaging of the thorax showed a large mediastinal fluid collection adjacent to the neo-oesophagus, compressing the left atrium of the heart ( figure 1). Additional cardiac ultrasound confirmed low cardiac output due to external compression of the left atrium with a subsequent decrease of cardiac inflow. At re-laparotomy on POD 3, the mediastinal collection was drained through a transhiatal approach using the upper abdominal incision. Immediate reduction in the patient’s need of vasopressors and inotropic support was noted as well as a marked decrease in heart rate following successful drainage. Central venous pressure decreased to 11 mm Hg. Postoperative cardiac ultrasound confirmed the presence of a normalized cardiac function. A medium-chain triglyceride (MCT) diet was started postoperatively. Netherlands Journal of Critical Care A rare cause of cardiac failure following transthoracic oesophagectomy Figure 1. CT images of the thorax (a: transverse, b: coronal) demonstrating a large mediastinal fluid collection (c) adjacent to the neo-oesophagus and compressing the left atrium of the heart Figure 2. Marked reduction of heart rate and improvement of blood pressure during re-laparotomy. Time 0 represents the beginning of surgery. Mediastinal drainage (d) occurred 2 to 3 minutes later 180 160 140 120 100 80 60 40 20 d 0 -5 0 HR BP syst BP dias MAP Due to continuing production of fluid in the upper abdominal drain (5 to 6 liters of chylous fluid per day), a re-thoracotomy was performed on POD 14. During surgery, leakage of lymph from the thoracic duct was noted. The thoracic duct was subsequently ligated, resulting in a marked improvement of patient recovery. Discussion Cases and management of postoperative chylothorax following oesophagogastrectomy have been frequently presented3,4. However, to our knowledge, the presence of a chylomediastinum has only been reported on a few occasions5-8. In addition, significant secondary haemodynamic consequences were described in only one paper8. Postoperatively, massive chylous chest tube effusion is suggestive of thoracic duct injury. Loculated mediastinal collection of chyle is, however, rare especially following a transthoracic procedure when the pleural cavity has been opened2. One could assume that in these cases sufficient fluid drainage is possible through the chest tubes. Due to the high volume of physiological lymph production, 5 10 15 20 Time insufficient mediastinal drainage may cause rapidly progressive mechanical obstruction of vital mediastinal organs. In our case, decreased left-sided cardiac inflow due to external left atrial compression resulted in a significant reduction of cardiac output. Interestingly, obvious improvement of cardiac function occurred following successful fluid drainage. Intra-operative monitoring demonstrated a marked subsequent reduction of heart rate and improvement of blood pressure ( figure 2). Usually, the presence of a chylothorax can be managed conservatively by TPN or an MCT diet, occasionally resolving within a few days. Only persisting chyle leakage necessitates re-operation and ligation of the thoracic duct. However, different thresholds of continuing fluid drainage per day that require re-operation are advised9,10. In general, operative therapy is suggested in case of a daily output of more than 2 liters after two days of optimal conservative therapy10. In our case, we observed an uncommonly high production of chyle of 5 to 6 liters per day. In cases of severe haemodynamic consequences, surgical intervention is urgently required. Some authors recommend prophylactic ligation of the thoracic duct during initial surgery to minimize the risk of postoperative morbidity and mortality11. Of course, mediastinal chyle collections need to be distinguished from a local abscess or anastomotic leakage. These complications require a different treatment approach. CT imaging is usually indicated to differentiate between these causes. In summary, chyle leakage following oesophagogastrectomy usually results in pleural effusion. Mediastinal collections may, however, occur with potentially significant haemodynamic consequences. Early recognition and subsequent management is essential. N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 31 Netherlands Journal of Critical Care Intra-operative recognition of the thoracic duct with or without prophylactic ligation remains crucial to prevent major complications due to chyle leakage. References 1. Cerfolio RJ. Chylothorax after esophagogastrectomy. Thorac Surg Clin 2006;16:49-52. 2. Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor-Lewis oesophagectomy: is there a difference? Aust N Z J Surg 1999;69:187-94. 3. Paul S, Altorki NK, Port JL, Stiles BM, Lee PC. Surgical management of chylothorax. Thorac Cardiovasc Surg 2009;57:226-8. 4. Nair SK, Petko M, Hayward MP. Aetiology and management of chylothorax in adults. Eur J Cardiothorac Surg 2007;32:362-9. 5. Lautin JL, Baran S, Dumitrescu O, Sakurai H, Halpern N, Lautin EM. Loculated mediastinal chylothorax resulting from esophagogastrectomy: a case report. J Thorac Imaging 1993;8:313-5. 6. Khwaja HA, Chaudhry SM. Mediastinal lymphocele following radical esophagogastrectomy. Can J Surg 2008;51:E48-9. 7. Lavis RA, Barrett JA, Kinsella DC, Berrisford RG. Recurrent dysphagia after oesophagectomy caused by chylomediastinum. Interact Cardiovasc Thorac Surg 2004;3:68-70. 8. Pera M, Belda J, Vidal O, Rubio M, Grande L. Mediastinal chyloma after esophageal cancer resection: an unusual complication causing left cardiac failure. J Thorac Cardiovasc Surg 2002;124:198-9. 9. Cerfolio RJ, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Postoperative chylothorax. J Thorac Cardiovasc Surg 1996;112:1361-5. 10. Lagarde SM, Omloo JM, Jong K, Busch OR, Obertop H, van Lanschot JJ. Incidence and management of chyle leakage after esophagectomy. Ann Thorac Surg 2005;80:449-54. 11. Lai FC, Chen L, Tu YR, Lin M, Li X. Prevention of chylothorax complicating extensive esophageal resection by mass ligation of thoracic duct: a random control study. Ann Thorac Surg 2011;91:1770-4. 32 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 Netherlands Journal of Critical Care Accepted January 2013 C ASE RE P OR T Elevated liver enzymes and renal failure, with a surprising outcome. Two similar cases A.E. Boendermaker1, D. Boumans2, R.A.A. van Zanten2, H. Idzerda3, H. van de Hout4, Th.F. Veneman1,2 1 Department of Intensive Care Medicine, Ziekenhuisgroep Twente, Almelo, The Netherlands 2 Department of Internal Medicine, Ziekenhuisgroep Twente, Almelo, The Netherlands 3 Department of Cardiology, Ziekenhuisgroep Twente, Almelo, The Netherlands 4 Department of Radiology, Ziekenhuisgroep Twente, Almelo, The Netherlands Correspondence A.E. Boendermaker – e-mail: [email protected] Keywords - Tamponade, shock, pericardial effusion, kidney failure Introduction The prevalence of elevated liver enzymes and acute renal failure is high and the differential diagnosis of both conditions, separately and combined, is extensive.1-3 We present two cases of rapidly increasing liver enzymes in combination with (oliguric) renal failure with surprising outcomes. In both cases the medical condition was caused by cardiac tamponade with almost complete restoration of both renal and liver function after pericardiocentesis. Pericardial effusion can be a complication of numerous medical conditions, such as malignancies, trauma, metabolic disorders and infections.4-6 In some cases, the accumulation of pericardial fluid results in cardiac tamponade with subsequent cardiogenic shock. This life-threatening condition can then lead to multiple organ dysfunction and, unless treated promptly, even to death.7,8 Both described cases of cardiac tamponade underline the necessity of a thorough search for the underlying cause of elevated liver enzymes and acute renal failure. Case A A previously healthy 49-year-old man (patient A) was admitted to our intensive care unit (ICU) with signs of haemodynamic impairment, elevated liver enzymes and renal failure. Several hours before admission to our ICU, the patient presented at the emergency department (ED) after an episode of transient loss of consciousness lasting a few seconds. His medical history was unremarkable. He complained of a slowly progressive cough with shortness of breath during exercise that he had had for a few months. During the few days prior to admission, he had experienced a sharp chest pain during coughing; this was accompanied by vomiting and a fever up to 38.5 o Celsius. His general practitioner had prescribed amoxicillin under the clinical suspicion of pneumonia. Furthermore, his body weight had been stable and his appetite was unchanged. In addition, he admitted nicotine abuse estimated at approximately 25 pack years. Physical examination performed by the ED resident showed a pale, slightly overweight man with a normal body temperature (37.2 o C), a blood pressure of 90/67 mmHg with a heart rate 116 bpm, a respiratory rate of 30 breaths per minute and a peripheral oxygen saturation of 99% without additional oxygen. Heart sounds were normal and no murmurs or pericardial rub were heard. An expiratory wheeze and inspiratory crackles were noticed in the lower lung fields bilaterally. Examination of the abdomen was unremarkable. There were no signs of neurological pathology. Determination of jugular vein distention (JVD), Kussmaul’s sign and pulsus paradoxus could at this point have directed towards obstructive cardiogenic shock. Unfortunately, none of these diagnostic tests were performed on admission. Laboratory investigation revealed normocytic anaemia, acute renal failure, elevated liver enzymes and markers of inflammation (table 1). The chest X-ray ( figure 1) showed a small consolidation of the left posterobasal segment of the lung, cardiac enlargement (cor thorax ratio (CTR) of 0.59) and loss of the aortopulmonary window. The electrocardiogram (ECG) showed a sinus rhythm Table 1. Laboratory data from case A Case A Units At admission At admission 22 days after admission ICU ED 29-11-2011 07-11-2011 06-11-2011 Haemoglobin mmol/L 7.4 6.8 C-reactive protein mg/L 186 190 7.8 22 Leucocyte count *10^9/L 15.9 17.5 9.5 Bilirubin total μmol/l 5 22 19 Alkaline phosphatase U/L 108 112 116 Gamma GT 91 88 40 U/L ASAT U/L 1.568 2.871 10 ALAT U/L 2.496 3.968 27 Lactate dehydrogenase U/L 3.607 4.749 184 Creatinine μmol/l 184 248 95 Urea mmol/L 20 26 8.3 Estimated GFR mL/min 34 24 73 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 33 Netherlands Journal of Critical Care Figure 1. Case A, Posteroanterior and lateral chest X-ray showing a small consolidation of the left posterobasal segment of the lung, cardiac enlargement and loss of the aortopulmonary window Figure 2. ECG Case A without microvoltages or electrical alternans, and abnormal concavely elevated ST-segments in V3-V6, II, III and a VF with slight depression of the PRa-interval ( figure 2). Patient A was admitted to the internal medicine ward with the preliminary diagnosis of a severe sepsis with signs of organ failure due to a community acquired pneumonia of the left lung. He was treated accordingly with fluid resuscitation and broad-spectrum antibiotics. Despite all efforts the patient’s condition deteriorated. Twelve hours after admission he was transferred to the ICU because of refractory hypotension (95/60 mmHg), signs of tissue hypoxia and progressive multiple organ dysfunction expressed by a marked increase of liver enzymes and progressive oliguric renal failure (table 1). The JVD was elevated and heart sounds were muffled. Intra-arterial blood pressure measurement showed a pulsus paradoxus. Abdominal ultrasound showed venous congestion within the portal vein, inferior vena cava and liver veins, with normal directions of blood flow, and a thickened gall bladder wall. The transthoracic echocardiogram revealed a normal left ventricular ejection fraction and a tricuspid aortic valve with normal morphology and function. It showed circular pericardial effusion of apical 3.5 cm and of 4.4 cm at the right ventricle with a swinging heart. There were paradoxal septal movements and compression of the right atrium consistent with pericardial tamponade. An emergency pericardial drainage was performed. Within 15 minutes after pericardial drainage, the 34 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 patient’s haemodynamic parameters improved and stabilized. In the following 12 hours, approximately 900 cc of sanguinolent pericardial fluid was drained. During the next few days, the liver enzymes, renal function and diuresis gradually improved (table 1). Pathologic investigation of the pericardial fluid revealed the presence of atypical cells, suspicious for metastases of adenocarinoma. The subsequent diagnostic work-up included a CT-scan of the abdomen and chest, and a bronchoscopy with lavage and biopsies. These studies confirmed the diagnosis of a cT1aN3M1a, stage IV adenocarcinoma of the lung without hepatic metastases. Treatment with palliative chemotherapy was initiated. Case B A 61-year-old man (patient B) presented at the ED with rapidly developing shortness of breath, a non-productive cough and peripheral oedema. His medical history revealed a viral pericarditis 12 years previously, a stent-graft reconstruction of the abdominal aorta 11 years previously, type 2 diabetes and chronic kidney disease stage III related to diabetic nephropathy. In addition, he admitted nicotine abuse estimated at approximately 15 pack years. Physical examination showed a dyspnoeic patient with a respiratory rate of 24 breaths per minute and peripheral oxygen saturation of 96 % while breathing room air. The patient’s blood pressure was 107/73 mmHg with a heart rate of 80 bpm and the body temperature was normal (36 o C). Chest auscultation revealed normal heart sounds without a heart murmur or pericardial rub, and mild to moderate bilateral inspiratory crackles. Furthermore, pitting oedema was seen in both legs. The presence of an increased JVD or a pulsus paradoxus was not tested. Laboratory investigation at admission showed an acute on chronic renal failure, normocytic anaemia and elevated C-reactive protein (CRP) and NT-proBNP (table 2). The chest X-ray revealed a right sided retrocardial consolidation suggestive of pneumonia without significant cardiac enlargement (CTR of 0.50) ( figure 3). The ECG showed a sinus rhythm with flattened ST-segments inferolateral and criteria for microvoltages were approximated but not met ( figure 4). Table 2. Laboratory data from case B Case B Units At admission At admission 5 days after admission CCU ED 12-12-2011 07-12-2011 05-12-2011 Haemoglobin mmol/L 7.1 6.4 C-reactive protein mg/L 56 67 6.3 51 Leucocyte count *10^9/L 8 8.3 7.9 Bilirubin total μmol/l 16 9 11 Alkaline phosphatase U/L 146 - 125 Gamma GT 81 117 77 U/L ASAT U/L 32 3.802 61 ALAT U/L 33 2.449 396 Lactate dehydrogenase U/L 258 3.161 239 Creatinine μmol/l 216 353 112 Urea mmol/L 13.7 25.4 7.5 Estimated GFR mL/min 27 15 58 NT-proBNP pmol/L 85 110 110 Netherlands Journal of Critical Care Elevated liver enzymes and renal failure, with a surprising outcome. Two similar cases Figure 3. Case B, Posteroanterior and lateral chest X-ray showing a right sided retrocardial consolidation suggestive of a pneumonia without significant cardiac enlargement Figure 4. ECG Case B with compression of the right atrium consistent with pericardial tamponade. An emergency pericardial drainage was performed. After drainage of a total 800 ml serosangulent pericardial fluid, the patient stabilized haemodynamically. During the next few days, his liver enzymes and renal function and diuresis improved gradually. Pathologic investigation of the pericardial fluid revealed the presence of adenocarcinoma-cells suspicious for metastases originating in the lung. CT-scan of the thorax and abdomen revealed a small mass in the apex of the left lung and bilateral pleural effusion. Thoracocentesis was performed showing malignant cells as well. This confirmed the diagnosis of adenocarcinoma of the lung with carcinomatous pericarditis and pleuritis (stage IV disease). Due to several complications in the course of the disease, palliative chemotherapy could not be initiated and the patient died four months later. The preliminary diagnosis was a community acquired pneumonia combined with right and left sided cardiac decompensation in presence of a previously unknown history of heart failure. Treatment was started accordingly with amoxicillin and intravenous administration of furosemide. The next day patient B became hypotensive and oliguric. Furosemide infusion was ceased and intravenous volume resuscitation was initiated. As a result, the blood pressure gradually normalized but despite this the patient’s condition deteriorated. Physical re-examination revealed increased bilateral lung crackles and peripheral oedema and elevated JVD, suggesting progressive heart failure for which furosemide infusion was restarted at a higher dose. During the next few hours, the patient became anuric, hypotensive and his respiratory distress progressed. Laboratory investigation showed a metabolic acidosis with respiratory compensation, dramatically increased parenchymal liver enzymes, further decrease in renal function and stable CRP (table 2). The chest X-ray (bed-side anterior posterior projection) now showed enlargement of the cardiac silhouette and the ECG remained unchanged. The patient was transferred to the Cardiac Care Unit (CCU). Emergency transthoracic echocardiography had limited visualization, but showed a normal left ventricular ejection fraction and circular pericardial effusion, apical of 3.2 cm and of 3.1 cm over the right ventricle. Paradoxal septal movement was seen in combination Discussion The most common disease of the pericardium is acute pericarditis.4-6 Major manifestations are a typical sharp retrosternal chest pain that is position dependent and intensifies on inspiration, a pericardial friction rub, typical ECG changes and pericardial effusion (PE). PE can also found by chance in asymptomatic patients during echocardiography. As a result of inflammation of the pericardium, PE can develop after an acute myocardial infarction, cardiac surgery, or as a consequence of autoimmune disease, trauma, metabolic disorders, infection and malignancies. Most cases are presumed to have a viral or autoimmune aetiology and follow a benign course.4-6 PE can lead to impairment of cardiac function and tamponade as a rare complication.7-8 Cardiac tamponade with subsequent obstructive cardiogenic shock, leading to hepatocellular damage and renal dysfunction, amongst other signs of end organ dysfunction, occurs in approximately 2 out of 10,000 people per year.5 Both pericarditis and cardiac tamponade are clinical diagnoses. They can, however, be supported by the results of additional diagnostics.4,6,8,10 As the pericardial sac is filled with excessive fluid a compressive pericardial syndrome occurs, in which especially right ventricular filling pressures are increased, diastolic filling of the heart is reduced, and the interventricular septum deviates towards the left ventricle impairing cardiac output.7-8,10 The septum deviation causes a pulsus paradoxus, in which the physiologic decrease in systolic blood pressure and pulse wave amplitude during inspiration become abnormally large.7-8,11 Rapid accumulation of PE leads to Beck’s triad of systolic hypotension, increased JVD and muffled heart sounds. The presence of Kussmaul’s sign, which is the paradoxically increased distension of the jugular vein at inspiration, is difficult to determine and commonly only present in tamponade when a constrictive disease exists.4-8 PE can be suspected on a chest X-ray and by changes in the ECG. An enlarged cardiac silhouette, especially with loss of the aortopulmonary window supports any suspicion of PE with more than 200 mL of fluid. The ECG can show the following abnormalities divided into 4 stages based upon progression of pericarditis: diffuse concavely elevated or flattened ST-segment deviations or diffuse N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 35 Netherlands Journal of Critical Care T-wave inversions, PR-depression, and microvoltages with or without electrical alternans, due to PE.7-8 Echocardiography is a simple, reliable, non-invasive and commonly used modality in the standard work-up of PE.10 In both patients described here, cardiac tamponade due to malignant pericarditis was the first presentation of disseminated lung cancer. An estimated four to seven percent of patients with pericarditis without known malignancy are ultimately diagnosed with malignant pericarditis (MP) as first presentation. In patients with a known malignancy, pericardial involvement occurs in one to twenty percent. The incidence of MP is the highest in lung carcinoma, followed by carcinoma of the breast, oesophagus, melanoma and lymphoma.5-6,9 Multi organ dysfunction expressed by acute kidney failure and elevated parenchymal liver enzymes preceded (refractory) haemodynamic instability in both cases. Circulatory shock in definition is haemodynamic failure to provide oxygen for end organ aerobic function. Three major phenomena of shock are hypotension, tachycardia and signs of end organ dysfunction. Due to compensatory mechanisms, hypotension can be a late sign of ongoing shock, as it was in our patients.7,11 The presence of acute renal failure in general is related to hypoperfusion, the so-called pre-renal kidney failure. This is generally due to hypotension or decreased cardiac output as a consequence of hypovolaemia, sepsis, cardiac failure or vasodilatation.1,11 In both cases, the gradual improvement of kidney function after pericardiocentesis supports the hypothesis that the cause was directly related to renal hypoperfusion as a result of the cardiac tamponade.1,7,11 Pericardial effusion as the cause of acute renal failure is uncommon. The literature is limited to only several case reports.12-14 Cardiac tamponade as a cause of the combination of acute renal failure and elevated liver enzymes, as in our patients, is also a rare finding.14 Increased liver enzymes can be caused by viral, toxic, or ischemic hepatitis. Hypoperfusion of the liver results in ischemia with hepatocellular damage which can be detected by a rapid rise in serum aminotransferase levels associated with an early massive rise in lactate dehydrogenase (LDH). Generally, the serum bilirubin level and phosphatase levels rise far less and hepatic synthetic function usually remains normal or is only mildly impaired.2-3 Without ongoing haemodynamic instability, the biochemical markers usually return to normal. In addition to hypoperfusion of the liver, congestion of blood (congestive hepatopathy) due to heart failure or obstruction of heart function, can play a role in the aetiology of the elevated liver enzymes.2-3,14 Different causes of the elevated liver enzymes, hepatic ischemia or congestive hepatopathy, could possibly explain the difference in elevation of serum aminotransferase levels and ASAT/ALAT ratio between patients A and B. Also, a combination of both conditions, with a different contribution of each cause, is possible in these patients. However, laboratory findings in both patients are highly suggestive of an ischemic cause since congestive hepatopathy is most commonly characterized by marked elevation of cholestatic liver enzymes and much lower levels of aminotransferase.2-3 36 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 When PE has been confirmed, a subsequent diagnostic and therapeutic pericardiocentesis can be performed either blinded or by means of ECG, echocardiographic, CT or fluoroscopic guidance.4-7,10 In cases of cardiac tamponade, pericardiocentesis is instantly required to prevent further life-threatening complications and even death.4-7 In patients with suspected malignancy, tuberculosis or purulent pericarditis, a pericardiocentesis should be performed as diagnostic measure, due to the necessity of specific therapy.4-7 In the cases described here, the initial evaluation and additional investigation either did not point directly to, or were not recognized as signs of the presence of pericardial effusion with cardiac tamponade. Both patients were initially considered to be suffering from hypoperfusion of the liver and kidneys due to severe pulmonary sepsis. However, in retrospect, misinterpretation of physical signs and additional diagnostics (ECG, chest X-ray and laboratory investigation) lead to the incorrect diagnosis on admission and eventually delayed the diagnosis of cardiac tamponade. This underlines the need for more awareness of PE as a cause of haemodynamic instability. In conclusion, we have described two rare cases in which the presence of acute renal failure and elevated liver enzymes are the result of PE with cardiac tamponade as a consequence of underlying malignant disease. Simultaneous development of kidney and liver failure should increase the suspicion of the presence of shock.1-3,11 Moreover, more rare forms of shock should be considered and sought for. Awareness amongst clinicians that signs of end organ dysfunction can precede haemodynamic shock, due to compensatory mechanisms, is necessary for prompt treatment of the underlying cause. References 1. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet. 2005;365(9457):417-30. 2. Birrer R, Takuda Y, Takara T. Hypoxic hepatopathy: pathophysiology and prognosis. Intern Med. 2007;46(14):1063. 3. Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR, Hypoxic hepatitis: Clinical and hemodynamic study in 142 consecutive cases. Medicine 2003; 82(6):392-406 4. Sagristà-Sauleda J, Sarrias Mercé A, Soler-Soler J. Diagnosis and management of pericardial effusion. World J Cardiol 2011; 3(5): 35-143 5. Jacob R, Grimm RA. Pericardial disease. Carvey WD ed. Cleveland Clinic: Current clinical medicine. 1st ed. Philadelphia, Saunders Elsevier, 2008, chap 2 6. Imazio M, Trinchero R. Triage and management of acute pericarditis. Int J Cardiol 2007; 118 (3): 286-94. 7. Spodick DH, Acute cardiac tamponade, N Engl J Med 2003; 349:684-90 8. Roy CL, Minor MA, Brookhart MA, Choudhry NK, Does this patient with a pericardial effusion have cardiac tamponade? JAMA, 2007;297 (16): 1810-1818 9. Lestuzzi C. Neoplastic pericardial disease: Old and current strategies for diagnosis and management. World J Cardiol 2010; 2(9): 270-279 10. Merce J, Sagrista-Sauleda J, Permanyer-Miralda G, Evangelista A, Soler-Soler J. Correlation between clinical and doppler echocardiographic findings in patients with moderate and large pericardial effusion: implications for the diagnosis of cardiac tamponade. Am Heart J 1999;138: 759-764. 11. Abboud, FM. Pathophysiology of hypotension and shock. In: Hurst, JW (Ed), The heart, New York, McGraw-Hill, 1982. p. 452 12. Saklayen M, Anne VV, Lapuz M. Pericardial effusion leading to acute renal failure: two case reports and discussion of pathophysiology. Am J Kidney Dis 2002;40: 837-841 13. Gluck N, Fried M, Porat R, Acute renal failure as the presenting symptom of pericardial effusion, Intern Med 2011; 50:719-721 14. Khan R, Gessert C, Bockhold S, Pericardial effusion presenting with anuric acute renal failure and hepatocellular damage, J Hosp Med 2009;4:68-70 Netherlands Journal of Critical Care Editorial Board of the Netherlands Journal of Critical Care A.B. Johan Groeneveld, Editor in Chief Dept. of Intensive Care Medicine Erasmus Medical Center Rotterdam PO Box 2040 3000 CA Rotterdam Jan Bakker, Section Editor Hemodynamics Dept. of Intensive Care Medicine Erasmus Medical Center Rotterdam PO Box 2040 3000 CA Rotterdam Alexander Bindels, Section Editor Endocrinology Dept. of Internal Medicine Catharina Hospital Michelangelolaan 2 5623 EJ Eindhoven Bert Bos, Section Editor Pediatrics Department of Pediatrics Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Frank Bosch, Section Editor Imaging Dept. of Internal Medicine Rijnstate Hospital PO Box 9555 6800 TA Arnhem Wolfgang Buhre, Section Editor Anesthesiology Dept. of Anesthesiology University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Heleen Oudemans-van Straaten, Section Editor Nephrology Dept. of Intensive Care Medicine VU University Medical Center PO Box 7057 1007 MB Amsterdam Hans van der Hoeven, Section Editor Mechanical Ventilation Dept. of Intensive Care Medicine Radboud University Nijmegen Medical Centre PO Box 9101 6500 HB Nijmegen Peter Pickkers, Section Editor Sepsis and inflammation Dept. of Intensive Care Medicine Radboud University Nijmegen Medical Centre PO Box 9101 6500 HB Nijmegen Can Ince, Section Editor Physiology Dept. of Physiology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Arjen Slooter, Section Editor General Dept. of Intensive Care University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Evert de Jonge, Section Editor Scoring and quality assessment Dept. of Intensive Care Medicine Leiden University Medical Center P.O. 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Of Intensive Care Medicine University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Michael Kuiper, Section Editor Neurology Dept. of Intensive Care Medicine Medical Center Leeuwarden PO Box 888 8901 BR Leeuwarden Maarten Nijsten, Section Editor Surgery Dept. of Intensive Care Medicine University Medical Center Groningen PO Box 30 001 9700 RB Groningen 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 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 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 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 N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013 37 Netherlands Journal of Critical Care Information for authors The Netherlands Journal of Critical Care (Neth J Crit Care) is the official journal of the Netherlands Society of Intensive Care (Nederlandse Vereniging voor Intensive Care-NVIC). The journal has a circulation of about 1,750 copies bimonthly in the Netherlands and Belgium. High quality reports of research related to any aspect of intensive care medicine, whether laboratory, clinical, or epidemiological, will be considered for publication in the Neth J Crit Care. 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Article in journals: Calandra T, Cometta A. Antibiotic therapy for gramnegative bacteremia. Infect Dis Clin North Am 1991;5:817-34 Books (-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 167-190. Conference Meetings: Rijneveld AW, Lauw FN, te Velde AA, et al. The role of interferongamma 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 Netherlands Journal of Critical Care. 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Table of abbreviations AIDS ALI ARDS APACHE BIPAP CCU COPD CPAP CT ECG ECMO EEG ELISA ETCO2 HDU HIV IC ICU IM INR IPPV IV MAP MODS MRI PACU PEEP PET SARS SIRS SOFA SPECT TIA TRALI acquired immunodeficiency syndrome acute lung injury adult respiratory distress syndrome acute phyisology and chronic health evaluation biphasic positive airways pressure coronary care unit chronic obstructive pulmonary disease continuous positive airway pressure computerized or computed tomography electrocardiogram extracorporeal membrane oxygenation electroencephalogram enzyme-linked immunosorbent assay end-tidal carbon dioxide high dependency unit human immunodeficiency virus intensive care intensive care unit intramuscular international normalized ratio intermittent positive pressure ventilation intravenous mean arterial pressure multiorgan dysfunction syndrome magnetic resonance imaging post anaesthesia care unit postive end expiratory pressure positron emission tomography severe adult respiratory syndrome systemic inflammatory response syndrome sequential or gan failure assessment single-photon emission ct transient ischemic attack transfusion-related acute lung injury