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Founded 1897 • Vol. CXVIII
Romanian Journal of
New series • No. 1/2015
Military
Medicine
REVISTA DE MEDICINĂ MILITARĂ
• The Romanian Military Medical System transformation strategy
• The diagnosis of sepsis using POCT in the Emergency Department. Medical and legal
implications
• Romanian sanitary system assisted by knowledge management
• Spondylodiskitis, etiology, diagnosis and treatment
• A cholestatic syndrome may be a surprising cause of medical error
• Capsule endoscopy
• Paraneoplastic Cushing’s syndrome in a patient with multiple tumors. Case report
• Median arcuate ligament syndrome (Dunbar syndrome). Case report
• October 2015, National Congress on Military Medicine
www.amfmr.ro
Editorial Board of Romanian Journal of Military Medicine
Under the patronage
Romanian Association of Military Physicians and Pharmacists
Honorary Editor
Victor Voicu MD, PhD
Editor-in-Chief
Daniel O. Costache MD, PhD, MBA
Dragoș Cuzino MD, PhD
Executive Editor
Florentina Ioniță Radu MD, PhD, MBA
Associate Editors
Mariana Jinga MD, PhD, MBA
Silviu Stanciu MD, PhD
Advisory Board
Dan Mischianu MD, PhD
Dragoș Vinereanu MD, PhD, EC, FESC
Redactors
Doina Baltaru MD, PhD – Cluj Napoca
Ovidiu Bratu MD, PhD – Bucharest
Ciprian Constantin MD, PhD – Balkan Military Medical Committee
Florin Miclea MD, PhD – Timișoara
Constantin Ștefani MD – Bucharest
Editorial Assistants
Dan Dobre MD
Cristina Solea
Claudia Țiglea
Technical Secretary
Oana Ciobanu
International Editorial Board
Natan Bornstein (Israel)
Raluca Ciornei MD (UK)
Mihai Coculescu MD, PhD (Romania)
Cris S. Constantinescu MD, PhD, FRCP (UK)
Daniel Dănilă MD, PhD (USA)
Mihai Moldovan (Denmark)
Ioan Opriș BS, PhD (USA)
Gerard Roul MD, PhD (France)
Adrian Săftoiu (Denmark)
Ioanel Sinescu MD, PhD (Romania)
Ionescu Târgovişte MD, PhD (Romania)
Radu Ţuţuian (Switzerland)
Victor Voicu MD, PhD (Romania)
Raluca S. Costache MD, PhD, MBA
Mircea Diculescu MD, PhD
Cosmin Dobrin PhD, MBA
Gabriela Droc MD, PhD
Silviu Dumitrescu MD, PhD
Cristian Gheorghe MD, PhD
Mihai E. Hinescu MD, PhD
Codorean Ioan MD, PhD
Florentina Ioniţă Radu MD, PhD
Mariana Jinga MD, PhD
Viorel Jinga MD, PhD
Ruxandra Jurcuţ MD, PhD
Dan Mischianu MD, PhD
Ovidiu Nicodin MD, PhD
Tudor Nicolaie MD, PhD
Emilian A. Ranetti MD, PhD
Corneliu Romanițan MD, PhD
Carmen Adella Sîrbu MD, PhD, MPH
Sorin Țiplică MD, PhD
Dragoş Vinereanu MD, PhD, EC, FESC
Scientific Publishing Committee
Adrian Barbilian MD, PhD
Anda Băicuş MD, PhD
Cristian Băicuş MD, PhD
Andra Bălănescu MD, PhD
Silviu Brad MD, PhD
Daciana Brănișteanu MD, PhD
Marian Burcea MD, PhD
Sofia Colesca PhD, MBA
Gabriel Constantinescu MD, PhD
Dan Corneci MD, PhD
REDACȚIA
Str. Institutul Medico-Militar nr. 3-5, sector 1, București, R-010919, Tel/fax 021.321.5386
Romanian Journal of Military Medicine (RJMM) is included in Romanian College of Physicians Medical Publications Index and
credited with 5 CME credits. RJMM is recognized by CNCSIS in the category C.
www.amfmr.ro
Romanian Journal of Military Medicine, vol. CXVIII, New Series, No 1/2015
ISSN 1222-5126
Vol. CXVIII • New Series • No. 1/2015 • Romanian Journal of Military Medicine
RJMM
Romanian Journal of Military Medicine
Founded 1897 • Vol. CXVIII
New Series • No. 1/2015
Edited by the Romanian Army Medical Directorate and Romanian Association of Military Physicians and Pharmacists.
Contents
EDITORIAL
Constantin Ștefani, Daniel Aron
 The Romanian Military Medical System transformation strategy
3
REVIEW ARTICLE
Bogdan C. Teușdea, Sebastian Dogaru, Florentina Ioniță Radu
 The diagnosis of sepsis using POCT in the Emergency Department. Medical and legal
implications
5
SYSTEMATIC REVIEWS, META-ANALYSIS
Daniel O. Costache, Cosmin Dobrin, Ruxandra Dinulescu, Laura Voicu, Raluca S. Costache
 Romanian sanitary system assisted by knowledge management
19
Cristian Bănică, Ion Ştefan
 Spondylodiskitis, etiology, diagnosis and treatment
25
ORIGINAL ARTICLES
Mihăiță Pătrășescu, Petruț Nuță, Raluca S. Costache, Săndica Bucurică, Bogdan Macadon, Andrada
Popescu, Mariana Jinga, Florentina Radu Ioniță
 A cholestatic syndrome may be a surprising cause of medical error
28
EDUCATION AND IMAGING
Raluca S. Costache
 Capsule endoscopy
33
CLINICAL PRACTICE
Adina Mazilu, Mona Gheorghiu, Mădălina Mușat, Narcis Tănase, Răzvan Petrescu, Adrian Ciuche, Augustin
Tudose, Florina Vasilescu
 Paraneoplastic Cushing’s syndrome in a patient with multiple tumors. Case report
34
Crina Laslo, Anamaria Puiu, Ștefan Mardale, Iulian Raus, Cosmin Căpușan
 Median arcuate ligament syndrome (Dunbar syndrome). Case report
38
VARIA
National Congress on Military Medicine
41
ADMINISTRATIVE ISSUES
Guidelines for authors
42
1
2
EDITORIAL
The Romanian Military Medical System
transformation strategy
Constantin Ștefani, Daniel Aron
Facing the Romanian military sistem changeover
determined by the affiliation to international security
alliances and by the necessity to adapt it to global
and regional security environment in order to be able
to cope with actual threats and risks, the military
medical system should be adapted in order to
become efficient in providing medical support in
operations and in the same time to provide medical
care for soldiers and their families.
The military medical system transformation strategy
represents the basic document which reflects the
picture of desired end state showing the roads to get
there.
The major challenge
harmonizing process
operational NATO laws
interoperability is one of
Security Strategy.
is represented by the
between national and
and rules, because the
the main tasks in National
Excellent trained medical personnel, establishing the
standards of medical logistic support and procedures,
the adapting process of the medical structures are
the key points of this strategy, being in the same time
the main courses of action.
Having the medical military system as a picture on
the wall, it can be described as a dual functional
mechanism, depending on its acting conditions:
operational medicine providing medical support in
operations, and stationary medicine providing
medical care in peace time. In order to be efficient,
the
military
medical
system should have the
following features: to be
Colonel CONSTANTIN ŞTEFANI
complete
from
the
battlefield through all stage
Chief of Medical Directorate,
Ministry
of National Defence,
off care, to be selfRomania
sustained, to be deployable
with troops, and to be able for integration in
multinational operational medical system and in the
national civilian medical system as well.
The two main missions of the medical military system
are preservation of health and the second, treating
casualties and healing ill soldiers and their families.
During all the actions, in order to accomplish both
previous missions, the following general principles
will be applied: the best medical practice, continuity
of care, the interest of patient and the importance of
the mission. This complex system works with
excellent trained medical personnel in military
medical educational system and combat medical
training centers, having a proper medical logistics. For
that, beside regulation domain, a significant financial
effort will be needed. Moreover, a coordinated long
time term financial strategic program to provide
proper medical supplies will solve logistical issues in
medical military system. Medical research and
standardization processes are the engines to progress
of all parts of the military medicine. A dedicated and
efficient command-control system, working under
well defined procedures will integrate medical
3
considerations in the complex military mechanism.
The implementation plan will have the Medical
Directorate in the center of the process, being
involved from the highest to the smallest level of the
medical support, using the military hospitals and the
others subordinate structures to coordinate medical
activities and to optimize the whole process.
Eventually, in the operational medicine domain every
battalion level unit will be supported by a ROL 1
medical facility, every brigade level unit by a ROL 2
medical facility, all military hospitals except Central
Universitary Emergency Military Hospital will fulfill
the ROL 3 medical facility criteria, and Central
Universitary Emergency Military Hospital will be the
Romanian ROL 4 medical facility.
An important goal in the development of military
hospitals will be represented by involving them in the
training activities in their area of responsibility, so six
military hospitals near the main ranges will have
specific capabilities in order to be able to solve all
medical situations with can be a result of high risk
activities.
4
The medical military system will be fully integrated in
the operations at all level by a professional and
dedicated medical planning system which is the key
of an effective medical support.
In the stationary medical domain, the target is to
grow up the quality of the medical act from primary
medicine to hospitals, in the mean time to prioritize
the access of soldiers and their families to military
medical system. Another important goal is to
optimize the procedures for soldiers to get their legal
rights regarding the payment for medical services and
pharmaceutically services.
Last but not least, the military medical system should
become the most available medical solution for
soldiers and their families on the free medical
services market.
The military medical system is a special medical
system serving a special structure which is Romanian
Military Force.
REVIEW ARTICLE
Article received on October 12, 2014 and accepted for publishing on November 21 2014.
The diagnosis of sepsis using POCT in the Emergency
Department – Medical and legal implications
Bogdan C. Teușdea1, Sebastian Dogaru1, Florentina Ioniță Radu1,2
Abstract: Sepsis, severe sepsis and septic shock are some of the most serious affections which
threaten the lives of the patients who come to the Emergency Department and which require fast
treatment because the more severe the sepsis was, the higher the mortality, up to 50% higher in
severe sepsis. That is why, at present, the 2013 Guides of Surviving Sepsis Campaign recommend
that the potential source of infection should be confirmed as soon as possible, in the first 6 hours
since the patient arrived in the Emergency Unit if possible, moreover the large spectrum antibiotics
therapy must be administered in one hour after the severe sepsis or the septic shock were
identified. That is why the identification of these patients at risk is very important and this
identification can only be made using POCT type devices.
This type of devices has the capacity to make precise determinations, in a short time (15-17
minutes), using minimum quantities of integral blood, without using test tubes, sepsis biomarkers
and other additional material. The possibility to fast diagnose sepsis, offers the doctors from the
Emergency Department, the capacity to fast initiate an antibiotic treatment, to hospitalize the
patient and at the same time, it gives them the certainty that they did not miss the sepsis
diagnosis, thus avoiding the situation of malpractice. A preliminary study, regarding the sepsis
biomarkers, which took place in the Emergency Unit of University Central Emergency Military
Hospital, is also presented within this article.
Keywords: sepsis, POCT, Emergency Department.
INTRODUCTION
Sepsis, severe sepsis and septic shock are some of the
most common affections which are handled in the
Emergency Departments and in the intensive therapy
sections and they still represent a major cause of
morbidity and mortality for critic patients despite the
use of respiratory and cardiovascular support,
modern antibiotics and resuscitation therapy. In
compliance with the newest guides published, fast
identification and the speed of implementation of an
adequate treatment in the first hours after the
patient came to the Emergency Department can
influence radically the prognostic of septic patients,
facts which determined the concentration on
biomarkers for precocious diagnosis, risk stratification
and the assessment of these patients’ prognostic.1
Sepsis is an exacerbated systemic reaction at
1 Carol
Davila Central Emergency Military Hospital,
Bucharest
2 Titu Maiorescu University, Faculty of Medicine, Bucharest
5
something which would normally be a common
infection. Although it was identified from the oldest
times, the sepsis is still a challenge for clinicians and it
remains, most of the times, a lethal complication.
During the last 10 years, in compliance with the
Protocol initiated by Surviving Sepsis Campaign for
the management of patients with sepsis, the
mortality was reduced from 37% to 30%,
nevertheless its percentage is still unacceptably high.2
The legal framework for the management of patients
who come to the Emergency Unit is provided in the
Order of the Health Ministry no. 1706/2007 regarding
the management and organization of the emergency
receiving units and compartments.
The patients who come to the Emergency
Department are taken over by the employees of the
department and they are selected according to the
emergency degree in compliance with the Order of
the Health Ministry no. 48/2009 – National Protocol
for the Selection of Patients from the Emergency
Receiving Structures.33 Patients’ selection is defined
by law as follows: the mechanism or procedure by
means of which the patients who come to the
Emergency Receiving Unit (ERU) or to the Emergency
Receiving Department (ERD) are assessed and
classified, upon arrival in ERU or ERD, by a competent
person (physician or average sanitary employee),
taking into consideration their clinical state and the
symptoms they declare, correlated with their age and
medical history, how stable their vital functions are,
the potential of exacerbation of their medical state,
the necessity to implement a treatment or to perform
some investigations, as well as other information
which are considered to be relevant, so that it can be
decided which is the priority for each patient to be
assisted and the level of assistance necessary for each
of them.33
Patients’ selection within the Emergency Department
represents the medical procedure used to assess and
categorize the patients arrived within the ERU by a
nurse/physician, in order to decide their priority for
medical care and its level. The nurse responsible with
the patients’ selection procedure is the nurse with
specific preparation and with appropriate experience
and abilities. The recommendation provided by the
6
law is that the time allowed for the patients’ selection
should not be longer than 2 minutes.33
The level of patients’ selection refers to all patients
who have the same priority degree according to the
severity and/or critical state of their pathology and to
the necessary resources. Priority levels are the
following:33
 Level I – resuscitation (Red Code): The patient who
requires an intervention to save his/her life NOW.
Maximum time allowed for the patient to be taken
over in the treatment area: 0 minutes.
 Level II – critical (Yellow Code): The patient who is
in a situation with major risk or altered mental status
(acute modification) or any intense pain or major
discomfort. Maximum time allowed for the patient
to be taken over in the treatment area: 10 minutes.
 Level III – urgent (Green Code): The patient with
stable vital functions who requires however, two or
more
medical
laboratory
or
paraclinical
investigations. Maximum time allowed for the patient
to be taken over in the treatment area: 30 minutes.
 Level IV – nonurgent (Blue Code): The patient with
stable vital functions who requires only one
laboratory or paraclinical investigation. Maximum
time allowed for the patient to be taken over in the
treatment area: 60 minutes.
 Level V – examination (White Code). The patient
who requires neither emergency medical assistance
nor laboratory or paraclinical investigations. This
category includes people who come for one of the
following reasons: vaccination; social case without
clinical symptoms; clinical and administrative issues
(medical certificates, prescriptions, etc.). Maximum
time allowed for the patient to be taken over in the
treatment area: 120 minutes.
The patient has the right to have his health state
periodically reevaluated if he has been taken over in
the treatment area after more than 30 minutes or if
there are significant modifications in his/her state,
which means that patients’ selection procedure
within the Emergency Department is periodically
resumed.33 More than once, this task is a difficult task
to be performed, taking into account the big number
of patients, insufficient personnel and the permanent
stress the personnel from the Emergency Department
has to deal with. In addition to these, the risk of bad
evolution for septic patients and not only for them is
quite high, therefore it is necessary that the diagnosis
methods in this department are fast, precise and
trustworthy.
We debate the issue of septic patients in this article
because this kind of patients have a rather
unpredictable evolution if they are not diagnosed
correctly and in due time. More than often, old
patients who also suffer from diseases in different
stages are neglected or superficially treated at home,
fact which makes the sepsis evolve frequently up to
advanced stages until patients come to the hospital.
This kind of patient is brought to the hospital with the
ambulances of the national system 112 (SMURD or
Ambulance Service) or by his/her relatives, being
already in a critical state, dehydrated, with high
temperature or with neurological signs.
Diagnosis of sepsis is not easy, it involves special
issues, because at present, the available methods are
related to the performance of the following
laboratory analyses: the number of leukocytes (WBC)
in the patient’s blood resulting from a complete
hemogram with leukocytes formula, the number of
germs, sepsis biomarkers, CRP (reactive protein C)
and last but not least the performance of bacterial
cultures from blood (hemocultures) and from other
fluids. Moreover when the physician from the
Emergency Department is under time pressure and
under pressure from the patients’ relatives as well as
from the other patients who do not understand the
patients’ selection Protocol mentioned above, a fast
diagnosis has an even greater importance. The main
topic of discussions is the fact that some patients
have higher priority than others, meaning that some
have to wait longer and others, who have just
arrived, are immediately taken over and treated in
the Emergency Department. The duty to introduce
the patients in the 5 levels of selection belongs to the
nurse from the patients’ selection and eventually to
the physician on duty; the two decide which patients
have a higher level of priority.
Therefore, the physician from the Emergency
Department should have available all necessary
resources in order to make a fast, correct and hard to
question diagnosis in the prospect of any malpractice
accusations. Sometimes, there are patients who
arrive in a state of septic shock and they have a fast
evolution to decease because of multisystem organ
failure (MSOF), so it is difficult for the patients’
relatives to understand the reason why a patient
having an apparently good state during the day, dies
in hospital in less than 24 hours. That is why the
physician from the Emergency Department
(emergency medicine physician or intensive care
physician) must make the correct diagnosis: SIRS,
sepsis, severe sepsis or septic shock, so that a fast,
appropriate and complex treatment can be initiated.
According to the law, the physician from the
Emergency Department has the possibility to require
all necessary examinations from different specialties
in order to make a diagnosis, the period of time
allowed before the patient is examined varies
between 10 and 60 minutes according to the level of
emergency – 10 minutes for red code and maximum
60 minutes for green code.(32)
It is important to have in mind that patients must be
subjected to a series of laboratory and paraclinical
investigations, as soon as possible upon their arrival,
especially in the case of patients belonging to the first
2 levels of priority. In view of a better understanding
of the phenomenon, we shall make a review of the
definitions of the Systemic Inflammatory Response
Syndrome (SIRS) and of the sepsis with its stages.
DEFINITIONS
Systemic Inflammatory Response Syndrome (SIRS) is
the clinical syndrome which results as a consequence
of an inadequate inflammatory response of the body
at a noninfectious origin lesion, such as: pancreatitis,
vasculitis, autoimmune affection, thrombembolism,
burns or surgery interventions.(3) SIRS diagnosis is
made in the presence of 2 or more of the following
criteria, as follows: temperature >38,5oC or <36°C;
ventricular rate >90/min; respiratory frequency
>20/min or PaCO2 <32 mmHg; leukocytes
>12000/mm3 or <4000/mm3;
Sepsis is the clinical syndrome which results as a
consequence of an inadequate inflammatory
7
response of the body at an infection. Sepsis can be
presumed if 2 or more of the conditions mentioned
above are present and the infection is identified
either through germs culture or visually.1
Severe sepsis: sepsis associated with the organ
dysfunction/insufficiency, impercipient perfusion or
hypotension.1
Septic shock: hypotension within sepsis, with all
appropriate replenishment.1
Multisystem organ dysfunction – MSOD: organ
dysfunction at a patient with an acute pathological
state so that homeostasis cannot be maintained
without medical intervention.1
WHY „POINT OF CARE TESTING – POCT”
DEVICES FOR EMERGENCY DEPARTMENTS?
Point-of-care testing (POCT) is defined as a medical
testing at or near the site of patient care.21,22 Another
definition would be the following: a group of
investigation, diagnosis or screening technologies,
which require neither personnel nor laboratory
conditions, performed on spot where medical
assistance is provided, within or outside a medical
unit. The purpose of POCT is to provide immediate,
convenient, and easy-to-use diagnostic testing that
shortens the therapeutic turnaround time when
providing care for a patient.
The objective is to provide rapid diagnostic
information that permits immediate clinical
management decisions to be made that will improve
patient safety and clinical outcomes, not to mention
patient satisfaction. It is important to be noticed that
these technologies do not require special spaces or
additional personnel, other than those that can be
found in any hospital/physician office. POCT can be
found in more environments: hospital bedside,
ambulatory care settings (clinics or physician offices),
alternate care (skilled nursing facilities), and home
settings.
In Romania, medical devices are governed by Law no.
176/2000 regarding medical devices, within this law,
in article 2 point a) and b) we find their definition as
follows29:
8
a) Medical device – any instrument, device,
mechanism, material or another article used alone or
in combination with others, including the necessary
software for its correct use, designed by the
manufacturer for human use and which does not
fulfill the main action for which it was designed in/or
on the human body by pharmacological,
immunological or metabolic means, but which can be
helped in its function by such means, with the
purpose of: diagnosis, prevention, monitoring,
treatment…;
b) Active medical device – any medical device whose
functioning is based on another source of power or of
energy than the one generated by the human body or
by gravity;
POCT benefits are numerous, below we are presenting the most important of them21,22:
 Positive patient identification;
 Immediate diagnostic test results (maximum 15-17
minutes) – reduced test and therapeutic turnaround
time, 24/24 hours;
 Reduction and/or elimination of specimen/sample
transport;
 Elimination of blood collection tubes and
centrifugation with fresh whole blood specimen;
 Reduced blood specimen volume;
 Reduced volume of reagents – POCT is a less
invasive method from the clinical point of view;
 Data management and connectivity – POCT
systems can be connected to the informatics systems
of the hospitals having as result: less transcription
errors, immediate data analysis – utilization, quality
control, compliance and data mining, development of
disease specific algorithms;
 Good cost-benefits report – although generally the
tests are more expensive, they can offer large
economical benefits, by reducing the number of visits
in hospital, days spent in hospital and repeated
hospitalizations.
Potential disadvantages21,22:
 Weak analyses quality;
 Lack of results interpretation;
 Wrong results which are difficult to trace;
 The possibility to make a battery of tests can lead
to the performance of unnecessary and inadequate
analyses;
 Lack of alignment with laboratory results –
reference intervals and results can be different to
those issued from the classical laboratory which
makes the comparison difficult.
The current diagnostic laboratory system has been
slow to change and is in need of change to a more
patient-centered system. Thus, today we need
personalized medicine and a patient-centered
medical system.
The model of centralized lab testing was developed in
the late 1960s but the new technologies and the
evolution of the health system demanded more rapid
testing which led to a significant increase of POCT.
The development of new technologies, such as „lab
on a chip”23,24 and DNA/RNA-based molecular
diagnostic tests25,26, 27,28, will expand the menu of
POCT tests and will lead to an increase in the use of
this device.
Taking into consideration all the benefits mentioned
above, POCT improves the diagnostic activity; the
most important aspects are immediate and precise
diagnostic, the use of whole blood specimen in an
extremely small quantity and reduction of
specimen/sample transport to the laboratory. Due to
the fact that it provides information to the
Emergency Department physician upon diagnosis and
patient’s critical state, it also offers him/her a certain
safety which, at the same time, eliminates the stress
related to malpractice.
The physician from the Emergency Department can
ask for interdisciplinary examinations, as already
mentioned, however, if he/she does not have any
investigations to show to his colleagues in order to
make at least a presumptive diagnosis, the physician
extends patient’s hospitalization time in the
Emergency Department waiting for the laboratory
analyses made in the central laboratory.
In addition to that, the Romanian legislation, more
precisely, the Order of the Health Ministry no.
1706/2007 – which regulates the activities from the
Emergency Departments, in Annex 1 – stipulates a
series of minimum mandatory paraclinical and
laboratory investigations which should always be
available for the patients from the Emergency
Departments.
These investigations complexity depends on the type
of the Emergency Department (I or II), as related to
imaging, but if we refer to basic analyses (hemogram,
blood glucose meter, electrolytes, sanguineous
gases), these are mandatory and it is preferable for
them to be made in the Emergency Department in
order to reduce the time until a diagnosis is made.
High level Emergency Departments – type I, must also
have the possibility to make toxicology analyses. All
these mandatory analyses, but also other analyses
which can lead to an immediate and precise
diagnosis, can only be made with the help of POCT
technology.
SEPSIS DIAGNOSIS
Biomarkers
Biomarkers can have an important role in proving the
presence, absence or stringency of sepsis and they
can make the difference between fungal and viral
infections, between systemic sepsis and local
infection. Other potential roles of the biomarkers
include prognostic, antibiotic therapy, evaluation of
treatment answer and postsepsis recovery,
differentiation between gram-negative and grampositive germs, the possibility to predict sepsis
complications and the development of organ
malfunctions (heart, kidneys, liver or multiple organ
malfunctions)4
Biomarkers definition. At present, the accepted
definitions for biomarkers are in compliance with the
studies made by U.S. National Institute of Health
(NIH) and by European Medicines Agency. A
biomarker is a “biological characteristic, objectively
measured
(with
acceptable
accuracy
and
reproducibility) and used as an indicator for a
physiological or pathological process or for the
activity of a medicine”.
In compliance with NIH standards, biomarkers can be
classified in two categories: prognostic markers –
which allow for the patients to be classified according
to the individual risk to have a specific prognostic,
9
regardless of the treatment (or lack of treatment) and
predictive markers – which allow the forecast of the
potential benefit (efficacy) and/or the risks (toxicity)
of a treatment according to the status of a biomarker
(absent/present)5.
The ideal biomarker in infectious diseases is used to
identify a high risk group or predisposing factors, as a
tool for disease identification or for treatment
prescription and classification of patients according
to their specific factors as well as/or as indicator of
the therapeutic management in order to avoid
reinfection. An ideal marker for infections would
combine the diagnostic, prognostic and treatment
follow-up characteristics and it should be easily and
fast available for clinic use6. Biomarkers should
evaluate the severity of an infection or predict an
evolution excluding complications to help the
clinician make a decision regarding the best
therapeutic approach in the most appropriate
environment (hospital or specialty ambulatory,
intensive therapy or hospital section). Furthermore, it
should help the clinician decide if it is necessary to
introduce or to continue antibiotic therapy.
Concluding, the “ideal” biomarker for sepsis diagnosis
should make different diagnosis between SIRS and
sepsis, between viral infections and bacterial ones, it
should also “detect” sepsis fast, reflect de severity of
the disease so that therapy can be monitored, have a
high predictive value, be stable in different samples
and eventually be quantified fast using “Point of
Care” devices.
During the last few years, more potential biomarkers
for infection were suggested and their analysis is a
complex task. The present tendency is to use
biomarkers – especially cytokine – in correlation with
multiple tests which measure simultaneously more
biomarkers from only one biological sample. The
main purpose is to examine if the clinical
performance and utility can be transposed in every
day clinical situations, taking into account the great
number of patients which come to the Emergency
Departments and the necessity to make a diagnosis
fast.
A
10
fast
diagnosis
allows
physicians
from
the
Emergency Department to implement a precocious
treatment which increases the patient’s survival rate
and which, at the same time, offers them the
certainty that they are not wrong and that they have
not passed by an infectious affection with lethal
potential for that patient. Thus, the malpractice risk
for the physicians from the Emergency Department is
lower, since it is known that they have to deal with a
great number of patients every day.
Available routine biomarkers
Three biomarkers fulfill the criteria mentioned above
and are available at all times: C reactive protein
(CRP), procalcitonine (PCT) and presepsin (PSEP).
CRP was tested in different studies but only some of
these studies focused on its use for the improvement
of antibiotic therapy. Further to these studies –
completed or ongoing – the use of CRP cannot be
recommended at present as a criterion for the
initiation or end of antibiotic therapy in adults;
however, for children, CRP can be probably used as
an indicator to end the antibiotic treatment although
the proofs obtained up to present are limited5.
Procalcitonine – PCT was tested on a larger scale for
the improvement of antibiotic therapy, both for
adults and for children. The conclusion of more
studies completed recently, which involved a
significant number of patients, is that the
introduction of procalcitonine values in the decision
algorithms for infection management in specific
infections is most likely adequate. It is however
necessary to continue researches for specific
infections which have not been examined enough up
to the present time, for a more precise definition of
procalcitonine role in the management of antibiotic
therapy5.
Presepsin – PSEP. In this article, we shall present a
new biomarker, which is a viable option for sepsis
precocious diagnosis – presepsin (sCD14-ST) and we
shall present its correlation with a score (MEDS score)
to supply the gaps which are related to this
biomarker, in comparison with what is used in
present in clinical practice. The biomarker was used
for the first time in 199332 and then in 1994 (Durieux
et al. Eur J Immunol 1994;24:2006-12). Presepsin was
studied starting with 2005 and it became an
important new marker for the diagnosis and
prognostic of sepsis in the last years.8,9,10,11,12.
CD14 is a glycoprotein expressed on the surface of
the monocytes/macrophages membrane (mCD14)
and it serves as receptor for lipopolysaccharides (LPS)
and for the protein which ties the LPS (LPBP). CD14
co-locates using a receptor 4, Toll-like type (TLR4).
When tying LPBP complex, CD14 activates the specific
pro-inflammatory signalizing cascade TLR4, thus
initiating the host inflammatory reaction against any
type of infectious agents.
LPS-LPBP-CD14 complex is released in circulation,
canceling CD14 from the cellular membrane, thus
soluble CD14 (sCD14) is produced. Nevertheless the
activity of the proteose from the plasma generates
another molecule sCD14, referred to as subtype
sCD14 (sCD14-ST) or presepsin – a protein of 13 kDa
which is actually a part of CD14, lysated at N-terminal
head (Durieux et al. Eur J Immunol 1994;24:2006-12).
PSEP levels were significantly higher at septic patients
than at those with SIRS or at those apparently
healthy. The increase of PSEP levels was more
precocious than the increase of IL-6 and D-dymers
levels in a study which created a model of bacteremia
on animals (cecal ligation and puncture on rabbit –
CLP). The determination of presepsin concentration
can be used not only for the diagnosis and prognostic
of sepsis, but also to monitor disease evolution and
feedback at therapeutical interventions. 8,9,10,11,12
Recently discovered biomarkers of potential interest
in the near future
At present, intensive efforts are being made in the
research field of some new prognostic and diagnostic
biomarkers which can be useful in antibiotics therapy
management from acute infections. For adults, three
of these seem promising: sTREM-1 (soluble Triggering
Receptor Expressed on Myeloid cells-1), suPAR
(Soluble urokinase-type Plasminogen receptor) and
ProADM (proadrenomeduline). These biomarkers are
accessible, they have proved sensitivity and/or
specificity and they were studied on a significant
number of patients so that they are worth to be
taken into consideration further on. For children and
babies other studies are also necessary.5, 13
STREM-1 is a member of immunoglobulins big family,
surface receptor which appears at mature monocites
and polimorphonuclears, they contribute at native
immunity. Its expression is upregulated when
phagocytes are exposed to bacterial fungic pathogens
but not during other noninflammatory processes.
TREM-1 amplifies the inflammatory response by
increasing the proinflammatory cytokines production,
inhibiting the synthesis of IL10. During the upadjustment of the surface receptor TREM-1, the
soluble form sTREM-1 increases in biological fluids
(blood, bronchoalveolar lavage fluid, cerebrospinal
fluid) and it can be determined with ELISA
commercial kits. According to some recent studies,
the dosage from the infection spot seems to be more
significant than the measurements made from
plasma.5,13
SuPAR (Soluble urokinase-type Plasminogen
Activator Receptor) or CD87 is a receptor for
inflammatory response spread on a large scale. It
appears only on the surface of a few cell types, such
as: endothelial cells and leukocytes (monocytes/
macrophages, polymorphonuclears).
Expression of its gene is under the control of immune
and inflammatory effectors, such as bacterial
products (LPS), cytokines (IFN-γ, TNF-α, IL-1β) and
growth factors (FGF-2, VEGF, TGF-β, EGF). During the
inflammatory and immune response, suPAR
expression is upregulated by epithelial cells, white
blood cells (lymphocytes), smooth muscle cells and
fibroblasts. Expression is also upregulated during
tumor growth and metastatic spread. The dosage
may be achieved using commercial ELISA kits
available on the market, but also as part of the
multiplex kit with multiple cytokines. However, suPAR
seems to be of limited value as a diagnostic test in
specific pathologies (patients at risk, HIV patients on
antiretroviral therapy, monitoring patients with nonpulmonary bacterial infection and children with
malaria with Plasmodium falciparum).5,13
Pro-ADM Adrenomedulin is a 52 amino acid peptide,
a marker of CALC gene family that works as a
11
mediator of cell proliferation, hormonal regulation
and embryogenesis. ADM is produced by the
endothelial cells where it induces vasodilation and
maintains homeostasis. Pro-hormonal fragments
(pro-ADM) are more stable than the complete
peptide and their levels in biological fluids can be
measured by automated methods TRACE (Time
Resolved Amplified Crypt-Emission) after the capture
of immunoassays. The secretion of proADM increases
during an immune response against viral or bacterial
products according to the size of the stimulus. ProADM is a valuable prognostic marker. As part of an
evaluation score of pneumonia severity, it can
identify patients in rather critical state which would
require monitoring/ hospitalization in an intensive
care unit.5,13
Future Biomarkers
Micro-RNA (miR) are newly discovered potential
biomarkers. miR are small molecules (approximately
20 nucleotides) present in eukaryotic cells, which act
as biological regulators by modulating posttranslational regulation. They are ubiquitous and
present in abundance in the lungs, liver and kidneys.
After binding to the appropriate smRNA sequence,
they regulate the expression of the gene by a
repressor effect or by altering the target sequence. A
fragment of miR can bind several smRNA. Their
expression can be measured by RT-PCR and
quantitative PCR. miR are potential candidates for
early diagnosis and/or prognostic markers in sepsis,
but other numerous studies are necessary to
understand their role in biochemical and
immunobiological processes before it can be used to
stratify, to make prognosis or therapeutic decision in
septic patients.5,13
The diagnostic and prognostic evaluation of presepsin
in sepsis in the Emergency Department was studied in
comparison to other available routine biomarkers, in
a study involving 859 patients, conducted by an
university hospital which has between 240,000 and
260,000 hospitalizations per year.10 These findings
were published recently, and the conclusions are
consistent both with literature data available in today
specialty literature and with personal observations
generated during similar studies in our hospital which
12
has 25,000 presentations through the Emergency
Department per year.
The efficiency of using presepsin to diagnose cases of
sepsis, severe sepsis and septic shock was
significantly increased by using MEDS score in
evaluating these patients as it will be shown below. It
is also worth mentioning that although PCT
(procalcitonin) can be used as a biomarker for the
diagnosis of sepsis, it increases in other situations,
such as: multiple injury, extensive burns, pancreatitis,
organ transplantation, major surgery and SIRS – not
only in infections, therefore, only the positive and
negative predictive values are not enough to exclude
or confirm sepsis.10 A recent meta-analysis showed
that the diagnostic performance of PCT was reduced,
with 71% (95% confidence interval 67-76%) sensitivity
and specificity for serum PCT, as a biomarker for
sepsis. In conclusion PCT can not clearly differentiate
sepsis from other diseases in critic adult
patients.10,14,14,16,17,18 Thus, to diagnose sepsis, severe
sepsis and septic shock, PSEP proved to be superior
to PCT, moreover, PSEP together with the assessment
by MEDS score was superior to PSEP taken as sole
indicator.10,19
In the 28-day mortality prognosis PSEP was inferior to
PCT, but these were lower to the correlated
interpretation and MEDS score. For septic patients
and prognostication of mortality after 28 days, PSEP,
MEDS and APACHE II score proved to be independent
predictors unlike PCT which did not have this
capacity. The mentioned study showed that plasma
levels of PSEP were a parameter closely related to the
severity of sepsis.10,19,20
Compared to the PCT, PSEP is a highly specific
biomarker for the diagnosis of a bacterial infection
because it is produced in conjunction with bacterial
phagocytosis.
PSEP was higher than PCT and had greater sensitivity,
specificity, positive predictive value, negative
predictive value and accuracy of prognosis in early
stages of sepsis which is consistent with the data
from the updated literature.
The more severe the sepsis was, mortality also
increased with over 50%, that is: mortality in severe
sepsis. Dellinger et all., in Early-Goal Directed Therapy
from 2013 guides of the Surviving Sepsis Campaign,
recommends that the potential source of infection
should be confirmed as quickly as possible, if possible
within 6 hours since presentation and that large
spectrum antibiotic therapy should be administered
within one hour from the identification of severe
sepsis or septic shock. Therefore identifying these
patients at risk is very important.
Table 1. MEDS Score (Mortality in Emergency Department Sepsis Score)30,31
Variables for MEDS Score
Points
Comorbidity fast terminal – fast terminal associated disease (metastatic cancer
or another condition that can cause death in 30 days)
6
Age >65 years
3
Septic shock (PAs<90 mmHg with all volemic repletion)
3
Number of plates <150000/mm3
3
Leukocytes premature unsegmented - bands (> 5% of total leukocytes)
3
Lower respiratory infection (clinical infiltrated pneumonia or chest RxG)
2
Altered mental status (level of alert or another change in the level of
consciousness)
2
Chronic patients treated at home
2
STUDY ON THE IMPORTANCE OF PRESEPSIN IN
ASSOCIATION WITH MEDS SCORE, SEPSIS
PRECOCIOUS DIAGNOSIS. PRELIMINARY DATA
In the Emergency Department of the Universitary
Central Emergency Military Hospital, a study was
made during a year, involving 300 patients suspected
of sepsis that came to the Emergency Department,
patients brought by their relatives or by the
ambulances from the national emergency system.
From these, 32 patients were introduced in the study
(19 men and 13 women), for which the following
inclusion and exclusion criteria were used:
Criteria for inclusion in the study:
• Age ≥18 years with clinical signs of severe infections
requiring blood sampling;
• The presence of 2 of 4 SIRS criteria: fever > 380 C
<360 C; heart rate> 90 / min; respiratory rate >
20/min or existence of hyperventilation (PaCO2 <4.3
kPa / 32 mmHg in arterial blood); leukocytosis>
12,000/ml, leukopenia<4000/ml or > 10% premature
unsegmented granulocytes (bands);
Exclusion criteria: age under 18 and refusal to sign
the consent.
All patients were examined by doctors of emergency
medicine and ATI employees of the Emergency
Department and after the former signed the
informed consent, venous peripheral approach was
made, blood was collected for laboratory testing and
they were subjected to other paraclinical
investigations (abdominal ultrasound, CT in different
regions, x-rays) in order to make a diagnosis and start
the appropriate treatment immediately.
The following laboratory tests were made: complete
blood count with differential, coagulation (Quick
time, fibrinogen), biochemistry (glucose, urea,
creatinine, ionogram, samples of liver, etc.),
presepsin, procalcitonin.
Analyses were performed in the Central Laboratory of
SUUMC, and the Emergency Department's own
laboratory, using "Point of care testing - POCT" and
PATHFAST® device type.
Evaluation of patients admitted to the Emergency
Department was made with the score MEDS - Sepsis
Mortality in Emergency Department19, 30, 31. The score
was developed to predict mortality for patients with
SIRS hospitalized in the Emergency Department. The
maximum score is 27 points, score variables and the
score awarded to each variable can be found in Table
1.
For all these variables, a score are awarded, score
13
which is summed up for each patient, the sum of the
obtained points offers a prognostic for mortality at 28
days.
The determination of presepsin was made using a
POCT type device, more precisely PATHFAST®, and the
evaluation of the patient’s state according to the
values/concentration of presepsin obtained was
made using the correlations from Table 3.
The patients included in the study were aged
between 18 and 92 and they were selected using the
inclusion and exclusion criteria mentioned above. The
existence of SIRS criteria was considered, the results
are those from Figure 1 (14 patients with fever, 25
with RR>20/minute, 22 with leucocytosis, 22 with
HR> 90/minute).
Table 2. Correlation between MEDS score and mortality at 28 days as percentage30,31
MEDS Score range
Mortality at 28 days (95% CI)
0-4
0,6% (0-3%)
5-7
5% (1-13%)
8-12
19% (11-29%)
13-15
32% (15-54%)
> 15
40% (12-74%)
Table 3. Correlation between PSEP values, diagnosis and measures to be taken 14,15,16,17,18,19
PSEP (pg/mL)
Diagnosis
Case management
Sepsis absence
It is not necessary to sample
hemocultures
200-300
Small probability of systemic infection
Other investigations are also
necessary among which bacterial
cultures (hemocultures etc.)
300-499
Possible systemic infection (SEPSIS)
Therapy with medicines starts after
samples were taken for bacterial
cultures
500-999
High risk of infection progression in the body
(SEVERE SEPSIS)
High risk of unfavorable prognostic
Surgery treatment must also be
taken into consideration
Under 200
Over 1000
Major risk of systemic infection progression
„Maximal” therapy
(SEVERE SEPSIS/ SEPTIC SHOCK), major risk of
mortality at 30 days – comparable with score 25
on APACHE II
Further to patients’ anamnesis, we obtained the data
represented in Figure 2, in which we resumed the
types of affections (number of cases): neurological –
9, neoplastic – 7, cardiac – 1, global cardiac
insufficiency – 5, coronary artery diseases – 5,
valvular heart diseases – 3), chronic renal diseases – 4
, diabetes – 4, pulmonary diseases (pneumonia – 5,
BPOC/asthma – 5), thyroid diseases – 2, others – 27
(HTA, digestive diseases etc).
Patients were evaluated using MEDS score which
varied between 3 – 21 points according to the health
state of each patient. Some of the laboratory
14
analyses were made in the Central Laboratory, that is
the blood cultures and other cultures sampled from
15 patients, out of which only 3 were positive. POCT
(Point of Care Testing) devices were used to
determine the biomarkers, in the case of PSEP;
presepsin had values between 102 – 7129 pg/mL, as
it can be seen in figure 3. In the case of
procalcitonine, the results were negative or they
reached the maximum value of >10 ng/mL, and for
PCT, the determination method that was used, was a
semiquantitative one, THERMO SCIENTIFIC BRAHMS,
which has the following intervals as possibilities:< 0,5;
≥0,5-≤2,0; ≥ 2,0-10; >10 ng/mL. Regarding the
diagnosis of sepsis in its different stages, there were
13 patients with SIRS, 8 patients with sepsis, 6
patients with severe sepsis and 5 patients with septic
shock who also had the highest values of presepsin.
Considering the affections which led to sepsis (Figure
4), the patients from the study can be divided as
follows: pulmonary diseases (COPD, asthma,
pneumonia) – 12 cases (5 ♀, 7 ♂), urinary infections –
9 cases (5 ♀, 4 ♂), digestive infections (acute
gangrenous appendicitis with generalized peritonitis
– 2, gangrenous acute cholecystitis – 4, bowel
obstruction – 1, diarrhea – 1, acute angiocholitis – 1)
– total 9 cases (3 ♀, 6 ♂), gynaecologycal infections – 1
case and acute endocarditis – 1 case (♂).
Figure 1. The correlation between the number of cases and SIRS criteria
Fever
RR>20/minute
Leucocytosis
HR> 90/minute
Figure 2. Anamnesis of the patients from the study
– number of cases according to the type of affection –
30
25
20
15
10
5
0
Number of cases
A total of 26 cases were hospitalized in Universitary
Central Emergency Military Hospital (81.25%), out of
which: 15 cases in medical wards, pulmonology – 2,
gastroenterology – 3, internal diseases – 4, oncology
– 1, neurology – 2, cardiology – 2 and dermatology –
1 case) and 11 cases in surgical departments
(gynecology – 1, urology – 2, general surgery – 8). Out
of the total of hospitalized patients, 11 were
admitted to ICU and 7 were mechanically ventilated.
Out of the 32 patients included in the study, 8 died in
hospital (25%) who had MEDS with values ranging
between 8-21 points, the values obtained for
presepsin were between 593-6745 pg/mL. 3 cases
were diagnosed with sepsis, 2 cases were diagnosed
with severe sepsis and 3 cases were diagnosed with
septic shock. The affections which were the starting
point for the development of sepsis were the
following types of infections: respiratory – 5 cases,
endocarditis – 1 case, diabetic ketoacidosis coma – 1
case, bowel obstruction – 1 case. Patients who died
had a number of associated diseases, some of which
were extremely serious, namely: neurological
diseases – 4 cases, malignancies – 2 cases, ischemic
15
heart disease – 3 cases.
Figure 3. The evolution of presepsin values for the patients involved in the study
8000
7000
6000
5000
4000
3000
2000
1000
0
Presepsin pg/mL
Figure 4. Correlation between the number of cases and the affections which led to sepsis
14
12
10
8
6
4
2
0
Preliminary conclusions of the study
Presepsinul is an important biomarker having a role in
rapid diagnosis of sepsis (17 minutes) to 30 minutes
for PCT (on the type of test that we had available), it
allows the patient evaluation and classification in a
risk category, and its association with MEDS score
increased the possibility to provide a correct
evaluation of the patients. Rapid diagnosis allows to
early start any kind of treatment, primarily the
antibiotic, right from the Emergency Department, and
in the unclear cases, the physician from the
Emergency
Department
requires
further
investigations to elucidate the diagnosis.
In selected cases - patients with unrecognized sepsis,
the determination of PSEP allows the physician from
16
Number of cases
the Emergency Department, to present their situation
to the doctors within Universitary Central Emergency
Military Hospital and to suggest and if necessary to
hospitalize the patient in cases with diagnostic on the
edge according to legal provisions.32 In our
experience related to the sepsis cases presented to
the Emergency Department, PSEP determination had
a special importance because we could demonstrate
the presence of sepsis and not of SIRS as it would
have been diagnosed unless for this biomarker.
Diagnosing sepsis favored the decision of
hospitalizing the patient, his/her close supervision,
the commencement of antibiotic treatment in the
Emergency Department, in some cases earlier surgical
intervention. All patients hospitalized in the
Emergency Department and then in the hospital,
were investigated using the imaging tools available in
the hospital (ultrasound, X-rays, CT with or without
contrast, etc.).
In addition to that, determination of the dynamic
values of PSEP in hospitalized patients with sepsis
allowed monitoring the effectiveness of the
implemented treatment, the cost-effectiveness ratio
was very good, given the early start of antibiotic
treatment and beyond.
In our study, we used the device type PATHFAST® of
the company Mitsubishi Chemical that has all the
advantages of POCT, namely: the results are
quantitative (using a chemiluminescence method
type), fast (between 17 minutes), they can be
obtained in our own laboratory at local level - from
the Emergency Department, can be printed easily,
there is a unit memory to store patient data, it uses
whole blood – 150 μL (no spin) as sampled from the
patient without the need for tube collection.
Moreover, the device is extremely precise (CV <5%),
quantitative results are obtained from the blood tests
carried out at the same time, because it results in the
same test / or up to 6 different assays for six patients
at the same time. Such determinations can be made
for 1 to 6 patients, making any combination of 1 to 6
tests required.
Presepsin determination by this method allowed risk
stratification in criticc patients, monitoring of disease
progression and very important, monitoring of the
response to drug therapy and other measures
(surgery, supportive treatment in the ICU, etc.).
As for forensic results by POCT, given that the sheets
can be printed and attached to Emergency
Department presentation sheets and general clinical
observation sheets, these are of particular
importance. It certifies permanent care of the patient
under close monitoring of blood different parameters
and not only those. With this type of equipment, we
can quickly modify patient treatment in real time to
correct the dysfunctions and inadequacies thus
arisen.
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analysis, competitive landscape and market forecast to
2018. 2012.
29. Legea nr. 176 din 18 octombrie 2000 privind
dispozitivele medicale, publicată în Monitorul Oficial,
Partea I nr. 544 din 02 noiembrie 2000
30. Jeffrey D. Sankoff, MD; Munish Goyal, MD; David F.
Gaieski, MD; Kenneth Dietch, DO; Christopher B. Davis, MD;
Allison L. Sabel, MD, PhD, MPH; Jason S. Haukoos, MD,
MSc: Validation of the Mortality in Emergency Department
Sepsis (MEDS) score in patients with the systemic
inflammatory response syndrome (SIRS) Crit Care Med
2008 vol.36 No.2
31. Shapiro NI, Wolfe RE, Moore RB, et al: Mortality in
Emergency Department Sepsis (MEDS) score: A
prospectively derived and validated clinical prediction rule.
Crit Care Med 2003; 31:670–675.
32. Labeta MO, Durieux JJ, Fernandez N, Herrmann R,
Ferrara P: Release from human monocyte cell line of two
different soluble forms of the lipopolysaccharide receptor
CD14. Eur. J Immunol 1993; 23:2144-51.
33. Ministerul Sănătăţii Publice, Ordin nr. 1.706 din 2
octombrie 2007 privind conducerea şi organizarea unităţilor
şi compartimentelor de primire a urgenţelor publicat în
Monitorul Oficial nr. 724 din 25 octombrie 2007.
34. Ministerul Sănătăţii, Ordinul nr. 48 din 26/01/2009:
Protocol national de triaj al pacientilor din structurile
pentru primirea urgentelor, publicat în Monitorul Oficial,
Partea I nr. 67 din 04/02/2009.
SYSTEMATIC REVIEW
Article received on January 12, 2015 and accepted for publishing on January 19 2015.
Romanian sanitary system assisted by knowledge
management
Daniel. O. Costache1, Cosmin Dobrin2, Ruxandra Dinulescu2, Laura Voicu1, Raluca S. Costache1,3
Abstract: As the medical sciences advances, so does the volume of information which becomes
more and more consistent.
The health care system is one of the most complex systems encountered in our society. Today,
knowledge management practices have been adopted in many Romanian business sectors.
However, Romanian health care system is slowly adopting such principles and concepts. This fact is
created mainly because of the organizational culture. In the sanitary industry, this barrier is
composed both from an organizational perspective and also, from an individual perspective.
Through the knowledge management practices, doctors could benefit from the amount of data
spread in different geographical regions.
Keywords: sanitary system, knowledge management, quality.
INTRODUCTION
In a normal health care system, the patient must be
in the center of all activities and any medical error
should be avoided, in order to protect the patient
from a fatal result. For this reason, a complex source
of knowledge could be of great help for doctors.
Health care delivery involves more than one could
know, more than a simple relation between doctor
and patient. Health care delivery covers health care
professionals like physicians, specialists, nurses, lab
technicians, social workers, counselors, etc. Also, it
includes further parties like hospital/clinic
administrators, managers in finances/accounting/
human resources/drug companies/ health care
insurance companies etc. What is more, health care
partners are dispersed around many areas, even if
they are acting on the same patient.
Therefore, it is well understood that the amount of
knowledge is extremely relevant and that any data
knowledge, created by one of the partners, is of great
importance to the others in order to deliver quality
care.
The term of “knowledge management” (KM)
appeared in the 20th century, from fields like
management, cognitive sciences and psychology. The
present activity of KM started in the 1980s along with
the wide use of information technologies in
enterprises. There, the main focus was on what
knowledge represented as an intangible asset.
1 Carol
Bucharest
2 Economic Sciences Academy, Management Faculty,
Bucharest
3 Carol Davila University of Medicine and Pharmacy,
Faculty of Medicine, Bucharest
19
Basically, the word KM was revealed in the 80s and
the academic field was created in 1995 (Stankosky,
2005).
WHAT EXACTLY IS “KNOWLEDGE”?
Basically, there are 3 major elements often used
together: data, information and knowledge. Still,
there are some differences between them, as
specified below:
 Data: represents a specific tact or figure, without a
specified context.
 Information: represents a data that is organized.
 Knowledge: built on the information, in order to
define a proper context.
The main difference between knowledge and
information is that knowledge lets us the power to
take action. Therefore, we are able to use it.
According to Bryan Duhon (1998), knowledge
management represents a discipline that promotes
an integrated approach in order to identify, capture,
evaluate, and share the amount of an enterprise's
information assets. These assets may include
databases, documents, policies, procedures, and
previously un-captured expertise and experience in
individual workers.
Basically, Knowledge management is essentially
especially for getting the right knowledge to the right
person at the right time. The main objective is to
create value and to leverage, improve, and refine the
firm's competences and knowledge assets in order to
meet organizational goals and targets.
When we look to implement knowledge
management, we have to take into consideration
several dimensions like:
- KM Strategy: Knowledge management strategy
must present a certain dependence on corporate
strategy. Its objective is to manage, share, and create
relevant knowledge assets that will help meet tactical
and strategic requirements
- Organizational Culture: The way people interact,
the context where knowledge is created, people’s
resistance towards change and also the way they
20
share (or not) knowledge are easily influenced by the
organizational culture.
- Organizational Processes: Are represented by the
right processes, environments, and systems that
enable knowledge management to be implemented
in a certain organization.
- Management & Leadership: KM needs competent
and experienced leadership at all levels. There are a
wide variety of KM-related roles that an organization
may or may not need to implement.
- Technology: Represents by the assembly of
systems, tools, and technologies that fit the
organization's requirements - properly designed and
implemented.
- Politics: The long-term support in order to
implement and sustain initiatives that involve
virtually all organizational functions, which may
require a higher cost for implementation (both from
the perspective of time and money), and which often
do not have a directly visible return on investment.
Knowledge management could be described in 3
ways:
 Explicit: represented by the information or
knowledge set out in a tangible form. Also, is
represented by the information that is easy to
capture, to structure or share with other people. For
example, in a hospital, an explicit knowledge could be
represented by the hospital’s documentation, like
internal policies and procedures, clinic methodologies
etc.
 Implicit: represented by the information or
knowledge that is not set out in tangible form but
could be made explicit.
 Tacit: represented by the information or
knowledge that would have extreme difficulty in an
operational process setting out in a tangible form.
What is more, this kind of knowledge is composed of
the amount of experience and skills that a doctor can
acquire overtime and apply to problems.
Unlike the explicit knowledge, tacit knowledge is
sometimes difficult to capture, to structure and/or
transfer to other individuals5.
Figure 1. Key elements that constitute the knowledge management infrastructure
(from Wickramasinghe and Sharma, 2004)
Infrastructure for
collaboration
Business
intelligence
infrastructure
KNOWLEDGE
MANAGEMENT
INFRASTRUCTURE
Knowledge
transfer network
TYPES OF HEALTHCARE KNOWLEDGE
a. Provider knowledge – also called “practitioner
knowledge”. This type of knowledge is the most
obvious one especially due to the fact that medical
professionals in this capacity have both explicit and
tacit knowledge.
An example is sustained by the fact that doctors have
to know standard medical information easily
comprehended from different reference materials
such as text books. Still, some may consider that one
of the most important types of providers’ knowledge
is of tacit form.
b. Patient knowledge – this type of knowledge
consists also in tacit knowledge. Nowadays, patients
have complex knowledge in past and current medical
conditions that doctors may not know about.
However, such knowledge is mandatory for doctors
to know.
c. Organizational knowledge – this type of knowledge
consists in sum of knowledge elements like medical
diagnostic systems, text-based materials, etc. What is
more, this field contains medical land treatment that
is strongly recommended by an institution or medical
society.
Why Romania needs to adopt knowledge
management practices in its clinics and hospitals?
Organizational
memory
Human asset
infrastructure
According to a report from the World Health
Organization in 2014, in Romania there are almost
40,000 doctors with free practice. This number is
relatively small, with a position that represents a total
of 2,5 physicians reported at 1000 individuals.
As we can observe in the above figure, in 2014
Romania was occupying the last position regarding
the number of medical personnel. Countries like
United Kingdom, France, Germany and even Bulgaria,
were in front of us.
Even if, in Romania there is not a huge number of
physicians, the information needs to circulate as well
as possible. That is why, every doctor has to have
knowledge of every new information that appears
regarding a medicine, a treatment, a diagnostic, etc.
Here are several reasons why KM needs to be
adopted by the Romanian sanitary system:
1. A significant amount of data is in multiple places.
Data collected from healthcare tend to be stored in
multiple places-from different systems like HR
software, to different departments, like radiology or
cardiology. Practically, healthcare data comes from
the entire hospital/clinic.
Another example is that healthcare data is under
multiple forms (like text, numeric, paper, digital, etc).
There are times when the same data exists in
21
different formats and in different systems
What sanitary institution could do, is to aggregate
this data into a single and central system, accessible
to every physician.
2. Healthcare data could be structured or
unstructured. In present, Romanian sanitary system is
strong related to the National Healthcare Insurance
House (NHIH), which created a software that is able
to capture consistent data from patients. This would
be helpful, but the software appeared only 3 years
ago, and before it, all the information regarding the
patients’ state were wrote down on a paper folder.
This is way, hospitals and clinics need KM – to gather
all the structured and unstructured data in the same
place.
3. Variable definitions; new research practices are
coming out daily. Often, healthcare data have
variable definitions (regarding a certain treatment,
diagnostic etc). There are cases when there may not
be a level of consensus about a particular treatment
or definition. What is more, the parts that are
conducting a certain discussion about a medicine,
treatment, etc. are constantly discovering new data
knowledge.
Figure 2. World Health Organization, Medical personnel per 1,000 people
4. The complexity of data. Searching for different
developing standard processes that are able to
improve quality has always been a main objective for
health care providers. Still, the number of data
variables involved makes this process more
challenging. In health care system, doctors are not
working with machines or computer; instead, they
work with individuals, more precisely, with human
body, which is an amalgam of complex information in
constant changing.
Seeing these reasons, we can be sure that healthcare
data will not get simpler in the future. On the
contrary, it will advance; it will need more than
simple software and will present challenges that only
a complex and well organized sanitary system could
cope.
22
A POSSIBLE EXAMPLE FOR APPLYING KM IN
ROMANIAN SANITARY SYSTEM
From the beginning of 2015, in Romania has been
implemented the so called “national health care
card”, which is nominative for each patient. Its role is
to show the doctor what medical treatment has the
patient followed, what was his diagnostic and at what
medical sections the patient went. In this way, if a
patient has firstly went to his family doctor, who
diagnosed him and gave him a certain treatment, the
second doctor (let’s say for example, the
dermatologist) would be able to see (with the help of
this new system by card) the day when the patient
was at his family doctor, the medicines prescribed
and the exact diagnose. So far, everything is in order.
Issue that needs to be solved through KM: The new
system shows the information only beginning with
the date that the card was introduced. In other
words, if a 40 years old patient comes for 10 years
(since 2005) at the same family doctor, and only this
year he had the card (2015), that means that the
information area from 2005 till 2015 (regarding his
treatments, illness, diagnostics, lab tests etc) is
missing on the software program (the doctor is able
to see the medical history from a patient only starting
with 2015).
Practically, this represents a gap both for physician
and also for the patient (of course that the
information from 2005 exists, written in the patient’s
medical record – a notebook, in most of the casesbut is not inserted in the medical informatics system).
Solution of KM: If KM practices would be applied, the
present informatics system could be extended, in a
manner that would include the whole patient’s
history from the beginning. Also, the system could
specify, for example, if a patient is allergic to some
substances (when the doctor prescribes a medicine, if
the patient is allergic to a certain substance from that
medicine, the program would alert the doctor and in
this way, the doctor would prescribe something else
– it is also a way of avoiding medical errors).
MAIN BENEFITS FOR IMPLEMENTING
KNOWLEDGE MANAGEMENT
The main advantage of introducing knowledge
management in Romanian sanitary system is that the
information between doctors is easily shared, and
most of all, that information is not lost if one of the
doctors is sick or has another reason for leaving the
cabinet earlier.
In this way, hospitals could be able to have
substantial savings. Doctors are brought up to speed,
and valuable knowledge assets are not lost (this
translates into fact that the hospital or clinic do not
lose time and money when doctors need to learn new
information quickly).
In a hospital, knowledge management has the power
to increase innovation and also to create better
patient relationship. For example, if a certain clinic
has a global team, knowledge management can
create a more powerful workforce when all cultures
are brought together in order to share assets (in
Romanian clinics, this example is more suitable for
private sanitary system).
Another important advantage is that KM could
reduce the medical errors and their cost, by providing
a decision support.
Next, we will present another KM advantages for
healthcare:
- Cooperation
between
different
health
care
providers;
-
Innovation;
Quality of care;
Efficiency of work;
Cost reduction.
All in all, knowledge management gives doctors the
capacity of knowledge they need to do their jobs
better. In this way, they become more productive.
CONCLUSION
The adoption of knowledge management practices
into the Romanian sanitary system could become
either a success or a failure. Like any other project,
just because a system has been put in place, with the
help of the appropriate methodologies or practices,
this does not mean that it will become successful in
terms of adoption and use.
Because healthcare data is so complex, it’s more than
relevant that a traditional approach to manage it will
not be able to succeed.
This is why, a different approach is needed. The new
approach needs to handle multiple sources,
structured and unstructured data, variability, the
complexity
within
a
constantly
changing
environment.
The use of KM in sanitary industry promises to
enhance the quality of care for patients. Its
implementation will allow healthcare partners to
conduct evidence based practice, and also to
collaborate relying on the best knowledge available.
To sum up, the implementation of knowledge
23
management practices and systems is a topic of great
interest for the healthcare community around the
world.
A complex KM system for health care industry would
represent a huge step, both for doctors (preventing
medical errors) and for patients.
References:
1. Abidi, S. S. R. (2001). Knowledge management in
healthcare: towards ‘knowledge-driven’ decision-support
services. International Journal of Medical Informatics, 63(12), 5-18
3. Choudhry, N. K., Fletcher, R. H., & Soumerai, S. B.(2005).
Systematic review: the relationship between clinical
experience and quality of health care. Annals of Internal
Medicine, 142(4), 260-273
2. Ardichvili, A., Maurer,M.,Li, W., Wentling, T., &
Stuedemann, R. (2006). Cultural Influences on Knowledge
Sharing Through Online Communities of Practice. Journal of
Knowledge Management, 10(1), 94–107. doi: 10.1108/
13673270610650139
4. Thomas H. Davenport and John Glaser, Just-in-Time
Delivery comes to Knowledge Management, Harvard
Business Review
24
5. Awad, E. M. (2010). Knowledge Management (2nd ed.).
North Garden, Virginia, USA: International Technology
Group, LTD
SYSTEMATIC REVIEW
Article received on November 1, 2014 and accepted for publishing on December 19 2014.
Spondylodiskitis, etiology, diagnosis and treatment
Cristian Bănică1, Ion Ştefan1
Spondylodiskitis is a spinal infection comprising
vertebral osteomyelitis and intervertebral disc.
Diagnosis can be difficult considering that the
symptomatology is not specific, low back pain is
common in people over 50 years.
The etiology of the disease includes pyogenic germs,
tuberculous, parasitic and fungal etiology. It is known
that staphylococcal and tuberculous etiology are
responsible for most cases in clinical practice, being
the main issue of differential etiological diagnosis.
Gram-negative germs are a rarer etiology, being
involved in secondary spinal infections as a
consequence of dissemination of retroperitoneal or
intra-abdominal collections. Other etiologies are very
rare: parasitic, fungal or Brucella.
Spinal infection has, in most cases, marrow
dissemination as pathogen mechanism; it is recorded
in
staphylococcal
sepsis
and
secondary
determinations of tuberculosis (Pott morbidity).
Contiguous infection from septic foci nearby is a rare
complication due to esophageal ruptures or
retropharyngeal abscess or aortic vascular prosthesis
infections. Iatrogenic, postoperative, postpuncture
infection is also recognized.
Due to the particularities of spine vasculature,
marrow infection includes intervertebral disc and
vertebral body; septic emboli cause infarcts within
bones,
leading
to
osteolysis,
mechanical
deformations, cavitation, mechanical instability.
Paravertebral abscesses could occur, the infection
can spread into the spinal canal.
The location of these spinal infections is more
common in the lower back, however, thoracic and
cervical locations are also common.
Initial infectious outbreaks are often difficult to
identify, less than 50% of cases are recognized as the
source of spondylodiskitis, skin and soft tissue
infections, genitourinary infections, respiratory
infections, endocarditis, ORL infections. Predisposing
factors are recognized and represented by
comorbidities, diabetes, rheumatic diseases, cirrhosis,
malignancy, immunosuppressive treatments.
Staphylococcus aureus is the most common nontuberculous
etiology,
methicillin-resistant
Staphylococcus is more and more common in both
community infections and in hospital infections.
Staphylococcal spondylodiskitis has as starting point,
infections of the soft tissues, infections of
intravascular devices, infectious endorcaditis and
iatrogenic infections: postpuncture, postoperative.
MRSA staphylococcus spectrum of resistance
comprises lately, besides penicillin, aminopenicillins,
3rd generation cephalosporins and other classes of
antibiotics: macrolides, clindamycin, aminoglycosides,
florochinolone rifampicin, moreover, the rate of
resistant strains is increasing.
Viridans streptococci represent less than 10% of the
etiology of spondylodiskitis, their association with
bacterial endocarditis in sepsis is known.
1 Carol
Bucharest
25
Pneumococcus, anaerobic bacteria represent a rare
etiology.
Tuberculosis is a constant presence in the range of
spinal infections. As a form of bone tuberculosis,
bone cold abscess has a slow, insidious, soundless
development and it is sometimes associated with
other bacillary determinations: psoas abscess, renal,
prostate, lung or even brain abscess.
Gram negative bacteria represent 10-30% of the
etiology of spinal infections, the most common germ
is Escherichia coli, followed by Proteus, Klebsiella and
Enterobater.
Rarely, spondylodiskitis etiology may be represented
by other bacteria: Brucella, Bartonella or fungi:
candida albicans (more frequently), Cryptococcus,
Coccidioides, blastomices. As an exception, cases of
spinal infection with Echinococcus granulosus are
described.
The difficulty of diagnosis lies in the poor symptoms;
lumbar spine pains are common in the general
population. Sometimes, the presence of low grade
fever or febrile episodes draws attention. Neurologic
deficit may occur in complicated cases with
radiculopathy and spinal cord compression. During
anamnesis, recent history of skin or soft tissue
infections, presence of an intravascular device or
surgery in the spine is presented. Patients with
comorbidities and immunosuppressive treatments
are more exposed to the risk of sepsis with secondary
determinations. Bacillary etiology is insidious,
diagnosis is retroactive.
Laboratory examination raises suspicion of infection
when neutrophilic leukocytosis is present, high ESR,
CRP is often higher in spondylodiskitis. Alkaline
phosphatase may be increased.
Radiological examination and magnetic resonance
imaging of the spine brings valuable proofs for
diagnosis, showing inflammatory modifications and
bone structure modifications of the vertebrae and
intervertebral disc, which also appear in degenerative
lesions and can therefore be difficult to interpret.
Technetium 99 scintigraphy and the one with Gallium
67 can bring sensitive data to support the diagnosis.
26
Computed tomography has good resolution for
changes in bone structure, it highlights destruction of
vertebral plateaus, bone formation seizure, but MRI is
superior in viewing abscesses and lesions in nervous
tissue. From the imaging point of view, RM lesions TB
are different because the intervertebral disc is not
affected but paravertebral abscesses are present,
bone destruction.
Proof of infectious etiology can be obtained by
biopsy-puncture and culture for aerobic bacteria,
anaerobes, mycobacteria and fungi. Blood cultures
can have a positive result in about 50% of cases,
infection is frequently marrow. Histopathological
examination of biopsies can guide diagnosis in
bacillary infections but also the differential diagnosis
of vertebral bone tumors and metastases.
Complications of the disease are caused by damage
to the spinal architecture and mechanics, with
neurologic and infectious complications.
Neurological complications can be significant, from
the root syndrome up to paralysis. Infectious
complications are: paravertebral abscesses, epidural
abscesses, secondary meningitis, but also sepsis
complications , in the context of which
spondylodiskitis was diagnosed.
Treatment is anti-infective, analgesic, immobilization
and surgery.
Antimicrobial treatment is injected on the basis of
probability criteria or after the results of biopsy or
blood culture. Antistaphylococcal antibiotics with
broad-spectrum are used depending on the
etiological suspicion. In the context of increasing
frequency of MRSA staphylococcus, Vancomycin,
Linezolid or Targocid is used for minimum 6 weeks.
Injectable antibiotic therapy may be continued orally
up to 3 months, depending on the disease evolution.
For bacillary etiology, tritherapy for 3 months, in the
4th month, the 4th antituberculosis antibiotic is
associated, then, the therapy continues with two
antibiotics up to 12 months.
The favorable evolution is clinically assessed,
especially by clinical evidence of inflammation in
normal limits, C-reactive protein and VSH within
normal limits, as well as the course of radiologic
imaging, magnetic resonance. If paraspinal, epidural
abscesses or neurological injuries secondary to
compression appear, surgery is required.
The prognosis is favorable by antimicrobial fair
treatment and surgery if necessary, spondylodiskitis
mortality is less than 5%. Prompt diagnosis and
antimicrobial treatment are essential.
References:
1. Hadjipavlou AG, Mader JT, Necessary JT, et al.
Hematogenous pyogenic spinal infections and their surgical
management. Spine (Phila Pa 1976) 2000;25:1668-79.
4. Hopkinson N, Stevenson J, Benjamin S. A case
ascertainment study of septic discitis: clinical,
microbiological and radiological features. QJM 2001
2. Chelsom J, Solberg CO. Vertebral osteomyelitis at a
Norwegian university hospital 1987–97: clinical features,
laboratory findings and outcome. Scand J Infect Dis
1998;30:147-51.
5. Jimenez-Mejias ME, de Dios Colmenero J, Sanchez-Lora
FJ, et al . Postoperative spondylodiskitis: etiology, clinical
findings, prognosis, and comparison with nonoperative
pyogenic spondylodiskitis. Clin Infect Dis 1999
3. 3. Grammatico L, Baron S, Rusch E, et al. Epidemiology of
vertebral osteomyelitis (VO) in France: analysis of hospitaldischarge data 2002–2003. Epidemiol Infect 2008;136:65360.
6. Butler JS, Shelly MJ, Timlin M, et al. Nontuberculous
pyogenic spinal infection in adults: a 12-year experience
from a tertiary referral center. Spine (Phila Pa 1976) 2006
27
ORIGINAL ARTICLES
Article received on November 15, 2014 and accepted for publishing on December 5, 2014.
A cholestatic syndrome may be a surprising cause
of medical error
M. Pătrășescu1, P. Nuță1, Raluca S. Costache1,2, Săndica Bucurică1,2, B. Macadon1, Andrada Popescu1, Mariana
Jinga1,2, Florentina Radu Ioniță1,3
Abstract: Autoimmune cholangitis defines a spectrum of cholestatic liver diseases that are
characterized by inflammation of bile ducts and a reasonable response to immunosuppressive
therapy. The two most common diseases associated with this term in the literature are: an overlap
syndrome of primary biliary cirrhosis and autoimmune hepatitis and a form of hyper IgG4
syndrome (currently associated with autoimmune pancreatitis). Liver biopsy is mandatory for the
diagnosis. There are, whatsoever, in clinical practice, many cases that do not meet current
diagnostic criteria but that have a good response to corticosteroid treatment.
Keywords: autoimmune cholangitis, primary biliary cirrhosis, hyper IgG4 syndrome.
Cholestatic syndromes are very often encountered in
gastroenterology practice. The causes may be quite
different but there is a largely accepted consensus of
classification into two categories: extrahepatic and
intrahepatic, rendering very different treatment and
prognosis. A proper diagnosis is mandatory for a
proper treatment. Conversely, a failure of a correct
diagnosis may result in wrong treatment and medicolegal issues. The subject of malpraxis legal actions is
often considered to be associated with an
embarrassing professional failure with only punitive
results. In fact, the conclusions of malpraxis cases
may, as well, give very documented information to
healthcare professionals in order to better improve
medical care.
The differential diagnosis of the causes of cholestatic
syndromes is quite challenging. An extrahepatic cause
is an obstructive one, may it be acute (billiary colic) or
slowly developing (benign or malign strictures,
28
pancreatic head tumor, ampuloma). The imaging
workup (CT scan, cholangioMRI) are sufficiently
revealing for an extrahepatic obstructive cause in
order to conduct a proper treatment. The
intrahepatic cholestatic syndromes are even more
challenging as there are a quite large array of very
different causes with very different treatment and
prognosis spanning from viral hepatitis to primary
billiary cirrhosis and primitive sclerosing cholangitis.
The rare the cause the frequent misdiagnosis and
medico-legal consequences.
Among rare intrahepatic causes, autoimmune
cholangitis is a term recently coined for a spectrum of
1 Carol
Bucharest
3 Titu Maiorescu University, Faculty of Medicine,
Bucharest
cholestatic liver diseases where an immunologic
pathological mechanism is highly suspected with
regard to the cause of inflammation of bile ducts. This
term implies also a fare response to
immunosuppressive therapy. There is, though, some
confusion in literature regarding this disease as it may
refer to several ailments: an overlap syndrome
between
primary
biliary
cirrhosis
AMA
(antimithocondrial
antibodies)
negative
and
autoimmune hepatitis, a form of hyper IgG4
syndrome (associated with autoimmune pancreatitis),
a separate entity as a transition form in spectrum of
cholestatic disorders. This confounding data makes
the diagnosis in this cases very difficult and, also, a
potential source of medico-legal issues
The name autoimmune cholangitis was coined for the
first time be Brunner et al1 to describe the situation of
three patients suffering of primary biliary cirrhosis
AMA negative; all those patients had antinuclear
antibody (ANA) and cholangiopancreatography
showed no abnormality. The therapy with
prednisolone and azathioprine was successful.
The antigen specificity for AMA was demonstrated to
be an inner membrane mithocondrial antigen, a 74
kDa E2 subunit of pyruvate dehidrogenase complex
(PDC-E2). The most sensitive lab test to assess the
presence of these antibodies is an ELISA using
recombinant or purified antigens.
5 to 8% of patients suffering of primary biliary
cirrhosis lack AMA in spite of having typical clinical
and histological features of this disease.2 All of these
patients had ANA (antinuclear antibodies), highly
suggestive of autoimmune hepatitis. Moreover the
level of serum IgM was significantly lower in these
patients then AMA positive counterparts.
Considering the fact that AMA may have a role in the
pathogenesis of the disease, a study by Kitami et al of
patients AMA negative and AMA positive
demonstrated that there is not truly AMA negative
primary biliary cirrhosis. Kitami performed an
exhaustive immunoblotting studies of various inner
mithocondrial membrane antigens that are not
currently looked for.3
From the pathologist's point of view AMA positive
patients have an increased risk of cirrhosis comparing
with AMA negative counterparts. Among histological
features, the granulomatous destruction of bile ducts
is the only histological marker highly specific for
primary biliary cirrhosis AMA negative or positive, but
this lacks sensitivity. These data further increases the
difficulty of diagnosis.4
What about the treatment: ursodeoxycholic acid is
the treatment of choice in both forms of primary
biliary cirrhosis with equal efficiency.
Autoimmune cholangitis may also be a manifestation
of immunoglobulin G4 associated systemic disease,
most commonly encountered in patients with
autoimmune pancreatitis. Autoimmune pancreatitis
(AIP) was first described by Yoshida and colleagues5 in
1995 referring to a type of chronic pancreatitis with
certain histopathologic and imaging features. Early or
atypical manifestations of autoimmune cholangitis
may not involve the pancreas, thus making the
diagnosis even more challenging. There are no
definitive diagnosis criteria so far, also some have
been proposed like Mayo criteria (HISORt) and Asian
Consensus Criteria. Two types of AIP have been
described: type I which is a pancreatitis associated
with immunoglobulin G4 systemic disease
characterized by lymphoplasmocitic infiltration and
elevated serum IgG4 levels; type II which is less
commonly associated with elevated serum IgG4
levels and involves a granulocytic infiltration. 44% of
all patients do not have hyper IgG4 serum levels.6 The
cholangitis is a sclerosing stricturing inflammation of
bile ducts. The occasional absence of pancreatic
involvement have been described. The natural course
of AIP involves relapses. Low dose steroid treatment
is very effective treatment.
Besides those two types of autoimmune cholangitis,
the clinical practice may come along different
situations where an intrahepatic cholestatic
syndrome may not have sufficient diagnostic criteria
to render a proper diagnosis also the response to
corticosteroids is straight forward. These situations
may be prevalent.
29
CASE PRESENTATION
Clinical data
We present the case of a male patient aged 48, living
in country area, driver, who is admitted in an
emergency department for biliary colic comprising of
Charcot triad (colicky pain, fever, jaundice), intense
itching, acolic stools and hyperchrome urine. This
clinical picture is elicited by a fatty meal. The patient
does not smoke cigarettes or drink alcohol and
personal as well as family disease history are
unremarkable.
Labs data
Labs indicates a cholestatic syndrome (increased total
bilirubine – 7.5 mg/dL, direct bilirubine – 5.3 mg/dL,
alkaline phosphatase – 190 UI/L, gammaglutamyl
transpeptidase – 130 UI/L), hepatocytolitic syndrome
(increased alanine aminotransferase ALAT – 300 UI/L,
aspartate aminotransferase ASAT – 120 UI/L),
minimum pancreatic reaction (increased serum
amylase – 200 UI/L).
Abdominal US indicated an increased common bile
duct (8 mm) with normal sized intrahepatic ducts,
thickened gall bladder walls (3 mm) with multiple
small (less than 1 cm) calculi. The clinical picture
subsides progressively due to a treatment with:
antispastics, antibiotics and proton pump inhibitors.
The itching and jaundice didn't subside, though. The
total bilirubine level reaches 5 mg/dL and direct
bilirubine 2.7 mg/dL. In this particular moment the
patient is referred to our clinic with the diagnosis of
remitted biliary colic and with indication of elective
endoscopic biliary sphincterotomy.
Clinical exam was remarkable for intense
sclerotegumentary jaundice, pruritus, dark urine and
white chalky stools.
Otherwise the patients had no complains.
Labs indicated normal CBC, cholestatic syndrome
(increased total bilirubine – 7.7 mg/dL, direct
bilirubine – 4.3 mg/dL, alkaline phosphatase – 199
UI/L, gammaglutamyl transpeptidase – 133 UI/L),
hepatocytolitic syndrome (increased ALAT – 307 UI/L,
aspartate aminotransferase ASAT – 107 UI/L), no
30
pancreatic reaction (serum amylase – 49 UI/L),
normal serum albumin, normal INR.
Imaging and and endoscopy data
Abdominal US indicated: normal size and ecogenicity
of the liver, normal sized common bile duct (6 mm),
normal gall bladder with minimal biliary sludge. We
performed superior digestive endoscopy and sideview duodenoscopy which were unremarkable for
pathologic changes, but indicated increased amount
of intraluminal bile and a normal papilla major. CT
scan with radiocontrast media was unremarkable.
Colangio MRI was, also, unremarkable.
Immunology data
In the meanwhile the level of total bilirubine
continued to increase to 8.5 mg/dL without the sharp
predominance of direct fraction. An extended lab
workup indicated: normal level of gammaglobulin,
AgHBs negative, Ab antiHBc negative, Ab anti HCV
negative, Ab anti HAV negative, CA 19-9 negative,
alpha fetoprotein normal, CEA negative, AMA
negative, Ab anti LKM1 negative, ANA negative,
ASMA negative, pANCA negative, cANCA negative, Ab
anti Ro negative, Ab anti La negative, Ab anti HIV
negative.
Histopathology data
Liver biopsy was performed: liver tissue sample with
marked biliary stasis predominantly intraductular,
biliary clots, areas of hepatocellular steatosis, chronic
inflammatory infiltrate of portal areas and
intralobular areas, hepatocellular regeneration,
interface hepatitis with bridging necrosis. (Figure 1,
Figure 2).
This description fits into pathology diagnosis of
autoimmune cholangitis.
Diagnosis and differential diagnosis
We agreed upon the final diagnosis: autoimmune
cholangitis; remitted biliary colic by passage of
microcalculi. Hence, it has been concluded that the
patient had two different causes of jaundice (acute
extrahepatic cholestasis and chronic intrahepatic
cholestasis), segregated by quite different prognosis
and treatment. Considering the presence of interface
hepatitis with chronic inflammatory infiltrate it had
suggested that future evolution of clinical,
serological, immunological and histopathology data
may be in the direction of an overlap syndrome
between AMA negative PBC and autoimmune
hepatitis. The differential diagnosis included:
primitive and secondary sclerosing cholangitis,
primitive biliary cirrhosis, HIV cholangitis, Sjogren
syndrome, non Hodgkin lymphoma.
The treatment was highly effective (32 mg of
methylprednisolone daily – 0.5 mg/kg prednisolon
equivalent – with tapering to 8 mg daily in one month
and ursodeoxicholic acid 10 mg/kg daily), resulting in
disappearance of cholestasis and hepatocitolysis after
2 month. The dosage of Medrol reached 4 mg per day
in the 4th month of treatment, the current clinical
and biological status of the patient being excellent.
Figure 1. Biliary clots (hematoxilin-eosine dye)
Figure 2. Interface hepatitis and bridging necrosis (hematoxilin-eosine dye)
DISCUSSION AND CONCLUSION
Autoimmune cholangitis is a very challenging
diagnosis in the face of a lack of international
consensus on terminology used in the literature. This
very particular confounding situation may come in
defense of the practitioner in case of a malpraxis legal
action as it may occur. On the other hand should the
diagnosis be late the disease may progress to
complications such as cirrhosis, liver failure and,
even, death. Referral of patient to a tertiary center of
hepatology may be a reasonable course of action to
31
fully benefit medical care act. This is not always very
handy.
A diagnosis workup involves various differential
diagnosis of cholestasis syndrome; among these
diagnosis AMA negative primary biliary cirrhosis,
primitive sclerosing cholangitis of small ductules and
hyperIgG4 cholangitis are the most important. Liver
biopsy, high definition imaging workup and
immunology panels are mandatory for a proper
diagnosis.
The response to corticosteroid treatment is highly
suggestive of immunologic process involved in the
pathogenesis of liver ailment but it is not,
whatsoever, pathognomonic as some are tempted to
consider. The diagnostic criteria may uncover
progressively in time, endorsing the idea of a
continuum in a spectrum of autoimmune cholestatic
diseases.
References:
1 Brunner G, Klinge 0. A cholangitis with antinuclear
antibodies (immunocholangitis)
resembling chronic destructive non-suppurative cholangitis.
Dtsch Med Wochenschr, 1987; 112: 1454-8.
2 Sherlock S, Scheuer PJ. The presentation and diagnosis of
100 patients with primary biliary cirrhosis. N Engl J Med
1973; 283: 674-8.
3 Kitami N, Komada T, Ishii H. Immunological study of antiM2 in mitochondrial antibody negative primary biliary
cirrhosis. Intern Med 1995; 34:496-501.
32
4 Margaret F. Bassendine, Chapter 15, Sherlock's Diseases
of the Liver and Biliary System, Twelfth Edition. Edited by
James S. Dooley, Anna S.F. Lok, Andrew K. Burroughs, E.
Jenny Heathcote.Blackwell Publishing Ltd. Published 2011
by Blackwell Publishing Ltd.
5 Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K,
Hayashi N: Chronic pancreatitis caused by an autoimmune
abnormality. Proposal of the concept of autoimmune
pancreatitis. Dig Dis Sci 1995, 40:1561-1568.
6 Gyanprakash A. Ketwaroo and Sunil Sheth; Autoimmune
pancreatitis; Gastroenterology Report (2013) 1-7
EDUCATION AND IMAGING
Article received on January 19, 2015 and accepted for publishing on January 30, 2015.
Capsule endoscopy
Raluca S. Costache1,2
We present the case of a 42 years old, female,
diagnosed with chronic hepatitis C viral infection
treated with peginterferon and ribavirin.
During the treatment she was admitted in the
hospital with persistent diarrhoea, weight loss, and
anemia. The serologic tests for celiac disease were
positive together with upper endoscopy.
We performed small bowel investigation with
Endocapsule in order to determine the extent of
disease.
The images (figures 1, 2 and 3) show typical aspects
of celiac disease: absence of normal villi, nodularity of
the jejunal mucosa with absent folds, fissuring and
mild nodularity of the valvulae coniventes.
The gluten free diet was beneficent for the patient
which continue the antiviral treatment with sustained
viral response.
33
CLINICAL PRACTICE
Article received on October 30, 2014 and accepted for publishing on December 15 2014.
Paraneoplastic Cushing’s Syndrome in a patient with
multiple tumors – case report
Adina Mazilu1; Mona Gheorghiu2,3; Mădălina Mușat2,3; N. Tănase1; R. Petrescu1; A. Ciuche1; A. Tudose1;
Florina Vasilescu1
INTRODUCTION
Paraneoplastic Cushing syndrome represents 5-10%
of all Cushing syndrome and has a severe prognosis
due to severe metabolic imbalance, denutrition,
associated infections and progression of tumoral
underlying pathology. The death is a rule in more
than 50% of cases. Some medication used to treat it –
Metirapone – is not available in Romania.
Ketoconazole was recently approved by CHMP for
treatment of paraneoplastic Cushing’s only in
November 2014.
CLINICAL CASE
A 67 years old woman presented on the 21st of
November with mental confusion, progressive weight
loss, severe edema and kypokalemia, without typical
features of Cushing or hyperpigmentation. Patient’s
behavior changed in the last 5 months, she was nasty
with her daughter, bickering, while diabetes and
hypertension aggravated in the last 3 months.
The electrolytic imbalance was severe at admission K
1.65 mmol/l, in spite of multiple attempts to correct
it with 150 mmol/day KCl on peripheral i.v. line, 40
mmol/day of KCl orally and 200 mg/day of
Spironolactone, treatment used initially in “C. I.
Parhon” National Institute of Endocrinology. Patient
was transferred in the I. C. U. of “Dr. Carol Davila”
Central Military Emergency Hospital for the weekend,
34
in order to obtain a better control using a central
intravenous catheter.
Laboratory work and imaging
One month prior to admittance patient had
hypercortisolism, with normal hepatic citolytic
enzymes and normal TSH, free T4 and calcitonin
values. Investigations at admittance revealed
paraneoplastic Cushing’s with ACTH 82.5 pg/ml,
cortisol levels more than 63 mcg/dl, UFC (urinary free
cortisol) 2,866 mcg/24 h (21-111); DHEA-sulfate 230.5
mcg/24 h; 2 mg Dexametasone suppression test
showed unsuppressed cortisol 59.17 mcg/dl, ACTH
123.8 pg/ml.
Patient also associated empty sella syndrome with
thyrotrophic and gonadotrophic insufficiency, normal
prolactin and IGF-1, normal mineralocorticoid
hormones, cathecolamines, serotonin and 5HIAA,
slightly enlarged cromogranine A – 148 ng/ml (upper
limit 125 ng/ml).
Patient had also left breast tumor, Helicobacter pylori
gastritis, polinodular goiter, denutrition and hepatic
dysfunction.
Imaging techniques: 99m Tc Tektrotyd scintigraphy
1 Carol
Bucharest
2 C.I. Parhon National Institute of Endocrinology, Bucharest
showed uptake at 10 minute in left breast and jejunal
loop; upper and lower endoscopy, echo endoscopy –
revealed no tumors; bronchoscopy – no visible tumor
(after procedure, patient suffered a syncope that
lasted 2 minutes); thyroid ultrasound – found nodule
of 15/18/22 mm located in the lower part of left lobe
– 15/18/22 mm, with low peripheral vascularisation,
uptakes iodine at CT scan and has a peripheral
calcification.
Figure 1. Abdominal CT-showed minimally enlarged right
adrenal gland, with nodule 0.88/0.88 cm; enlarged left
adrenal gland, with nodule of 1.03/1.24 cm.
interstitial pneumonia – fibrinogen 660 mg/dl, with
high liver enzymes – AST 87-160 UI/l, ALT 95-103
UI/L, GGT 348-365 UI/l, total bilirubine 2.44 mg/dl,
leucocytes 13,400/mm3, granulocytes 8,500/mm3.
Cortisol levels were 26.3-29.2 mcg/dl and
Ketoconazole was increased to 1,200 mg/day, also
associating Tavanic 500 mg initially, then Tigecycline
100 mg/day. The high values of ALT and AST were
due to sepsis and did not increase after doubling
Ketoconazole dosage. After 1 day of high dose
Ketoconazole, K was 4.7 mmol/l, allowing
introduction of Mifepristone 200 mg/day. The
seventh day after Mifepristone was introduced,
cortisol levels were 18.7 mcg/dl (4.2-38.4), allowing
surgery.
Due to denutrition, pulmonary sepsis, lack of
localization of tumor – lung/thyroid/ileum, recent
syncope, severe brain atrophy with cognitive
impairment, we decided to perform left adrenal gland
resection.
The adrenal resection was difficult due to diffuse
bleeding and lack of tissue elasticity.
Figure 2. Thoracic CT revealed pulmonary tumor located in
Fowler segment of left superior lung lobe.
Hepatic biopsy showed periportal fibrosis, but no
necrosis of hepatocytes, probably due to toxic
substances used at work; left adrenal was 7/3/1.5 cm
in diameters, with focal hemorrhage. Imunochemistry
– Ck7, Ck20, CEA, TF1, ER – negative, MELAN A
positive – suggested diffuse hyperplasia of left
adrenal gland.
Evolution of patient
One hour after left adrenalectomy – cortisol was 18.2
mcg/dl, ACTH 42.3 pg/ml, patient needed inotrop
support with Noradrenaline, hydrocortisone 75 mg 1
day, 50 mg in the second day.
Treatment
We initiated treatment with Ketoconazole 400 mg, 1
day, and then 600 mg, for 2 days, but with
inadequate correction of alkalosis and kypokalemia –
pH was 7.54-7.59, BE 5.7-9.8 mmol/l, K 3.16 mmol/l.
The third day patient became septic (probably MRSA
Staphylococcus) due to central catheter and
The third day cortisol desupressed to 51.25 mcg/dl,
ACTH 43 pg/ml (3-66), K decreased again to 2.9
mmol/l, Hb was 8.4 g/dl. Ketoconazole 600 mg/day
was started again. Patient had fever, delirium,
pulmonary riles, so Meronem was initiated for 2 days,
then Tigecycline 3 days, then 7 days of Klacid at
home, also Calcium 1 g/day, 1,000 UI D3, 0.5 mcg of 1
alfa-calcidol/day, hepatic protection, vitamins, basal
insulin.
35
Figure 3. Cromogranine staining – magnification 20X –
proves neuroendocrine tumor.
Evolution after second surgery: 1 day after carcinoid
resection ACTH was 5.95 pg/ml (3-66), cortisol 17.38
mcg/dl – labs were done at „C. I. Parhon”Institute.
12 days after carcinoid resection: ACTH 16.56 pg/ml
(7.2-63); Cortisol 10.72 mcg/dl (6.2-19.4).
At 22 days: she lost 8 kg, ACTH 19.1 pg/ml, normal
ALT and AST, GGT 236 UI/l, Mg 1.39 mg/dl, Ca 9.96
mg/dl.
At 47 days: she lost 15 kg, ACTH 16.5 pg/ml; cortisol 9
mcg/dl, Mg low even with supplementation.
Figure 4. Ki67 staining – magnification 40X – reveals Ki67 of
3% in pulmonary nodule (well-differentiated tumor).
At 78 days: GGT 259 UI/l (5-36), Mg 1.45 mg/dl, K
3.83 mmol/l, glucose 142 mg/dl, cortisol 20.87
mcg/dl, TSH 2 microUi/ml.
At 3 months: basal cortisol 11.2 mcg/dl (6.2-19.4),
basal ACTH 17.46 pg/ml (3-88), cortisol 24 EET – 3.24
mcg/dl, cortisol during suppression test with
Dexamethasone 1 mg overnight – 0.48 mcg/dl, PTH
12.32 pg/ml (15-165), low 25OH–D 12.8 ng/ml (30100), UFC 40.3 mcg/24 h (21-111).
We also performed control thoracic CT – revealed left
breast tumor of 0.76/1.21 cm, right adrenal with
stationary aspect; portal vein was enlarged 14.5 mm;
patient performed FNAB of left thyroid nodule on 20
April 2015, showing benign adenoma.
Figure 5. ACTH staining – magnification 20X – ACTH
receptor is present in carcinoid tumor.
Mild kypokaliemia and hypomagnesemia, even with
oral supplementation, sartan therapy and normal
levels of cortisol and ACTH persisted after surgery,
probably due to severe deficit of intracellular
compartment, even at 3 months after carcinoid
resection. Patient does not remember the 2 months
prior to surgery, even if cognitive impairment is mild
now.
COMMENTS
10 days after adrenal resection cortisol was 26.6
mcg/dl, K 3.9 mmol/l, calcium was normal, Mg was
1.57 mg/dl, allowing second operation – resection of
lung tumor – proved to be typical carcinoid with ki-67
3%, ACTH, synaptophysin and cromogranine positive.
36
This case was difficult due to metabolic challenges,
multiple associated pathology, lack of SSTR2 and
SSTR5 receptors on lung carcinoid with negative scan,
mild elevation of cromogranine A levels despite a
typical bronchial carcinoid. Patient’s sister was
operated for adrenal adenoma confirmed on
histology exam, her daughter had papillary thyroid
cancer, but no MEN association was proven in this
family. Patient needed more than 30 days of hospital
admittance in two different hospitals and five clinics
in order to obtain a good clinical result. The vital risk
was high due to sepsis, denutrition, metabolic and
ionic imbalance, hepatic lesions, anesthesia, brain
atrophy, relative adrenal insufficiency after surgery.
cortisol levels to be reached before surgery, nor the
duration of Ketoconazole wash-out to prevent
adrenal insufficiency.
Recently the patient discovered ductal invasive left
breast carcinoma, operated at 6 months after
thoracic surgery and will soon start chemotherapy.
There are no guidelines that state the adequate
References:
1. Paraneoplastic Syndromes: An Approach to Diagnosis
and Treatment, Lorraine C. Pelosof MD, PhD and David E.
Gerber MD, Mayo Clin Proc. 2010 Sep; 85(9): 838–854. doi:
10. 4065/mcp. 2010. 0099
2. Paraneoplastic Cushing’s syndrome presenting as
psychosis – case report, Cristina Spiroiu, Aurelian Emil
Ranetti, Ana-Maria Mihai, Adina Mazilu & Nicolae Diaconu,
Endocrine Abstracts (2007) 14 P501
3. Ketoconazole in the management of paraneoplastic
Cushing's
syndrome
secondary
to
ectopic
adrenocorticotropin production. Winquist EW, Laskey
J, Crump M, Khamsi F, Shepherd FA, Journal of Clinical
Oncology, 1995 Jan; 13(1):157-64.
4. Extraordinary effect of ketoconazole in treatment of
ACTH-dependent paraneoplastic Cushing syndrome, Andrea
Boháciková, Michal Kulich & Peter Vanuga, Endocrine
Abstracts (2013) 32 P565 , DOI:10. 1530/endoabs. 32. P565
37
CLINICAL PRACTICE
Article received on October 12, 2014 and accepted for publishing on November 15 2014.
Median arcuate ligament syndrome (Dunbar Syndrome)
Crina Laslo1, Anamaria Puiu1, Ștefan Mardale2, Iulian Raus2, Cosmin Căpușan2
This rare condition is caused by extrinsic
compression, given the low abnormal insertion of
median arcuate ligament or fibrous bands and
ganglion periaortitis tissue from the celiac plexus. The
ligament is composed of tendon medial edges of the
two poles of the diaphragm which meet in the
median plane to form an arch before the aorta.
Figure 1. Graphic image of the arcuate ligament compressing the celiac trunk
Case courtesy of Dr Matt Skalski, Radiopaedia.org, rID: 36837
The clinical presentation is variable:
- In most cases asymptomatic
- Weight loss
- Chronic abdominal pain
- Postprandial abdominal discomfort
- Hypertension and tachycardia in the case of renal
artery compression
The diagnosis is one of exclusion. Symptomatic
patients have numerous investigations for most cases
of abdominal pain and underwent cholecystectomies
and appendectomies, many unnecessary in order to
38
alleviate the pain. Diagnosis methods: Doppler, angioCT, angiography or MRI. The gold standard is the
angioCT.
Angio-CT: it is highlighted, on sagittal reconstruction,
a focal stenosis in the proximal portion of the celiac
trunk, bent (hooked appearance). 3D reconstructions
can be helpful in identifying stenosis. Gastroduodenal and hepatic arteries can often be seen as
prominent with multiple collaterals.
Differential diagnosis based on imaging is made with
atherosclerotic disease.
Our patient D.G., male, aged 53, known with
hypertension responsive to treatment and diabetes
type II non-insulin requiring, with no clinical
complaints, came to the Nephrology Department
where an abdominal ultrasound was performed and a
pancreatic formation was detected. He came to our
department for abdominopelvic CT with contrast iv.
Treatment
During examination, multiple arterial branches arising
from the pancreatic duodenal artery and superior
mesenteric artery (arch pancreatitis) are observed,
which include pancreatic duodenal region; filiform
stenosis in the aortic origin of the celiac trunk,
through the median arcuate ligament.
As treatment methods may be used: conventional
laparotomy, laparoscopy or endovascular methods
(percutaneous transluminal angioplasty, stent
implantation).
Figure 2. Axial section acquired during early arterial time
that highlights arterial type collateral circulation between
AMS and the celiac trunk at the level of the pancreatic
duodenal arch.
The goal of the treatment is to decompress and
obtain celiac artery revascularization.
Treatment options are quite limited and the
revascularization surgery has a risk of morbidity and
mortality of 5% to 15%.
Laparotomy, by retroperitoneal approach via left
subcostal incision or by transabdominal approach via
midline incision, allows surgical separation of the
median arcuate ligament fibers to decompress the
celiac artery. Decompression is completed by celiac
ganglion resection and evaluation of celiac artery
blood
flow
using
a
Doppler
ultrasound
intraoperatively. In case of low blood flow, celiac
artery revascularization is performed.
Figure 4. 3D VR Image highlighting the filiform stenosis at
the origin of the celiac trunk
Figure 3. Sagittal MPR highlighting the trunk celiac filiform
stenosis..
Revascularization methods
bypass, angioplasty patch.
include
aorto-celiac
Literature studies show that classical laparotomy is
no longer prefered, due to an increased risk of
morbidity and mortality, especially in patients with
associated pathologies.
Laparoscopy is used more frequently compared to
laparotomy because it is less invasive presenting a
lower risk of morbidity and mortality, with low cost
due to short hospitalization.
39
Laparoscopic intervention also allows decompression
of celiac artery, but if the celiac artery requires
revascularization, surgical management should be
changed and the classic approach should be used
(laparotomy).
Stent implantation offers a metallic support that
prevents elastic recoil and thus decreases the
complications of this type. The risks of this method
include distal embolism with secondary ischemia, fat
embolism, aortic dissection.
Percutaneous balloon angioplasty is an attractive
method because it is a minimally invasive procedure,
ideal for patients with associated comorbidities. This
method delivers suboptimal results because most
lesions develop in the ostium. Percutaneous balloon
angioplasty in ostial lesions is associated with more
severe residual stenosis due to intense elastic recoil
caused by a large number of circular elastic fibers
from the ostium. Because of this, the rate of
complications (acute occlusion) and restenosis
increases.
Percutaneous angioplasty and stent implantation,
according to a 2009 study, are complementary
methods to laparoscopy after decompression of
celiac artery was performed.
DISCUSSION
The peculiarity of this case is that the patient did not
present any symptoms. This may be due to the
development of a rich collateral blood supply that
compensates for celiac artery stenosis.
References:
1. Baccari P, Civilini E, Dordoni L, Melissano R: Celiac artery
compression syndrome managed by laparoscopy. Journal of
vascular surgery, vol. 50 pp.134-139 2009.
3. Radiopaedia.org (internet).UBM Medica network; c20052015 rID:1143 Accesed at http://radiopaedia.org/articles/
coeliac artery compression syndrome.
2. Muqeetadnan M, Amer S, Rahman A, Nusrat S, Hassan S:
Celiac artery compression syndrome. Case reports in
gastrointestinal Medicine, vol.2013, article ID 934052, 3
pages, 2013.
4. Schaan de Quadros A, Sarmento-Leite R, Moraes C. Stent
Implantation in Critical Stenosis of Celiac Trunk: Enlarging
the Frontiers of Percutaneous Vacular Interventio. Arquivos
Brasileiros de Cardiologia, vol 83, no.5 pp. 445-447, 2004.
40
VARIA
41
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42
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The journal employs a plagiarism detection system. By
submitting your manuscript to this journal you accept that
your manuscript may be screened for plagiarism against
previously published works.
Committee on Publication Ethics
The journal subscribes to the principles of the Committee
on Publication Ethics (COPE).
MANUSCRIPT CATEGORIES AND SPECIFICATIONS
All articles, with the exception of Editorials, must contain an
abstract of no more than 250 words. Abstracts for original
articles should be formatted into subheadings, as detailed
below. Titles must not be longer than 120 characters
(including spaces).
Editorials
These are invited by the Editor-in-Chief or their delegated
editor, and should be a brief review of the subject
concerned, with reference to and commentary about one
or more articles published in the same issue of RJMM.
Editorials are generally 1200–1500 words, may contain one
table or figure and cite up to 15 references, including the
source article [this should be cited as Military Med. Today
(year); (vol): [this issue].
Review Articles
RJMM welcomes reviews of important topics across the
scientific basis of medicine, and advances in clinical
practice. Most published reviews are in response to
editorial invitation, including thematically related “miniseries” of reviews. Authors considering submitting a review
for RJMM are advised to canvas their possible review with
the Editor-in-Chief or a colleague editor; this avoids early
rejection if the subject matter is not deemed a high priority
for the Journal at the time of submission. Reviews are
limited to 3500–5000 words, with an abstract of up to 250
words and up to 75 references and 3–7 figures or tables.
Meta-Analyses or Systematic Reviews
RJMM particularly welcomes submission of Meta-Analyses
and Systematic Reviews, which underpin evidence-based
medicine. Guidelines for preparation of Meta-Analysis and
Systematic Reviews are similar to other reviews, and
articles are subject to the usual peer review process. MetaAnalyses and Systematic Reviews have a word limit of
3500–5000 words, with an abstract of up to 250 words and
up to 75 references and 3–7 figures or tables.
Original Articles (including clinical trials)
RJMM welcomes original articles concerned with clinical
practice and research in the fields of medicine. Papers can
cover the medical, surgical, radiological, pathological,
biochemical, physiological, ethical and/or historical aspects
of the subject areas. Clinical trials are afforded expedited
publication if deemed suitable. RJMM also deals with the
basic sciences and experimental work, particularly that with
a clear relevance to disease mechanisms and new
therapies. Original articles are limited to 3000 words, with
an abstract of up to 250 words and up to 50 references and
3–7 figures and tables.
Education and Imaging
The Editors welcome contributions to the Education and
Imaging section. The purpose is to present imaging for the
evaluation of unusual features of common conditions or
diagnosis of unusual cases. Contributions will be reviewed
by the Education and Imaging Coordinating Editors. The
format of the Images pages involves two parts, each of
which will occupy up to one journal page. In part 1, a case
will be described briefly, including a summary of the
presentation, clinical features and key laboratory results.
One to two key images will then be presented. It is helpful
to the reader if the author responds to questions that
follow from the images of the case, such as ‘What is your
diagnosis? What are the features indicated on the CT scan?
What is the differential diagnosis?’ Part 2 will briefly
describe the imaging features, particularly those that lead
to diagnosis or which are critical for management.
Differential diagnosis should be mentioned. It will be useful
to include either further images or pathological details that
validate the imaging diagnosis. Occasionally, presentation
of analogous cases or related images from a similar case
might be appropriate. Please include between one and
three references to definitive studies and appropriate
reviews of the subject. The format of the Images page
involves a brief background to and description of the
disorder of interest together with two figures of high
quality. Colored photographs are encouraged. The
submission may take the form of a case report or may
illustrate particular features from more than one patient.
MANUSCRIPT PREPARATION
Style
Manuscripts should follow the style of the Vancouver
agreement detailed in the International Committee of
Medical Journal Editors’ revised ‘Uniform Requirements for
Manuscripts Submitted to Biomedical Journals: Writing and
Editing for Biomedical Publication’, as presented at
http://www.ICMJE.org/.
Spelling. The journal uses US spelling and authors should
therefore follow the latest edition of the MerriamWebster’s Collegiate Dictionary.
Units. All measurements must be given in SI units as
outlined in the latest edition of Units, Symbols and
Abbreviations: A Guide for Biological and Medical Editors
and Authors (Royal Society of Medicine Press, London).
Abbreviations should be used sparingly and only where
they ease the reader’s task by reducing repetition of long
technical terms. Initially use the word in full, followed by
the abbreviation in parentheses. Thereafter use the
abbreviation.
Trade names should not be used. Drugs should be referred
to by their generic names, rather than brand names.
Parts of the Manuscript
The manuscript should be submitted in separate files: title
page; main text file; figures.
Title page
The title page should contain (i) a short informative title
that contains the major key words. The title should not
contain abbreviations; (ii) the full names of the authors (if
possible, not more than 5 authors per title); (iii) the
author's institutional affiliations at which the work was
carried out; (iv) the full postal and email address, plus
telephone number, of the author to whom correspondence
about the manuscript should be sent; (v) disclosure
statement; and (vi) acknowledgements. The present
address of any author, if different from that where the
work was carried out, should be supplied in a footnote.
Disclosure statement
The source of financial grants and other funding should be
acknowledged, including a frank declaration of the authors’
43
industrial links and affiliations. In the case of clinical trials or
any article describing use of a commercial device,
therapeutic substance or food must state whether there
are any potential conflicts of interest for each of the
authors: failure to make such a statement may jeopardize
the article being sent out for peer-review.
Acknowledgments
The contribution of colleagues or institutions should also be
acknowledged. Thanks to anonymous reviewers are not
allowed.
Main text
As papers are double-blind peer reviewed the main text file
should not include any information that might identify the
authors. The main text of the manuscript should be
presented in the following order: (i) abstract and key
words, (ii) text, (iii) references, (iv) tables (each table
complete with title and footnotes), (vii) figure legends.
Figures and supporting information should be submitted as
separate files. Footnotes to the text are not allowed and
any such material should be incorporated into the text as
parenthetical matter.
Abstract and keywords
Original articles must have a structured abstract that states
in 250 words or less the purpose, basic procedures, main
findings and principal conclusions of the study. Divide the
abstract with the headings: Background and Aim, Methods,
Results, Conclusions. The abstracts of reviews need not be
structured. The abstract should not contain abbreviations
or references. Three to five keywords should be supplied
below the abstract and should be taken from those
recommended by the US National Library of Medicine’s
Medical
Subject
Headings
(MeSH)
browser—
(http://www.nlm.nih.gov/mesh/meshhome.html).
Text
Authors should use subheadings to divide the sections of
their
manuscript: Introduction,
Methods,
Results,
Discussion, Acknowledgments and References.
References
The Vancouver system of referencing should be used. In the
text, references should be cited using superscript Arabic
numerals in the order in which they appear. If cited only in
tables or figure legends, number them according to the first
identification of the table or figure in the text. In the
reference list, the references should be numbered and
listed in order of appearance in the text. Cite the names of
all authors when there are six or less; when seven or more
list the first three followed by et al. Names of journals
should be abbreviated in the style used in MEDLINE.
Reference
to unpublished data and
personal
communications should appear in the text only.
References should be listed in the following form:
Number references in the order cited as Arabic numerals in
parentheses on the line. Only literature that is published or
in press (with the name of the publication known) may be
numbered and listed; abstracts and letters to the editor
may be cited, but they must be less than 3 years old and
identified as such. Refer to only in the text, in parentheses,
other material (manuscripts submitted, unpublished data,
personal communications, and the like) as in the following
44
example: (Chercheur X, unpublished data). If the owner of
the unpublished data or personal communication is not an
author of the manuscript under review, a signed statement
is required verifying the accuracy of the attributed
information and agreement to its publication. Use Index
Medicus as the style guide for references and other journal
abbreviations. List all authors up to six, using six and "et al."
when the number is greater than six.
Tables
Tables should be self-contained and complement, but not
duplicate, information contained in the text. Number tables
consecutively in the text in Arabic numerals. Type tables on
a separate page with the legend above. Legends should be
concise but comprehensive – the table, legend and
footnotes must be understandable without reference to
the text. Vertical lines should not be used to separate
columns. Column headings should be brief, with units of
measurement in parentheses; all abbreviations must be
defined in footnotes. Footnote symbols: †, ‡, §, ¶ should be
used (in that order) and *, **, *** should be reserved for Pvalues. Statistical measures such as SD or SEM should be
identified in the headings.
Figure legends
Type figure legends on a separate page. Legends should be
concise but comprehensive – the figure and its legend must
be understandable without reference to the text. Include
definitions of any symbols used and define/explain all
abbreviations and units of measurement Indicate the stains
used in histopathology. Identify statistical measures of
variation, such as standard deviation and standard error of
the mean.
Figures
All illustrations (line drawings and photographs) are
classified as figures. Figures should be numbered using
Arabic numerals, and cited in consecutive order in the text.
Each figure should be supplied as a separate file, with the
figure number incorporated in the file name.
Preparation of Electronic Figures for Publication: Although
low quality images are adequate for review purposes,
publication requires high quality images to prevent the final
product being blurred or fuzzy.
SUBMISSION REQUIREMENTS
Manuscripts
should
be
submitted
online
at
[email protected]
A cover letter containing an authorship statement should
be included.
The cover letter should include a statement covering each
of the following areas:
1. Confirmation that all authors have contributed to and
agreed on the content of the manuscript, and the
respective roles of each author.
2. Confirmation that the manuscript has not been published
previously, in any language, in whole or in part, and is not
currently under consideration elsewhere.
3. A statement outlining how ethical clearance has been
obtained for the research, particularly in relation to studies
involving human subjects, and animal experimentation. The
institutional ethics committees approving this research
must comply with acceptable international standards (such
as the Declaration of Helsinki) and this must be stated.
4. For research involving pharmacological agents, devices or
medical technology, a clear Conflict of Interest statement in
relation to any funding from or pecuniary interests in
companies that could be perceived as a potential conflict of
interest in the outcome of the research.
5. For clinical trials, that these have been registered in a
publically accessible database (see more under 'ETHICAL
CONSIDERATIONS (Further Information)' later in these
guidelines).
If the above items are not included in the cover letter,
manuscripts cannot be sent for review.
Please also note that the cover letter does not require a
detailed or lengthy description of the content or structure
of the manuscript itself.
Two Word-files need to be included upon submission: A
title page file and a main text file that includes all parts of
the text in the sequence indicated in the section 'Parts of
the manuscript', including tables and figure legends but
excluding figures which should be supplied separately.
The main text file should be prepared using Microsoft
Word, doubled-spaced. The top, bottom and side margins
should be 30 mm. All pages should be numbered
consecutively in the top right-hand corner, beginning with
the first page of the main text file.
Each figure should be supplied as a separate file, with the
figure number incorporated in the file name. For
submission, low-resolution figures saved as .jpg or .bmp
files should be uploaded, for ease of transmission during
the review process. Upon acceptance of the article, highresolution figures (at least 300 d.p.i.) saved as .eps or .tif
files will be required.
PUBLICATION PROCESS AFTER ACCEPTANCE
Accepted papers will be passed to production team for
publication. The author identified as the formal
corresponding author for the paper will receive an email,
being asked to complete an electronic license agreement
on behalf of all authors on the paper.
Accepted Articles
The accepted ‘in press’ manuscripts are published online
very soon after acceptance, prior to copy-editing or
typesetting. Accepted Articles are published online a few
days after final acceptance, appear in PDF format only, are
given a Digital Object Identifier (DOI), which allows them to
be cited and tracked. After print publication, the DOI
remains valid and can continue to be used to cite and
access the article. Given that copyright licensing is a
condition of publication, a completed copyright form is
required before a manuscript can be processed as an
Accepted Article.
Proofs
Once the paper has been typeset, the corresponding author
will receive an e-mail alert containing instructions on how
to provide proof corrections to the article. It is therefore
essential that a working e-mail address is provided for the
corresponding author. Proofs should be corrected carefully;
the responsibility for detecting errors lies with the author.
The proof should be checked, and approval to publish the
article should be emailed to the Publisher by the date
indicated; otherwise, it may be signed off on by the Editor
or held over to the next issue.
Offprint
A PDF reprint of the article will be supplied free of charge to
the corresponding author. Additional printed offprint may
be ordered for a fee.
COPYRIGHT, LICENSING AND ONLINE OPEN
Details are on the Copyright Agreement Form that must be
completed and signed when the Article is accepted.
45
Romanian Journal of Military Medicine
Vol. CXVIII, New Series, No 1/2015
ISSN 1222-5126

Romanian Journal of - Spitalul Universitar de Urgenţă Militar Central

Transcription

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