Netherlands Journal of Critical Care

Volume 17 - No 1 - February 2013 

Netherlands Journal of Critical Care 

Bi-monthly journal of the Dutch Society of Intensive Care 

Editorial 

Pericardial effusion: to drain or not to drain? 

W.K. Lagrand, J.A.P. van der Sloot 

Review 

The SSEP on the ICU: current applications and 

pitfalls 

M.C. Cloostermans, J. Horn, M.J.A.M. van Putten 

Case report 

Gastric dilatation and perforation due to 

binge eating 

J.A.M. Heijneman, R. Tahmassian, T. Karsten, 

E.R. van der Vorm, I.A. Meynaar



Executive editorial board 

A.B.J. Groeneveld, editor in chief 

J. Box, language editor 

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inhoud 

EDITORIAL 

3 Pericardial effusion: to drain or not to drain? 

W.K. Lagrand, J.A.P. van der Sloot 

REVIEWs 

5 The SSEP on the ICU: current applications and pitfalls 

M.C. Cloostermans, J. Horn, M.J.A.M. van Putten 

12 The pharmacologic treatment of alcohol withdrawal syndrome in the ICU 

D.P.F. van Nunen, D.H.T. Tjan 

GUIDELINE 

10 Recommendations for the timing and dosing of CRRT in critically ill 

patients with AKI 

H.M. Oudemans-van Straaten, C.S.C. Bouman, M. Schetz, A.B.J. Groeneveld, A.C. de Pont, 

A.M. van Alphen, H. de Geus, W. Boer 

CASE REPORTS 

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: 

EMBASE EMCare Scopus 

Neth j crit care – volume 17 – no 1 – february 2013 

1


Accepted January 2013 

EDITORIAL 

Pericardial effusion: to drain or not to drain? 

W.K. Lagrand 1 , J.A.P. van der Sloot 

1 

Department of Intensive Care Adults, room C3-430, Academic Medical Center, Amsterdam, The Netherlands 

Correspondence 

W.K. Lagrand – e-mail: w.k.lagrand@amc.uva.nl 

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 tamponade 1 . 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 tumour 2,3 . 

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 malignancies 2 . 

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 


3


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 shock 4,5 . 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 effusion 6 . 

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 Neth j crit care – volume 17 – no 1 – february 2013



REVIEW 

The SSEP on the ICU: current applications and pitfalls 

M.C. Cloostermans 1,2 , J. Horn 3 , M.J.A.M. van Putten 1,2 

1 

Clinical Neurophysiology, MIRA – Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands 

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 


J. Horn – e-mail: j.horn@amc.uva.nl 

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 thalamus 1,2 . 

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 cortex 1 . 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 population 1 . 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 layers 3,4 . 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 sedation 1 . As the 


5


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 arrest 1 . 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 outcome 5,6,7 . 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 patients 7 . 

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 outcome 10 . 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 studies 8,9,10 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 

Thalamus 

Cuneate 

nucleus 

Postcentral 

gyrus 

Recent studies show that already during the period of hypothermia 

the SSEP is a reliable tool to predict a poor outcome 9,11,12,13 . 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 al 9 . 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 

registration 9 . 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 silence 4 . 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 synapses 4 . 

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 positives 14 . In contrast, in several other studies TBI patients were 

described with initially bilateral absent N20 responses who regained 

consciousness and had only minor disabilities 1,15,16 . 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 oedema 1 . 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 value 1,14,15 . 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. 

Median 

nerve 

Lower 

brainstem 

Spinal cord 

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 course 17 . 

Sepsis 

In patients with severe sepsis and septic shock, prolonged cortical 

SSEP peak latencies occur in 84% of the patients. These prolonged 




latencies can be used to diagnose septic encephalopathy and its 

severity is associated with the severity of illness 18 . 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 

agreement 19 . 

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 

ratio 19 . 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 stimulus 19 . 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 

stimuli 1,19 . 

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 system 1,19 . 

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 EEG 1,19 . Propofol produces minimal to less than 

10% suppression of the SSEP amplitude 20-23 . Also midazolam and 

opioids have only moderate effect on the SSEP amplitude and 

latency 20-23 . 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 room 20 . 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 

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 10 ms 


7


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 EEG 13 and the mismatch 

negativity and P300 responses 24,25 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 

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 10 ms 




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. 


9



GUIDELINE 

Recommendations for the timing and dosing of CRRT in critically 

ill patients with AKI 

H.M. Oudemans-van Straaten 1 , C.S.C. Bouman 2 , M. Schetz 3 , A.B.J. Groeneveld 4 , A.C. de Pont 2 , A.M. van Alphen 5 , H. de Geus 6 , W. Boer 7 

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 


H.M. Oudemans-van Straaten – e:-mail: h.oudemans@vumc.nl 

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). 

• 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 

admission 1 or at randomization 2 . 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 acidosis 3 . 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 



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 trials 1,2 

was not confirmed in the two recent large multicenter trials 3,4 . 

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 

circulation 5 . 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 stay 6 . 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 classification 4 , 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). 

Table 1. Grading of guideline recommendations 

Grade of 

recommendation 

Implications 

Policy 

Level 1 

‘‘We recommend’’ 

Level 2 

‘‘We suggest’’ 

No grade 

Most patients should receive 

the recommended course of 

action. 

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 can 

be evaluated as a candidate 

for developing a policy or a 

performance measure. 

The recommendation is 

likely to require substantial 

debate and involvement of 

stakeholders before policy 

can be determined. 

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). 

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). 

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. 


11



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 


DHT Tjan – e-mail: TjanD@zgv.nl 

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. 

symptoms are usually mild, 5-10% of alcohol-dependent patients 7 

develop a severe dysautonomic and encephalopathic state known as 

‘delirium tremens’ (DT) after 48-72 hours of abstinence 8,9 . 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 infarction 8 . 

The natural course of AWS is a gradual lessening of symptoms 

72 hours after its onset 9,10 . 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 journals 11 . 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 

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 dependence 1 . 

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 activities 2 . Symptoms 

of alcohol withdrawal may occur in up to 91% of alcohol-dependent 

patients after acute abstinence 3,4 . The syndrome of alcoholic 

withdrawal consists of signs and symptoms (see table 1 2 ) developing 

in alcohol-dependent individuals within 6 to 48 hours after their 

last intake of alcohol or reduction in intake 5,6 . Although these 

Table 1. DSM-IV-TR Alcohol withdrawal – diagnostic criteria 2 

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 



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 depression 10,12 . 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 

tolerance 10,12 . 

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 autoinhibition 12 . 

The hallucinations experienced during withdrawal are caused by 

an enhanced dopaminergic transmission following disinhibition 

of dopaminergic neurons through reduced GABAergic activity 10 . 

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 alcohol 13 . 

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 AWS 15 . 

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 moment 9,12 . 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 time 17 . 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 

1969 18 . 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 alcohol 7 . 

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-Smith 19 conducted a meta-analysis of six prospective, placebocontrolled 

trials from the 1960s to 1980s involving three 


13


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



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 

controversial 45,46 . 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 AWS 47 . 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 site 9,48 . 

Research into the employment of ethanol for the treatment of 

AWS generally consists of small case series with varying quality 

of methodology 46 . 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 rate 50 . Moreover, the oral administration of 

ethanol has been reported to expose patients to taste and behavioural 

clues promoting relapse into past drinking behaviour 51 . 

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 control 52 . 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 drug 53 . 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 diazepam 51,55 . 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 nausea 56 . 

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 AWS 61 . Three small trials 57-59 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 


15


this was combined with clonidine rather than haloperidol 49 . 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 seizures 62 . 

Dexmedetomidine, a derivative of the veterinary sedative and 

analgesic medetomidine, has eight times the affinity of clonidine for 

the α2-receptor 61 . 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 benzodiazepines 63-67 . 

Antipsychotics 

Although antipsychotic or neuroleptic drugs, especially haloperidol, 

are routinely employed in the treatment of AWS 9 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-analysis 19 

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



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17



CASE REPORT 

Gastric dilatation and perforation due to binge eating: 

a case report 

J.A.M. Heijneman 1 , R. Tahmassian 2 , T. Karsten 3 , E.R. van der Vorm 4 , I.A. Meynaar 1 

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 


J.A.M. Heijneman – e-mail: j.heijneman@rdgg.nl 

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. 

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 

After surgery, the patient was admitted to the Intensive Care 

Unit (ICU), where she was mechanically ventilated and treated in 



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 dilatation 1 . Experimental 

models have shown that gastric infarction will only appear when 

both venous and arterial occlusion is present 2 . In a massively 

distended stomach, the intragastric pressure can reach over 30cm 

H 2 

O exceeding the gastric venous pressure, therefore compromising 

venous drainage of the stomach 3 . 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 al 4 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 stomach 5,6,7 . 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 distension 9 . 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 wall 10 ). 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. 


19


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 drug 12,13 . 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 SWAB 15 

treatment guidelines for candidiasis recommend an echinocandin 

for the treatment of candidemia in patients who are considered to be 

‘moderately severe’ or ‘severely’ ill 14 . 

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 

Conclusion 

Massive gastric dilatation caused by psychogenic polyphagia can 

progress to gastric necrosis and perforation. Therefore, physicians 

should always consider the possibility of acute gastric dilatation 

when a patient complains of abdominal pain after the ingestion of 

a large meal, especially in patients with psychiatric co-morbidity. 

Gastric dilatation can often be treated conservatively, but progressive 

gastric dilatation may result in ischemia, gastric perforation and 

subsequent multiple organ failure. 

References 

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by acute gastric dilatation: report of a case. Surg Today. 2003;33:302-4 

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Behav. 2001;74:743-6 

5. 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 

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10. Billitier AJ, Abrams BJ, Brunetto A. Radiographic imaging modalities for the patient in 

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1996;14:789-850 

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Infect Control Hosp Epidemiol. 1998;19:846-50 

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epidemiology, risk factors, and predictors of mortality. Clin Infect Dis. 1992;15:414-21 




CASE REPORT 

Trichoderma: an unusual bystander in invasive pulmonary 

aspergillosis 

K. Ariese 1 , L. Hulshoff 1 , R. Jansen 2 , P.H.J. van der Voort 3 

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 


K. Ariese-Beldman – e-mail: k.beldman@nki.nl 

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 


21


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. 

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 

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 groups 2 , 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 nowadays 3,4 . 

The first case of an invasive Trichoderma infection was described 

by Robertson, concerning an accidental intravenous infusion of 

contaminated fluid 5 . 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 



Trichoderma: an unusual bystander in invasive pulmonary aspergillosis 

Table 2. IFD criteria by the EORTC 

Host criteria 

• Recent history of neutropenia (0.5x109 

neutrophils/L for >10 days) temporally related to 

the onset of fungal disease 

• receipt of an allogeneic stem cell transplant 

• prolonged use of corticosteroids (excluding 

among patients with allergic bronchopulmonary 

aspergillosis) at a mean minimum dose of 0.3 mg/ 

kg/day of prednisone equivalent for 13 weeks 

• 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) 

Clinical criteria 

(of the respiratory tract) 

• The presence of 1 of the following 3 signs on CT: 

- dense, well-circumscribed lesions(s) with or 

without a halo sign 

- air-crescent sign 

- cavity 

or 

• tracheobronchial ulceration, nodule, 

pseudomembrane, plaque, or eschar seen on 

bronchoscopic analysis 

Microbiologic criteria 

• 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 hyalo hyphomycosis 

7 . 

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-fingerprinting 8 . 

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 level 9,10,11,12 . 

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 reported 7 . Apparent susceptibility to 

voriconazole has been described 13,14 . Recent data indicate that 

there may be resistance to amphotericin B 15,16,17 . There is a lack of 

information about the efficacy of caspofungin, although low mics 

have been recorded 6,18 . 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 antifungals 18 . 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 laboratory 19,20,21 . 

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. 


23


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patient: species identification and review of the literature. J Clin Micriobiol 

1999;37:1154-60 

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invasive aspergillosis. Cancer 2006;107: 2888-97. 




CASE REPORT 

Drug induced lung injury – a case of fatal bleomycin 

interstitial pneumonitis 

S. van der Sar-van der Brugge 1 , H. van Ravenswaay Claasen 2 , L. Dawson 3 

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 


S. van der Sar-van der Brugge – e-mail: svandersar@gmail.com 

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 decades 1 , 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 PaO 2 

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 


25


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 O 2 

/min by nose prong, his 

SpO 2 

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; pCO 2 

3,7 kPa; 

bicarbonate 20 mmol/l; base excess -3.6; pO 2 

4.8; O 2 

saturation 65%. 

Further lab results were: Haemoglobin 6.5 mmol/l; leucocytes 12.4 

*10 9 /l, thrombocytes 132*10 9 /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 

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 (FiO 2 

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 



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 toxicity 2 . 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 fibrosis 2 . The 

incidence of BIP increases with cumulative dose up to 18% in patients 

who receive a dose of over 360 units of bleomycin 3 , but it can occur 

even with doses < 50 units. Fatal toxicity has been reported in 0-3% 

of all patients receiving bleomycin-containing chemotherapy 4,5 . 

Patients surviving the acute phase of BIP, however, usually recover 

completely with total recovery of all lung function parameters after 

two years 6 . 

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 survival 4 . 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 


27


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 toxicity 2 . 

Bleomycin causes activation of alveolar macrophages by an unknown 

mechanism, resulting in release of inflammatory, profibrotic 

cytokines 7 . Tumour necrosis factor α, transforming growth factor β 

and platelet-derived growth factor receptor α are believed to play a 

role in formation of fibrosis 8 . 

Bleomycin interstitial pneumonitis typically (but not exclusively) 

develops subacutely during treatment, up to six months afterwards 2 . 

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 chemotherapy 9 . Deterioration of 

vital capacity (VC) or total lung capacity (TLC) also occurs in patients 

on bleomycin and is more specific for BIP 9 . 

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 BIP 10 . 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 

pneumonia 12 . 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 ARDS 13 . 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 neutrophils 14 . 

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. 

Table 2. High resolution computed tomography manifestations of different 

histopathological types associated with bleomycin toxicity 11 

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 

Nonspecific interstitial 

pneumonia 

Cryptogenic organizing 

pneumonia and 

bronchiolitis obliterans 

Eosinophilic pneumonia 

Bilateral ground glass opacities and/or small poorly 

defined centrilobular nodules. Air trapping 

Patchy bilateral or diffuse ground glass opacities 

with associated reticular opacities. Mainly lower lung 

zones and subpleural regions involved 

Ground glass opacities in bilateral random 

distribution. Airspace consolidation in subpleural or 

peribronchial distribution. Rarely solitary nodules 

Airspace consolidation and ground glass opacities 

in predominantly peripheral distribution, involving 

middle and upper lung zones 

Table 3. Risk factors for bleomycine pulmonary toxicity 2,15 

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 FiO 2 

, 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 FiO 2 

-restriction and postoperative 

pulmonary morbidity or survival 16 . Usual practise is to keep FiO 2 

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 effect 5 . 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 

failed 17 . 

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 



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. 


29



CASE REPORT 

A rare cause of cardiac failure following 

transthoracic oesophagectomy 

D.A. Wicherts 1 , S. Hendriks 2 , W.L.E.M. Hesp 1 , J.A.B. van der Hoeven 1 , H.H. Ponssen 2 

1 

Albert Schweitzer Hospital, Department of Surgery, Dordrecht, The Netherlands 

2 

Albert Schweitzer Hospital, Department of Intensive Care Medicine, Dordrecht, The Netherlands 


D.A. Wicherts – e-mail: d.a.wicherts@asz.nl 

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 chylothorax 1 . 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 used 2 . 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. 

At preoperative work-up, including endoscopic ultrasound as well 

as computed tomography (CT) imaging of the thorax and abdomen, 

it was classified as a cT 3 

N 1 

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. 



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 

5 10 15 20 

Time 

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 presented 3,4 . However, 

to our knowledge, the presence of a chylomediastinum has only been 

reported on a few occasions 5-8 . In addition, significant secondary 

haemodynamic consequences were described in only one paper 8 . 

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 opened 2 . 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, 

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 advised 9,10 . In 

general, operative therapy is suggested in case of a daily output of 

more than 2 liters after two days of optimal conservative therapy 10 . 

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 mortality 11 . 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. 


31


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. 




CASE REPORT 

Elevated liver enzymes and renal failure, with a surprising 

outcome. Two similar cases 

A.E. Boendermaker 1 , D. Boumans 2 , R.A.A. van Zanten 2 , H. Idzerda 3 , H. van de Hout 4 , Th.F. Veneman 1,2 

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 


A.E. Boendermaker – e-mail: a.boendermaker@zgt.nl 

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 

ED 

06-11-2011 

At admission 

ICU 

07-11-2011 

22 days after 

admission 

29-11-2011 

Haemoglobin mmol/L 7.4 6.8 7.8 

C-reactive protein mg/L 186 190 22 

Leucocyte count *10^9/L 15.9 17.5 9.5 

Bilirubin total μmol/l 22 19 5 

Alkaline phosphatase U/L 108 112 116 

Gamma GT U/L 91 88 40 

ASAT U/L 1.568 2.871 10 

ALAT U/L 2.496 3.968 27 

Lactate 

U/L 3.607 4.749 184 

dehydrogenase 

Creatinine μmol/l 184 248 95 

Urea mmol/L 20 26 8.3 

Estimated GFR mL/min 34 24 73 


33


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 

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. 

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 

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 

ED 

05-12-2011 

At admission 

CCU 

07-12-2011 

Haemoglobin mmol/L 7.1 6.4 6.3 

C-reactive protein mg/L 56 67 51 

Leucocyte count *10^9/L 8 8.3 7.9 

Bilirubin total μmol/l 9 11 16 

Alkaline phosphatase U/L 146 - 125 

Gamma GT U/L 81 117 77 

ASAT U/L 32 3.802 61 

ALAT U/L 33 2.449 396 

Lactate 

U/L 258 3.161 239 

dehydrogenase 

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 

5 days after 

admission 

12-12-2011 



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 

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 

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. 

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 


35


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 

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. 1 st 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 



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 


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 

Hans van der Hoeven, Section Editor 

Mechanical Ventilation 


Radboud University Nijmegen 

Medical Centre 

PO Box 9101 

6500 HB Nijmegen 

Can Ince, Section Editor 

Physiology 

Dept. of Physiology 





Evert de Jonge, Section Editor 

Scoring and quality assessment 


Leiden University Medical Center 

P.O. Box 9600 

2300 RC Leiden 

Nicole Juffermans 

Section Editor 

Hemostasis and Thrombosis 

Dept. of Intensive Care 





Heleen Oudemans-van Straaten, 

Section Editor Nephrology 


VU University Medical Center 

PO Box 7057 

1007 MB Amsterdam 

Peter Pickkers, Section Editor 

Sepsis and inflammation 


Radboud University Nijmegen 

Medical Centre 

PO Box 9101 

6500 HB Nijmegen 

Arjen Slooter, Section Editor 

General 

Dept. of Intensive Care 


PO Box 85500 


Peter Spronk, Section Editor 

General 


Gelre Hospital, location Lukas 

PO Box 9014 

7300 DS Apeldoorn 

Jaap Tulleken, Section Editor 

General 


University Medical Center 

Groningen 

PO Box 30001 

9700 RB Groningen 

Anton van Kaam, Section Editor 

Neonatology 

Dept. of Neonatal Intensive Care 

Emma Children’s Hospital, 





Jozef Kesecioglu, Section Editor 

Pulmonology 

Dept. Of Intensive Care Medicine 


PO Box 85500 


Michael Kuiper, Section Editor 

Neurology 


Medical Center Leeuwarden 

PO Box 888 

8901 BR Leeuwarden 

Maarten Nijsten, Section Editor 

Surgery 


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 


37


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. This includes original articles, reviews, 

case reports, clinical images, book review, structured abstracts of papers 

from the literature, notes, correspondence etc. All manuscripts pass through 

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The journal is indexed by Embase, Emcare and Scopus. A Medline annotation 

is in prepara tion. The following manuscript types apply. 

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All manuscripts should be submitted with structured abstracts as described 

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appear in the text of the manuscript. 

Manuscripts should include an abstracts of no more than 300 words using the 

following headings: Background and objectives, Design, Methods and results 

and Conclusions. For the sake of brevity, parts of the abstract may be written 

as phrases rather than complete sentences. 

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State the precise primary objective of the review. Indicate whether the review 

emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention 

and include information about the specific population, intervention, exposure, 

and tests or outcomes that are being reviewed. 

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Describe the design of the study indicating, as appropriate, use of randomization, 

blinding, gold standards for diagnosis test and temporal direction (retrospective 

or prospective). 

Methods and results 

Summarize here accurately, although concisely, summarize how you will 

proceed in learning the answer to the objective. Also provide the main 

outcomes of the study. 

Conclusions 

The conclusions and their applications (clinical or otherwise) should be 

clearly stated, limiting interpretation to the domain of the review. 

Original articles/reviews 

Articles should describe original investigations that have been brought to an 

acceptable degree of completion. Articles should not exceed 3000 words. The 

editorial board also welcomes review papers which should also not exceed 

3000 words. 

The manuscript should be clear in outline (with subheadings) for maximum 

clarity. Only a limited number of figures (coloured figures are encouraged 

without extra charge) and tables may be included; double presentations in 

the form of figures and tables should be avoided. The text should follow 

the IMRAD format and contain an abstract, introduction, materials and 

methods, results, discussion section and references. The abstract should 

not exceed 250 words and should be structured. Authors should provide 

a minimum of three keywords, a running title, and list not more than 30 

references for original articles and 70 references for review articles. 

Case Reports 

The text of a case reports should also include an abstract, introduction, case 

report/case history, discussion section, legends for figures and references. The 

abstract should not exceed 250 words and may be unstructured. The journal 

kindly requests authors to provide a minimum of three keywords and to list 

not more than 30 references. 

Clinical Images 

A clinical image should contain one or two pictures and a short case history, 

and should preferably not be referenced. The legend to the image should 

succinctly present relevant clinical information, including a short description 

of the patient’s history, relevant physical and laboratory findings, clinical 

course, response to treatment (if any), and condition at last follow-up. The 

journal kindly requests authors to provide a minimum of three keywords. 

General information 

The original manuscript and two copies (or electronic file) are to be submitted 

to the editor in chief at the NVIC office by e-mail (see below). The manuscript 

must be accompanied by a cover letter stating the following: the complete 

mailing address, e mail address, telephone number and fax number of the 

corresponding author, and if it is a re submission, the previous Neth J Crit 

Care number and year. Receipt of the manuscript will be acknowledged 

in writing within 14 days. If this is not the case, authors are requested to 

check. The language of the journal is British English. Authors who are unsure 

of proper English usage will have their manuscript checked by someone 

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Layout 

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should be double spaced, on one side of the paper and with a wide margin. 

The manuscript pages, including references and legends, must be sequentially 

numbered throughout. 

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with headings and kept separate from the text. 

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Figures must also be numbered with Arabic numbers and kept separate from 

the text. Legends must be given on a separate sheet. Schematic line drawings 

are preferred. Figures already published elsewhere cannot usually be included, 

except in survey articles. Colour figures can be published. Short, clear legends 

make additional description in the text unnecessary. The desired placement 

of figures and tables can be marked in the margins of the manuscript sheets. 

Figures should be provided in electronic format TIFF or better. 

References 

Only articles cited in the text are to be listed. They are to be arranged in order 

of appearance in the text …. and numbered consecutively. Only the reference 

number should appear in the text. Include all author names (unless there are seven 

or more, in which case abbreviate to three and, add ‘et al.’), and page numbers. 

Article in journals: Calandra T, Cometta A. Anti biotic therapy for gram negative 

bacteremia. Infect Dis Clin North Am 1991;5:817-34 

Books (-sections): Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent 

J L (eds). Clinical trials for the treatment of sepsis. (Update in intensive care and 

emergency medicine, volume 19). Berlin Heidelberg New York, Springer, 1995, 

pp 167-190. Conference Meetings: Rijneveld AW, Lauw FN, te Velde AA, et al. 

The role of interferon gamma in murine pneumococcal pneumonia. 

38th Interscience Conference on Antimicrobial Agents and Chemotherapy 

(ICAAC). San Diego, Ca., 1998, pp 290 

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. Authors must disclose any potential financial or ethical conflicts of 

interest regarding the contents of the submission. Any relevant papers that may 

be considered as duplicating in part the current submission should be reported. 

How to submit 

Submit manuscript directly to: Editorial office e-mail: nethjcritcare@nvic.nl 


39


Proofs 

The corresponding author will receive proofs by e-mail. Corrected proofs 

must be returned within 48 hours of receipt. 

Production process 

Decisions of the editors are final. All material accepted for publication is 

subject to copyediting. The original manuscript will be discarded one month 

after publication unless the publisher is requested to return the originals to 

the author Neth J Crit Care reserves the right to edit for house style, clarity, 

precision of expression, and grammar. Authors review these changes at the 

proof stage but must limit their alterations in proof to correcting errors and 

to clarifying misleading statements. 

For guidelines on the NJCC’s house style see website 

General guidelines on house style 

• The title of manuscript should be in typeface Times New Roman, size 20. 

With the exception of the first word and proper nouns, initial capitals are 

not used in the title. 

• The names of departments should be in typeface Times New Roman, size 12. 

• The names of hospitals should be written in English. 

• Generally, abbreviations should not be used in the title (see Table of 

standard abbreviations) for exceptions). 

• The corresponding author need only provide their e-mail address on the 

title page. 

• Please provide a minimum of three keywords and a running title. 

• In addresses write The Netherlands. In running text, the Netherlands. 

• The abstract should be written in the structured format (with the exception 

of case reports). 

• Unstructured abstracts should take the form of a single paragraph. 

• The abstract should be bold typeface Times New Roman, size 12. 

• Headings must be in bold. 

• Non-standard abbreviations (see Table of standard abbreviations) should 

always be explained and their use kept to a minimum. 

• Please use British English spelling, except in titles of institutions that have 

chosen to use US spelling, e.g. Academic Medical Center, Amsterdam. 

• The journal uses British English spelling, e.g. aetiology, oestradiol, anaemia, 

haemorrhage, oesophagus, practice (noun), practise (verb), fetus. This 

should be used consistently. Use z-spellings, e.g. minimize, organization 

(Oxford spelling). 

• Do not use exclamation marks except in direct quotes from other sources. 

• No full stops in initials,abbreviations and academic titles. 

• Reference numbers go after commas and full stops, before semicolons and 

colons. 

• Quotation marks – please use double, not single, inverted commas for 

reported speech Full stops go inside quotation marks. 

• Genus names should be in italics, e.g. Staphylo coccus aureus, S. aureus. 

• Numbers under 10 are spelled out except for measurements with a unit (10 

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

6 rats, 12 gerbils). 

• When referring to tables or figures in the text use a capital letter, e.g. see 

Table 2. 

Guidelines on writing style for Dutch-speaking authors 

• Following English language convention prof. dr. should be written as 

Professor. 

• The gender of an author is not specifically reported. Do not use Ms or Mrs 

in front of Professor or Doctor. 

• Spell check your article before submission using UK English (references 

keep original spelling). 

• Abbreviating names. Use initials only J Smit not Joh Smit. 

• Avoid “he” as a general pronoun. Make nouns and pronouns plural, use 

“they”. If this is not possible then use “he or she”. 

• Drugs should be referred to by their English language non-proprietary 

names, e.g. not fosfomycin but phosphomycin. 

• Brackets. In English, information in brackets is not crucial to the meaning 

of the sentence and may be omitted without detracting from its meaning. 

The Dutch convention of using brackets to contain information crucial 

to the sentence should not be applied, e.g. (immuno) histology should be 

written as immunohistology and histology, (un) sterile gloves as sterile or 

unsterile gloves. 

• Apostrophe. In English the apostrophe is used to indicate possession or 

omission, e.g. the patient’s notes, not to form a plural, e.g. ECG’s should be 

ECGs. 

• “False friends.” Please be aware that although some words sound like 

they have the same meaning they do not, e.g. adequaat is not always 

synonymous with adequate (adequate = toereikend), e.g. “Bij 98% werd 

technisch adequate wervelmorfometrie verricht” becomes “In 98% spinal 

morphometry was technically successful.” “Klachten” may not universally 

be translated as “complaints”; please use “signs and/or symptoms” where 

appropriate. 

• ± is a mathematical symbol and should not be used in a non-mathematical 

context to mean approximately or about. 

• Generally, organizations and groups of people take single verbs, e.g. the 

team has researched. 

Table of abbreviations 

AIDS 

acquired immunodeficiency syndrome 

ALI 

acute lung injury 

ARDS 

adult respiratory distress syndrome 

APACHE acute phyisology and chronic health evaluation 

BIPAP 

biphasic positive airways pressure 

CCU 

coronary care unit 

COPD 

chronic obstructive pulmonary disease 

CPAP 

continuous positive airway pressure 

CT 

computerized or computed tomography 

ECG 

electrocardiogram 

ECMO 

extracorporeal membrane oxygenation 

EEG 

electroencephalogram 

ELISA 

enzyme-linked immunosorbent assay 

ETCO2 

end-tidal carbon dioxide 

HDU 

high dependency unit 

HIV 

human immunodeficiency virus 

IC 

intensive care 

ICU 

intensive care unit 

IM 

intramuscular 

INR 

international normalized ratio 

IPPV 

intermittent positive pressure ventilation 

IV 

intravenous 

MAP 

mean arterial pressure 

MODS 

multiorgan dysfunction syndrome 

MRI 

magnetic resonance imaging 

PACU 

post anaesthesia care unit 

PEEP 

postive end expiratory pressure 

PET 

positron emission tomography 

SARS 

severe adult respiratory syndrome 

SIRS 

systemic inflammatory response syndrome 

SOFA 

sequential or gan failure assessment 

SPECT 

single-photon emission ct 

TIA 

transient ischemic attack 

TRALI 

transfusion-related acute lung injury

Netherlands Journal of Critical Care

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