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Volume 17 - No 1 - February 2013
Netherlands Journal of Critical Care
Bi-monthly journal of the Dutch Society of Intensive Care
Editorial
Review
Case report
Pericardial effusion: to drain or not to drain?
W.K. Lagrand, J.A.P. van der Sloot
The SSEP on the ICU: current applications and
pitfalls
M.C. Cloostermans, J. Horn, M.J.A.M. van Putten
Gastric dilatation and perforation due to
binge eating
J.A.M. Heijneman, R. Tahmassian, T. Karsten,
E.R. van der Vorm, I.A. Meynaar
Netherlands Journal of Critical Care
Netherlands Journal of Critical Care
E x e c u ti v e e dit o r i a l b o a r d
A.B.J. Groeneveld, editor in chief
J. Box, language editor
C O P YR I G H T
inhoud
ED I TOR IAL
Netherlands Journal of Critical Care
ISSN: 1569-3511
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The SSEP on the ICU: current applications and pitfalls
M.C. Cloostermans, J. Horn, M.J.A.M. van Putten
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Pericardial effusion: to drain or not to drain?
W.K. Lagrand, J.A.P. van der Sloot
C ASE RE P OR T S
18
Gastric dilatation and perforation due to binge eating: a case report J.A.M. Heijneman, R. Tahmassian, T. Karsten, E.R. van der Vorm, I.A. Meynaar 21
Trichoderma: an unusual bystander in invasive pulmonary aspergillosis
K. Ariese, L. Hulshoff, R. Jansen, P.H.J. van der Voort
25
Drug induced lung injury – a case of fatal bleomycin interstitial
pneumonitis
S. van der Sar-van der Brugge, H. van Ravenswaay Claasen, L. Dawson
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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
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International advisory board
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N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
Accepted January 2013
E D I T OR I AL
Pericardial effusion: to drain or not to drain?
W.K. Lagrand1, J.A.P. van der Sloot
Department of Intensive Care Adults, room C3-430, Academic Medical Center, Amsterdam, The Netherlands
1
Correspondence
W.K. Lagrand – e-mail: [email protected]
Key words - Hepatic and renal dysfunction, pericardial effusion, cardiac tamponade
In this issue of the Netherlands Journal of Critical Care,
Boendermaker et al. describe two cases of hepatic and renal
dysfunction caused by neoplastic pericardial effusion and resulting
in cardiac tamponade1. The incidence of hepatic and renal
dysfunction in critically ill patients is high and can have various
causes. Because pericardial effusion, of oncologic origin, is not the
most likely cause of these organ dysfunctions, critical care clinicians
often omit considering cardiac tamponade as the underlying cause.
In most cases of pericardial effusion, the condition is found more
or less by surprise. Once found, the question arises whether the
pericardial effusion is symptomatic (i.e. cardiac tamponade) or
asymptomatic (i.e. an innocent bystander without therapeutic
consequences). The cases described by Boendermaker et al. nicely
illustrate the clinical and therapeutic considerations and place of
pericardial effusion and/or tamponade in the differential diagnosis
of hepatic and renal dysfunction.
The etiology of pericardial effusion is quite diverse: it may be caused
by infection (bacterial, viral, fungal, mycobacteria, protozoal),
inflammation (auto-immune diseases), myocardial infarction
(Dressler syndrome), cardiac surgery, trauma or chemical e.g.
uraemia. Pericardial effusion resulting from a malignant process,
such as neoplastic pericardial effusion, may occur directly (from
the malignant process itself) or as a consequence of therapy e.g.
radiotherapy, chemotherapy, necessary to treat the tumour2,3.
The signs and symptoms of cardiac effusion may manifest gradually,
ranging from overt tamponade to no clinical signs at all. Besides
this, most symptoms of cardiac tamponade are nonspecific, like
anorexia, cough, hypotension, tachycardia, dyspnoea, tachypnoea
and sometimes circulatory collapse. Also, like the cases presented
by Boendermaker et al., patients may present with the complications
of cardiac tamponade due to reduced organ perfusion resulting in
hepatic and renal failure. In cases of pericardial effusion, physical
examination may also reveal specific and nonspecific findings.
Besides tachycardia, heart sounds may be attenuated, due to the
isolating effects of the pericardial fluid. Clinically significant
tamponade usually results in hypotension or shock. (i.e. Beck’s
triad: hypotension, tachycardia and muffled heart tones). Jugular
venous distention is usually present but may be absent in cases
of hypovolemia. A key finding in cases of cardiac tamponade is
pulsus paradoxus (PP)2,4,5. PP, however, is not pathognomonic for
tamponade. It may also be present in cases of massive pulmonary
embolism, profound haemorrhagic shock, and obstructive
pulmonary diseases. PP is defined as a decline of 10 mmHg or more
in systolic arterial blood pressure after inspiration during normal
breathing. It may be palpable, but sometimes arterial catheterisation
is needed to identify PP.
It has to be emphasized that cardiac tamponade is a clinical
diagnosis. Additional investigations, however, may support the
diagnosis of tamponade. Electrocardiography (ECG) may reveal
signs of pericardial effusion: micro voltages, electrical alternans (as
a sign of a swinging heart), PR-segment depression, ST-T segment
alterations such as elevation and/or depression. These ECG findings
are also not specific but may fit in with the diagnosis of pericardial
effusion. Chest radiography may depict an enlarged cardiac
silhouette with a tent-like shape. The cardiac silhouette, however,
may also remain normal despite a large amount of pericardial
effusion. Echocardiography is the principal tool for making the
diagnosis pericardial effusion. Echocardiographic signs of cardiac
tamponade include collapse of the right atrium and/or right
ventricle. Left atrial collapse occurs in approximately 25% of patients
and is highly specific for tamponade. Doppler echocardiography may
show respiratory variations in transvalvular blood flow. This would
be an indication that signs of PP can be demonstrated by Doppler
echocardiography. By subcostal echocardiographic examination the
inferior vena cava (IVC) can be visualized. In cases of tamponade,
the IVC is usually dilated, with little or no collapse after inspiration
during normal breathing. CT-scanning, MRI and right and left heart
catheterisation may be considered but are generally not needed in
the evaluation of pericardial effusion, unless it is necessary to search
for underlying diseases such as malignancies2.
So, what do we learn from the cases presented by Boendermaker et
al.? First, pericardial effusion and tamponade should be considered
in patients with hepatic and renal dysfunction that has been caused
by diminished hemodynamics, thereby compromising the function
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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of multiple organs including the kidneys and liver. Pericardial
effusion in itself does not always result in cardiac tamponade: when
it develops slowly, large amounts of pericardial fluid (> 2000 mL)
may not result in tamponade, whereas small amounts of pericardial
fluid (< 100 mL), accumulating in a very short time, may cause
severe obstructive cardiogenic shock4,5. Neoplastic pericardial
effusion usually develops slowly with gradual clinical deterioration
over time due to inflow obstruction; this may eventually result in
cardiac tamponade, as described in the presented cases. Second,
cardiac tamponade remains a clinical diagnosis. Echocardiography
is essential to assess the existence of pericardial effusion and
to find clues for the severity of inflow obstruction. It is to be
emphasized, however, that even when there are negative signs of
cardiac tamponade by echocardiography, a cardiac tamponade may
be present. Clinical signs of cardiac tamponade, in the presence
of pericardial effusion, are to be diagnosed as cardiac tamponade
unless proven otherwise. Removal of the pericardial fluid either by
pericardiocentesis or surgery, should not be postponed in cases of
clinically manifest tamponade with negative echocardiographic
signs of inflow obstruction. In all patients who are hemodynamically
unstable, pericardial drainage has to be considered when there is a
pericardial effusion6.
References
1.
Boendermaker AE, Boumans D, van Zanten RAA, Idzerda H, van de Hout H, Veneman
ThF. Elevated liver enzymes and renal failure, with a surprising outcome. Two similar
cases. Neth J Crit Care 2012;2013;17:33-6.
2.
LeWinter MM, Kabbani S. Pericardial diseases. In: Braunwald E, Zipes DP, Libby, eds.
Heart disease: a textbook of cardiovascular medicine. 7th ed. Vol. 2. Philadelphia: W.B.
Saunders, 2005:1757-80.
3.
Refaat MM, Katz WE. Neoplastic pericardial effusion. Clin Cardiol 2011;34:593-598
4.
Spodick DH. Acute cardiac tamponade. N Engl J Med 2003;349:684-90.
5.
Reddy PS, Curtiss EI, O’Toole JD, Shaver JA. Cardiac tamponade: hemodynamic observations in man. Circulation 1978;58:265
6.
Ariyarajah V, Spodick DH. Cardiac tamponade revisited: a postmortem look at cautionary case. Tex Heart Inst J 2007; 34:347-51.
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N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Netherlands Journal of Critical Care
Accepted January 2013
REV I E W
The SSEP on the ICU: current applications and pitfalls
M.C. Cloostermans1,2, J. Horn3, M.J.A.M. van Putten1,2
Clinical Neurophysiology, MIRA – Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
1
2
Departments of Clinical Neurophysiology and Neurology, Medisch Spectrum Twente, Enschede, The Netherlands
3
Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Correspondence
J. Horn – e-mail: [email protected]
Key words - Somatosensory evoked potentials, prognostication, post-anoxic coma, traumatic brain injury, subarachnoid haemorrhage
Abstract
Clinical neurological evaluation of patients in the intensive care unit
(ICU) is often limited. Registration of the somatosensory evoked
potential (SSEP) can assist in the neurological evaluation in these
patients. In this paper, we discuss the principles, applications and
limitations of the SSEPs in the ICU with a focus on prognostication
in comatose patients. Registration of the SSEP is a very reliable and
reproducible method, if it is performed and interpreted correctly. A
bilateral absent cortical SSEP response is a reliable predictor for poor
neurological outcome in patients with a post-anoxic coma, but not in
patients with traumatic brain injury or subarachnoid haemorrhage.
During SSEP recordings, great care should be taken in improving
the signal to noise ratio. Since the interpreting clinician is often
not present during the actual SSEP registration itself, the role of the
lab technician is crucial in obtaining reliable SSEP results. If the
noise level is too high, the peripheral responses are abnormal, or the
response is not reproducible in a second set of stimuli, interpretation
of the SSEP cannot be done reliably.
Introduction
Neurological evaluation of patients in the intensive care unit (ICU)
is often limited, and clinical neurophysiology has provided several
techniques to assist in the evaluation of the central and peripheral
nervous system in these conditions. Techniques include the electroencephalogram (EEG), brainstem auditory evoked potentials (BAEP)
and the somatosensory evoked potential (SSEP). In this paper, we
discuss the principles, applications and limitations of the SSEP. SSEPs
are used in a variety of clinical settings, including the evaluation of
coma, neuromonitoring in the operating theatre, and the evaluation
of traumatic spinal cord injury. Here, we focus on the use of the SSEP
registration in the prognostication of comatose patients in the ICU.
SSEP: Principles
The somatosensory evoked potential is a small (< 10-50 µV)
electrical signal, that can be recorded noninvasively from the skull,
after giving a set of electrical stimuli to one of the peripheral nerves.
Measurement of the SSEP evaluates the complete pathway from the
peripheral sensory nervous system to the sensory cortex, which
runs via the dorsal column lemniscal pathway via the spinal cord,
brainstem and thalamus1,2.
The dorsal column-lemniscal pathway consists of four neuronal
populations. The cell bodies of the first-order neurons are situated
in the dorsal root ganglia, the trigeminal ganglion, the midbrain
trigeminal nucleus, and the vagal ganglion nodosum. The
second-order neuron lies in the dorsal column nuclei (the cuneate
nucleus and the gracile nucleus). Axons of these second neurons
cross the midline and project to the ventroposterior nuclei of the
thalamus (third-order neuron). From there the pathway projects
into the network of somatosensory cortex areas (fourth-order
neurons), which include primary and secondary somatosensory
cortex, posterior parietal cortex, posterior and mid-insula, and
mid-cingulate cortex1. Figure 1 shows the anatomical connections
evaluated by the median nerve SSEP.
SSEPs are usually evoked by bipolar transcutaneous electrical
stimulation applied on the skin over the selected nerve, and
registered with disk-electrodes along the tract. For example, in
SSEP recordings of the median nerve registration electrodes can be
placed at the elbow, Erb’s point, cervical, parietal and frontal cortex.
The cortical response can only be interpreted reliably, when the
peripheral responses are present.
In the nomenclature of SSEP waveforms, N or P followed by
an integer (e.g. N20) are used to indicate the polarity and the
nominal post-stimulus latency (in ms) of the recorded wave in
the healthy population1. The earliest cortical potential is the N20,
which is generated in the primary somatosensory cortex, where
thalamocortical cells make synaptic connections with the superficial
and deep pyramidal cell layers3,4. In comparison to the later cortical
responses, the N20 is the most robust, and is the latest waveform to
disappear during increasing levels of encephalopathy. Furthermore,
the N20 is relatively independent to the level of sedation1. As the
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Netherlands Journal of Critical Care
later cortical waveforms (P45, N60 and P/N100) are less reliable
and more susceptible to changes by sedation, the N20 is used in all
prognostic clinical routines.
The N20 SSEP in Prognostication
Postanoxic Coma
Bilateral absence of short latency (N20) SSEP response has been
identified as the most powerful predictor of poor outcome in
patients who are unconscious after circulatory arrest1. In patients
not treated with hypothermia, bilateral absence of cortical N20
responses 24 hours or more after the ischemic event is a reliable
predictor for a poor neurological outcome5,6,7. A systematic review
of Robinson showed a false positive rate (FPR) of 0%6, while a meta
analyse of Wijdicks et al. found a 0.7% false positive rate for bilateral
absent N20 responses in those patients7.
In patients treated with therapeutic hypothermia, absence of the
N20 also indicates a poor prognosis. In two large prospective studies,
including 228 patients, the median nerve SSEP was found to be a
reliable tool to predict a poor outcome after rewarming with an FPR
of 0%8,9. However, a retrospective study of Leithner in 122 available
SSEPs revealed one patient treated with therapeutic hypothermia
after cardiac arrest with bilateral absent N20 responses at day 3
with good neurological outcome10. This SSEP was measured on day
3 under sedation with midazolam and fentanyl in a patient with
alcoholic polyneuropathy. Despite this single case, pooled analysis
of these three recent studies8,9,10 on cardiac arrest patients after
hypothermia still give very low FPRs of 0.9%, indicating that bilateral
absence of the N20 should still be viewed as a reliable predictor for
poor outcome in patients treated with hypothermia.
Figure 1. The anatomical connections evaluated by the median nerve SSEP
Postcentral
gyrus
Thalamus
Cuneate
nucleus
Lower
brainstem
Median
nerve
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N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Spinal cord
Recent studies show that already during the period of hypothermia
the SSEP is a reliable tool to predict a poor outcome9,11,12,13. A pooled
analysis of these four prospective studies (424 patients), shows an
FPR of 1.5% with a sensitivity of 28%. The FPR of 1.5% results from
three patients with good neurological outcome and bilateral absent
N20 responses during hypothermia, who were reported in the study
of Bouwes et al9. However, in a post hoc assessment of these SSEP
registrations it was concluded that these three SSEP recordings
were undeterminable because there was too much noise in the
registration9. Correction of these results led to an FPR of 0%.
Unfortunately, preservation of the N20 does not imply a favourable
outcome in patients after cardiac arrest. In fact, only a small proportion
of patients with a poor outcome after resuscitation have negative SSEP
responses resulting in a low sensitivity. This low sensitivity of the SSEP
is also reflected in the large variability of EEG patterns that can be
observed in patients with a preserved N20, including status epilepticus
or even electro-cerebral silence4. As pyramidal cell synaptic function
is mainly reflected by the EEG, while SSEP mainly evaluates the
thalamocortical synaptic function, a possible explanation is selective
hypoxic damage to the cortical pyramidal cells’ synaptic function, with
preserved thalamocortical synapses4.
Traumatic Brain Injury
In patients with severe traumatic brain injury (TBI), the results
available on the reliability of SSEP to predict outcome have been
contradictive. Sleigh et al. showed in a prospective blinded cohort
study including 105 patients that the median nerve SSEP is a reliable
predictor for poor neurological outcome, with a 43% sensitivity and no
false positives14. In contrast, in several other studies TBI patients were
described with initially bilateral absent N20 responses who regained
consciousness and had only minor disabilities1,15,16. These results show
that absence of cortical SSEP responses is not a reliable predictor in
TBI patients. The most likely explanation is that in head trauma, a
transient N20 disappearance may be consecutive to focal midbrain
dysfunction due to oedema1. Therefore, SSEPs should never be used as
a single test in TBI patients, but integrated with other neurophysiologic
tools and clinical examination to improve the predictive value1,14,15. In
TBI patients it is especially important to rule out traumatic lesions of
the peripheral nerves, nerve roots or spinal cord when using clinical
neurophysiologic tests. Clinical examination of the peripheral nerves
can be difficult in patients with a diminished consciousness.
Subarachnoid haemorrhage
In patients with subarachnoid haemorrhage, neither median or tibial
nerve SSEP, flash-visual evoked potential, BAEP nor central conduction
time of the median nerve SSEP can be used as a valid predictor for
outcome. The patient’s initial clinical grading still provides the only
satisfying predictor, independent of the patient’s clinical course17.
Sepsis
In patients with severe sepsis and septic shock, prolonged cortical
SSEP peak latencies occur in 84% of the patients. These prolonged
Netherlands Journal of Critical Care
The SSEP on the ICU: current applications and pitfalls
latencies can be used to diagnose septic encephalopathy and its
severity is associated with the severity of illness18. In these patients
SSEP cannot be used to determine prognosis.
Pitfalls and limitations of SSEPs at the ICU
Noise
The most severe limitation of the SSEP is the moderate interobserver
agreement, which is extensively described in a study of Zandbergen
et al.19. In their study, SSEPs of 56 consecutive patients with anoxic–
ischaemic coma were interpreted independently by 5 experienced
clinical neurophysiologists. The interobserver agreement for SSEPs
in anoxic–ischaemic coma was only moderate (kappa 0.52, 95% CI
0.20–0.65). The main source of disagreement was related to the
noise levels. For recordings with a noise level of 0.25 µV or more,
mean kappa was 0.34 (fair agreement); for recordings with a noise
level below 0.25 µV mean kappa was 0.74, which is a substantial
agreement19.
Efforts should be made to improve the registration and diminish
noise as much as possible. Zandbergen et al. recommend that the
peak-to-peak amplitude of noise of the cortical and cervical leads
should be lower than 0.25 µV after averaging, especially in the
frequency of the SSEPs themselves (20-500 Hz)19. Giving muscle
relaxants can often improve the quality of the SSEP in patients
with too much muscle activity; an example is given in figure 2.
Furthermore, disturbing electrical ICU equipment should be turned
off if possible. Also, giving more stimuli (up to 1000 or more) and
increasing the stimulus intensity could improve the signal-to-noise
ratio19. Since the interpreting clinician is often not present during
the actual SSEP registration itself, the role of the lab technician is
crucial in obtaining reliable SSEP results. As the quality of the SSEP
recording depends on the skills of the technician, it is important that
they are well trained and sufficiently familiar with SSEP registrations
in the ICU. In those situations where significant artifacts appear to
be present, the referring physician should be informed. Furthermore,
it is always the role of the interpreting clinician to check the quality
and signal-to-noise ratio of the SSEP registration, and to decide
whether the SSEP registration is reliable enough for clinical decision
making.
Interpretation Criteria
Despite the noise level, also other criteria for reliable results can be
given. An N20 peak on one side can only be considered as present if
it fulfils all the following criteria:
• It should have an appropriate latency (i.e. at least 4.5 ms longer
than the corresponding N13 peak in normal-stature adults)19.
• It should be present on the contralateral side, and there should
be a clear difference with the recording from the side ipsilateral
to the stimulus19. Therefore it is recommended to record not
only the contralateral sensory cortex after stimulation, but also
co-register the ipsilateral side. This prevents misinterpretation of
the N18, which has its origin in the brainstem, as a N20 potential.
• Any potentials found should be reproducible in a second set of
stimuli1,19.
Bilateral absence of N20 peaks requires the presence of normal
potentials over Erb’s point and the neck (N13) to ensure that the
impulses have arrived in the central nervous system1,19.
Disturbing factors and sedation
Cortical responses are not influenced by moderate sedation
or metabolic disturbances, factors that often hamper clinical
neurological examination in the ICU. However, intoxication or
metabolic disturbances and other explanations for absent SSEP
potentials, for example a high cervical lesion, should be ruled out.
The N20 is relatively independent to the level of sedation, and
remains present even at a sedation level that is sufficient to induce
an isoelectric EEG1,19. Propofol produces minimal to less than
10% suppression of the SSEP amplitude20-23. Also midazolam and
opioids have only moderate effect on the SSEP amplitude and
latency20-23. Furthermore, remifentanyl can supress the cortical SSEP
components by 20-80%, when given in a high dose (0.8 mg/kg/min)
as used during neuromonitoring in the operation room20. On the
other hand, in a small percentage of cases it may be even useful to
Figure 2. Example of the effect of Esmeron on a SSEP after stimulation of the right n. medianus in a patient after resuscitation. The evoked potential is
measured cortical (CP3), cervical (Cerv), at Erb’s point and at the elbow (Elb)
Before administration of muscle relaxants
10 ms
CP3
2.5 µV
After administration of muscle relaxants
CP3
2.5 µV
Cerv
10 µV
Cerv
10 µV
Erb
10 µV
Erb
10 µV
Elb
10 µV
Elb
10 µV
10 ms
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
give sedation in low dose to improve the quality of the SSEP. This is
especially the case in patients with generalized periodic discharges,
which in some situations can be supressed after administration of
propofol. These periodic discharges often have large amplitudes in
comparison to the evoked potential and can disturb the cortical
response. An illustration of a positive effect of propofol on the
quality of the SSEP recording is given in figure 3.
Discussion
Prognostication of comatose patients in the ICU using clinical
examination is often difficult and neurophysiological assessment
may assist in clinical decision making. The SSEP is a relatively simple,
inexpensive, and non-invasive method to evaluate functional damage
to the complete sensory pathway from the peripheral nervous
system, dorsal column of the spinal cord, lemniscal pathways in the
brainstem, with eventual arrival at the somatosensory cortex.
The SSEP can be used in the prediction of the neurological outcome
in comatose patients with different aetiologies. However, it is
only sufficiently reliable in predicting poor neurological outcome
in patients with a post-anoxic coma, although the sensitivity for
predicting a poor outcome is relatively low. For the prediction of a
favourable neurological outcome the SSEP cannot be used. Other
neurophysiologic tools, such as continuous EEG13 and the mismatch
negativity and P300 responses24,25 may provide additional or even
improved information in these cases.
In TBI patients, SSEPs can assist in the prognosis, but should never
be considered in isolation but integrated with other neurophysiologic
tools and clinical examination. In patients with subarachnoid
haemorrhage or sepsis the SSEP has no prognostic value.
Since the SSEP is usually recorded for prognostication, absent
cortical responses almost always lead to withdrawal of intensive
care treatment, the clinician interpreting the results of the SSEP
recording has to be 100% certain. Decisions to withdraw treatment
are irreversible and therefore the N20 SSEPs should be considered as
‘not bilaterally absent’ in cases of doubt.
In conclusion, the SSEP is a very reliable and reproducible method,
if it is performed and interpreted correctly. A bilateral absent N20
response is a reliable predictor for poor neurological outcome in
patients with a postanoxic coma. In postanoxic patients treated with
hypothermia, the SSEP can reliable be measured after rewarming and
probably also during the period of hypothermia. In other comatose
patients, such as TBI patients or patients with a subarachnoid
haemorrhage, the SSEP measurement is not reliable enough for the
prognosis of poor outcome to use as a single parameter in clinical
decision making. During SSEP measurements great care should be
taken in improving the signal to noise ratio. If the noise level is too
high, the peripheral responses are abnormal, or the response is not
reproducible in a second set of stimuli, interpretation of the SSEP
cannot be done reliably and the SSEP should be measured again in
a later stage.
References
1.
Cruccu G, Aminoff MJ, Curio G, et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol 2008;119:1705-1719
2.
Morgalla MH, Bauer J, Ritz R, Tatagiba M. Coma. The prognostic value of evoked potentials in patients after traumatic brain injury. Anaesthesist 2006;55:760-768 In German.
3.
Allison T, McCarthy G, Wood CC, Jones SJ. Potentials evoked in human and monkey
cerebral cortex by stimulation of the median nerve a review of scalp and intracranial
recordings. Brain 1991;114:2465–503
4.
van Putten MJAM. The N20 in post-anoxic coma: Are you listening? Clin Neurophsyiol
2012;123;1460-4
5.
Zandbergen EG, de Haan RJ, Stoutenbeek CP, et al. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998;352:1808-1812
6.
Robinson LR, Micklesen PJ, Tirschwell DL, Lew HL. Predictive value of somatosensory
evoked potentials for awakening from coma. Crit care med 2003;31:960-967
7.
Wijdicks EFM, Hijdra A, Young GB, Bassetti CL Wiebe A. Practice parameter: Prediction
of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2006;67;203-210
8.
Rossetti AO, Oddo M, Logroscino G, Kaplan PW. Prognostication after cardiac arrest and
hypothermia: A prospective study. Ann Neurology 2010;67:301-307
9.
Bouwes A, Binnenkade JM, Kuiper MA et al. Prognosis of coma after therapeutic hypothermia: A prospective cohort study. Ann Neurology 2012;71:206-212
10. Leithner C, Ploner CJ, Hasper D, Storm. Does hypothermia influence the predictive
value of bilateral absent N20 after cardiac arrest? Neurology 2010;74:965-969
Figure 3. Example of the effect of Esmeron and Propofol on a SSEP after stimulation of the right n. medianus in a patient after resuscitation. The evoked
potential is measured cortical (CP3), cervical (Cerv), at Erb’s point and at the elbow (Elb). Before administration of propofol the EEG showed generalized
periodic discharges, while after the administration of propofol the EEG showed diffuse delta activity
Before administration of propofol
10 ms
8
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
CP3
2.5 µV
After administration of propofol
CP3
2.5 µV
Cerv
10 µV
Cerv
10 µV
Erb
10 µV
Erb
10 µV
Elb
10 µV
Elb
10 µV
10 ms
Netherlands Journal of Critical Care
The SSEP on the ICU: current applications and pitfalls
11. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory
evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med
2005;33:1736-1740
12. Bouwes A, Binnekade JM, Zandstra DF, et al. Somatosensory evoked potentials during
mild hypothermia after cardiopulmonary resuscitation. Neurol 2009;73:1457-1461
13. Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJAM. Continuous
EEG monitoring for early prediction of neurological outcome in postanoxic patients
after cardiac arrest: A prospective cohort study. Crit Care Med 2012;40;12867-2875
14. Sleigh JW, Havill JH, Frith R, Kersel D, Marsh N, Ulyatt D. Somatosensory evoked potentials in severe traumatic brain injury: a blinded study. J Neurosurg 1999;91:577-580
15. Lew HL, Dikmen S, Slimp J, et al. Use of somatosensory-evoked potentials and cognitive event-related potentials in predicting outcomes of patients with severe traumatic
brain injury. Am J Phys Med Rehabil 2003;82:53-61
16. Carter BG, Butt W. Are somatosensory evoked potentials the best predictor of outcome
after severe brain injury? A systematic review. Intensive Care Med 2005;31:765-775
17. Wachter D, Christophis P, Stein M, Oertel MF. Use of multimodal electrophysiological
monitoring to predict outcome after subarachnoid hemorrhage? A prospective series.
J Neurosurg Sci 2011;55:179-187
18. Zauner C, Gendo A, Kramer L, et al. Impaired subcortical and cortical sensory evoked
potential pathways in septic patients. Crit Care Med 2002;30:1136-1139
19. Zandbergen EGJ, Hijdra A, de Haan RJ, et al. Interobserver variation in the interpretation
of SSEPs in anoxic-ischaemic coma. Clin Neurophysiol 2006;117:1529-1535
20. Asouhidou I, Katsaridis V, Vaidis G, et al. Somatosensory Evoked Potentials suppression due to remifentanil during spinal operations; a prospective clinical study. Scoliosis
2010;5:8
21. Langeron O, Vivien B, Paqueron X, et al. Effects of propofol, propofol–nitrous oxide and
midazolam on cortical somatosensory evoked potentials during sufentanil anaesthesia
for major spinal surgery. Br J Anaesth 1999;82:340-345
22. Laureau E, Marciniak B, Hébrard A, Herbaux B, Guieu JD. Comparative study of propofol
and midazolam effects on somatosensory evoked potentials during surgical treatment
of scoliosis. Neurosurgery 1999;45:69-74
23. Taniguchi M, Nadstawek J, Pechstein U, Schramm J. Total intravenous anesthesia for
improvement of intraoperative monitoring of somatosensory evoked potentials during
aneurysm surgery. Neurosurgery 1992;31:891-897
24. Fischer C, Luauté J, Némoz C, Morlet D, Kirkorian G, Mauguiere F. Improved prediction
of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med 2006; 34: 1520-1524
25. Fischer C, Dailler F, Morlet D. Novelty P3 elicited by the subject’s own name in comatose
patients, Clin Neurophysiology 2008; 119: 2224-2230.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
9
Netherlands Journal of Critical Care
Accepted January 2013
G U I D EL I NE
Recommendations for the timing and dosing of CRRT in critically
ill patients with AKI
H.M. Oudemans-van Straaten1, C.S.C. Bouman2, M. Schetz3, A.B.J. Groeneveld4, A.C. de Pont2, A.M. van Alphen5, H. de Geus6, W. Boer7
1
Department of Intensive Care, VU University Medical Center, Amsterdam, 2 Academic Medical Center, Amsterdam, 3 Universitary Hospital Leuven, Belgium,
4
Erasmus Medical Center, Rotterdam, 5 Department of Nephrology, Maasstad Hospital, Rotterdam, 6 Erasmus Medical Center, Rotterdam, 7 Hospital
Oost Limburg, Genk, Belgium
Correspondence
H.M. Oudemans-van Straaten – e:-mail: [email protected]
Key words Continuous renal replacement therapy, hemofiltration, hemodialysis, acute kidney injury, guideline, fluid balance
Introduction
This guideline is part of the guideline for renal replacement therapy
(RRT) in intensive care (IC) patients and concerns recommendations
for the timing and dosing of continuous renal replacement therapy
(CRRT) in IC patients with acute kidney injury (AKI). Below we
present a summary of the guideline. The full version and a summary
of appraised studies is presented on http://www.nvic.nl/. Intermittent
hemodialysis is an alternative option for stable IC patients. However, the
considerations that need to be made for the choice between continuous
or intermittent treatment are beyond the scope of this guideline.
Considerations regarding the timing of initiation
Early initiation can improve metabolic homeostasis, volume balance
and body temperature and thereby contribute to the stabilization
of the circulation and improve clinical outcome. In contrast, early
initiation may unnecessarily expose the patient to possible adverse
effects associated with the treatment should renal function recover
soon. Late initiation may contribute to worsening of the patient’s
condition as a result of metabolic disturbances, fluid accumulation
and circulating uremic toxins.
The following aspects should be considered when timing CRRT:
• The etiology and short-term reversibility of the acute renal
insufficiency. With persistent need of high dose vasopressors
and continued exposure to other risks of AKI, renal function will
likely not recover soon.
• Urinary output in the context of the patient’s fluid balance and
fluid needs.
• The severity and consequences of the fluid overload for the
individual patient (e.g. gas exchange, tissue perfusion and cellular
oxygen delivery).
• The severity of the metabolic disturbance and associated harm
for the patient (e.g. consequences of acidosis and uremic toxicity
on circulation, respiratory distress, inspiratory pressures,
oxidant stress).
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N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
• The trend of renal function (a decreasing-upward or downward
slope of the serum creatinine curve in time indicates
improvement of function).
• Metabolic consequences of fluid removal. In contrast to the use
of diuretics, ultrafiltration during CRRT allows the iso-osmotic
removal of large amounts of fluids without inducing inevitable
diuretic related disturbances of acid base and electrolyte balance.
• Costs and adverse effects. CRRT is a complex and expensive
extracorporeal treatment with inevitable blood activation, needing
catheter insertion and anticoagulation, and there are associated
risks of bleeding, thrombosis and metabolic derangements.
Considerations regarding the dose
The dose of CRRT corresponds to effluent flow (dialysate+filtrate volume for continuous hemodialysis or hemodiafiltration,
CVVHD(F), or filtrate volume for continuous hemofiltration,
CVVH), expressed per time and kilograms of body weight) (ml/kg/h).
The large randomized studies used the body weight before ICU
admission1 or at randomization2. It should be noted that the dose
of CRRT (25-45 ml/kg/h) is always less than normal renal function
(120 ml/min). Dose should minimally be adequate to remove uremic
toxins and metabolic acidosis3. The production of uremic toxins and
metabolic acids is likely to be higher in hypermetabolic patients with
sepsis, while the loss of beneficial substances, such as water soluble
vitamins and drugs is also higher when CRRT dose is high.
Furthermore, delivered dose is always lower than prescribed dose.
The so-called filter down-time is due to a delay in the exchange
of bags, stagnation of flow due to access or circuit clotting,
discontinuation of treatment due to interventions, investigations
or the circuit change. Prescribed dose should be corrected for
down-time, which is often 20-25%. In case of predilution, dose
should further be corrected for the dilution of blood in the filter.
Correction factor is (blood flow +ultrafiltrate flow)/blood flow.
Based on the available randomized controlled trials, there is
currently no proof that a CRRT dose of 35 ml/kg/h, as was
Netherlands Journal of Critical Care
Recommendations for the timing and dosing of CRRT in critically ill patients with AKI
recommended in the previous guideline, provides a better patient
survival than a dose of 20-25 ml/kg/h. The benefit of a higher dose
(35-45 ml/kg/h) as found in previous single center clinical trials1,2
was not confirmed in the two recent large multicenter trials3,4.
Furthermore, previous non-randomized clinical and animal
studies suggested a benefit of early high volume hemofiltration
in patients with severe septic shock on stabilization of the
circulation5. However, a recent meta-analysis including randomized
controlled trials and subgroups from randomized controlled trials
could not show any benefit of CRRT versus no CRRT or a higher
dose of CRRT in patients with severe sepsis or septic shock on
survival, hemodynamics, pulmonary gas exchange, multiple organ
dysfunction syndrome or length of stay6. The effect of CRRT on
survival was not modified by CRRT dose. Finally, preliminary results
of the multicenter IVOIRE study (http://www.clinicaltrials.gov),
which compared hemofiltration doses of 35 ml/kg/h to 70 ml/kg/h
in patients with septic shock, AKI, and multiple organ failure, do not
show a survival benefit of the higher dose (personal communication).
Therefore, the best available evidence does not support the routine
use of high-volume CRRT in patients with severe sepsis or septic
shock. However, CRRT is recommended in patients with AKI and
metabolic derangement or diuretic-resistant fluid overload, and dose
should be sufficient for the control of acidosis.
Appraisal of the literature and grading of the recommendations
We appraised the literature according to the guidelines of the
NVIC (A-D), but decided to grade the recommendations (1-2) in
agreement with the KDIGO Guidelines (http://www.kdigo.org/ ),
which are derived from the GRADE classification4, used in the sepsis
guidelines. KDIGO is an acronym for Kidney Disease Improving
Global Outcomes, an initiative of the National Kidney Foundation. In
the KDIGO system there is room for giving a strong recommendation
on clinical grounds while the level of evidence is low.
We finally based the grade of recommendation on the level of
evidence in the literature, the physiological effects and the risks and
costs of the treatment (see table 1).
Recommendations
1. The timing of initiation of CRRT
Absolute indications
We recommend initiating CRRT immediately in patients with
life-threatening AKI-related symptoms of fluid, electrolyte and
acid-base balance (1C).
Relative indications
We suggest starting CRRT if, despite optimization of the circulation
and other supporting interventions, the patient has AKI and
• persistent AKI-related metabolic derangements and/or
• severe diuretic-resistant fluid overload
if and when uremic complications and organ damage are expected
to develop (2C).
Table 1. Grading of guideline recommendations
Grade of
Implications
recommendation
Policy
Level 1
‘‘We recommend’’
Most patients should receive
the recommended course of
action.
The recommendation can
be evaluated as a candidate
for developing a policy or a
performance measure.
Level 2
‘‘We suggest’’
Different choices will be
appropriate for different
patients. Each patient needs
help to arrive at a management
decision consistent with his or
her values and preferences.
The recommendation is
likely to require substantial
debate and involvement of
stakeholders before policy
can be determined.
No grade
Used, typically, to provide guidance based on common
sense or where the topic does not allow adequate
application of evidence.
Consider starting CRRT in a patient with AKI and AKI-related
metabolic derangements
• before the patient is being exposed to new risk factors for AKI
to improve his metabolic and fluid status and optimize his
condition (no grading).
Do not apply RRT if
• AKI is mild (mild metabolic derangements) and probably
transitory (2D);
• treatment is expected to be futile (no grading).
2. The dose of CRRT
We recommend delivering an effluent (filtrate+dialysate) dose of at
least 20-25 ml/kg/h for CRRT in AKI. (IA)
We recommend compensating for a decrease of dose due to
• filter down-time;
• predilution.
We recommend assessing the actual delivered dose and adjust
prescription to reach target. (1B)
CRRT dose can be increased individually to correct severe metabolic
derangements more rapidly (no grading).
References
1.
Ronco C, Belomo R, Homel P, Brendolan A, Dan M, Piccinni P, La Greca G: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal
failure: a prospective randomised trial. EDTNA ERCA J 2002, Suppl 2: 7-12.
2.
Saudan P, Niederberger M, De Seigneux S, Romand J, Pugin J, Perneger T, Martin PY:
Adding a dialysis dose to continuous hemofiltration increases survival in patients with
acute renal failure. Kidney Int 2006, 70: 1312-1317.
3.
Palevsky PM, Zhang JH, O’Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel
K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan
A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with
acute kidney injury. N Engl J Med 2008, 359: 7-20.
4.
Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S,
Myburgh J, Norton R, Scheinkestel C, Su S: Intensity of continuous renal-replacement
therapy in critically ill patients. N Engl J Med 2009, 361: 1627-1638.
5.
Bouman CS, Oudemans-van Straaten HM, Schultz MJ, Vroom MB: Hemofiltration in
sepsis and systemic inflammatory response syndrome: the role of dosing and timing.
J Crit Care 2007, 22: 1-12.
6.
Latour-Perez J, Palencia-Herrejon E, Gomez-Tellot V, Baeza-Roman A, Garcia-Garcia
MA, Sanchez-Artola B: Intensity of continuous renal replacement therapies in patients
with severe sepsis and septic shock: a systematic review and meta-analysis. Anaesth
Intensive Care 2011, 39: 373-383.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
11
Netherlands Journal of Critical Care
Accepted January 2013
review
The pharmacologic treatment of alcohol withdrawal
syndrome in the ICU
D.P.F. van Nunen, D.H.T. Tjan
Department of Intensive Care, Gelderse Vallei Hospital Ede, The Netherlands
Correspondence
DHT Tjan – e-mail: [email protected]
Keywords - Alcohol withdrawal syndrome, delirium tremens, withdrawal seizures, benzodiazepines, anticonvulsants, gamma-hydroxybutyrate, α2-agonists, antipsychotics
Abstract
Alcohol withdrawal syndrome (AWS) presents a significant problem
among new admissions to the intensive care unit. In patients with
a history of alcohol abuse, AWS manifests itself with symptoms
of autonomic hyperactivity, tremors, hallucinations, agitation,
anxiety, and seizures. Progression of AWS, called delirium tremens
(DT), is associated with increased mortality. Traditionally, AWS
is treated with benzodiazepines which have a well-established
record for reducing symptoms of withdrawal and provide adequate
control of both seizures and DT. However, the side-effects of
benzodiazepines have prompted the introduction of alternative
agents. Anticonvulsants and gamma-hydroxybutyrate do suppress
symptoms of AWS, but their effectiveness in the prevention of
seizures and DT is doubtful. Ethanol results in less sedation
than benzodiazepines, although the evidence for its role in AWS
remains limited. Alpha-2 agonists are potent against symptoms
of noradrenergic overdrive and are suitable as adjuvants to
benzodiazepines. Antipsychotics have no demonstrable effectiveness
in AWS and may even be harmful.
Introduction
The incidence of alcohol dependence and associated disorders is
high amongst ICU patients. Although there are no epidemiological
data for the Netherlands, in the United States between 10% and 33%
of patients admitted to the ICU suffer from alcohol dependence1.
According to the fourth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) alcohol dependence is
formally defined as a maladaptive pattern of alcohol use resulting
in clinical impairment or stress as manifested by the development
of tolerance and withdrawal, unsuccessful efforts to abstain,
consumption of ever greater quantities and the involvement of a
considerable amount of time that limits other activities2. Symptoms
of alcohol withdrawal may occur in up to 91% of alcohol-dependent
patients after acute abstinence3,4. The syndrome of alcoholic
withdrawal consists of signs and symptoms (see table 12) developing
in alcohol-dependent individuals within 6 to 48 hours after their
last intake of alcohol or reduction in intake5,6. Although these
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N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
symptoms are usually mild, 5-10% of alcohol-dependent patients7
develop a severe dysautonomic and encephalopathic state known as
‘delirium tremens’ (DT) after 48-72 hours of abstinence8,9. In this
progression of alcohol withdrawal syndrome (AWS) the autonomic
disarray is further exacerbated and the patient’s cognition and level
of consciousness can change within a short period of time. DT is
associated with a mortality rate of 5% which is attributable to
complications of its clinical symptomatology like coronary spasms,
arrhythmias and myocardial infarction8.
The natural course of AWS is a gradual lessening of symptoms
72 hours after its onset9,10. However, given the high mortality and
morbidity, early treatment of AWS is warranted. Since the first
clinical descriptions of the syndrome in the nineteenth century,
many pharmacologic and therapeutic treatments have been
published in medical journals11. Reviews of this body of literature are
few and inconsistent. The objective of this review is to examine the
evidence supporting the popular pharmacologic treatment options
for AWS. The subsequent discussion is based on a systematic search
of the electronic literature database MEDLINE (PubMed). For each
Table 1. DSM-IV-TR Alcohol withdrawal – diagnostic criteria2
A.
Cessation of (or reduction in) alcohol use that has been heavy and
prolonged
B.
Two (or more) of the following, developing within several hours to a few
days after Criterion A
- Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)
- Increased hand tremor
- Insomnia
- Nausea or vomiting
- Transient visual, tactile, or auditory hallucinations or illusions
- Psychomotor agitation
- Anxiety
- Grand mal seizures
C.
Clinically significant distress or impairment in social, occupational, or
other important areas of functioning
D.
The symptoms are not due to a general medical condition and are not
better accounted for another mental disorder
Netherlands Journal of Critical Care
The pharmacologic treatment of alcohol withdrawal syndrome in the ICU
pharmacologic agent a search query was composed of synonyms
for the respective agent in combination with ‘alcoholwithdrawal’,
‘AWS’, ‘delirium tremens’ and ‘DT’. The search results were filtered
for relevant meta- analyses, trials, cohort studies and case series.
Previous reviews describing a segment of the literature were also
consulted.
The resulting review is structured as follows. First, the pathophysiology
of alcohol dependency and withdrawal is elucidated. Second,
the method of diagnosing AWS is discussed. Third, the evidence
supporting the popular pharmacotherapies is presented. The fourth
and final section summarizes and concludes.
Pathophysiology
Alcohol or ethanol influences multiple stages of the neurotransmission
cascade in the central nervous system. Genetic, pharmacological
and electrophysiological studies have demonstrated that alcohol
modifies synaptic transmission by altering neuronal excitability
through an interaction with ligand and voltage-gated ion channels.
The sedative effects of alcohol are principally thought to be the
result of its interference with two neurotransmission systems. At
low concentrations (< 100 mg/dl) alcohol enhances transmission
of gamma-aminobutyric acid (GABA), by promoting chloride
conductance through the GABAA-receptor. At higher concentrations
(> 250 mg/dl) alcohol works directly on the GABAA-receptor and
causes a prolonged opening of its chloride channel that is independent
of the neurotransmitter GABA. This second mechanism makes
alcohol toxic in overdose. A prolonged opening of the chloride channel
causes excessive influx of chloride into neurons of the respiratory
system resulting in respiratory depression10,12. Continued exposure to
alcohol leads to tolerance with downregulation of GABAA-receptors.
Besides reinforcing the inhibitory effects of GABA, alcohol
tempers excitatory neurotransmission mediated by glutamate. This
neurotransmitter binds N-methyl-D-aspartate (NMDA)-receptors
resulting in a calcium influx depolarizing the neuron. One of the
results of NMDA stimulation is an enhancement of signal transmission
between neurons called long-term potentiation which underlies
learning and the development of memory. Alcohol serves as a blocker
of the NMDA-receptors inhibiting this process and contributing to
amnesia and depression of cerebral function. Over time the brain’s
reaction is to increase the number of NMDA-receptors which allow
normal functioning in the presence of alcohol, the formation of
tolerance10,12.
In AWS, GABA neurotransmission is decreased while glutamatergic
neurotransmission is increased resulting in a state of heightened
excitability. Furthermore, the increased sympathetic activity is due
to an overstimulation of noradrenergic neurons following increased
glutamate function and the loss of noradrenergic autoinhibition12.
The hallucinations experienced during withdrawal are caused by
an enhanced dopaminergic transmission following disinhibition
of dopaminergic neurons through reduced GABAergic activity10.
Research has shown that the increased susceptibility to seizures
seen in patients is likely to have its origin in the deep layers of the
superior colliculus where NMDA-receptor mediated excitation is no
longer chronically suppressed by alcohol13.
Diagnosis
AWS should be considered as a diagnosis of exclusion. If the
patient’s history and physical findings prompt clinical suspicion
then alternative etiologies must be ruled out, such as infection
(meningitis), head trauma (intracerebral hemorrhage), epilepsy,
electrolyte or metabolic disturbances, hepatic failure, intoxication
or withdrawal from other substances. The formal diagnostic
criteria are listed in table 1. The clinical spectrum varies from
uncomplicated withdrawal syndrome with patients having a clear
sensorium with signs of autonomic hyperactivity and increased
sympathetic stimulation. Worsening of the symptoms can result
in hallucinations and progression to DT with or without seizures.
When the history on alcohol consumption is unavailable or
unreliable, biomarkers such as gammaglutamyl transferase (GGT)
and carbohydrate-deficient transferrin (CDT) may provide clues
for chronic alcohol overuse with combined sensitivities of 81-90%
and specificities of 63-95%14. Ethanol levels on admission have no
predictive value for AWS15.
After the diagnosis of AWS hs been made, the severity of symptoms
can be quantified by the Clinical Institute Withdrawal Assessment
Scale for Alcohol (CIWA-Ar)16,19.
Treatment
Without therapy the symptoms of alcohol withdrawal are expected
to reach their peak 72 hours after the last ingestion of alcohol
and generally resolve within four days after this moment9,12. In
most cases the symptoms are relatively mild and no pharmacotherapeutic management is required. However, in manifest AWS
treatment is indicated to avoid DT or seizures. The pharmacotherapeutic management of AWS entails the substitution of a
long-acting agent for alcohol and subsequently to taper its dosage
over time17. Historically, many different classes of drugs have been
tried in the management of AWS. This section provides an overview
of the primary pharmacologic agents. The discussion of supportive
measures is beyond the scope of this article.
Benzodiazepines
Benzodiazepines have been the mainstay of pharmacotherapeutic
treatment of AWS and the prevention of secondary seizures since
196918. Benzodiazepines produce their effect by increasing the
affinity of GABAA-receptors for the neurotransmitter GABA. This
results in a greater influx of calcium into the neuron which inhibits
neurotransmission. In this way benzodiazepines serve as a direct
substitute for the GABA-modulating effects of alcohol7.
The evidence supporting the use of benzodiazepines in AWS is
relatively solid with three good quality meta-analyses independently
concluding benzodiazepines to be the preferred treatment.
Mayo-Smith19 conducted a meta-analysis of six prospective, placebocontrolled trials from the 1960s to 1980s involving three
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
13
Netherlands Journal of Critical Care
different benzodiazepines and concluded that benzodiazepines
are more effective than placebo in reducing the occurrence of
DT (risk reduction of 4.9 cases of delirium per 100 patients,
P=0.04) and in seizure prophylaxis (risk reduction of 7.7 seizures
per 100 patients treated, P<0.001). A second meta-analysis was
authored by Holbrook et al.20 and included three randomized,
placebo-controlled trials from the 1980s with a total of 112 patients
and three benzodiazepines21-23. Benzodiazepines were superior to
placebo in reducing the signs and symptoms of AWS as measured
with the CIWA-Ar score two days after the initiation of therapy
(OR 3.28, 95% CI 1.30-8.28). The authors also analyzed eight other
randomized, placebo- controlled trials in which benzodiazepines
were compared with alternative control drugs. The heterogeneity of
the studies prevented pooling but there was no manifest superiority
of any alternative agent over benzodiazepines. Benzodiazepines
were not appreciably safer when compared with a dopamine-agonist,
an anticonvulsant and a tri-cyclic antidepressant (OR 0.67, 95% CI
0.34-1.32). In a more recent meta-analysis, Amato et al.24 included
three randomized, placebo- controlled trials from the 1970s
and 1980s with a total of 324 patients in which benzodiazepines
were compared with placebo18,21,23. Their analysis showed that
benzodiazepines perform significantly better in seizure prophylaxis
with a relative risk of 0.16 (95% CI 0.04-0.69). When compared with
alternative drugs, benzodiazepines demonstrate a non-significant
tendency to deliver better seizure and delirium control, fewer
adverse effects and a lower dropout rate24.
The class of benzodiazepines comprises several drugs with
varying properties concerning speed of onset, half-life and route
of metabolism. Trials comparing different benzodiazepines have
failed to produce evidence in favour of the distinct superiority of
one benzodiazepine over any other in the treatment of AWS19,20,24.
There are, nonetheless, several considerations which may guide the
choice of benzodiazepine. The longer-acting drugs in this class may
provide a smoother course of withdrawal and even be more effective
in seizure control. In a meta-analysis of three prospective, controlled
trials, a non-significant trend was found towards improved seizure
control with longer- acting agents (6.7 fewer cases of seizures per
100 patients, P=0.07)19,25-27. Another issue influencing the choice of
benzodiazepine is the safety in patients with cirrhotic and other
liver diseases. Both diazepam and chlordiazepoxide have a complex
metabolism in the liver with active metabolites prolonging the
half-lives of both drugs. Decreased liver function enhances and
lengthens their sedative effects. In contrast, the shorter acting
lorazepam has a simpler metabolism, is less influenced by cirrhosis
of the liver and has only inactive metabolites. Consequently, the
behaviour of lorazepam is more predictable in patients with hepatic
dysfunction. Another potential risk with diazepam is the fact that
it is more lipophilic than lorazepam and chlordiazepoxide. This
characteristic results in a rapid onset of action because of a swift
distribution into the brain. Yet it also causes a rapid redistribution
to peripheral fat which may quickly reverse this effect. Given
that peripheral fat becomes saturated at an uncertain pace, this
14
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
effect may lead to oversedation when high doses of diazepam are
administered6.
Anticonvulsants
The sedative side-effects of benzodiazepines and their potential for
addiction prompted a search for alternative agents in the treatment
of AWS. The beneficial effects of anticonvulsants in the prevention of
epileptic seizures resulted in trials examining their use in AWS. The
best evidence is available for carbamazepine, an anticonvulsant whose
mechanism of action in AWS may be explained by its GABAergic
activity28 and blockade of NMDA-receptors29. A recent review by
Barrons & Roberts30 identified three randomized double blinded
trials31-33 in which carbamazepine was compared to a benzodiazepine.
In each trial carbamazepine and the benzodiazepine proved equally
effective at reducing symptoms of alcohol withdrawal. Moreover,
in two trials31,33 carbamazepine demonstrated significantly greater
reduction of symptoms on days 6-7 after the start of treatment.
This result remained present in a meta-analysis of the trials by the
Cochrane Collaboration34. A seizure was observed in just one of the
studies42. Carbamazepine has also been compared to placebo in a
double blinded randomized trial with 105 patients with mild AWS
in an outpatient setting. In the group receiving carbamazepine,
withdrawal symptoms diminished significantly faster on the second
day of treatment with a non-significant tendency continuing on days
4-735. Oxcarbazepine was studied in a single blinded randomized
trial in which it demonstrated similar effectiveness to carbamazepine
in controlling symptoms of withdrawal36. However, when compared
to placebo in a group of patients with severe AWS in a double
blinded randomized trial, oxcarbazepine was not superior neither in
suppressing symptoms, nor in seizure prevention37.
The effectiveness of the GABA-activity enhancing anticonvulsant
valproic acid in AWS has been studied in several small trials38.
In a double blinded placebo-controlled study of 43 patients with
moderate withdrawal symptoms, the group randomized to valproic
acid needed significantly less oxazepam for symptom control39. In
comparison to benzodiazepines, two trials showed that valproic
acid is just as effective in reducing symptoms in patients with mild,
uncomplicated AWS40,41.
The potential of the antiglutamergic anticonvulsants topiramate
and lamotrigine in treating AWS was assessed in a single blinded
randomized trial of 127 patients with significant symptoms42.
Compared to placebo, both medications were able to significantly
reduce withdrawal severity, dysphoric mood and supplementary
diazepam administration. However, their performance was no
different from that of the control-drug diazepam. Among the older
anticonvulsants, phenytoine has not shown to be effective in the
treatment of AWS and DT43, while phenobarbital has demonstrated
comparable performance to benzodiazepines44 but has an
unattractive side-effect profile.
In summary, anticonvulsants seem efficacious in the treatment
of mild AWS. Nonetheless, their capability for preventing DT or
seizures in severe AWS remains unknown.
Netherlands Journal of Critical Care
The pharmacologic treatment of alcohol withdrawal syndrome in the ICU
Ethanol
The use of ethanol in the prophylaxis and treatment of AWS has
mostly been limited to surgical wards and intensive care units and is
controversial45,46. A nation-wide survey in the Netherlands published
a decade ago showed that 16% of intensive care units occasionally
used ethanol in the context of AWS47. In the surgical specialties,
ethanol is perceived to possess several advantages over other agents.
First, compared with benzodiazepines ethanol does not readily
cause drowsiness which may hamper the evaluation of a patient, for
example, in a trauma setting. The lack of drowsiness also allows for
rapid mobilization of patients in the postoperative period. Second, in
comparison with benzodiazepines ethanol is seen to carry less risk
of respiratory depression which facilitates weaning and participation
in pulmonary toilet. In non-surgical specialties ethanol is not as
popular due to a short duration of action, a narrow margin of safety
and possible tissue damage at the infusion site9,48.
Research into the employment of ethanol for the treatment of
AWS generally consists of small case series with varying quality
of methodology46. Two randomized controlled trials have been
published. Spies et al.49 randomized 197 alcohol-dependent surgical
patients to four prophylactic regimens started on admission to
the ICU: 50 patients received intravenous ethanol, 48 flunitrazepam-clonidine, 49 chlormethiazole-haloperidol and 50 patients
were given flunitrazepam- haloperidol. No differences were found
between the groups with respect to symptoms of AWS as measured
by the CIWA-Ar scale, length of stay in the intensive care and
major cardiovascular and pulmonary complications. Weinberg
et al.48 randomized 49 trauma patients with a history of severe
alcohol abuse into two groups on admission to the intensive care
unit. 26 patients were administered ethanol (5%, max 200 ml/hour)
intravenously while 24 patients received diazepam by intravenous
or enteral route (max 20 mg/4 hours). The ethanol group proved
to be significantly more difficult to keep in a calm and cooperative
state when measured with the Riker Sedation- Agitation Scale. All
patients managed to wean from therapy 96 hours after initiation with
no appreciable difference between the two groups. Note that in both
trials ethanol was given intravenously. The enteric administration of
ethanol is not recommended because of its narrow margin of safety
and the dependency of its intestinal absorption on the presence
and composition of gastric contents, smoking habits, medications
(ranitidine, erythromycin) and inter- and intra- individual differences
in the gastric emptying rate50. Moreover, the oral administration of
ethanol has been reported to expose patients to taste and behavioural
clues promoting relapse into past drinking behaviour51.
Gamma-hydroxybutyrate (GHB)
Gamma-hydroxybutyrate or GHB is a metabolite of GABA, to which
it is structurally similar. GHB is naturally present in the human
brain and is involved in the regulation of sleep cycles, temperature
regulation, cerebral glucose metabolism and blood flow, memory,
and emotional control52. Regarding its use in the treatment of AWS,
GHB has the interesting characteristic of being a weak agonist of
GABAB-receptors and the fact that exogenous GHB is converted to
GABA which results in an indirect activation of GABAA-receptors.
Consequently, GHB partly mimics the actions of alcohol in the brain
and may therefore act as a substitute drug53. Compared with placebo,
GHB is effective in the treatment of AWS as demonstrated by the
results of a single published trial. Gallimberti et al.54 randomized 23
patients with AWS to placebo or GHB (50 mg/kg) and scored their
symptoms on a 30- point scale during seven consecutive hours. At
the end of the observation period the withdrawal symptoms in the
GHB-group had virtually disappeared while in the placebo group
the level of agitation had increased. In two similar trials, GHB has
been compared with diazepam51,55. A total of 102 alcohol-dependent
patients were randomized to either GHB (50 mg/kg) or diazepam
(0.5-0.75 mg/kg) and for periods of up to three weeks their
symptoms were measured with the CIWA-Ar scale. In both trials
GHB performed at least as well as diazepam in treating AWS. In sub
scores of the CIWA-Ar scale, GHB proved to be faster in suppressing
symptoms of anxiety and agitation.
Concerns for the use of GHB are possible side-effects and its addiction
potential. In a review by the Cochrane Collaboration of 13 trials of
GHB for the treatment of alcohol related disorders 20% of patients
developed transitory vertigo or dizziness at a dose of 50 mg/kg,
while 0.6 to 2.5% reported diarrhea, headache, rhinitis or nausea56.
No serious adverse events occurred. Craving was only seen in the
treatment of alcohol dependence in up to 10% of patients.
α2-agonists
The symptoms of AWS are partly the product of noradrenergic
overdrive. One of the prime receptors for noradrenergic transmission
in the brain is the α2-receptor. Normally this receptor inhibits the
firing of the presynaptic norepinephrine neuron, but during AWS
its sensitivity is impaired which results in augmented noradrenergic
transmission. Accordingly, an exogenous high affinity α2-agonist
could potentially reinforce noradrenergic auto-inhibition and be of
use in the treatment of AWS61. Three small trials57-59 investigated
the application of the α2-agonist clonidine in the prophylaxis for
withdrawal in alcohol-dependent patients. Compared with either the
sedative chlormethiazole, or the benzodiazepine chlordiazepoxide,
no significant difference was found in observer rated symptoms of
AWS. However, the groups treated with clonidine had significantly
lower blood pressure and heart rate. In another trial, Robinson
et al. 60 randomized 32 patients with symptoms of acute alcohol
withdrawal to clonidine or chlormethiazole. In the clonidine
group eight patients dropped out of treatment due to orthostatic
hypotension, seizures or hallucinations. These symptoms were not
observed in the chlormethiazole group. Adinoff et al. 61 examined
the loading doses required to control symptoms of withdrawal in 25
alcohol-dependent males for diazepam, alprazolam, diazepam and
placebo. In contrast to both benzodiazepines, clonidine proved to
be no more effective than placebo but did decrease systolic blood
pressure significantly. Spies et al. reported that lower median doses
of flunitrazepam were required to control symptoms of AWS when
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
15
Netherlands Journal of Critical Care
this was combined with clonidine rather than haloperidol49. All in
all, the above-mentioned research shows that clonidine is effective
in the treatment of symptoms of AWS related to noradrenergic
overdrive, but does not support clonidine monotherapy for
preventing delirium or seizures62.
Dexmedetomidine, a derivative of the veterinary sedative and
analgesic medetomidine, has eight times the affinity of clonidine for
the α2-receptor61. In the context of AWS, a limited number of case
reports demonstrate successful employment of dexmedetomidine
for controlling symptoms of noradrenergic overdrive, mainly as an
adjunct to benzodiazepines63-67.
Antipsychotics
Although antipsychotic or neuroleptic drugs, especially haloperidol,
are routinely employed in the treatment of AWS9 no randomized,
placebo-controlled trials have ever been published demonstrating
their effectiveness. The evidence is limited to predominantly
non-randomized benzodiazepine controlled studies and only for
the older category of atypical antipsychotic drugs (phenothiazines,
haloperidol). In the context of AWS, no human studies have been
conducted with the newer atypical antipsychotics (clozapine,
olanzapine, risperidone)68. Mayo-Smith performed a meta-analysis19
of four prospective trials in which phenothiazines (chlorpromazine
and promazine) were compared with benzodiazepines (diazepam
or chlordiazepoxide) or placebo. Phenothiazines were no more
effective than placebo in preventing delirium and less effective
than benzodiazepines (6.6 more cases of delirium per 100 patients,
P=0.002). Moreover, in comparison with benzodiazepines, treatment
with phenothiazines increased the incidence of seizures (+ 11.4 cases
per 100 patients, P<0.001). This finding is compatible with the clinical
experience that chlorpromazine lowers the threshold for seizures69,70.
Haloperidol was compared to chlordiazepoxide in a double blinded
randomized trial71 including 49 patients with symptoms of acute
withdrawal. After four hours of treatment haloperidol was able to
suppress symptoms in 70% of patients, whereas chlordiazepoxide
controlled symptoms in just 44% of patients. No statistical analysis
was presented.
All studies considered there is insufficient evidence to suggest a
prime role for antipsychotics in the treatment of AWS. Moreover,
the typical antipsychotics are known for their sometimes severe
side-effects including the extra-pyramidal syndrome, the
neuroleptic malignant syndrome and the possibility of ventricular
tachyarrhythmias induced by a prolongation of the QTc interval9.
Conclusion
In ICU patients, AWS is a major problem associated with significant
morbidity and mortality. Treatment is aimed at reducing symptoms
of withdrawal and at preventing seizures and the development of DT.
Benzodiazepines have proven to be effective for all these objectives
and remain the gold standard in treatment. Anticonvulsants and
GHB have both demonstrated to diminish symptoms of withdrawal,
but their adequacy in preventing seizures and DT is not known.
16
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Ethanol may result in less sedation than benzodiazepines, but good
quality evidence supporting its role in AWS is scant. There is no
indication for antipsychotics in the treatment of AWS. Finally,
α2-agonists could serve as adjuvant agents to benzodiazepines in
order to suppress noradrenergic overdrive.
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Netherlands Journal of Critical Care
Accepted January 2013
C ASE RE P OR T
Gastric dilatation and perforation due to binge eating:
a case report
J.A.M. Heijneman1, R. Tahmassian2, T. Karsten3, E.R. van der Vorm4, I.A. Meynaar1
1
Department of Intensive care, Reinier de Graaf Hospital, Delft, The Netherlands
2
Department of Clinical Pharmacy, Reinier de Graaf Hospital, Delft, The Netherlands
3
Department of Surgery, Reinier de Graaf Hospital, Delft, The Netherlands
4
Department of Clinical Microbiology, Reinier de Graaf Hospital, Delft, The Netherlands
Correspondence
J.A.M. Heijneman – e-mail: [email protected]
Keywords - Gastric dilatation, gastric ischemia, binge eating, Candida albicans, fluconazole, caspofungin
Abstract
We present a case of massive gastric dilatation and necrosis in
a patient with psychogenic polyphagia. The patient developed a
Candida albicans sepsis due to gastric perforation and was treated
with antifungal therapy and multiple surgical interventions.
Case
A 43-year-old female attended the emergency department with
complaints of severe abdominal pain. The pain, mainly localized
in the epigastric area, arose after the ingestion of a large amount
of food one day prior to admission. The patient was suffering from
nausea but was unable to vomit. She was afebrile and did not
complain of altered bowel movements. Her medical history reported
a lumbar sympathectomy, psychosis and an eating disorder (periods
of polyphagia alternated with periods of extreme anorexia). An
erect abdominal X-ray ( figure 1) showed a remarkably distended
stomach. The patient was admitted to the surgical ward with the
suspected diagnosis of gastric distension, possibly caused by delayed
gastric emptying provoked by her anti-psychotic drugs, namely
Olanzapine and Clomipramine. She was put on ‘nil by mouth’
and was given a nasogastric tube, which immediately drained 2.5
litres of gastric fluid. However, in the next few hours the patient’s
condition deteriorated, showing signs of shock with progressive
tachypnoea, tachycardia, cold extremities and falling blood
pressure. At emergency laparotomy, the ventral side of the stomach
was found to be completely necrotic and had perforated from the
distal oesophagus to the pylorus. Further, 3.5 litres of gastric fluid
and undigested food particles had leaked into the abdominal cavity.
Extensive abdominal lavage was performed, followed by resection
of the necrotic ventral side with reconstruction of a “tube-like”
stomach, using the vital dorsal side of the stomach.
After surgery, the patient was admitted to the Intensive Care
Unit (ICU), where she was mechanically ventilated and treated in
18
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
accordance with the ICU’s sepsis protocol (inotropes, cefotaxime,
metronidazole and a single dose of gentamicin), continuous
venovenous hemofiltration and administration of amphotericin,
colistin and tobramycin in mouth and stomach (routine selective
decontamination of the digestive tract). Although at this stage
Figure 1. Abdominal X-ray showing a massively distended stomach
Netherlands Journal of Critical Care
Gastric dilatation and perforation due to binge eating: a case report
there was only slight clinical suspicion of candidemia, fluconazole
was added as a precautionary action because of the severity of the
sepsis. On the fifth day of admission, abdominal cultures taken at
the laparotomy as well as a blood culture showed Candida albicans
and fluconazole was replaced by caspofungin. All intravenous
and arterial lines were replaced. Fundoscopy of both eyes by an
ophthalmologist did not show signs of Candida endophthalmitis.
Subsequent blood cultures (9 sets) on different days were negative
for C.albicans. Despite the antifungal treatment with caspofungin,
the patient’s abdominal fluid remained positive for C.albicans. After
seven days of caspofungin monotherapy, fluconazole was again
added to the antifungal regimen in order to augment the treatment
with higher tissue levels. C.albicans was found in abdominal samples
up to 3 weeks after admission. The C.albicans found in the blood
and peritoneal fluid was sensitive to fluconazole, tested in the Vitek
system (Biomerieux). A total of 16 re-laparotomies were performed
in the following five weeks because of recurrent gastrointestinal
leakage and inadequate source control. This eventually resulted in a
subtotal gastrectomy. Both the oesophagus and the leaking antrum
stump were drained by Foley catheters. Also the left hemicolon was
resected together with a large part of the small bowel due to ongoing
leakage from various fistulas. The patient had a surgical procedure
for end colostomy of the transverse colon. Eventually the patient’s
Figure 2. Abdominal X-ray showing a massively distended stomach
clinical condition stabilized. She was weaned from mechanical
ventilation and no longer in need of inotropic agents. All antifungal
therapy was stopped after 29 days and cultures remained negative
thereafter.
After 46 days of ICU-admission the patient was transferred to
the surgical ward for further recovery. Eventually, 118 days after
admission, the patient was transferred to a university hospital for
home parenteral nutrition (TPN) training. After almost one year of
TPN, bowel continuity was restored in a ten hour surgical procedure
in which, after extensive adhesiolysis, a Roux and Y oesophagojejunostomy was created with reconstruction of the abdominal wall
with a Ramirez-plasty. The patient is currently recovering from this
surgery.
Discussion
It is well known that the stomach has rich vascularisation and
collateral blood supply. As a result, gastric infarction due to an
insufficient perfusion is a rather rare condition and its exact
pathophysiology remains unclear. The reported causes of gastric
infarction are diverse and include volvulus, acute necrotizing
gastritis, intrathoracic herniation, the ingestion of caustic materials,
vascular compromise and acute gastric dilatation1. Experimental
models have shown that gastric infarction will only appear when
both venous and arterial occlusion is present2. In a massively
distended stomach, the intragastric pressure can reach over 30cm
H2O exceeding the gastric venous pressure, therefore compromising
venous drainage of the stomach3. In healthy individuals, satiety
mechanisms prevent over-distension of the stomach. However, in
patients suffering from eating disorders, these satiety mechanisms
are often insufficient or absent. Geliebter et al4 showed that patients
with bulimia nervosa have a significantly larger stomach capacity,
possibly due to repetitive expansion of the stomach during binge
eating. Some studies have found evidence of delayed gastric emptying
in bulimic patients, possibly due to smaller gastric contractions in
the enlarged stomach5,6,7. These gastrointestinal changes in patients
with eating disorders might lead to a higher risk of developing
gastric infarction. The incidence of acute gastric dilatation in
anorexia and psychogenic polyphagia seems to be higher in females
(67%)8. A distended abdomen and the urge to vomit are the most
common early signs of gastric distension9. With progression of the
gastric distension, continuous abdominal pain and the inability to
vomit are the predominant findings. An abdominal X-ray may show
gastric dilatation (and, in rare cases of recurrent gastric distension,
gastric pneumotosis caused by gas-forming pathogenic bacteria
infiltrating the injured stomach wall10). With clinical signs of gastric
distension, prompt decompression by nasogastric suctioning should
be initiated.
When gastric decompression is delayed, progression of the gastric
distension may lead to gastric infarction and subsequently gastric
perforation. The overall mortality of gastric infarction is 73%11.
Mortality can often be attributed to severe sepsis and multi-organ
failure as a result of gastric perforation.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
19
Netherlands Journal of Critical Care
In our case, necrosis and perforation of the stomach resulted in
an ongoing peritonitis and candidemia. Candidemia requires
systemic antifungal treatment. Studies show a high mortality rate
associated with candidemia, which is highest in those patients
who are not treated with an antifungal drug12,13. In a patient who is
clinically suspected of candidemia (e.g. presenting with classic skin
or eye lesions), preemptive antifungal therapy should be initiated
while awaiting the return of blood cultures. Yet most patients
have no obvious signs suggesting the presence of candidiasis. In
those cases, depending upon the acuity of the patient’s condition,
clinicians should consider whether it is appropriate to initiate
empiric treatment with an antifungal agent. The 2009 Infectious
Diseases Society America (IDSA)14, and the 2008 Dutch SWAB15
treatment guidelines for candidiasis recommend an echinocandin
for the treatment of candidemia in patients who are considered to be
‘moderately severe’ or ‘severely’ ill14.
Conclusion
Massive gastric dilatation caused by psychogenic polyphagia can
progress to gastric necrosis and perforation. 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
1.
Turan M, Sen M, Canbay E, Karadayi K, Yildiz, E. Gastric necrosis and perforation caused
by acute gastric dilatation: report of a case. Surg Today. 2003;33:302-4 2.
Babkin BP, Armour JC, Webster DR. Restoration of the Functional Capacity of the Stomach
when Deprived of its Main Arterial. Blood Supply. Can Med Assoc J. 1943;48:1-10
3.
Edlich RF, Borner JW, Kuphal J, Wangensteen OH. Gastric blood flow. I. Its distribution
during gastric distention. Am J Surg. 1970;120-35-7
4.
Geliebter A, Hashim SA. Gastric capacity in normal, obese, and bulimic women. Physiol
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
6.
Anderson L, Shaw JM, McCargar L. Physiological effects of bulimia nervosa on the gastrointestinal tract. Can J Gastroenterol. 1997;11:451-9
7.
Kamal N, Chami T, Andersen A, Rosell FA, Schuster MM, Whitehead WE. Delayed gastrointestinal transit times in anorexia nervosa and bulimia nervosa. Gastroenterology
1991;101:1320-4
8.
Gomez MA, Blum L, Scotto B, Besson M, Roger R, Alison D. Gastric necrosis from acute
dilatation without underlying psychiatric disorder. J Radiol. 2004;85:643-5
9. Werner Harmse ChB, Vicci Smith DA, Aisne Stoker DMRD. Intramural gastric air – gastric
pneumatosis or emphysematous gastritis? SA J Radiol. 2007;57-8
10. Billitier AJ, Abrams BJ, Brunetto A. Radiographic imaging modalities for the patient in
the emergency department with abdominal complaints. Emerg Med Clin North Am.
1996;14:789-850
11. Kerstein MD, Goldberg B, Panter B, Tilson D, Spiro H. Gastric infarction. Gastroenterology.
1974;67:1238-9
12. Nucci, M, Colombo, AL, Silveira, F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol. 1998;19:846-50
13. Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G. Candidemia in a tertiary care hospital:
epidemiology, risk factors, and predictors of mortality. Clin Infect Dis. 1992;15:414-21
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14. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al.
Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin
Infect Dis. 2009;48:503-35.
15. SWAB-richtlijnen voor de behandeling van invasieve schimmelinfecties. Stichting
Werkgroep Antibioticabeleid (SWAB), September 2008. Prof. dr. B.J. Kullberg (voorzitter) et al. 16. Hernandez S, López-Ribot JL, Najvar LK, McCarthy DI, Bocanegra R, Graybill
JR. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient
with progressive Candida esophagitis. Antimicrob Agents Chemother. 2004;48:1382-3
17. Pfaller MA, Diekema DJ, Gibbs DL, Newell AV, Meis JS, Gould IM, et al. Results from the
ARTEMIS DISK Global Antifungal Surveillance study, 1997 to 2005: an 8.5-year analysis
of susceptibilities of Candida species and other yeast species to fluconazole and
voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol.
2007;45:1735-45
Netherlands Journal of Critical Care
Accepted January 2013
C ASE RE P OR T
Trichoderma: an unusual bystander in invasive pulmonary
aspergillosis
K. Ariese1, L. Hulshoff1, R. Jansen2, P.H.J. van der Voort3
1
Department of Anaesthesiology and Intensive Care, NKI-AvL, Amsterdam, The Netherlands
2
Department of Microbiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
3
Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
Correspondence
K. Ariese-Beldman – e-mail: [email protected]
Keywords - Trichoderma, invasive fungal disease, immunocompromised, HIPEC
Abstract
In this case report we present a 64-year old female patient who was
admitted to our intensive care unit (ICU) with an abdominal sepsis
six days after a laparotomy and a hyperthermic intraperitoneal
chemotherapy (HIPEC)-procedure. During her ICU admission she
developed a pneumonia and sepsis. Bronchoalveolar lavage (BAL)
was positive for Aspergillus species and an unknown fungus species.
Despite maximum treatment for invasive aspergillosis, the patient
died after being on the ICU for 29 days. Evaluation of the unknown
species in the BAL showed Trichoderma. This case reports focuses
on the clinical relevance of finding the Trichoderma species in
the BAL. In addition, we provide a literature overview concerning
Trichoderma species infections.
Introduction
Trichoderma species has always been considered as a contaminant
in organ site cultures. However, in the recent literature, Trichoderma
species has been increasingly reported as etiologic agents in human
infections, especially in immunocompromised patients. We describe
a case report and discuss recent literature in order to achieve
increased awareness of this frequently fatal infection.
Case
A 64-year old female, with a medical history of hypertension and
a right sided hemicolectomy for carcinoma three months prior to
admission was admitted to our intensive care unit following a
mitomycin-C hyperthermic intraperitoneal chemotherapy (HIPEC)
procedure for metastatic carcinoma of the colon. The patient did not
receive chemotherapy in the six months before the HIPEC procedure.
Six days following the procedure, the patient developed abdominal
pain and sepsis. A diagnostic laparotomy was performed which
showed a perforation of the small intestine and an extensive faecal
peritonitis. The perforation was surgically closed and an abdominal
lavage was performed. The patient was hemodynamically unstable
and mechanically ventilated at the time of admission to the ICU.
Antibiotic treatment was started with amoxicillin, ceftriaxone and
metronidazol. In addition, she received selective digestive tract
decontamination consisting of amphotericin B, colistin/polymyxin
and tobramycin in oral paste and gastric suspension. Blood cultures
remained negative except for one anaerobic blood culture, dated just
before the re-laparotomy, showing Bacteroides species. The patient’s
condition deteriorated and a second look laparotomy was performed
on day two of ICU admission. A necrotizing pancreatitis was found,
most probably due to low-flow state during sepsis, and antibiotic
treatment was changed to meropenem, dosed 500 mg twice daily
(adjusted for renal function). On the third day of ICU admission the
cultures of the abdominal fluid showed positive for Enterococcus
faecium for which vancomycin was added to the meropenem.
Seven days after ICU admission the patient stabilized and infection
parameters improved. Antibiotic treatment was stopped after 12 and
11 days of meropenem and vancomycin treatment respectively.
At day 16 of ICU admission, the patient’s infection parameters
deteriorated. After obtaining cultures from the wound, drain
fluids, and sputum, meropenem and vancomycin were re-initiated.
The cultures were negative except for the tracheal aspirate which
showed less than five colonies of Aspergillus fumigatus ( figure 1).
Aerosolized amphotericin B was added to the antibiotic regiment as
topical treatment, as the positive tracheal aspirates were considered
to reflect colonization. Because the patient could not be weaned
from mechanical ventilation and continued to have fever between
38 and 39° Celsius, a computer tomogram of the thorax and
abdomen was performed on day 22 of ICU stay. It showed increasing
pulmonary consolidations in both inferior lobes and the right
superior lobe. Multiple sputum cultures grew Aspergillus fumigatus,
susceptible for itraconazole (minimal inhibitory concentration [mic]
after incubation for 48 hours by E-test and broth microdilution on
Sabouraud dextrose agar was 0.75 mg/ml) and amphotericine B (mic
0.38 mg/ml).
Because of potential invasive fungal infection, caspofungin was
added on day 22 to the antibiotic regimen, initially dosed at 70 mg
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
Figure 1. Aspergillus
Figure 2. Trichoderma
daily then reduced to 50 mg daily. Liver function abnormalities
precluded the prescription of azoles. At day 27, the chest X-ray
showed a cavity in the right middle lobe. The antifungal regime
was intensified by adding voriconazole (6 mg/kg twice daily,
followed by 4 mg/kg) to the already prescribed caspofungin and a
broncho-alveolar lavage (BAL) was performed. The galactomannan
test in the BAL was strongly positive (optical density index of 9.3,
cut off 0.5 for serum). Galactomannan in serum was not performed.
A CT-scan of the thorax performed on day 29 showed progression
of consolidations compared with the previous one. These
consolidations were highly suspicious for invasive aspergillosis
because of extensive cavitation. The patient’s condition worsened
and she subsequently died on day 29 in the ICU.
Cultures from the tracheal aspirate taken two days before her death
revealed the same Aspergillus species and another fungus which
was difficult to identify. It was ultimately determined by the Dutch
tertiary reference centre for fungal infections (Department of Medical
Microbiology Radboud University, Nijmegen) as Trichoderma species
( figure 2), which showed relative susceptibility to voriconazole
and anidulafungin. The mic for Trichoderma as were (in mg/ml):
itraconazole: >16, fluconazole: >64, amphotericin B: 2.0, 5-flucytosine:
>64, voriconazole: 1.0, anidulafungin: 0.25 and posaconazole: >16.
An autopsy was performed. The pulmonary slides showed
(bilaterally) necrotizing pneumonia with clusters of mould-cords
consistent with Aspergillus with vascular invasive growth.
Trichoderma could not be detected in the obtained tissue samples.
infection. Criteria for IFD have been developed by the EORTC
(European Organization for the Research and Treatment of Cancer)
for patients with haematological malignancies to standardize
clinical and epidemiological research (table 1)1. Despite this they
are often applied to such patient groups2, as we did on day 22,
facing an immunocompromised patient with increasing pulmonary
consolidations on CT and moulds found in multiple sputum
cultures. The autopsy results confirmed our diagnosis by showing a
necrotising pneumonia with clusters of hyphae conform Aspergillus
with invasive growth in vascular structures.
In our patient, Trichoderma was found in combination with
Aspergillus in the BAL-material. In the tissue samples obtained
by autopsy, Trichoderma could not be identified. The relative
contribution of Trichoderma in the clinical course is undetermined.
Indeed, Trichoderma could just be an unusual bystander in invasive
pulmonary Aspergillosis, emphasizing the severe immune-incompetence of our patient. However, the clinician confronted with
a culture containing Trichoderma should be aware of this emerging
pathogen in immunocompromised patients, as we have described,
and should make a therapeutic decision.
Previously, Trichoderma species were considered to be contaminants.
Trichoderma infections in humans appeared to be rare, but they are
increasingly reported as emergent pathogens, probably due to their
opportunistic behaviour, but also because of the increasing number
of immunocompromised patients nowadays3,4.
The first case of an invasive Trichoderma infection was described
by Robertson, concerning an accidental intravenous infusion of
contaminated fluid5. In the last decades of the past century, the
majority of described patients suffered peritonitis as a result of
peritoneal dialysis. Mortality was high, with less than fifty percent
survival rate. The majority of the non-peritonitis cases contain
Discussion
The diagnosis of invasive fungal disease (IFD) is challenging, since
moulds are ubiquitously present in the environment and detection
in a clinical sample does not necessarily represent invasive fungal
22
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Netherlands Journal of Critical Care
Trichoderma: an unusual bystander in invasive pulmonary aspergillosis
Table 2. IFD criteria by the EORTC
Host criteria
Clinical criteria
(of the respiratory tract)
Microbiologic criteria
• The presence of 1 of the following 3 signs on CT:
• Recent history of neutropenia (0.5x109
- dense, well-circumscribed lesions(s) with or
neutrophils/L for >10 days) temporally related to
without a halo sign
the onset of fungal disease
- air-crescent sign
• receipt of an allogeneic stem cell transplant
-cavity
• prolonged use of corticosteroids (excluding
or
among patients with allergic bronchopulmonary
• tracheobronchial ulceration, nodule,
aspergillosis) at a mean minimum dose of 0.3 mg/
pseudomembrane, plaque, or eschar seen on
kg/day of prednisone equivalent for 13 weeks
bronchoscopic analysis
• treatment with other recognized T cell
immunosuppressants, such as cyclosporine, TNF-a
blockers, specific monoclonal antibodies (such as
alemtuzumab), or nucleoside analogues during the
past 90 days
• inherited severe immunodeficiency (such as
chronic granulomatous disease or severe combined
immunodeficiency)
• Direct test (cytology, direct microscopy, or culture)
- mold in sputum, bronchoalveolar lavage fluid,
bronchial brush, or sinus aspirate samples,
indicated by 1 of the following:
• presence of fungal elements indicating a mold
• recovery by culture of a mold
• indirect tests (detection of antigen or cell-wall
constituents):
-aspergillosis
• galactomannan antigen detected in plasma,
serum, bronchoalveolar lavage fluid, or CSF
- invasive fungal disease other than cryptococcosis
and zygomycoses
• β-d-glucan detected in serum
Proven IFD is defined as recovering a fungal species from a sterile compartment of the body (e.g. positive microscopy or culture from blood, cerebrospinal fluid or sterile tissues).
Probable IFD requires the presence of a host factor, a clinical criterion and a microbiological criterion.
Possible IFD is established when cases meet the criteria for a host factor and a clinical criterion but for which mycological criteria are absent.
opportunistic infections complicating the course of haematological
malignancies and solid organ transplantations.
Little is recorded about the clinical manifestations of Trichoderma,
perhaps because the clinical image seems very un-specific.
Symptoms appear predominantly in immunocompromised patients
as nodular pulmonary infiltrates, sometimes mimicking invasive
aspergillosis 6, localized (ulceronecrotic) cutaneous lesions or
disseminated infection, including the central nervous system. In
the case of peritonitis (due to infected peritoneal dialysis catheters)
the symptoms range from mild (abdominal discomfort) to more
severe (bowel obstruction). Sometimes fever is present. None of
these symptoms could suggest a fungal rather than a bacterial
origin. This makes the definitive diagnosis of Trichoderma difficult.
The diagnosis relies on the demonstration of hyphae in tissue
sections associated with positive culture results in non-biopsy
specimens, obtained from accessible sites, e.g. skin, upper- or lower
airways, or urine, sputum cultures, wound swabs etc. Once hyphae
have been demonstrated in tissue sections, Trichoderma infection
can easily be misdiagnosed as aspergillosis or other hyalohyphomycosis, because the hyphae are morphologically quite similar.
Guarro et al. emphasized the complexity of the branching pattern
of Trichoderma hyphae in tissue, compared to the other hyalo­hyphomycosis7.
Also the identification of Trichoderma isolates at species level may
be difficult by only relying on morphology, sometimes leading to
erroneous species identification. Nowadays molecular techniques
are used for species identification, since Kuhls et al. identified the
human pathogenic Trichoderma isolates by PCR-fingerprinting8.
The prognosis for patients with Trichoderma infections is poor. For
disseminated infections the mortality is as high as 100%. Favourable
outcome of the infection is associated with immunocompetence,
catheter or drain removal in cases of peritonitis and surgical
debridement of the localized lesion. The major problem with
Trichoderma genus is its poor susceptibility to antifungal drugs.
The minimal inhibitory concentrations for fluconazole and
5-fluorocytosine are far above the human toxicity level9,10,11,12.
Possible susceptibility (i.e. fungal mic for which non-toxic blood
levels are achievable) is reported for itraconazole, ketoconazole
and miconazole, although for itraconazole and ketoconazole high
mic levels have also been reported7. Apparent susceptibility to
voriconazole has been described13,14. Recent data indicate that
there may be resistance to amphotericin B15,16,17. There is a lack of
information about the efficacy of caspofungin, although low mics
have been recorded6,18. No clinical trials have been performed
directing the treatment of Trichoderma infections. Susceptibility
testing is of utmost importance, and preferably antifungal
drugs with low mics should be used. There is no evidence for
advising a specific antifungal agent in the empirical setting (i.e.
before susceptibility testing). The most recent case report uses a
combination of an echinocandine (caspofungin) in combination
with voriconazole, both more tolerable than amphotericin B, with
the aim that Trichoderma will at least be susceptible to one of
these antifungals18. Since for other susceptible fungal infections
duo therapy is not proven to be superior to monotherapy, we advise
switching to monotherapy when results for susceptibility testing
become available from the laboratory19,20,21.
Conclusion
A case of an invasive opportunistic pulmonary infection with
Aspergillus and possibly Trichoderma spp. is presented. Awareness
of this frequently fatal invasive Trichoderma infection is warranted
for critical care physicians. Clinical backgrounds and considerations
concerning the diagnosis have been discussed and suggestions for
treatment are given in this article.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
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Netherlands Journal of Critical Care
Accepted January 2013
C ASE RE P OR T
Drug induced lung injury – a case of fatal bleomycin
interstitial pneumonitis
S. van der Sar-van der Brugge1, H. van Ravenswaay Claasen2, L. Dawson3
1
Department of Internal Medicine, Reinier de Graaf Hospital Delft, The Netherlands
Currently: Department of Pulmonology, Haga Hospital, Den Haag, The Netherlands
2
Department of Pathology, Reinier de Graaf Hospital Delft, The Netherlands
3
Department of Intensive Care, Reinier de Graaf Hospital Delft, The Netherlands
Correspondence
S. van der Sar-van der Brugge – e-mail: [email protected]
Keywords - Drug induced lung injury, bleomycin, interstitial pneumonitis, intensive care unit
Abstract
Bleomycin is an antineoplastic agent that is known for its potential
for fatal lung toxicity. Cell injury occurs through the formation of
free radicals.
Timely detection of bleomycin-induced pneumonitis (BIP) can be
difficult and it is vital to keep a low index of suspicion in patients
receiving bleomycin. We describe a patient with Hodgkin’s lymphoma
who died of bleomycin-induced lung injury in our intensive care unit.
We discuss treatment options and review the literature.
Introduction
With the knowledge that the prognosis of patients with
haematological malignancies in the ICU has been improved in the
past decades1, dealing with life-threatening conditions in these
patients forms a major challenge for the ICU clinician. Usually,
respiratory failure and /or sepsis are the main reasons for ICU
admission.
Less often we are involved in the treatment of toxicity of
chemotherapy in patients cured of haematological malignancy. We
report a patient with Hodgkin’s lymphoma who died in our ICU due
to a complication of bleomycin-containing chemotherapy.
Case description
A 74-year old patient was transferred from the haematology-oncology department to our ICU because of respiratory failure.
He had been diagnosed with M. Hodgkin stage IVB with cervical,
mediastinal and retroperitineal localisations and was treated with
six courses of adriamycine, bleomycine, vinblastine and dacarbazine
in a 4-weekly schedule. His previous medical history included a
myocardial infarction and CABG at the age of 55. For the past 54 years
he had smoked one pack of cigarettes per day, and never managed to
quit despite counselling. Pulmonary function tests performed before
the initiation of chemotherapy showed COPD GOLD stadium II,
without reversibility and without complaints (table 1).
After the first two rounds of chemotherapy, however, the patient
complained of rhinitis, an irritable cough and dyspnoea on exertion.
CT thorax at that point showed no intrapulmonary abnormalities,
and pulmonary function tests were stable (table 1). Treatment for
an upper respiratory tract infection was given, and chemotherapy
continued as scheduled. Chest X-ray and pulmonary function
tests were repeated after the fourth month of chemotherapy, and
again there were only minor changes and as his symptoms had not
worsened, chemotherapy continued (table 1).
After the sixth ABVD-course, the patient underwent a FDG-PET-scan,
and as staff members noticed considerable dyspnoea, he was referred
to the haematology-oncology department for admission afterwards.
Progressive dyspnoea and cough had developed since his last round
of chemotherapy three weeks earlier.
On examination the patient was not acutely ill, but mildly distressed
with a respiratory rate of 16 breaths per minute, reaching a PaO2 of
8.2 kPa and an oxygen saturation of 92%. The temperature was 37.3
°C. Laboratory analysis showed: ESR 21 mm/hr, C-reactive protein
29 mg/l, haemoglobin 7.5 mmol/l, LDH 544 mmol/l, creatinine 61
mmol/l. The PET-CT thorax revealed diffuse ground glass opacities
Table 1. Pulmonary function tests during chemotherapy
VC max [L]
VC [% of
predicted]
FEV-1 [L]
FEV-1 [% of
predicted]
TLC-He [L]
TLC-He [% of
predicted]
DLCOc [mmol/
min/kPa]
Baseline
3.98
93
2.30
73
6.90
95
5.62
Two months
3.94
92
2.38
76
6.90
94
7.12
Four months
3.56
83
2.02
65
6.91
95
6.34
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
and thickening of intra- and interlobular septa ( figure 1), but no new
localisations of Hodgkin’s lymphoma.
Given the subacute onset of dyspnoea after administration of
bleomycin, the absence of fever and relatively low inflammation
markers, the working diagnosis was bleomycin interstitial
pneumonitis rather than pneumonia. However, as the patient was
immunocompromised, bacterial (super)infection or an opportunistic
infection (especially Pneumocystis jirovecii pneumonia) had to be
considered as well. Therefore, treatment with prednisone (100 mg/
day), cefuroxime and high-dose cotrimoxazole was commenced.
Administration of oxygen was kept to a minimum, aiming for an
oxygen saturation level of 90%. The consulting pulmonologist
decided to review the patient shortly after admission in order to
schedule a broncho-alveolar lavage for further diagnostic steps.
During admission, however, the patient’s clinical condition
deteriorated rapidly with major changes in behaviour, and
progressive hypoxaemia.
On day 2 of hospital admission, the ICU’s rapid response team was
called to the haematology-oncology ward to assess the patient.
We saw a distressed, restless and at times aggressive patient who
responded to verbal stimuli. His airway was clear. With 22 breaths
per minute and administration of 2 L O2/min by nose prong, his
SpO2 was 80%. On auscultation bilateral crackles were heard. His
blood pressure was 135/80 mmHg, with a sinus tachycardia of 110
beats per minute, and a temperature of 37.4°C. Further examination
was unremarkable.
Blood gas analysis at that point showed: pH 7.46; pCO2 3,7 kPa;
bicarbonate 20 mmol/l; base excess -3.6; pO2 4.8; O2saturation 65%.
Further lab results were: Haemoglobin 6.5 mmol/l; leucocytes 12.4
*109/l, thrombocytes 132*109/l, CRP 38 mg/l, LDH 570 U/l. A CXR
showed bilateral consolidations ( figure 2).
We transferred the patient to the ICU where high flow oxygen
through nasal cannulae (Optiflow™) was given, aiming for an oxygen
saturation of 88-90%. Morphine and sedatives were administered
for comfort.
Figure 1. CT thorax: Bilateral airspace consolidation and ground glass
opacities
26
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Figure 2. Chest X-ray with bibasal consolidations
We considered bleomycin interstitial pneumonitis to be the
most likely diagnosis, but were also concerned about possible
PJP-infection. Alternative diagnoses (atypical pneumonia, acute lung
injury due to a different, unknown cause) were considered much
less likely. Therefore high-dose prednisolone and cotrimoxazole
were continued and to include Pseudomonas aeruginosa coverage,
ceftazidim was substituted for cefuroxim.
We discussed intubation and mechanical ventilation of the patient
in order to perform a broncho-alveolar lavage. But considering the
fact that bleomycin toxicity was the most likely diagnosis, given
the subacute onset and slowly progressive course coupled with a
relatively low CRP, we decided against intubation. Treatment with
Optiflow™ had the main advantage of the patient being able to
communicate with his relatives. Over the next two days, the patient’s
condition was poor but stable. His CRP-level dropped slightly, and
consolidations on CXR barely improved. He remained strictly
dependent on Optiflow (FiO2 55%, 50L/min), with oxygen saturation
levels between 85-94% and had considerable respiratory distress on
incidental removal of the Optiflow™ cannulae. Academic institutions
were consulted for their opinion regarding the benefit of mechanical
ventilation, e.g. extracorporeal membrane oxygenation (ECMO) or
other experimental therapies. However, as lung damage was severe,
and no short-term improvement was to be expected, they advised
continuing the conservative treatment.
We informed the patient and his relatives of the prognosis, with a
very poor chance of survival in an acceptable condition. They agreed
to withhold further active treatment. Patient comfort was ensured
by continuous administration of morphine and midazolam. The
patient died a few hours after cessation of therapy.
Permission for autopsy was obtained, and findings were as follows:
Both lungs were heavy and solid, with white-yellow to grey
discolorations. Microscopic examination revealed areas of
Netherlands Journal of Critical Care
Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis
congestion and haemorrhage in alveolar septa ( figure 3 and 4) and
fibroblast-plugging in alveoli ( figure 5). Macrophages in alveoli
were noted as well as a few hyaline membranes. These findings are
consistent with diffuse alveolar damage and organizing pneumonia,
which are both known patterns of lung reaction to toxic drugs,
like bleomycin. Additional PAS and Grocott-stain of the lungs
did not reveal any micro-organisms, and culture for Aspergillus
was negative. There was mediastinal lymphadenopathy but on
microscopy no atypical lymphoid cells were found.
Figure 5. Diffuse alveolar damage: Late phase of organizing pattern with
intra-alveolar plugs, and dense connective tissue
Figure 3. Diffuse alveolar damage: acute and organising pattern.
Congestion of alveolar capillaries in the alveolar septal wall (left) and
rupture of this wall by young organizing fibrine, fibroblasts and type II
pneumocytes (right)
In conclusion, there was diffuse alveolar damage and organizing
pneumonia, consistent with bleomycin pulmonary toxicity, but
no evidence of an opportunistic infection or recurrence of the
Hodgkin’s lymphoma.
Figure 4. Diffuse alveolar damage: acute and organizing patterns.
Erythrocyte extravasation in alveolar spaces (upper left), congestion of
erythrocytes in septal capillary (right below) and fibrosis in alveolar septal
wall consisting of loose organizing type of connective tissue. Prominent
hyperplastic type 2 pneumocytes line the alveolar walls
Discussion
Drug-induced lung injury is an important cause of respiratory
failure, but presentation is usually non-specific. In patients treated
with antineoplastic agents, differentiation between drug toxicity
and other causes of lung injury like (opportunistic) infection,
cardiovascular disease or progression of primary disease can be
difficult.
Bleomycin is an antineoplastic agent that is known for its potential
for fatal lung toxicity2. This toxicity can present in several distinct
patterns, including eosinophilic hypersensitivity, organizing
pneumonia and bronchiolitis obliterans and interstitial pneumonitis
(BIP), which may eventually progress to pulmonary fibrosis2. The
incidence of BIP increases with cumulative dose up to 18% in patients
who receive a dose of over 360 units of bleomycin3, but it can occur
even with doses < 50 units. Fatal toxicity has been reported in 0-3%
of all patients receiving bleomycin-containing chemotherapy4,5.
Patients surviving the acute phase of BIP, however, usually recover
completely with total recovery of all lung function parameters after
two years6.
The main indications for bleomycin are disseminated germ cell
tumours and Hodgkin’s disease. Omission of bleomycin from
the standard treatment for germ cell tumours has been shown to
decrease the disease free survival4. In patients at high risk for BIP,
however, alternative chemotherapeutic regimens can be used.
The antineoplastic effect of bleomycin occurs by inducing cell-death
through induction of free radicals. Bleomycin binds to Fe(II), which
is oxidized to Fe(III), resulting in free radicals formation. These free
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
radicals cause single- and double-strand breaks in DNA (scission),
leading to cell-death. The enzyme bleomycine hydrolase deactivates
the drug, but as this enzyme has low activity in the skin and the
lungs, these organs are most susceptible to bleomycin toxicity2.
Bleomycin causes activation of alveolar macrophages by an unknown
mechanism, resulting in release of inflammatory, profibrotic
cytokines7. Tumour necrosis factor α, transforming growth factor β
and platelet-derived growth factor receptor α are believed to play a
role in formation of fibrosis8.
Bleomycin interstitial pneumonitis typically (but not exclusively)
develops subacutely during treatment, up to six months afterwards2.
Symptoms are nonspecific and include dyspnoea on exertion,
dry cough, tachypnoea and fever. On examination, bibasilar fine
crepitations and hypoxaemia can be noted.
Pulmonary function tests (PFTs) are usually obtained before initiation
of bleomycin. Subsequent PFTs are usually performed as clinically
indicated. Diffusing capacity of the lung for carbon monoxide (DLCO)
decreases in most patients on bleomycin, but also decreases in patients
receiving non-bleomycin-containing chemotherapy9. Deterioration of
vital capacity (VC) or total lung capacity (TLC) also occurs in patients
on bleomycin and is more specific for BIP9.
Diagnosis is by exclusion. Cultures including viral and PCRs on
blood, sputum or broncho-alveolar lavage (BAL) fluid can be done
to rule out infection including opportunistic. Usually empiric
antibiotic treatment is started pending culture results. BAL-fluid
can also be checked for malignant cells.
Chest radiographic findings can be normal, but typically bibasilar
infiltrates, progressing to diffuse alveolar or interstitial consolidation
are found. Rarely, pneumothorax and pneumomediastinum have
been reported in BIP10. On high resolution computed tomography
(HRCT) abnormalities may be detected earlier than on plain chest
radiography. HRCT is useful in characterizing the pattern and
distribution of abnormalities. HRCT findings vary with underlying
histopathologic pattern (table 2)11. Rarely, organizing pneumonia
due to bleomycin presents with subpleural nodules, which should
not be mistaken for progression of primary disease.
Lung biopsy can be obtained for histopathological examination,
but findings may be nonspecific. Histopathologic patterns of
bleomycin-induced lung injury include diffuse alveolar damage
(DAD), nonspecific interstitial pneumonia, cryptogenic organizing
pneumonia (COP) and bronchiolitis obliterans and eosinophilic
pneumonia12. DAD, which was also found in our patient, is the
most common form but is nonspecific. It is also the most common
histopathologic pattern seen in ARDS13. It is characterized by diffuse
alveolar septal thickening, patchy or diffuse airspace organization
and focal or diffuse hyaline membranes, in the absence of signs of
infection (including viral), granulomas and prominent eosinophils
or neutrophils14.
Risk factors for development of BIP have been identified (table 3)2,15.
A previous history of pulmonary disease has not been reported
as a risk factor, but the risk of dealing another blow to an already
compromised organ seems obvious.
28
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Table 2. High resolution computed tomography manifestations of different histopathological types associated with bleomycin toxicity11
Diffuse alveolar damage
Bilateral airspace consolidation and ground glass
opacities involving dependent lung regions
Alveolar haemorrhage
Extensive bilateral ground glass opacities with or
without superimposed interlobular linear opacities
(‘crazy paving’)
Hypersensitivity
pneumonitis
Bilateral ground glass opacities and/or small poorly
defined centrilobular nodules. Air trapping
Nonspecific interstitial
pneumonia
Patchy bilateral or diffuse ground glass opacities
with associated reticular opacities. Mainly lower lung
zones and subpleural regions involved
Cryptogenic organizing
pneumonia and
bronchiolitis obliterans
Ground glass opacities in bilateral random
distribution. Airspace consolidation in subpleural or
peribronchial distribution. Rarely solitary nodules
Eosinophilic pneumonia
Airspace consolidation and ground glass opacities
in predominantly peripheral distribution, involving
middle and upper lung zones
Table 3. Risk factors for bleomycine pulmonary toxicity2,15
Age
Renal insufficiency
Smoking
Radiation therapy
High fraction of inhaled oxygen
Concurrent use op granulocyte colony stimulating factor
Concurrent use of cisplatin
The role of high FiO2-administration is controversial. The
pathogenetic mechanism (with a central role for formation of free
radicals) suggests a possibly harmful effect of high FiO2, which
has been confirmed by most studies in animals. In humans, this is
supported by reports of patients developing acute respiratory failure
postoperatively after previous treatment with bleomycin. A major
review article in 77 patients who received bleomycin, however, failed
to show a correlation between FiO2-restriction and postoperative
pulmonary morbidity or survival16. Usual practise is to keep FiO2 as
low as possible. In hypoxemic patients, oxygen is supplemented as
needed to reach an oxygen saturation of 89-92%.
Once BIP has been diagnosed, further bleomycin treatment should
be withheld. Patients can be treated with glucocorticoids (for
example, prednisone 0.75-1 mg/kg day up to 100 mg/day). There are
no controlled studies of glucocorticoids, but observational studies
have suggested a beneficial effect5. Response may vary according to
histopathological pattern. Further treatment is mainly supportive.
Shortly after we lost our patient, an interesting case report was
published, describing a patient with life-threatening BIP, who was
completely cured with imatinib-mesylate, after steroid treatment
failed17.
Our patient was at increased risk of bleomycin pulmonary toxicity
due to his age, smoking status and COPD. In retrospect, he had
already showed symptoms of BIP after the first two rounds of
chemotherapy. His symptoms were given clinical attention, but
unfortunately the treating physicians were lured into a false sense of
Netherlands Journal of Critical Care
Drug induced lung injury – a case of fatal bleomycin interstitial pneumonitis
security by the normal findings on CT-scan and pulmonary function
testing and bleomycin-containing chemotherapy was continued.
During ICU admission we were faced with the difficult decision
regarding intubation or palliative treatment. Though the patient’s
chances seemed poor, there would have been a small chance of
survival with aggressive management. The patient and his relatives,
however, decided against this as they were afraid of prolonged
suffering and a poor clinical and functional outcome.
Conclusion
Bleomycin treatment is often complicated by pulmonary toxicity,
which can be severe. Screening tests (like radiographic imaging or
pulmonary function tests) are unreliable, making it vital to keep
a low index of suspicion especially in patients with risk factors.
Withholding further bleomycin from patients with dyspnoea or a
non-productive cough should be seriously considered, even in the
absence of abnormalities on CT-scans or PFTs.
As establishing the diagnosis is mainly by exclusion and patients
are also prone to infection whether opportunistic or not, this can
be problematic. Once BIP is suspected, treatment with high-dose
glucocorticoids should be started. Excess administration of oxygen
is to be avoided, but in patients with respiratory failure, adequate
tissue oxygenation should be maintained. Initiation of mechanical
ventilation requires careful consideration as the effect on BIP is
unknown. Treatment with high flow oxygen allows comfort and
verbal communication. By admitting this severely hypoxaemic
patient to the ICU we were able to gain some valuable time for him
through good palliative treatment.
13. Parambil JG, Myers JL, Aubry MC, Ryu JH. Causes and prognosis of diffuse alveolar
damage diagnosed on surgical lung biopsy. Chest 2007;132:50-7.
14. American Thoracic Society; European Respiratory Society. American Thoracic Society/
European Respiratory Society International Multidisciplinary Consensus Classification
of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic
Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS
board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J
Respir Crit Care Med 2002;16:277-304.
15. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the
risk of bleomycin lung toxicity in patients with germ cell tumours. Ann Oncol 2003;14:91-6.
16. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen
restriction necessary? J Urol 1998;160:1347-52.
17. Carnevale-Schianca F, Gallo S, Rota-Scalabrini D, et al. Complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a
patient with Hodgkin’s lymphoma: hope for severe chemotherapy-induced toxicity?
J Clin Oncol 2011;29:e691-3.
References
1.
Ferrà C, Marcos P, Misis M, et al. Outcome and prognostic factors in patients with hematologic malignancies admitted to the intensive care unit: a single-center experience.
Int J Hematol. 2007;85:195-202.
2.
Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001;120:617-24.
3.
De Wit R, Roberts JT, Wilkinson PM, et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in
good-prognosis germ cell cancer: a randomized study of the European Organization
for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group
and the Medical Research Council. J Clin Oncol 2001;19:1629-40.
4.
Simpson AB, Paul J, Graham J, Kaye SB. Fatal bleomycin pulmonary toxicity in the west of
Scotland 1991-95: a review of patients with germ cell tumours. Br J Cancer 1998;78:1061-6.
5.
White DA, Stover DE. Severe bleomycin-induced pneumonitis. Clinical features and
response to corticosteroids. Chest 1984;86:723-8.
6.
Van Barneveld PW, Sleijfer DT, van der Mark TW, et al. Natural course of bleomycin-induced pneumonitis. A follow-up study. Am Rev Respir Dis 1987;135:48-51.
7.
Denholm EM, Phan SH. Bleomycin binding sites on alveolar macrophages. J Leukoc
Biol 1990;48:519-23.
8.
Yoshida M, Sakuma J, Hayashi S, et al. A histologically distinctive interstitial pneumonia
induced by overexpression of the interleukin 6, transforming growth factor beta 1, or
platelet-derived growth factor B gene. Proc Natl Acad Sci U S A. 1995;92:9570-4.
9.
Sleijfer S, van der Mark TW, Schraffordt Koops H, Mulder NH. Decrease in pulmonary
function during bleomycin-containing combination chemotherapy for testicular
cancer: not only a bleomycin effect. Br J Cancer 1995;71:120-3.
10. Keijzer A, Kuenen B. Fatal pulmonary toxicity in testis cancer with bleomycin-containing chemotherapy. J Clin Oncol 2007;25:3543-4.
11. Silva CI, Müller NL. Drug-induced lung diseases: most common reaction patterns and corresponding high-resolution CT manifestations. Semin Ultrasound CT MR 2006, 27:111-6.
12. Godoy MC, Nonaka D, Raphael BG, Vlahos I. Diffuse ground-glass opacities in a patient
with Hodgkin lymphoma and progressive respiratory failure. Chest 2008;134:207-12.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
Accepted January 2013
C ASE RE P OR T
A rare cause of cardiac failure following
transthoracic oesophagectomy
D.A. Wicherts1, S. Hendriks2, W.L.E.M. Hesp1, J.A.B. van der Hoeven1, H.H. Ponssen2
1
Albert Schweitzer Hospital, Department of Surgery, Dordrecht, The Netherlands
2
Albert Schweitzer Hospital, Department of Intensive Care Medicine, Dordrecht, The Netherlands
Correspondence
D.A. Wicherts – e-mail: [email protected]
Keywords - Oesophagectomy, cardiac failure, chylomediastinum, chylothorax
Abstract
Following elective transthoracic oesophagectomy in a 75-year old
female, sudden haemodynamic instability occurred on the second
postoperative day, requiring re-intubation and inotropic support. A
large mediastinal fluid collection with mechanical compression of the
heart was found with computed tomography imaging of the thorax.
Restoration of cardiac function was noted following successful surgical
fluid drainage. Subsequent ligation of the thoracic duct because of
persisting leakage of chylous fluid resulted in final patient recovery.
Chyle leakage following oesophagogastrectomy usually results in pleural
effusion. However, a chylomediastinum may sometimes occur with
potentially significant haemodynamic consequences. Recognition of the
thoracic duct at initial surgery with or without prophylactic ligation is
crucial for preventing major complications caused by chyle leakage.
Introduction
During oesophagogastrectomy, injury to the main thoracic duct or
its branches often occurs. This is related to the close anatomical
proximity of the thoracic duct to the oesophagus. As a consequence,
lymphatic fluid may leak into the thoracic cavity, resulting in
a so-called chylothorax1. This complication causes significant
morbidity, but fortunately is relatively uncommon. The overall
incidence is reported to be around 2% to 3%, depending on the type
of surgical approach used2. Opening the thoracic cavity during a
transthoracic approach logically increases the risk of a chylothorax
compared to a transhiatal oesophagogastrectomy.
A chylothorax usually presents as a high-volume lymphatic output
from a chest tube or an undrained pleural effusion on a chest
radiograph. A chylomediastinum (mediastinal chyle collection),
however, may have significant haemodynamic consequences due to
its close relationship with the heart and major vascular structures.
This situation is illustrated in the following case report.
Case report
A 75-year old female was admitted to our hospital with a
biopsy-proven squamous cell carcinoma of the distal oesophagus.
30
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
At preoperative work-up, including endoscopic ultrasound as well
as computed tomography (CT) imaging of the thorax and abdomen,
it was classified as a cT3N1 tumour. Following standard preoperative
chemoradiotherapy, a transthoracic oesophagectomy was performed
with a primary anastomosis located in the neck.
During surgery, the oesophagus and surrounding lymph nodes were
mobilized through a right thoracotomy and incisions in the upper
abdomen and neck. The anastomosis was made between the cervical
oesophagus and the fundus of the stomach. The initial surgery was
uneventful. Drains were situated in the neck, right pleural cavity
and upper abdomen. Postoperatively, the patient was admitted to
the Intensive Care Unit and was extubated the following day without
any problems.
On postoperative day (POD) 2, the patient suddenly deteriorated
haemodynamically (hypotension, tachycardia and increased central
venous pressure [23 mm Hg]), requiring re-intubation and inotropic
support. The chest radiograph showed bilateral pleural effusions
for which an additional chest tube was placed at the left side,
draining a large amount of typical chylous (milky) fluid. Laboratory
analysis showed an elevated level of triglycerides (5.3 mmol/L)
suggestive for chyle. Fluid cultures were negative. Additionally,
conservative treatment with total parenteral nutrition (TPN) was
started. However, the patient did not improve. Subsequent CT
imaging of the thorax showed a large mediastinal fluid collection
adjacent to the neo-oesophagus, compressing the left atrium of
the heart ( figure 1). Additional cardiac ultrasound confirmed low
cardiac output due to external compression of the left atrium with
a subsequent decrease of cardiac inflow. At re-laparotomy on POD
3, the mediastinal collection was drained through a transhiatal
approach using the upper abdominal incision. Immediate reduction
in the patient’s need of vasopressors and inotropic support
was noted as well as a marked decrease in heart rate following
successful drainage. Central venous pressure decreased to 11 mm
Hg. Postoperative cardiac ultrasound confirmed the presence of a
normalized cardiac function. A medium-chain triglyceride (MCT)
diet was started postoperatively.
Netherlands Journal of Critical Care
A rare cause of cardiac failure following transthoracic oesophagectomy
Figure 1. CT images of the thorax (a: transverse, b: coronal) demonstrating
a large mediastinal fluid collection (c) adjacent to the neo-oesophagus and
compressing the left atrium of the heart
Figure 2. Marked reduction of heart rate and improvement of blood
pressure during re-laparotomy. Time 0 represents the beginning of
surgery. Mediastinal drainage (d) occurred 2 to 3 minutes later
180
160
140
120
100
80
60
40
20
d
0
-5
0
HR
BP syst
BP dias
MAP
Due to continuing production of fluid in the upper abdominal
drain (5 to 6 liters of chylous fluid per day), a re-thoracotomy was
performed on POD 14. During surgery, leakage of lymph from the
thoracic duct was noted. The thoracic duct was subsequently ligated,
resulting in a marked improvement of patient recovery.
Discussion
Cases and management of postoperative chylothorax following
oesophagogastrectomy have been frequently presented3,4. However,
to our knowledge, the presence of a chylomediastinum has only been
reported on a few occasions5-8. In addition, significant secondary
haemodynamic consequences were described in only one paper8.
Postoperatively, massive chylous chest tube effusion is suggestive
of thoracic duct injury. Loculated mediastinal collection of chyle
is, however, rare especially following a transthoracic procedure
when the pleural cavity has been opened2. One could assume that
in these cases sufficient fluid drainage is possible through the chest
tubes. Due to the high volume of physiological lymph production,
5
10
15
20
Time
insufficient mediastinal drainage may cause rapidly progressive
mechanical obstruction of vital mediastinal organs. In our case,
decreased left-sided cardiac inflow due to external left atrial
compression resulted in a significant reduction of cardiac output.
Interestingly, obvious improvement of cardiac function occurred
following successful fluid drainage. Intra-operative monitoring
demonstrated a marked subsequent reduction of heart rate and
improvement of blood pressure ( figure 2).
Usually, the presence of a chylothorax can be managed conservatively
by TPN or an MCT diet, occasionally resolving within a few days.
Only persisting chyle leakage necessitates re-operation and ligation
of the thoracic duct. However, different thresholds of continuing
fluid drainage per day that require re-operation are advised9,10. In
general, operative therapy is suggested in case of a daily output of
more than 2 liters after two days of optimal conservative therapy10.
In our case, we observed an uncommonly high production of chyle of
5 to 6 liters per day. In cases of severe haemodynamic consequences,
surgical intervention is urgently required. Some authors recommend
prophylactic ligation of the thoracic duct during initial surgery to
minimize the risk of postoperative morbidity and mortality11. Of
course, mediastinal chyle collections need to be distinguished from
a local abscess or anastomotic leakage. These complications require
a different treatment approach. CT imaging is usually indicated to
differentiate between these causes.
In summary, chyle leakage following oesophagogastrectomy usually
results in pleural effusion. Mediastinal collections may, however,
occur with potentially significant haemodynamic consequences.
Early recognition and subsequent management is essential.
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
Intra-operative recognition of the thoracic duct with or without
prophylactic ligation remains crucial to prevent major complications
due to chyle leakage.
References
1.
Cerfolio RJ. Chylothorax after esophagogastrectomy. Thorac Surg Clin 2006;16:49-52.
2.
Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor-Lewis oesophagectomy: is there a
difference? Aust N Z J Surg 1999;69:187-94.
3.
Paul S, Altorki NK, Port JL, Stiles BM, Lee PC. Surgical management of chylothorax.
Thorac Cardiovasc Surg 2009;57:226-8.
4.
Nair SK, Petko M, Hayward MP. Aetiology and management of chylothorax in adults. Eur
J Cardiothorac Surg 2007;32:362-9.
5.
Lautin JL, Baran S, Dumitrescu O, Sakurai H, Halpern N, Lautin EM. Loculated mediastinal chylothorax resulting from esophagogastrectomy: a case report. J Thorac Imaging
1993;8:313-5.
6.
Khwaja HA, Chaudhry SM. Mediastinal lymphocele following radical esophagogastrectomy. Can J Surg 2008;51:E48-9.
7.
Lavis RA, Barrett JA, Kinsella DC, Berrisford RG. Recurrent dysphagia after oesophagectomy caused by chylomediastinum. Interact Cardiovasc Thorac Surg 2004;3:68-70.
8.
Pera M, Belda J, Vidal O, Rubio M, Grande L. Mediastinal chyloma after esophageal
cancer resection: an unusual complication causing left cardiac failure. J Thorac
Cardiovasc Surg 2002;124:198-9.
9.
Cerfolio RJ, Allen MS, Deschamps C, Trastek VF, Pairolero PC. Postoperative chylothorax. J Thorac Cardiovasc Surg 1996;112:1361-5.
10. Lagarde SM, Omloo JM, Jong K, Busch OR, Obertop H, van Lanschot JJ. Incidence and
management of chyle leakage after esophagectomy. Ann Thorac Surg 2005;80:449-54.
11. Lai FC, Chen L, Tu YR, Lin M, Li X. Prevention of chylothorax complicating extensive
esophageal resection by mass ligation of thoracic duct: a random control study. Ann
Thorac Surg 2011;91:1770-4.
32
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
Netherlands Journal of Critical Care
Accepted January 2013
C ASE RE P OR T
Elevated liver enzymes and renal failure, with a surprising
outcome. Two similar cases
A.E. Boendermaker1, D. Boumans2, R.A.A. van Zanten2, H. Idzerda3, H. van de Hout4, Th.F. Veneman1,2
1
Department of Intensive Care Medicine, Ziekenhuisgroep Twente, Almelo, The Netherlands
2
Department of Internal Medicine, Ziekenhuisgroep Twente, Almelo, The Netherlands
3
Department of Cardiology, Ziekenhuisgroep Twente, Almelo, The Netherlands
4
Department of Radiology, Ziekenhuisgroep Twente, Almelo, The Netherlands
Correspondence
A.E. Boendermaker – e-mail: [email protected]
Keywords - Tamponade, shock, pericardial effusion, kidney failure
Introduction
The prevalence of elevated liver enzymes and acute renal failure is
high and the differential diagnosis of both conditions, separately
and combined, is extensive.1-3 We present two cases of rapidly
increasing liver enzymes in combination with (oliguric) renal failure
with surprising outcomes. In both cases the medical condition was
caused by cardiac tamponade with almost complete restoration of
both renal and liver function after pericardiocentesis. Pericardial
effusion can be a complication of numerous medical conditions, such
as malignancies, trauma, metabolic disorders and infections.4-6 In
some cases, the accumulation of pericardial fluid results in cardiac
tamponade with subsequent cardiogenic shock. This life-threatening
condition can then lead to multiple organ dysfunction and, unless
treated promptly, even to death.7,8 Both described cases of cardiac
tamponade underline the necessity of a thorough search for the
underlying cause of elevated liver enzymes and acute renal failure.
Case A
A previously healthy 49-year-old man (patient A) was admitted
to our intensive care unit (ICU) with signs of haemodynamic
impairment, elevated liver enzymes and renal failure.
Several hours before admission to our ICU, the patient presented at
the emergency department (ED) after an episode of transient loss
of consciousness lasting a few seconds. His medical history was
unremarkable. He complained of a slowly progressive cough with
shortness of breath during exercise that he had had for a few months.
During the few days prior to admission, he had experienced a sharp chest
pain during coughing; this was accompanied by vomiting and a fever
up to 38.5 o Celsius. His general practitioner had prescribed amoxicillin
under the clinical suspicion of pneumonia. Furthermore, his body
weight had been stable and his appetite was unchanged. In addition, he
admitted nicotine abuse estimated at approximately 25 pack years.
Physical examination performed by the ED resident showed a pale,
slightly overweight man with a normal body temperature (37.2 o
C), a blood pressure of 90/67 mmHg with a heart rate 116 bpm, a
respiratory rate of 30 breaths per minute and a peripheral oxygen
saturation of 99% without additional oxygen. Heart sounds were
normal and no murmurs or pericardial rub were heard. An expiratory
wheeze and inspiratory crackles were noticed in the lower lung fields
bilaterally. Examination of the abdomen was unremarkable. There
were no signs of neurological pathology. Determination of jugular
vein distention (JVD), Kussmaul’s sign and pulsus paradoxus could
at this point have directed towards obstructive cardiogenic shock.
Unfortunately, none of these diagnostic tests were performed on
admission.
Laboratory investigation revealed normocytic anaemia, acute
renal failure, elevated liver enzymes and markers of inflammation
(table 1). The chest X-ray ( figure 1) showed a small consolidation
of the left posterobasal segment of the lung, cardiac enlargement
(cor thorax ratio (CTR) of 0.59) and loss of the aortopulmonary
window. The electrocardiogram (ECG) showed a sinus rhythm
Table 1. Laboratory data from case A
Case A
Units
At admission At admission 22 days after
admission
ICU
ED
29-11-2011
07-11-2011
06-11-2011
Haemoglobin
mmol/L
7.4
6.8
C-reactive protein
mg/L
186
190
7.8
22
Leucocyte count
*10^9/L
15.9
17.5
9.5
Bilirubin total
μmol/l
5
22
19
Alkaline phosphatase U/L
108
112
116
Gamma GT
91
88
40
U/L
ASAT
U/L
1.568
2.871
10
ALAT
U/L
2.496
3.968
27
Lactate
dehydrogenase
U/L
3.607
4.749
184
Creatinine
μmol/l
184
248
95
Urea
mmol/L
20
26
8.3
Estimated GFR
mL/min
34
24
73
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
33
Netherlands Journal of Critical Care
Figure 1. Case A, Posteroanterior and lateral chest X-ray showing a small
consolidation of the left posterobasal segment of the lung, cardiac enlargement and loss of the aortopulmonary window
Figure 2. ECG Case A
without microvoltages or electrical alternans, and abnormal
concavely elevated ST-segments in V3-V6, II, III and a VF with slight
depression of the PRa-interval ( figure 2).
Patient A was admitted to the internal medicine ward with the
preliminary diagnosis of a severe sepsis with signs of organ failure due
to a community acquired pneumonia of the left lung. He was treated
accordingly with fluid resuscitation and broad-spectrum antibiotics.
Despite all efforts the patient’s condition deteriorated. Twelve hours
after admission he was transferred to the ICU because of refractory
hypotension (95/60 mmHg), signs of tissue hypoxia and progressive
multiple organ dysfunction expressed by a marked increase of liver
enzymes and progressive oliguric renal failure (table 1).
The JVD was elevated and heart sounds were muffled. Intra-arterial
blood pressure measurement showed a pulsus paradoxus.
Abdominal ultrasound showed venous congestion within the portal
vein, inferior vena cava and liver veins, with normal directions of
blood flow, and a thickened gall bladder wall. The transthoracic
echocardiogram revealed a normal left ventricular ejection fraction
and a tricuspid aortic valve with normal morphology and function.
It showed circular pericardial effusion of apical 3.5 cm and of 4.4 cm
at the right ventricle with a swinging heart. There were paradoxal
septal movements and compression of the right atrium consistent
with pericardial tamponade. An emergency pericardial drainage
was performed. Within 15 minutes after pericardial drainage, the
34
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
patient’s haemodynamic parameters improved and stabilized. In the
following 12 hours, approximately 900 cc of sanguinolent pericardial
fluid was drained. During the next few days, the liver enzymes, renal
function and diuresis gradually improved (table 1).
Pathologic investigation of the pericardial fluid revealed the presence
of atypical cells, suspicious for metastases of adenocarinoma.
The subsequent diagnostic work-up included a CT-scan of the
abdomen and chest, and a bronchoscopy with lavage and biopsies.
These studies confirmed the diagnosis of a cT1aN3M1a, stage IV
adenocarcinoma of the lung without hepatic metastases. Treatment
with palliative chemotherapy was initiated.
Case B
A 61-year-old man (patient B) presented at the ED with rapidly
developing shortness of breath, a non-productive cough and
peripheral oedema. His medical history revealed a viral pericarditis
12 years previously, a stent-graft reconstruction of the abdominal
aorta 11 years previously, type 2 diabetes and chronic kidney disease
stage III related to diabetic nephropathy. In addition, he admitted
nicotine abuse estimated at approximately 15 pack years.
Physical examination showed a dyspnoeic patient with a respiratory rate
of 24 breaths per minute and peripheral oxygen saturation of 96 % while
breathing room air. The patient’s blood pressure was 107/73 mmHg
with a heart rate of 80 bpm and the body temperature was normal (36
o
C). Chest auscultation revealed normal heart sounds without a heart
murmur or pericardial rub, and mild to moderate bilateral inspiratory
crackles. Furthermore, pitting oedema was seen in both legs. The
presence of an increased JVD or a pulsus paradoxus was not tested.
Laboratory investigation at admission showed an acute on chronic
renal failure, normocytic anaemia and elevated C-reactive protein
(CRP) and NT-proBNP (table 2). The chest X-ray revealed a right
sided retrocardial consolidation suggestive of pneumonia without
significant cardiac enlargement (CTR of 0.50) ( figure 3). The ECG
showed a sinus rhythm with flattened ST-segments inferolateral and
criteria for microvoltages were approximated but not met ( figure 4).
Table 2. Laboratory data from case B
Case B
Units
At admission At admission 5 days after
admission
CCU
ED
12-12-2011
07-12-2011
05-12-2011
Haemoglobin
mmol/L
7.1
6.4
C-reactive protein
mg/L
56
67
6.3
51
Leucocyte count
*10^9/L
8
8.3
7.9
Bilirubin total
μmol/l
16
9
11
Alkaline phosphatase U/L
146
-
125
Gamma GT
81
117
77
U/L
ASAT
U/L
32
3.802
61
ALAT
U/L
33
2.449
396
Lactate
dehydrogenase
U/L
258
3.161
239
Creatinine
μmol/l
216
353
112
Urea
mmol/L
13.7
25.4
7.5
Estimated GFR
mL/min
27
15
58
NT-proBNP
pmol/L
85
110
110
Netherlands Journal of Critical Care
Elevated liver enzymes and renal failure, with a surprising outcome. Two similar cases
Figure 3. Case B, Posteroanterior and lateral chest X-ray showing a right
sided retrocardial consolidation suggestive of a pneumonia without significant cardiac enlargement
Figure 4. ECG Case B
with compression of the right atrium consistent with pericardial
tamponade. An emergency pericardial drainage was performed.
After drainage of a total 800 ml serosangulent pericardial fluid, the
patient stabilized haemodynamically. During the next few days, his
liver enzymes and renal function and diuresis improved gradually.
Pathologic investigation of the pericardial fluid revealed the presence
of adenocarcinoma-cells suspicious for metastases originating in the
lung. CT-scan of the thorax and abdomen revealed a small mass in the
apex of the left lung and bilateral pleural effusion. Thoracocentesis
was performed showing malignant cells as well. This confirmed
the diagnosis of adenocarcinoma of the lung with carcinomatous
pericarditis and pleuritis (stage IV disease). Due to several
complications in the course of the disease, palliative chemotherapy
could not be initiated and the patient died four months later.
The preliminary diagnosis was a community acquired pneumonia
combined with right and left sided cardiac decompensation
in presence of a previously unknown history of heart failure.
Treatment was started accordingly with amoxicillin and intravenous
administration of furosemide.
The next day patient B became hypotensive and oliguric. Furosemide
infusion was ceased and intravenous volume resuscitation was
initiated. As a result, the blood pressure gradually normalized
but despite this the patient’s condition deteriorated. Physical
re-examination revealed increased bilateral lung crackles and
peripheral oedema and elevated JVD, suggesting progressive heart
failure for which furosemide infusion was restarted at a higher dose.
During the next few hours, the patient became anuric, hypotensive
and his respiratory distress progressed. Laboratory investigation
showed a metabolic acidosis with respiratory compensation,
dramatically increased parenchymal liver enzymes, further decrease
in renal function and stable CRP (table 2). The chest X-ray (bed-side
anterior posterior projection) now showed enlargement of the
cardiac silhouette and the ECG remained unchanged. The patient
was transferred to the Cardiac Care Unit (CCU).
Emergency transthoracic echocardiography had limited visualization,
but showed a normal left ventricular ejection fraction and circular
pericardial effusion, apical of 3.2 cm and of 3.1 cm over the right
ventricle. Paradoxal septal movement was seen in combination
Discussion
The most common disease of the pericardium is acute pericarditis.4-6
Major manifestations are a typical sharp retrosternal chest pain that
is position dependent and intensifies on inspiration, a pericardial
friction rub, typical ECG changes and pericardial effusion (PE).
PE can also found by chance in asymptomatic patients during
echocardiography. As a result of inflammation of the pericardium,
PE can develop after an acute myocardial infarction, cardiac surgery,
or as a consequence of autoimmune disease, trauma, metabolic
disorders, infection and malignancies. Most cases are presumed to
have a viral or autoimmune aetiology and follow a benign course.4-6
PE can lead to impairment of cardiac function and tamponade
as a rare complication.7-8 Cardiac tamponade with subsequent
obstructive cardiogenic shock, leading to hepatocellular damage and
renal dysfunction, amongst other signs of end organ dysfunction,
occurs in approximately 2 out of 10,000 people per year.5
Both pericarditis and cardiac tamponade are clinical diagnoses.
They can, however, be supported by the results of additional
diagnostics.4,6,8,10 As the pericardial sac is filled with excessive fluid
a compressive pericardial syndrome occurs, in which especially
right ventricular filling pressures are increased, diastolic filling
of the heart is reduced, and the interventricular septum deviates
towards the left ventricle impairing cardiac output.7-8,10 The septum
deviation causes a pulsus paradoxus, in which the physiologic
decrease in systolic blood pressure and pulse wave amplitude during
inspiration become abnormally large.7-8,11 Rapid accumulation of
PE leads to Beck’s triad of systolic hypotension, increased JVD and
muffled heart sounds. The presence of Kussmaul’s sign, which is the
paradoxically increased distension of the jugular vein at inspiration,
is difficult to determine and commonly only present in tamponade
when a constrictive disease exists.4-8
PE can be suspected on a chest X-ray and by changes in the
ECG. An enlarged cardiac silhouette, especially with loss of the
aortopulmonary window supports any suspicion of PE with more
than 200 mL of fluid. The ECG can show the following abnormalities
divided into 4 stages based upon progression of pericarditis: diffuse
concavely elevated or flattened ST-segment deviations or diffuse
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
35
Netherlands Journal of Critical Care
T-wave inversions, PR-depression, and microvoltages with or without
electrical alternans, due to PE.7-8 Echocardiography is a simple,
reliable, non-invasive and commonly used modality in the standard
work-up of PE.10
In both patients described here, cardiac tamponade due to malignant
pericarditis was the first presentation of disseminated lung cancer.
An estimated four to seven percent of patients with pericarditis
without known malignancy are ultimately diagnosed with malignant
pericarditis (MP) as first presentation. In patients with a known
malignancy, pericardial involvement occurs in one to twenty percent.
The incidence of MP is the highest in lung carcinoma, followed by
carcinoma of the breast, oesophagus, melanoma and lymphoma.5-6,9
Multi organ dysfunction expressed by acute kidney failure
and elevated parenchymal liver enzymes preceded (refractory)
haemodynamic instability in both cases. Circulatory shock in
definition is haemodynamic failure to provide oxygen for end
organ aerobic function. Three major phenomena of shock are
hypotension, tachycardia and signs of end organ dysfunction. Due
to compensatory mechanisms, hypotension can be a late sign of
ongoing shock, as it was in our patients.7,11
The presence of acute renal failure in general is related to
hypoperfusion, the so-called pre-renal kidney failure. This is generally
due to hypotension or decreased cardiac output as a consequence
of hypovolaemia, sepsis, cardiac failure or vasodilatation.1,11 In both
cases, the gradual improvement of kidney function after pericardiocentesis supports the hypothesis that the cause was directly related
to renal hypoperfusion as a result of the cardiac tamponade.1,7,11
Pericardial effusion as the cause of acute renal failure is uncommon.
The literature is limited to only several case reports.12-14 Cardiac
tamponade as a cause of the combination of acute renal failure and
elevated liver enzymes, as in our patients, is also a rare finding.14
Increased liver enzymes can be caused by viral, toxic, or ischemic
hepatitis. Hypoperfusion of the liver results in ischemia with
hepatocellular damage which can be detected by a rapid rise in
serum aminotransferase levels associated with an early massive rise
in lactate dehydrogenase (LDH). Generally, the serum bilirubin level
and phosphatase levels rise far less and hepatic synthetic function
usually remains normal or is only mildly impaired.2-3 Without
ongoing haemodynamic instability, the biochemical markers
usually return to normal. In addition to hypoperfusion of the liver,
congestion of blood (congestive hepatopathy) due to heart failure or
obstruction of heart function, can play a role in the aetiology of the
elevated liver enzymes.2-3,14
Different causes of the elevated liver enzymes, hepatic ischemia or
congestive hepatopathy, could possibly explain the difference in
elevation of serum aminotransferase levels and ASAT/ALAT ratio
between patients A and B. Also, a combination of both conditions,
with a different contribution of each cause, is possible in these
patients. However, laboratory findings in both patients are highly
suggestive of an ischemic cause since congestive hepatopathy is most
commonly characterized by marked elevation of cholestatic liver
enzymes and much lower levels of aminotransferase.2-3
36
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
When PE has been confirmed, a subsequent diagnostic and
therapeutic pericardiocentesis can be performed either blinded or by
means of ECG, echocardiographic, CT or fluoroscopic guidance.4-7,10
In cases of cardiac tamponade, pericardiocentesis is instantly
required to prevent further life-threatening complications and even
death.4-7 In patients with suspected malignancy, tuberculosis or
purulent pericarditis, a pericardiocentesis should be performed as
diagnostic measure, due to the necessity of specific therapy.4-7
In the cases described here, the initial evaluation and additional
investigation either did not point directly to, or were not recognized
as signs of the presence of pericardial effusion with cardiac
tamponade. Both patients were initially considered to be suffering
from hypoperfusion of the liver and kidneys due to severe pulmonary
sepsis. However, in retrospect, misinterpretation of physical signs and
additional diagnostics (ECG, chest X-ray and laboratory investigation)
lead to the incorrect diagnosis on admission and eventually delayed
the diagnosis of cardiac tamponade. This underlines the need for
more awareness of PE as a cause of haemodynamic instability.
In conclusion, we have described two rare cases in which the presence
of acute renal failure and elevated liver enzymes are the result of PE
with cardiac tamponade as a consequence of underlying malignant
disease. Simultaneous development of kidney and liver failure should
increase the suspicion of the presence of shock.1-3,11 Moreover, more
rare forms of shock should be considered and sought for. Awareness
amongst clinicians that signs of end organ dysfunction can precede
haemodynamic shock, due to compensatory mechanisms, is
necessary for prompt treatment of the underlying cause.
References
1.
Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet. 2005;365(9457):417-30.
2.
Birrer R, Takuda Y, Takara T. Hypoxic hepatopathy: pathophysiology and prognosis.
Intern Med. 2007;46(14):1063.
3.
Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR, Hypoxic hepatitis:
Clinical and hemodynamic study in 142 consecutive cases. Medicine 2003; 82(6):392-406
4.
Sagristà-Sauleda J, Sarrias Mercé A, Soler-Soler J. Diagnosis and management of pericardial effusion. World J Cardiol 2011; 3(5): 35-143
5.
Jacob R, Grimm RA. Pericardial disease. Carvey WD ed. Cleveland Clinic: Current clinical
medicine. 1st ed. Philadelphia, Saunders Elsevier, 2008, chap 2
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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
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Lestuzzi C. Neoplastic pericardial disease: Old and current strategies for diagnosis and
management. World J Cardiol 2010; 2(9): 270-279
10. Merce J, Sagrista-Sauleda J, Permanyer-Miralda G, Evangelista A, Soler-Soler J.
Correlation between clinical and doppler echocardiographic findings in patients with
moderate and large pericardial effusion: implications for the diagnosis of cardiac tamponade. Am Heart J 1999;138: 759-764.
11. Abboud, FM. Pathophysiology of hypotension and shock. In: Hurst, JW (Ed), The heart,
New York, McGraw-Hill, 1982. p. 452
12. Saklayen M, Anne VV, Lapuz M. Pericardial effusion leading to acute renal failure: two
case reports and discussion of pathophysiology. Am J Kidney Dis 2002;40: 837-841
13. Gluck N, Fried M, Porat R, Acute renal failure as the presenting symptom of pericardial
effusion, Intern Med 2011; 50:719-721
14. Khan R, Gessert C, Bockhold S, Pericardial effusion presenting with anuric acute renal
failure and hepatocellular damage, J Hosp Med 2009;4:68-70
Netherlands Journal of Critical Care
Editorial Board of the Netherlands Journal of Critical Care
A.B. Johan Groeneveld, Editor in
Chief
Dept. of Intensive Care Medicine
Erasmus Medical Center
Rotterdam
PO Box 2040
3000 CA Rotterdam
Jan Bakker, Section Editor
Hemodynamics
Dept. of Intensive Care Medicine
Erasmus Medical Center
Rotterdam
PO Box 2040
3000 CA Rotterdam
Alexander Bindels, Section Editor
Endocrinology
Dept. of Internal Medicine
Catharina Hospital
Michelangelolaan 2
5623 EJ Eindhoven
Bert Bos, Section Editor
Pediatrics
Department of Pediatrics
Academic Medical Center
University of Amsterdam
Meibergdreef 9
1105 AZ Amsterdam
Frank Bosch, Section Editor
Imaging
Dept. of Internal Medicine
Rijnstate Hospital
PO Box 9555
6800 TA Arnhem
Wolfgang Buhre, Section Editor
Anesthesiology
Dept. of Anesthesiology
University Medical Center Utrecht
PO Box 85500
3508 GA Utrecht
Heleen Oudemans-van Straaten,
Section Editor Nephrology
Dept. of Intensive Care Medicine
VU University Medical Center
PO Box 7057
1007 MB Amsterdam
Hans van der Hoeven, Section Editor
Mechanical Ventilation
Dept. of Intensive Care Medicine
Radboud University Nijmegen
Medical Centre
PO Box 9101
6500 HB Nijmegen
Peter Pickkers, Section Editor
Sepsis and inflammation
Dept. of Intensive Care Medicine
Radboud University Nijmegen
Medical Centre
PO Box 9101
6500 HB Nijmegen
Can Ince, Section Editor
Physiology
Dept. of Physiology
Academic Medical Center
University of Amsterdam
Meibergdreef 9
1105 AZ Amsterdam
Arjen Slooter, Section Editor
General
Dept. of Intensive Care
University Medical Center Utrecht
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3508 GA Utrecht
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Scoring and quality assessment
Dept. of Intensive Care Medicine
Leiden University Medical Center
P.O. Box 9600
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Section Editor
Hemostasis and Thrombosis
Dept. of Intensive Care
Academic Medical Center
University of Amsterdam
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General
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Gelre Hospital, location Lukas
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General
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University Medical Center
Groningen
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Dept. of Neonatal Intensive Care
Emma Children’s Hospital,
Academic Medical Center
University of Amsterdam
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1105 AZ Amsterdam
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Dept. Of Intensive Care Medicine
University Medical Center Utrecht
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Neurology
Dept. of Intensive Care Medicine
Medical Center Leeuwarden
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Dept. of Intensive Care Medicine
University Medical Center
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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
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CHU Liege – Domaine Universitaire
Liege, Belgium
Yasser Sakr
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Intensive Care
Friedrich-Schiller University Hospital
Jena, Germany
Hannah Wunsch
Dept. of Anaesthesia
New York Presbyterian Columbia
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Netherlands Journal of Critical Care
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Background and objectives
State the precise primary objective of the review. Indicate whether the review
emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention
and include information about the specific population, intervention, exposure,
and tests or outcomes that are being reviewed.
Design
Describe the design of the study indicating, as appropriate, use of randomization,
blinding, gold standards for diagnosis test and temporal direction (retrospective
or prospective).
Methods and results
Summarize here accurately, although concisely, summarize how you will
proceed in learning the answer to the objective. Also provide the main
outcomes of the study.
Conclusions
The conclusions and their applications (clinical or otherwise) should be
clearly stated, limiting interpretation to the domain of the review.
Original articles/reviews
Articles should describe original investigations that have been brought to an
acceptable degree of completion. Articles should not exceed 3000 words. The
editorial board also welcomes review papers which should also not exceed
3000 words.
The manuscript should be clear in outline (with subheadings) for maximum
clarity. Only a limited number of figures (coloured figures are encouraged
without extra charge) and tables may be included; double presentations in
the form of figures and tables should be avoided. The text should follow
the IMRAD format and contain an abstract, introduction, materials and
methods, results, discussion section and references. The abstract should
not exceed 250 words and should be structured. Authors should provide
a minimum of three keywords, a running title, and list not more than 30
references for original articles and 70 references for review articles.
Case Reports
The text of a case reports should also include an abstract, introduction, case
report/case history, discussion section, legends for figures and references. The
abstract should not exceed 250 words and may be unstructured. The journal
kindly requests authors to provide a minimum of three keywords and to list
not more than 30 references.
Clinical Images
A clinical image should contain one or two pictures and a short case history,
and should preferably not be referenced. The legend to the image should
succinctly present relevant clinical information, including a short description
of the patient’s history, relevant physical and laboratory findings, clinical
course, response to treatment (if any), and condition at last follow-up. The
journal kindly requests authors to provide a minimum of three keywords.
General information
The original manuscript and two copies (or electronic file) are to be submitted
to the editor in chief at the NVIC office by e-mail (see below). The manuscript
must be accompanied by a cover letter stating the following: the complete
mailing address, e­mail address, telephone number and fax number of the
corresponding author, and if it is a re­submission, the previous Neth J Crit
Care number and year. Receipt of the manuscript will be acknowledged
in writing within 14 days. If this is not the case, authors are requested to
check. The language of the journal is British English. Authors who are unsure
of proper English usage will have their manuscript checked by someone
proficient in the English language.
Layout
Paragraphs starting immediately under headings and subheadings should
begin at the left margin. Subsequent paragraphs should be indented. All text
should be double spaced, on one side of the paper and with a wide margin.
The manuscript pages, including references and legends, must be sequentially
numbered throughout.
Tables
Tables are to be numbered independently of the figures with Arabic numbers,
with headings and kept separate from the text.
Figures
Figures must also be numbered with Arabic numbers and kept separate from
the text. Legends must be given on a separate sheet. Schematic line drawings
are preferred. Figures already published elsewhere cannot usually be included,
except in survey articles. Colour figures can be published. Short, clear legends
make additional description in the text unnecessary. The desired placement
of figures and tables can be marked in the margins of the manuscript sheets.
Figures should be provided in electronic format TIFF or better.
References
Only articles cited in the text are to be listed. They are to be arranged in order
of appearance in the text …. and numbered consecutively. Only the reference
number should appear in the text. Include all author names (unless there are seven
or more, in which case abbreviate to three and, add ‘et al.’), and page numbers.
Article in journals: Calandra T, Cometta A. Anti­biotic therapy for gram­­negative
bacteremia. Infect Dis Clin North Am 1991;5:817-34
Books (-sections): Thijs LG. Fluid therapy in septic shock. In: Sibbald WJ, Vincent
J­L (eds). Clinical trials for the treatment of sepsis. (Update in intensive care and
emergency medicine, volume 19). Berlin Heidelberg New York, Springer, 1995,
pp 167-190. Conference Meetings: Rijneveld AW, Lauw FN, te Velde AA, et al.
The role of interferon­gamma in murine pneumococcal pneumonia.
38th Interscience Conference on Antimicrobial Agents and Chemotherapy
(ICAAC). San Diego, Ca., 1998, pp 290
Copyright
Copyright ownership is to be transferred in a written statement, which must
accompany all manuscript submissions and must be signed by all authors.
The agreement should state, “The undersigned authors transfer all copyright
ownership of the manuscript (title of article) to the Netherlands Journal of
Critical Care. 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: [email protected]
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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Netherlands Journal of Critical Care
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. Staphylo­coccus 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.
40
N e th j cr it c ar e – vo lume 17 – n o 1 – february 2013
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
ALI
ARDS
APACHE
BIPAP
CCU
COPD
CPAP
CT
ECG
ECMO
EEG
ELISA
ETCO2
HDU
HIV
IC
ICU
IM
INR
IPPV
IV
MAP
MODS
MRI
PACU
PEEP
PET
SARS
SIRS
SOFA
SPECT
TIA
TRALI
acquired immunodeficiency syndrome
acute lung injury
adult respiratory distress syndrome
acute phyisology and chronic health evaluation
biphasic positive airways pressure
coronary care unit
chronic obstructive pulmonary disease
continuous positive airway pressure
computerized or computed tomography
electrocardiogram
extracorporeal membrane oxygenation
electroencephalogram
enzyme-linked immunosorbent assay
end-tidal carbon dioxide
high dependency unit
human immunodeficiency virus
intensive care
intensive care unit
intramuscular
international normalized ratio
intermittent positive pressure ventilation
intravenous
mean arterial pressure
multiorgan dysfunction syndrome
magnetic resonance imaging
post anaesthesia care unit
postive end expiratory pressure
positron emission tomography
severe adult respiratory syndrome
systemic inflammatory response syndrome
sequential or gan failure assessment
single-photon emission ct
transient ischemic attack
transfusion-related acute lung injury