Download Number 1 January/March 2015 Volume 21

Number 1
January/March 2015
Volume 21
Volume 21, Number 1, pp 1 - 76
January/March 2015
4
New ICU - Central Medical Building - Clinical Center University of Sarajevo
Nova Intenzivna njega - Klinički Centar Univerziteta u Sarajevu
5
New Central Medical Building - Clinical Center University of Sarajevo
Novi Centralni Medicinski Blok - Klinički Centar Univerziteta u Sarajevu
Medical Journal
www.kcus.ba
www.kcus.ba
Medical Journal
PUBLISHER
Institute for Research and Development
Clinical Center University of Sarajevo
71000 Sarajevo, Bolnička 25
Bosnia and Herzegovina
For publisher:
Rusmir Mesihović, MD, PhD
General Manager
CCUS
AIMS AND SCOPE
The Medical Journal is the official quarterly journal of the Institute for Research and Development of the Clinical Center University of Sarajevo and has been published regularly since 1994. It
is published in the languages of the people of Bosnia and Herzegovina i.e. Bosnian, Croatian and
Serbian as well as in English.
The Medical Journal aims to publish the highest quality materials, both clinical and scientific, on all
aspects of clinical medicine. It offers the reader a collection of contemporary, original, peer-reviewed papers, professional articles, review articles, editorials, along with special articles and case
reports.
Copyright: the full text of the articles published in the Medical Journal can be used for educational and personal aims i.e. references cited upon the authors’ permission. If the basic aim is
commercial no parts of the published materials may be used or reproduced without the permission of the publisher. Special permission is available for educational and non-profit educational
classroom use. Electronic storage or usage: except as outlined above, no parts of this publication
may be reproduced, stored in a retrieval system or transmitted in any form or by any means
without prior written permission from the Publisher.
All rights reserved©2015. Institute for Research and Development CCUS.
Notice: The authors, editor and publisher do not accept responsibility for any loss or damage
arising from actions or decisions based on information contained in this publication; ultimate
responsibility for the treatment of patients and interpretation of published materials lies with the
medical practitioner. The opinions expressed are those of the authors and the inclusion in this
publication of materials relating to a specific product, method or technique does not amount to
an endorsement of its value or quality, or of the claims made by its manufacturer.
EDITORIAL OFFICE
Address:
Medical Journal, Institute for Research and Development,
Clinical Center University of Sarajevo,
71000 Sarajevo,
Bolnička 25,
Bosnia and Herzegovina,
Phone: +387 33 668 415; +387 33 297 264.
Email: [email protected]
Web. www.kcus.ba
Technical secretariat: [email protected]
Editor-in-Chief: [email protected]
SUBSCRIPTION
Annual subscription rates: Bosnia and Herzegovina € 50; Europe € 80; and other € 100.
Editor-in-Chief
Mirza Dilić
Editorial Board
Zoran Hadžiahmetović, President,
Rusmir Mesihović, Ismet
Gavrankapetanović, Damir Aganović,
Mehmed Gribajčević, Safet Guska,
Almira Hadžović-Džuvo, Bećir Heljić,
Sebija Izetbegović, Adnan Kapidžić,
Abdulah Kučukalić, Bakir Mehić,
Senka Mesihović-Dinarević, Nermina
Obralić, Łilijana Oruč, Sead
Redžepagić, Svjetlana Radović,
Senija Rašić, Sandra Vegar-Zubović,
Mustafa Hiroš, Secretary
International Advisory Board
Kenan Arnautović (USA), Raffaele
Bugiardini (Italy), Erol Ćetin (Turkey),
Maria Dorobantu (Romania), Oktay
Ergene (Turkey), Zlatko Fras (Slovenia),
Dan Gaita (Romania), Mario Ivanuša
(Croatia), Steen Dalby Kristensen
(Denmark), Mimoza Lezhe (Albania),
Mario Marzilli (Italy), Milica MedićStojanovska (Serbia), Davor Miličić
(Croatia), Fausto Pinto (Portugal),
Mihailo Popovici (Moldova),
Marcella Rietschel (Germany), Nadan
Rustemović (Croatia), Georges Saade
(Lebanon), Petar Seferović (Serbia),
Dragan Stanisavljević (Slovenia),
Bojan Tršinar (Slovenia), Panos Vardas
(Greece), Gordan Vujanić (UK), Jose
Zamorano (Spain)
English language revision
Svjetlana Baroševčić
Medical Journal is
Indexed in
EBSCO publishing
USA
www.ebscohost.com
SUPPLEMENTS, REPRINTS AND CORPORATE SALES
For requests from industry and companies regarding supplements, bulk articles reprints, sponsored subscriptions, translation opportunities for previously published material, and corporate
online opportunities, please contact;
Email: [email protected]
PRINT
Eurografika Zvornik
Printed on acid-free paper.
TECHNICAL EDITOR
Eurografika
CIRCULATION
500 copies
Member of National Journals
Networks of the European
Society of Cardiology
Content
Medical Journal (2015) Vol. 21, No. 1
Original article
Evaluation of the intraoperative risk factors for deep vein thrombosis after knee arthroplasty........................ Amel Hadžimehmedagić, Ismet Gavrankapetanović, Đemil Omerović, Haris Vranić, Nermir Granov,
Faris Gavrankapetanović, Faruk Lazović
9
Risk factors associated with malignancy in paraneoplastic dermatomyositis .......................................................... 13
Asja Prohić, Adnan Hadžimuratović, Suada Kuskunović-Vlahovljak, Anes Jogunčić
Relationship between nonenzymatic antioxidant component and free radical nitric oxide in patients with
schizophrenia ............................................................................................................................................................................... 17
Amra Memic, Abdulah Kučukalić, Lilijana Oruč, Jasminko Huskić, Lejla Burnazović, Nafija Serdarević
Osteoporosis and physical activity......................................................................................................................................... 22
Rubina Alimanović-Alagić, Mensur Vrcić, Ramë Miftari, Senad Alagić, Senad Pešto, Elma Kučukalic-Selimović
Significance of bioelastic extramedullary bone osteosynthesis in clinical practice .............................................. 27
Zoran Hadžiahmetović, Narcisa Vavra-Hadžiahmetović
Relevance of fine-needle aspiration cytology compared to histopathology in differentiated thyroid
carcinoma .................................................................................................................................................................................... 30
Šejla Cerić, Timur Cerić, Miran Hadžiahmetović, Selma Agić, Elma Kučukalić-Selimović, Amela Begić, Nermina Bešlić, Sadat Pušina
Contemporary treatment of pathological pregnancies in the first trimester ....................................................... 34
Naima Imširija, Lejla Imširija, Zulfo Godinjak, Sanjin Deković, Mohamad Abou El-Ardat
Alternative approach to supracricoid partial laryngectomy......................................................................................... 38
Predrag Špirić, Sanja Špirić, Dmitar Travar, Slobodan Spremo, Mirjana Gnjatić
Professional article
Sarcopenia ................................................................................................................................................................................... 43
Ksenija Miladinović
Major trauma care at Clinic of Emergency Medicine of the Clinical Center University of Sarajevo ................. 47
Gjulera Dedović Halilbegović, Zoran Hadžiahmetović, Adnana Talić-Tanović, Samra Halilović, Lejla Aldžuz
Outcome of the surgical repair of high and intermediate anorectal malformations in children ........................ 51
Sejdi Statovci, Nexhmi Hyseni, Islam Rashiti, Murat Berisha, Antigona Hasani, Butrint Xhiha, Ali Aliu
Review article
European sterilization standards in the Clinical Center University of Sarajevo . ..................................................... 55
Adnana Talić-Tanović, Aida Pitić, Mahir Trnka, Azra Muzurović
Carbapenem resistant Enterobacteriaceae - increasing issue for global healthcare ............................................. 59
Amela Dedeić-Ljubović
Case report
Recurrent aphthous ulceracions as an initial clinical and patohistological biomarker of Crohn’s disease ........ 63
Amira Dedić, Mersiha Avdić-Saračević, Ljiljana Kesić, Mia Hodžić, Alma Kantardžić
Heroin overdose caused by intranasal administration (sniffing) causes coma, rhabdomyolysis, acute kidney
failure and diffuse hepatopathy .......................................................................................................................................... 67
Amina Godinjak, Amer Iglica, Selma Jusufović, Anes Ajanović, Ira Tančica, Adis Kukuljac, Senad Pešto
Long term survival of unoperated patient with the left ventricular pseudoaneurysm .......................................... 70
Zlatko Šantić, Slobodan Kožul, Katica Mustapić-Šantić
Instructions to authors ............................................................................................................................................................. 72
Uputstva autorima ..................................................................................................................................................................... 74
Original article
Medical Journal (2015) Vol. 21, No. 1, 9 - 12
Evaluation of the intraoperative risk factors for deep
vein thrombosis after knee arthroplasty
Evaluacija intraoperativnih faktora rizika za nastanak
duboke venske tromboze nakon artroplastike koljena
Amel Hadžimehmedagić1*, Ismet Gavrankapetanović2, Đemil Omerović2, Haris Vranić1,
Nermir Granov1, Faris Gavrankapetanović2, Faruk Lazović2
Clinic of Cardiosurgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina,
Orthopedic Clinic, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
2
* Corresponding author
ABSTRACT
SAŽETAK
We researched the association between incidence of deep vein
thrombosis (DVT) after knee arthroplasty and several intraoperative
risk factors: changes of diameter (mm) and flow velocity in posterior tibial vein (PTV) in simulated operative positions; anesthesia duration, and
total duration of operative forced positions (min.). Average values of the
ranges of PTV diameter were the greatest in simulated position 90°+
(3.9725) with statistical significant difference compared to other three
measurements (p<0,05). Average values of the ranges of flow velocity in PTV were the greatest in simulated position „90°+“ (1.0000) with
statistical significant difference compared to other three measurements
(p<0.05). Analysing DVT and non-DVT cases through receiver operating characteristic (ROC) we got critical value of PTV diameter (cut-off:
>2.96 mm), critical value for flow velocity (cut-off: ≤11.71 cm/sec), critical
value for anestesia duration (cut-off: >185 min), and critical value for total
duration of forced position (cut-off: >80 min). The greatest relative risk
(RR) for DVT occurence RR=3.789 (p<0.0001) have had the patients
with anesthesia duration more than 185 minutes. RR was very high at the
patients with forced position duration more than 80 minutes (RR=2.992,
p<0.0001). RR was moderately high at the patients with flow velocity in
simulated position „90°+” ≤11.71 cm/sec (RR=2.091, p<0.0001). We also
noted a signifficant relative risk for vein diameter <2.96 mm in maximal
flexion (RR=1.312, p=0.0028). By the direct logistic regression we made
model to estimate influence of observed parameters on DVT occurence
which precisely classified 83.52% of patients.
Istraživali smo povezanosti između incidence (DVT) nakon artroplastike koljena sa jedne strane i izmjene promjera (mm) i brzina
protoka (cm/sec) u veni tibialis posterior (PTV) u simuliranim operativnim položajima, te dužine trajanja anestezije i ukupne dužine trajanja
prinudnih operativnih položaja (min.) sa druge strane. Prosječne vrijednosti rangova dijametara PTV bile su najveće u simuliranom položaju 90°+ (3.9725) sa značajnom razlikom u odnosu na mjerenja u ostala
tri položaja (p<0.05). Prosječne vrijednosti rangova brzina u PTV bile
su najveće u simuliranoj poziciji „90°+“ (1.0000) sa značajnom razlikom
u odnosu na ostala tri mjerenja (p<0.05). Analizom DVT i non-DVT
slučajeva kroz receiver operating characteristic (ROC) odredili smo
granične vrijednosti promjera (cut-off: >2.96 mm), i brzine protoka u
PTV (cut-off: ≤11.71 cm/sec), te granične vrijednosti trajanja anestezije
(cut-off: >185 min), kao i ukupnog trajanja prinudnog položaja (cutoff: >80 min). Najveći relativni rizik (RR) za nastanak DVT RR=3.789
(p<0.0001) imali su pacijenti kojima je operacija trajala duže od 185
minuta. RR je bio vrlo visok kod pacijenata kojima je prinudni položaj
trajao više od 80 minuta (RR=2.992, p<0.0001). RR je bio visok kod
ispitanika kojima je protok u simuliranim pozicijama bio ≤11.71 cm/sec
(RR=2.091, p<0.0001). Također, značajan rizik imali su i pacijenti koji
su u maksimalnoj fleksiji imali dijametar PTV <2.96 mm (RR=1.312,
p=0.0028). Direktnom logističkom regresijom napravili smo model
za procjenu uticaja posmatranih parametara na nastanak DVT koji je
percizno klasificirao 83.52% pacijenata.
Key words: deep vein thrombosis, haemodynamics, knee arthroplasty, risk factors
Ključne riječi: duboka venska tromboza, hemodinamika, artroplastika koljena, riziko- faktori
INTRODUCTION
ready known. However, analyzes build upon the Virchow’s triad still
do not have a direct answer to the question whether the occurrence
of DVT is a result of dominant influence of one factor, or a result of
cumulative action of several of them for long enough duration.
It has already been proven that certain operative positions are
leading to a complete interruption of venous flow (1). Also, there is
well known evidence of association between increased age, obesity,
a history of thromboembolism, varicose veins, contraceptive thera-
We are witnesses of a daily progress in optimising surgical techniques and strategics, anesthesiological improvements, and postoperative treatment progress. Intensive dynamics in practice requires
equal dynamics in research activities. Thus, the research of surgically
induced deep vein thrombosis (DVT) and its complications has become a kind of a moving target. All the risk factors for DVT are al-
10
A. Hadžimehmedagić et al.
py, malignancy, Factor V Leiden gene mutation, general anaesthesia
and orthopaedic surgery, with higher rates of postoperative DVT (2).
We have researched the association between incidence of DVT
after knee arthroplasty and several independent variables that we
consider as intraoperative risk factors: changes of diameter (mm)
and flow velocity in posterior tibial vein (PTV) in simulated opertative positions; anesthesia duration, and total duration of intraoperative forced positions (min.).
MATERIALS AND METHODS
We observed patients with proper indication for total knee replacement who satisfied our criterion for inclusion in the study. According to protocol all the patients had echosonography in grey scale
and colour Doppler to notice morphological and haemodynamic
changes in four different simulated operative position (extension 0°,
semiflexion 30-60°, flexion 90° and maximal flexion 90°+). Target
vein was PTV in distal calf. After initial ultrasound sample (N=91)
was divided in two groups according to vein flow velocity. Patients
with flow velocity lower than 10cm/sec in any of forced position
were in investigated group (Nb=38), and patients who had more
favourable haemodynamic in forced position were in control group
(Na=53). Intraoperatively we have measured anaesthesia duration
and total duration of all forced positions (in minutes). All patients
had the same anestesiological and surgical protocol for uncemented
total knee replacement. During 42 days of postoperative follow-up
period patients were protected with low molecular weight heparin.
In the same time, we were looking for ultrasound signs of DVT in
regular intervals. The results we got were the basis for statistical
analysis and model creation for assessing the impact of the observed
parameters on the occurrence of postoperative DVT.
RESULTS
Total number of DVT was 19; in group N-a 7 (13.2%), and in
group N-b 12 (31.57%) cases. We did not find statistical significance
in a difference between the groups (X2=3.478; p=0.0622). The largest PTV diameter in extension was 4.2 mm, and the smallest one was
2.12 mm. The largest PTV diameter in semiflexion (300-600) was 4,0
mm, and the smallest one was 2.12 mm. The largest PTV diameter
in 900 flexion was 4.22 mm, and the smallest one was 2.26 mm. The
largest PTV diameter in maximal flexion (900+) was 4.28 mm, and
the smallest one was 2.42 mm. Arithmetical middle values are presented in Table 1.
Table 1 Posterior tibial vein diameter (mm).
Extension - 00
Flexion 300-600
Flexion 900
DIAMETER
Mean
3,085
2,955
3,266
0,5013
SD
0,5131
0,4817
3,060
Median
2,940
3,260
2,740 - 3,485
2,600 - 3,300
2,880 - 3,670
25 - 75P
Flexion 900+
3,439
0,4774
3,480
3,025 - 3,870
Average values of the ranges were the greatest in simulated position 90°+ (3.9725) with statistical significant difference compared
to other three measurements (p<0.05).
Analysing DVT and non-DVT cases through receiver operating
characteristic (ROC curve) we got critical value of posterior tibial
vein diameter (cut-off: >2.96mm). Sensitivity for cut off >2.96mm
of posterior tibial vein in simulated position „900+“ (maximal flexion) was 94.7%, specificity 27.8%, positive predictivity 25.7%, and
negative predictivity 95.2%. Accuracy was 41.8%, confidence interval 0.400-0.613, and probability p<0.916. Area under the curve
(AUC) was 0.507 (Figure 1).
Figure 1 Sensitivity and specificity for posterior tibial vein in
simulated position (90+) ; DVT (n=19); NDVT (n=72).
The highest velocity in full knee extension was 34.72 cm/sec.
And the lowest in the same position was 19.28 cm/sec. The highest
velocity in knee semiflexion (300-600) was 35.81 cm/sec, and the
lowest in the same position was 21.44 cm/sec. The highest velocity
in 900 knee flexion was 30.18 cm/sec, and the lowest in the same
position was 13.26 cm/sec. The highest velocity in maximal knee
flexion (900+) was 26.99 cm/sec, and the lowest 8.12 cm/sec. Arithmetical middle values are presented in Table 2.
Table 2 Flow velocity in posterior tibial vein (cm/s).
Extension 0
Flexion 30 -60
Flexion 90
Flexion 90 +
Mean
27.512
29.067
20.624
13.703
SD
3.9309
3.6353
4.8873
5.4327
Median
28.000
29.120
20.180
11.730
25 - 75P
24.390 - 29.882
26.497 - 30.855
16.445 - 24.817
9.170 - 18.960
VELOCITY
0
0
0
0
0
Average values of the ranges were the greatest in simulated
position „90°+“ (1.0000) with statistical significant difference compared to other three measurements (p<0,05). Using ROC curves
we defined critical value for flow velocity (cut-off: ≤11.71 cm/sec).
Sensitivity for cut-off: ≤11.71 cm/sec in simulated position (90°+)
was 84.21%, specificity was 59.72%, positive predictivity 35.56%,
and negative predictivity 93.48%. Confidence interval was 0.6340.824, accuracy 64.28%; p<0.0001. Area under the curve was 0.737
(Figure 2).
Evaluation of the intraoperative risk factors for deep vein thrombosis after knee arthroplasty
Figure 2 Sensitivity and specificity for velocity in PTV in sim- ulated position (90+) DVT (n=19); NDVT (n=72).
The longest anesthesia duration was 271 minutes, and the shortest was 92 minutes. Arithmetical middle values are presented in Table 3.
Table 3 Anesthesia duration in groups.
Na = 53
N = 91
ANEST. DURAT.
Mean
164.623
171.429
SD
36.3589
38.4945
11
The longest forced position duration was 149 minutes, and the
shortest 46 minutes. Arithmetical middle values are presented in Table 4.
Table 4 Forced position duration.
Na = 53
Nb = 38
N = 91
FORCED POSITION
85.789
75.000
79.505
Mean
34.3969
28.5212
31.3852
SD
77.500
60.000
75.000
Median
60.000 - 120.000
57.500 - 90.000
60.000 - 93.750
25 - 75P
Using ROC curves we defined critical value for total duration
of forced position (cut-off: >80min). Sensitivity for cut-off: >80min
of forced position duration was 78.9%, specificity was 73.6%, positive predictivity 44.1%, and negative predictivity 93.0%. Accuracy
was 74.7%, Confidence interval 0.662-0.845, p<0.0001. AUC was
0.762. (Figure 4).
Nb = 38
180.921
39.8452
Median
170.000
165.000
180.000
25 - 75P
150.000 - 198.750
148.750 - 180.000
150.000 - 210.000
Using ROC curves we defined critical value for anestesia duration (cut-off: >185 min). Sensitivity for cut-off >185 min anestesia duration was 63.2%, specificity 83.3%, positive predictivity was
50.0%, and negative predictivity was 89,6%. Accuracy was 79.1%,
confidence interval was 0.659-0.843, probability p<0.0001. Area
under the curve was 0.760 (Figure 3).
Figure 3 Sensitivity and specificity for anesthesia duration DVT (N=19); NDVT (N=72).
Figure 4 Sensitivity and specificity for forced position duration DVT (N=19); NDVT (N=72).
After we have determinated cut-off values, we calculated relative risk (RR) of DVT in case of borderline values of parameters.
The greatest RR=3.789 (p<0.0001) was noted in patients with anesthesia duration over 185 minutes. RR was very high in patients
with forced position duration more than 80 minutes (RR=2.992,
p<0.0001). RR was moderately high in patients with flow velocity
in simulated ≤11.71 cm/sec (RR=2,091, p<0.0001). We also noted
a signifficant relative risk for vein diameter <2.96 mm in simulated
„90°+“ position (RR=1.312, p=0.0028) .
By direct logistic regression we made model to estimate influence of four independent variable (total anesthesia duration, total forced position duration, flow velocity in maximal flexion, and
vein diameter in maximal flexion) on dependent variable defind as
negative outcome (DVT). The whole model with all his predictors
was statisticaly significant (χ2(4, N=91)=21.104; p=0.0003), which
means that model can recognise patients who will have DVT in 42
days after the knee arthroplasty. Our model precisely classified
83.52% of patients.
12
A. Hadžimehmedagić et al.
DISCUSSION
REFERENCES
There are several models of DVT risk assessment both for surgical and nonsurgical patients. The most commonly used is Caprini
score system which covers a risk assessment based on generalized individual characteristics (3). However, the specific intraoperative risk
factors are still under-researched. Some of them should be considered through the so-called dominant influence period of their duration (4). There are several studies that emphasize the influence of the
duration of exposure to a particular risk factor for the occurrence of
postoperative DVT. Thus, the group of authors from the University
Hospital of Sao Paulo presented the fact that in 75% of patients with
DVT after total knee arthroplasty, surgery lasted more than 150 minutes (5,6).
Study from the Clinic of Gynecology and Obstetrics in North
Carolina conducted on a sample of 411 patients showed that interventions completed within 120 minutes carry a 5% risk of DVT
occurrence. Operations completed within 120-300 minutes carry a
14% risk of DVT occurrence, and those longer than 300 minutes
carry 32% risk of postoperative DVT occurrence (7). The fact is
that postoperative DVT developed even when the risks according to
existing scales of assessment are minimal, so we can discuss about
the presence of insufficiently explored or incorrectly assessed risk
factors.
There are reports concerning the mechanical impact of joint positions on the morphologic and hemodynamic changes in the vein
(8,9,10). Reports of the cumulative impact of all known factors of
DVT initiation and occurrence of its manifest forms are expected.
1. Warwick D. Thromboembolism in orthopaedics-observation and experiment. Ann
R Coll Surg Engl. 2002;84(2):118-121.
2. Edmonds MJ, Crichton TJ, Runciman WB, Pradhan M. Evidence-based risk factors
for postoperative deep vein thrombosis. ANZ J Surg. 2004;74:1082–97.
3. Caprini JA. Risk assessment as a guide for the prevention of the many faces of
venous thromboembolism. Am J Surg. 2010;199(1):3-10.
4. Australian Government NHMRC. Clinical Practice Guideline for the Prevention of
Deep Vein Thrombosis and Pulmonary Embolism in Patients Admitted to Australian
Hospitals. Commonwealth of Australia 2009.
5. Hernandez AJ, De Almeida AM, Fávaro E, Sguizzato GT. The influence of tourniquet use and operative time on the incidence of deep vein thrombosis in total knee
arthroplasty. Clinics. 2012;67(9):1053-7.
6. Chann M, Hamza N, Ammori BJ. Duration of surgery independently influences
risk of venous thromboembolism after laparoscopic surgery. Surg Obes Relat Dis.
2013;9(1):88-93.
7. Clarke-Pearson D, Maxwell L. Deep vein thrombosis in gynecologic surgery (Chapter 95) in: Gynecology and Obsterics; Lippincot Williams&Wilkins 2004.
8. Levine A, Huber J, Huber D. Changes in popliteal vein diameter and flow velocity
with knee flexion and hyperextension. Phlebology. 2011;26(7):307-10.
9. Westrich GH, Winiarsky R, Betsy M, Maun L, Sculco TP. Effect on deep vein thrombosis with flexion during total knee arthroplasty. HSS J. 2006;2(2):148-53.
10. Huber DE, Huber JP. Popliteal vein compression under general anestesia. Eur J Vasc
Endovasc Surg. 2009;37(4):464-9.
CONCLUSIONS
Our investigation is an attempt to incorporate known but underestimated parameters measured in real time during the simulation or intraoperatively among the other DVT risk factors as an
addition to current list of them in order to form a concrete model
of DVT risk assessment.
Conflict of interest: none declared.
Reprint requests and correspondence:
Amel Hadžimehmedagić, MD, PhD
Clinic of Cardiosurgery
Clinical Center University of Sarajevo
Bolnička 25, 71000 Sarajevo
Bosnia and Herzegovina
Email: [email protected]
Original article
Medical Journal (2015) Vol. 21, No. 1, 13 - 16
Risk factors associated with malignancy in
paraneoplastic dermatomyositis
Faktori rizika povezani sa malignitetom kod
paraneoplastičnog dermatomiozitisa
Asja Prohić1*, Adnan Hadžimuratović2, Suada Kuskunović-Vlahovljak3, Anes Jogunčić4
Clinic of Dermatovenerology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of Pediatric Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 3Institute of Pathology, Faculty of Medicine, University of Sarajevo,
Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina, 4Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
In some patients, dermatomyositis (DM) appears as a paraneoplastic syndrome, however the incidence and factors that indicate the
coexisting malignancy still remain unclear. The purpose of our study
was to investigate the connection of DM and malignancy and to identify risk factors associated with cancer in this group of patients. Clinical and laboratory data of 40 patients with DM, treated over a 30
year period (from 1985 to 2014) at the Clinic of Dermatovenerology
were reviewed retrospectively. The main recorded parameters included: association with cancer, age, gender, presence of some clinical
signs and biological tests. Statistical analysis was performed to investigate differences between patients with and without associated malignancy. The mean age was 55 years and the sex ratio (female/male)
was 1.2. Malignant tumors were detected in 10 (25%) patients (mean
age: 63.7 years, sex ratio=1). Malignancies related to colon cancer (3
patients), ovarian cancer (3 patients) and the remaining cancers were
those of lung, breast, pancreas and prostate. Factors significantly associated with malignancy were cutaneous necrosis and elevation in
muscle enzymes. Our data indicate that necrotic skin ulcerations and
high muscle enzyme levels are highly associated with a concomitant
malignancy. An extensive search for malignancy should be provided
in a subset of patients with DM, and predictive factors of malignancy.
Dermatomiositis (DM) se kod nekih bolesnika javlja kao paraneoplastični sindrom, međutim njegova učestalost i faktori koji ukazuju
na postojeći malignitet i dalje su nejasni. Svrha našeg istraživanja bila
je ispitati povezanost DM i maligniteta i utvrditi faktore rizika koji
su povezani sa tumorom u ovoj skupini bolesnika. Retroaktivno su
pregledani klinički i laboratorijski podaci o 40 bolesnika s DM, koji su
liječeni u razdoblju od 30 godina (1985-2014) na Klinici za Dermatovenerologiju. Zabilježeni podaci obuhvaćali su: povezanost s tumorom, dob, spol, prisutnost nekih kliničkih znakova i biološke testove.
Statistička analiza je sprovedena s ciljem da se utvrde razlike između
bolesnika sa i bez postojećeg maligniteta. Prosječna dob bila je 55
godina, a omjer spolova (žene/ muškarci) iznosio je 1,2. Maligni tumori
su otkriveni kod 10 (25%) bolesnika (srednja dob: 63,7 godina, odnos
spolova = 1). Maligne bolesti obuhvatale su tumor kolona (3 pacijenta), tumor jajnika (3 pacijenta), dok su preostali maligni tumori bili
tumori pluća, dojke, gušterače i prostate. Faktori značajno povezani
s malignitetom su postojanje kožnih nekroza i povišene vrijednosti
mišićnih enzima. Naši podaci pokazuju da su nekrotične ulceracije
kože i visok nivoi mišićnih enzima značajno povezani s postojećim malignitetom. Opsežno traganje za malignitetom trebao bi biti osiguran
u podskupini bolesnika s DM i prediktivne čimbenike malignosti.
Key words: dermatomyositis, malignancy, risk factors, cutaneous necrosis, muscle enzymes
Ključne riječi: dermatomyositis, malignitet, faktori rizika, kožne
nekroze, mišićni enzimi
INTRODUCTION
tantly with DM and is discovered on the basis of clinical signs, symptoms or abnormal routine blood tests.
The association of DM and malignancy is greater than that in the
general population (1,3-7) and in the first years following the disease
diagnosis (4,5).
Many different clinical and serological signs have been suggested
as possible predictive factors for DM malignancy: older age (8-17),
male gender (10,12,13,17), rapid onset of the disease (18), presence
of cutaneous necrosis and periungual erythema (19-23), signs of severity (10,¸15,24), elevated erythrocyte sedimentation rate (ESR)
(17-19,25), rapid progression to muscle weakness (12,19,21,25),
Dermatomyositis (DM) is an idiopathic inflammatory myopathy
with characteristic cutaneous manifestations and proximal muscle
myopathy (1). A clinically distinct amyopathic variant with typical
skin signs but without muscle inflammation has been described as
well (2).
However, due to a paraneoplastic syndrome DM may also be
associated with malignant disease, in particular ovarian, lung, pancreatic, stomach, colorectal cancers and non-Hodgkin’s lymphoma
(3-7). In most cases, malignant disease precedes or occurs concomi-
14
A. Prohić et al.
elevation of the muscular enzymes (9,18,23) and presence of myositis-specific autoantibodies (anti-p155 or anti-p155/p140 antibodies (14,26). Biopsy evidence of cutaneous leukocytoclastic vasculitis
(27) and no lung impairment (15) has also been implicated as potentially indicative of underlying malignancy in DM.
The purpose of our study was to determine the association of
DM and malignancy and to evaluate some clinical and laboratory
data and diagnostic procedures as predictive factors of concomitant
neoplasia in patients with DM.
MATERIALS AND METHODS
Over the 30 year period (from 1985 to 2014) we performed a
retrospective case-control study on 40 patients with DM (22 females
and 18 males, aged 11-81 years) hospitalized in our Dermatovenerology Department.
Demographic, clinical, and laboratory data were obtained from
a systematic review of the patients’ medical records. Diagnosis of
DM based on the Bohan and Peter criteria, included the following
features:
1.
2.
3.
4.
5.
Symmetric proximal muscle weakness
Typical rash of DM
Elevated serum muscle enzymes
Myopathic changes on electromyography
Characteristic muscle biopsy abnormalities and the absence of histopathologic signs of other myopathies
DM was considered definitive with four criteria (including rash),
probable with three criteria (including rash) and possible with the
presence of two criteria (including rash) (28). Amyopathic DM was
diagnosed if clinical and laboratory evidence of muscle involvement
was absent for at least 6 months.
The main recorded data included an association with cancer,
age at the time of the diagnosis, gender, clinical presentation (cutaneous manifestations and muscle involvement), a rapid onset of
symptoms (considered if the diagnosis was made within 3 months
after the appearance of initial symptoms) and signs of severity (presence of dyspnoea and/or dysphagia and arthralgia and/or arthritis).
Moreover, some biological data was also evaluated: ESR (superior to
40 mm during the first hour), CRP (C-reactive protein; superior to
10 mg/L), serum muscle enzymes levels - creatine phosphokinase
(CPK), lactate dehydrogenase (LDH), aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) as well as presence of antinuclear autoantibodies (ANA).
In our department, screening for neoplasia in all patients with
suspected initial DM is routine, related to the assessment of breasts,
genitourinary and gastrointestinal tracts, lungs, hematologic system
(particularly lymphoma) and skin.
Collected data was compared between patients with and without associated malignancy.
Statistical analysis was evaluated using Fisher’s exact test for
qualitative and Mann-Whitney’s test for quantitative data. The difference was considered significant at p<0.05. The 95% confidence interval was calculated (mean ± 2SD) for qualitative data. All statistical
analysis was done using the SPSS/PC statistical package.
RESULTS
The medical records of 40 patients with DM were studied. Typical cutaneous signs (heliotrope rash, Gottron’s papules and characteristically distributed macular erythemas) and muscular involvement (proximal muscle weakness and/or elevated muscle enzymes
and/or electromyography findings and/or muscle histology) were
observed in all patients. No case of amyopathic DM was diagnosed.
The diagnosis of DM was definite in 30 patients (75%) and probable in 10 patients (25%). The mean age of onset was 55.1 years and
sex ratio female/male was of 1.2.
Malignancy was found in 10 patients (25%), with equal number
of female and male patients. The mean age of onset in this group
of patients was 63.7 years, compared to 53.2 in the group without
cancer.
The main characteristics of malignancies associated with DM are
presented in Table 1. Malignant tumors included colon cancer (3 patients), ovarian cancer (3 patients) and the remaining cancers were
those of lung, breast, pancreas and prostate. DM preceded cancer
by 14 months in one case, was concomitant to it in 8 cases and in
only one case cancer preceded the diagnosis of DM by 8 months.
The mean follow-up time from the disease onset was 24 months
(range 6-36). Eight patients with malignancy were followed up for a
mean duration of 14 months (range 6-18) and the mean follow-up
time in 22 out of 30 patients without malignancy was 30 months
(range 10-36). Seven patients with cancer and five patients without
associated cancer died within the follow-up time (70% vs 16.7%;
p=0.005).
Table 2 compares demographic, clinical, and laboratory data of
patients with and without malignancy.
Cutaneous necrosis (defined as cutaneous and/or mucosal necrotic lesions or ulcerations) was presenting sign in 80% of our patients with cancer and in only 10% of the patients without cancer
(0.001).
Patients with significantly higher muscle enzymes levels (CPK,
p=0.001, LDH, p=0.046, AST, p=0.032, ALT, p=0.019) tended to
have malignancy associated disease.
We found no significant differences for age, gender, clinical presentation (except cutaneous necrosis), clinical muscle involvement, a
rapid onset of the disease, signs of severity, a higher mean ESR and
CRP and the presence of ANA between malignancy and non-malignancy DM.
Table 1 Characteristics of patients with paraneoplastic
dermatomyositis.
Gender
Age
Classification
of DM
Type of
cancer
Chronology of DM
as related to cancer
1
F
60
Definite
Ovary
Concomitant
6
2
F
62
Definite
Ovary
Concomitant
11
3
F
60
Probable
Breast
Concomitant
unknown
4
M
57
Definite
Lung
14 months before
16
5
F
66
Definite
Colon
Concomitant
16
6
F
65
Definite
Ovary
Concomitant
18
7
M
70
Probable
Colon
Concomitant
unknown
8
M
58
Definite
Pancreas
Concomitant
10
9
M
61
Definite
Colon
Concomitant
> 18
10
M
78
Definite
Prostate
8 months after
> 18
PATIENT NO
DM = dermatomyosits, F = female, M = male
Survival
(months)
Risk factors associated with malignancy in paraneoplastic dermatomyositis
Table 2 Comparison of demographic, clinical, and laborato ry between DM with malignancy and without malignancy.
VARIABLE
DM with malignancy DM without malignancy
P value
(n = 10)
(n = 30)
Mean age at DM diagnosis
63.7 ± 6.05
53.2 ± 6.92
0.248
5/5
17/13
0.966
Gender (F/M)
Cutaneous manifestations
Photodistributed rash
10 (100%)
28 (93.3%)
0.836
9 (90%)
papule
28 (93.3%)
0.790
Gottron’s
8 (80%)
Heliotrope rash
26 (86.7%)
0.835
8 (80%)
3 (10%)
0.001
Cutaneos necrosis
6 (60%)
Poikiloderma
25 (83.3%)
0.896
6 (60%)
15 (50)
0.654
Periungual erythema
2 (20%)
Calcinosis
11 (36.7%)
0.822
Vasculitis lesions
2 (20%)
7 (23.3%)
0.758
Muscle involvement
Clinical muscle involvement
9 (90%)
26 (86.7%)
0.792
Laboratory evidence of myositis
1236.2 ± 411.53
CK
382.5 ± 139.61
0.001
LDH
684 ± 123.16
510.3 ± 80.51
0.046
188.2 ± 42.98
AST
129.0 ± 20.26
0.032
ALT
169.4 ± 36.11
120.2 ± 16.24
0.019
4 (40%)
Rapid onset
14 (46.7%)
0.875
Signs of severity
4 (40%)
14 (46.7%)
0.875
Dysphagia
2 (20%)
Dyspnoea
11 (36.7%)
0.834
Arthritis/arthralgia
6 (60%)
14 (46.7%)
0.606
Laboratory findings
ESR (>40 mm/h)
8 (80%)
15 (50%)
0.179
5 (50%)
14 (46.7%)
(>10 mg/L)
0.791
CRP
5 (50%)
12 (40%)
Positive ANA
0.588
Data are given as number (percentage) of cases or mean value
± 2 SD (Standard deviation), DM = dermatomyosits, CPK = creatine phosphokinase (normal values 10 - 120 IU/L), LDH = lactate
dehydrogenase (normal values 105 - 333 IU/L) , AST = aspartate
aminotransferase (normal values 10 to 34 IU/), ALT = alanine aminotransferase (normal values 10 to 40), CRP = C-reactive protein;
ESR = erythrocyte sedimentation rate.
DISCUSSION
An association between DM and malignancy was first suggested
in 1916 (29) and since than some population-based cohort (3-5) and
many retrospective studies (6-27) variously reported an incidence
of malignancy. Large population-based epidemiologic studies from
Sweden, Finland, Denmark, Scotland, Australia, and Taiwan have
shown an overall increased incidence for malignancies at the same
time or after the diagnosis of myositis with a frequency from 9% to
42% (30). In our study, malignancies were found in 25% of patients,
in accordance with a study of Whitmore et al. (2), and comparable to many other studies, reporting frequencies between 22-28%
(6,15,17,20,21,24,25,27). Some authors have reported higher frequencies of underlying cancers which may be explained by a large
number of patients with DM included in large population based studies (3-5). On the contrary, two studies conducted in Brazil reported
a significantly lower incidence of malignancy in DM with frequency of
6.8% and 6.4%, respectively (31,32).
The type of malignancy also varies depending on the age, gender
and geographical location.
According to Western literature, the malignancies most strongly
associated with DM are ovarian and breast carcinoma in women and
lung and prostate carcinoma in men (3-5). However, nasopharyngeal
carcinoma has been reported as the predominant cancer associated
with DM in many Asian countries (11,12,17). We observed that the
types of malignancies found in association with DM parallel those
previously described in an age-matched general population in our
country (33).
15
As suggested by some authors, the increase in risk of harboring
a cancer is highest in the first year after diagnosis but can persist up
to five years (4,5). András et al. (34) have reported that neoplasias
may precede myopathy by two years, while Maoz et al. (35) have
described malignancy in DM even after five years of disease.
These results support some propositions that patients with DM,
especially with a history of cancer should be subjected to a more
aggressive cancer screening which may be difficult and expensive
(2,18,32). Therefore, it might be important to define some risks factors that indicate the coexisting malignancy in DM patients. Some
authors have pointed out that paraneoplastic DM has specific clinical
signs and serologic evaluations compared with idiopathic form, suggesting an association with cancer (7-27).
We found that the age at diagnosis of paraneoplastic DM (64
years) was higher than that of idiopathic DM (53 years), but the difference was not statistically significant, which may be due to the small
sample size. However, all patients with malignancy were over the
age of 57, confirming that the risk of malignancy increased with age
(8-17). Moreover, only in multivariate analysis, older age at onset
(>45 years) has been proposed as predictive factor for developing
malignancy in DM with significant difference (12).
Malignancies were found in equal number in female and male, in
agreement with a previous report (23), although majority of authors
reported paraneoplastic DM more frequently in male gender, even
as predictive factor for developing cancer (10,12,13,17). Contrary
to these findings, Sigurgeirsson et al. (4) showed that the neoplasias
affect predominantly women.
Although the development of necrotic lesions in the context of
DM is a rare occurrence, some previously published studies indicated that DM patients with cutaneous necrosis faced a significantly
higher risk of malignancy (19, 21-23). Including our trial, cutaneous
necrosis is thought to increase the probability of occult malignancies
in 80% of cases associated with cancer, opposite to 10% cases of DM
without cancer. The results of our study highlight this clinical parameter, which can be easily identified by a dermatologist, and is probably
one of the most important indications for a detailed investigation
of underlying cancer in DM. Other skin findings such as periungal
erythema, hyperkeratotic follicular papules and vesiculo-bullous lesions have been proposed as markers of underlying cancer, even as a
marker of poor prognosis and aggressive internal malignancy, particularly in gynaecological malignancies (36).
We found that DM patients with malignancy had elevated muscle enzyme levels, especially elevated level of CPK. The validity of
this criterion has been confirmed by most formerly published trials
(18,23) but is contrary to some studies that normal muscle enzyme
levels tend to be a risk factor in developing cancer (2,3,7). Although
the number of patients included in our study was small, this may give
a tantalizing clue as to serum markers for predicting malignancy in
DM patients.
Identifying DM patients who face a high risk for malignancy is
important from a public health and clinical perspective as this identification would facilitate early detection of malignancy and treatments
as well. Therefore, further prospective studies with larger sample
are needed to clarify which clinical and biological examination is frequently considered predictive of cancer. Depending on these results,
dermatologists will be able to perform more comprehensive cancer
screening to detect malignancy in an early, potentially treatable stage.
16
CONCLUSIONS
We can confirm that factors predictive of concomitant malignancy are the presence of cutaneous necrosis and elevation of the
muscular enzymes. These parameters which are easy to evaluate by
clinicians highlight the importance of serious malignancy screening
particularly in DM cases with atypical or extensive cutaneous symptoms and elevated enzyme levels, particularly CPK.
Conflict of interest: none declared.
REFERENCES
1. Iaccarino L, Ghirardello A, Bettio S, Zen M, Gatto M, Punzi L, et al. The clinical
features, diagnosis and classification of dermatomyositis. J Autoimmun. 2014;4849:122-7.
2. Whitmore SE, Watson R, Rosenhein NB, Provost TT. Dermatomyositis sine myositis: association with malignancy. J Rheumatol. 1996;23:101-5.
3. Airio A, Pukkala E, Isomaki H. Elevated cancer incidence in patients with dermatomyositis: a population based study. J Rheumatol. 1995;22:1300-3.
4. Sigurgeeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients
with dermatomyositis or polymyositis. A population-based study. N Engl J Med.
1992;326:363-7.
5. Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A. Frequency
of specific cancer types in dermatomyositis and polymyositis: a population-based
study. Lancet. 2001;357:86-100.
6. Marschalkó M, Pónyai G, Ablonczy E, Horváth A. Dermatomyositis: clinical study of
34 patients. Orv Hetil. 2000;141:225-9.
7. Di Rollo D, Abeni D, Tracanna M, Capo A, Amerio P. Cancer risk in dermatomyositis: a systematic review of the literature. G Ital Dermatol Venereol.
2014;149(5):525-37.
8. Cox. Lawrence CM, Langtry JA, Ive FA. Dermatomyositis. Disease associations and
an evaluation of screening investigations for malignancy. Arch Dermatol. 1990;126:
61-5.
9. Rose C, Hatron PY, Bowman RL, Pearson CM. Predictive signs of cancers in dermatomyositis. Study of 29 cases. Rev Med Interne. 1994;15:19-24.
10.Selvaag E, Thune P, Austad J. Dermatomyositis and cancer. A retrospective study.
Tidsskr Nor Laegeforen. 1994;114:2378-80.
11.Leow YH, Goh CL. Malignancy in adult dermatomyositis. Int J Dermatol.
1997;36:904-7.
12. Chen YJ, Wu CY, Shen JL. Predicting factors of malignancy in dermatomyositis and
polymyositis: a case-control study. Br J Dermatol. 2001;144:825-31.
13. Wakata N. Kurihara T, Saito E, Kinoshita M. Polymyositis and dermatomyositis associated with malignancy: a 30-year retrospective study. Int J Dermatol. 2002;41:72934.
14.Chinoy H, Fertig N, Oddis CV, Ollier WE, Cooper RG. The diagnostic utility of
myositis autoantibody testing for predicting the risk of cancer-associated myositis.
Ann Rheum Dis. 2007;66:1345-9.
15.Azuma K, Yamada H, Ohkubo M, Yamasaki Y, Yamasaki M, Mizushima M, et al.
Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis. Mod Rheumatol. 2011;21(2):178-83.
16. de Souza FH, Shinjo SK. Newly diagnosed dermatomyositis in the elderly as predictor of malignancy. Rev Bras Reumatol. 2012;52(5):713-21.
17. Chen D, Yuan S, Wu X, Li H, Qiu Q, Zhan Z, et al. Incidence and predictive factors
for malignancies with dermatomyositis: a cohort from southern China. Clin Exp
Rheumatol. 2014;32(5):615-21.
18. Sparsa A, Liozon E, Herrmann F, Ly K, Lebrun V, Soria P, et al. Routine vs extensive
malignancy search for adult dermatomyositis and polymyositis: a study of 40 patients. Arch Dermatol. 2002;138:885-90.
19. Basset-Seguin N, Roujeau JC, Gherardi R, Guillaume JC, Revuz J, Touraine R. Prognosis factors and predictive signs of malignancy in adult dermatomyositis. Arch Der-
A. Prohić et al.
matol. 1990;126:633-7.
20. Hidano A, Torikai S, Uemura T, Shimizu S. Malignancy and interstitial pneumonitis as
fatal complications in dermatomyositis. J Dermatol. 1992;19:153-60.
21. Gallais V, Crickx B, Belaïch S. Facteurs pronostiques et signes prédictifs de cancer au
cours de la dermatomyosite de l’adulte. Ann Dermatol Venereol. 1996;123:722-6.
22.Mautner GH, Grossman ME, Silvers DN, Rabinowitz A, Mowad CM, Johnson BL.
Epidermal necrosis as a predictive sign of malignancy in adult dermatomyositis. Cutis. 1998;61:190-4.
23.Burnouf M, Mahe E, Verpillat P, Descamps V, Lebrun-Vignes B, Picard-Dahan C.
Cutaneous necrosis is predictive of cancer in adult dermatomyositis. Ann Dermatol
Venereol. 2003;130:313-6.
24. So MW, Koo BS, Kim YG, Lee CK, Yoo B. Idiopathic inflammatory myopathy associated with malignancy: a retrospective cohort of 151 Korean patients with dermatomyositis and polymyositis. J Rheumatol. 2011;38(11):2432-5.
25.Amerio P, Girardelli CR, Proietto G, Forleo P, Cerritelli L, Feliciani C, et al. Usefulness of erythrocyte sedimentation rate as tumor marker in cancer associated
dermatomyositis. Eur J Dermatol. 2002;12:165-9.
26.Trallero-Araguás E, Rodrigo-Pendás JÁ, Selva-O’Callaghan A, Martínez-Gómez X,
Bosch X, Labrador-Horrillo M, et al. Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis.
Arthritis Rheum. 2012;64(2):523-32.
27.Hunger RE, Durr C, Brand CU. Cutaneous leukocytoclastic vasculitis in dermatomyositis suggests malignancy. Dermatology. 2001;202:123-6.
28.Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J
Med. 1975;292:344-7.
29. Stertz G. Polymyositis. Berl Klin Wochenschr. 1916;53:489.
30.Zahr ZA, Baer AN. Malignancy in myositis. Curr Rheumatol Rep. 2011;13(3):20815.
31.Scola RH, Werneck LC, Prevedello DM, Toderke EL, Iwamoto FM. Diagnosis
of dermatomyositis and polymyositis: a study of 102 cases. Arq Neuropsiquiatr.
2000;58:789-99.
32.Ortigosa LC, dos Reis VM. Dermatomyositis: analysis of 109 patients surveyed
at the Hospital das Clínicas (HCFMUSP), São Paulo, Brazil. An Bras Dermatol.
2014;89(5):719-27.
33.Nikšić D, Kurspahić-Mujičić A, Pilav A, Nikšić H. Cancer mortality, recent trends
and perspectives. Bosn J Basic Med Sci. 2006;6:67-71.
34. András C, Ponyi A, Constantin T, Csiki Z, Szekanecz E, Szodoray P, Dankó K. Dermatomyositis and polymyositis associated with malignancy: a 21-year retrospective
study. J Rheumatol. 2008;35(3):438-44.
35. Maoz CR, Langevitz P, Livneh A, Blumstein Z, Sadeh M, Bank I, Gur H, Ehrenfeld M.
High incidence of malignancies in patients with dermatomyositis and polymyositis:
an 11-year analysis. Semin Arthritis Rheum. 1998;27(5):319-24.
36. Zangrilli A, Papoutsaki M, Bianchi L, Teoli M, Chimenti S. Bullous dermatomyositis:
a marker of poor prognosis and aggressive internal malignancy? Acta Derm Venereol. 2008;88(4):393-4.
37.Fudman EJ, Schnitzer TJ. Dermatomyositis without creatine kinase elevation: poor
prognosis sign. Am J Med. 1986;80:329-32.
Reprint requests and correspondence:
Asja Prohić, MD, PhD
Clinic of Dermatovenerology
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 298136
Fax: + 387 33 298 701
Email: [email protected]
Original article
Medical Journal (2015) Vol. 21, No. 1, 17 - 21
Relationship between nonenzymatic antioxidant
component and free radical nitric oxide in patients with
schizophrenia
Odnos ne-enzimske antioksidativne komponente i
slobodnog radikala nitričnog oksida kod shizofrenije
Amra Memic1*, Abdulah Kučukalić1, Lilijana Oruč1, Jasminko Huskić2, Lejla Burnazović3,
Nafija Serdarević4
Clinic of Psychiatry, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Institute of Physiology and Biochemistry,
Faculty of Medicine, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina, 3Institute of Pharmacology, Faculty of Medicine, Čekaluša 90, 71000 Sarajevo, Bosnia
and Herzegovina, 4Clinical Chemistry and Biochemistry, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
Findings in schizophrenia (Sch) include elevated nitric oxide (NO)
production and imbalanced serum level of bilirubin as an indicator of
nonenzymatic antioxidant component. The aim of this study was to investigate possible interaction between NO and bilirubin. The study was
consisted of 50 patients with Sch and 50 healthy controls. In both of
groups we investigated the levels of NO which is determined by conversion of nitrate to nitrite using elemental zinc and then measuring concentration with Greiss reagent. However, in the group of patients who
are suffering from Sch we measured the mean levels of total bilirubin
(TBI) using Dimension (Siemens) clinical chemistry system, within the
course of illness. Statistically significant differences are present between
the course of illness and total bilirubin, where the maximum value is
presented with respect to first hospitalization. Correlation between
total bilirubin and NO for patients with Sch was small (R2= 0.12758),
while for patients with positive psychotic symptoms that we accrued
using the scale for the assessment of positive and negative symptoms
(PANSS) the correlation is moderate (R2=0.3068). Our results confirm
the hypothesis that the antioxidant capacity in patients with Sch decreases with the progress of the disease. Increased bilirubin consumption may
be resulting from increased oxidative stress that accompanies sch. Possibility of relationship between NO and bilirubin participates in Sch.
Kod shizofrenije (Sch) je dokazana povećana razina nitričnog
oksida (NO) i neuravnotežen nivo bilirubina u serumu, kao indikatora ne-enzimskih antioksidativnih komponenti. Cilj ovoga
rada bio je istražiti moguću interakciju između NO i bilirubina.
Istraživanje je uključilo 50 pacijenata oboljelih od Sch i 50 zdravih
kontrola. U obje grupe određen je nivo NO, konverzijom nitrata u nitrite koristeći elementarni cink, a zatim mjerenje koncentracije s Greiss reagensom, a u grupi pacijenata koji boluju od
Sch određen je nivo ukupnog bilirubina (TBI) pomoću Dimension
(Siemens) kliničkog hemijskog sistema, u odnosu na tok bolesti.
Statistički signifikantna razlika je prisutna između toka oboljenja i nivoa bilirubina, gdje su najviše vrijednosti u vezi sa prvom
hospitalizacijom. Korelacija između ukupnog bilirubina i NO kod
pacijenata sa Sch bila je mala (R2 = 0,12758), a umjerena (R2
= 0,3068) kod pacijenata sa pozitivnim psihotičnim simptomima
koje smo dobili upotrebom skale za procjenu pozitivnih i negativnih simptoma (PANSS). Naši rezultati potvrđuju hipotezu da se
antioksidativni kapacitet kod pacijenata sa Sch smanjuje sa napredovanjem bolesti. Povećana potrošnja bilirubina može biti rezultat povećanja oksidativnoga stresa koji prati Sch. Kod Sch moguća
je povezanost između NO i bilirubina.
Key words: schizophrenia, nitric oxide, total bilirubin
Ključne riječi: shizofrenija, nitrični oksid, ukupni bilirubin.
INTRODUCTION
a large number of articles that investigate oxidative stress, and the
potential role of nitric oxide (NO) in the pathophysiology of Sch
and a lot of evidence of altered antioxidant capacity in patient who
suffer from Sch (1, 2, 3). Nitric oxide is a simple, gas permeable
membrane, a distinctive chemistry that transmits signals in the intra and intercellular space, synthesized under the influence of nitric
oxide synthase enzyme that catalyzes the oxidation of L-arginine to
L-citrulline and nitric oxide (4, 5, 6). In the brain, the neurotransmitter actions of NO are believed to impact the processes of
Schizophrenia (Sch) is a serious mental disorder consisting of
specific psychopathological symptoms that are consequence of disturbed biochemical processes of the brain. This implies a general
tendency toward disorganization and deterioration of personality.
The findings confirm the participation of biological factors in the
pathogenic processes that underlie this serious and complex disorder but etiopathogenic process remains unknown. Today we have
18
learning and memory. There are enormous proofs in recent years
that nitric oxide plays an important role in the pathophysiology of
schizophrenia. NO has a neuroprotective role in excess neurotoxic because free-radical mediated abnormalities may play a role for
the progress of a number clinically significant consequences including well-known negative symptoms (7). Surplus, NO production
further leads to alteration of neuron structure and function that
includes neuronal membrane damage and increased appearance of
lipid peroxidation. Akyol et all. (8) show important role of oxygen
free radicals in the pathophysiology of the abovementioned disorder. At the same time they do not exclude the potential role of
antioxidants in therapeutic purposes (8, 9). Until recently, bilirubin
was considered a degradation product of hem, but in the last twenty years many papers claim that the bile pigments with strong antioxidant activity are able to prevent cell damage caused by reactive
nitrogen species as well as better known peroxynitrite resulting in
excess NO that undergoes oxidation /reductive reactions (6). Interesting scientific fact is that bilirubin acts as an endogenous scavenger of NO and RNS and the protective role of it induces other
reactive species within the cellular milieu, giving him the role of
antioxidant that is reduced in patients suffering from schizophrenia
(10, 11, 12), as the total antioxidant capacity is impaired as well.
Several studies have recently investigated the interaction of bilirubin, the final product of hem catabolism, which plays a crucial role
in protecting cells from oxidative and nitric repetitive stress, and
NO, the gas involved in many psychological functions that is able to
induce cytotoxicity and cell death if produced in excess. Donors of
nitric oxide induced expression of hem oxygenase-1 in endothelial cells (13). The specific nitric oxide scavenger hydroxocobalamin
reduces the activity of endothelial hem oxygenase. Moreover, nitric
oxide-mediated induction of hem oxygenase-1 was significantly reduced with N-acetyl-cysteine precursor of glutathione syntheses
by stabilizing nitric oxide through the formation of S-nitrosothiol group. These results indicate that reactive derivative of nitric
oxide is associated with nitric oxide mediated induction of hem
oxygenase-1. Accordingly, peroxynitrite (ONOO-) strong oxidant
formed in the reaction of nitric oxide with superoxide anion was a
powerful inducer of expression of hem oxygenase-1. Peroxynitrite
also increases apoptosis and induces cytotoxicity, while a scavenger
of peroxynitrite reduces this effect. It is interesting that pretreatment of endothelial cells with hemin inducer of hem oxygenase-1
increased the production of UCB and reduced apoptosis mediated
peroxynitrite. Furthermore, the resources that released nitric oxide and peroxynitrite are causing decay in plasma concentration of
direct bilirubin and biliverdin. These findings suggest that UCB and
biliverdin protects cells from damage caused by the uncontrolled
creation of nitric oxide (14).
The formation of bilirubin-nitric oxide compound has not
happened only in the reconstituted system, but was confirmed in
fibroblasts of rats exposed to pro-oxidant stimuli. These results
provide insight into the antioxidant properties of bilirubin through
its interaction with the gaseous neurotransmitter nitric oxide with
well-known dual effect, the neuroprotective under physiological
conditions, or if produced in excess of neurotoxic effects, and propose that bilirubin-nitric oxide as a new biomarker of oxidative/
nitrosative stress (15).
A. Memić et al.
MATERIALS AND METHODS
The study was consisted of inpatients (n=50) who suffering from
Schizophrenia (Sch) according to DSM-IV diagnostic criteria confirmed by Structured Clinical Interview (SCID 1) treated in Psychiatric Clinic, Clinical Centre University of Sarajevo (KCUS) and healthy
controls (n=50). To assess the presence of positive and negative
psychopathology symptoms, Positive and Negative Syndrome Scale
was also applied to each patient. Exclusion criteria from the study
were: individuals younger than 18 years and older than 65, any information in the history of past or current psychiatric comorbidity, and
information about substance abuse, chronic somatic disease, diabetes mellitus, hypertension, gastrointestinal disorders, impaired renal
or pancreatic function, neurological disorder, cataract, inflammatory
or autoimmune disease. The study was carried out with the approval
of the local Ethic Committee of KCUS and both of groups had confirmed their voluntary participation by signing an informed consent
after being given a complete description and protocol of the study.
Laboratory investigation
The samples of patient blood were collected in serum separator Vacutainer test tubes (Becton Dickinson, Rutherford, NJ 07,070
U.S.) in volume of 3.5 mL. We used test tubes with gel. Serum samples were obtained by centrifugation at 3000 rpm using centrifuge
(Sigma 4-10). The patients and controls were fasting 12 hours before laboratory testing. After centrifuging, serum concentration of
total bilirubin was determined. The total bilirubin (TBI) levels were
measured using Dimension (Siemens) clinical chemistry system. It is
an in vitro diagnostic test intended to quantitatively measure TBI in
human serum. Bilirubin (unconjugated) in the sample is solubilized
by dilution in a mixture of caffeine/benzoate/acetate/EDTA. Upon
addition of the diazotized sulfanilic acid, the solubilized bilirubin
including conjugated bilirubins (mono and diglucoronides) and the
delta form (biliprotein-bilirubin covalenty bound to albumin) is converted to diazo-bilirubin, a red chromophore representing the total
bilirubin which absorbs at 540 nm and is measured using bichromatic
(540,700 nm) endpoint technique (16). The serum TBI was measured at Institute for Chemistry and Biochemistry, Clinical Centre
University of Sarajevo.
The determination of nitric oxide
The concentration of NO in blood was done with measurement of nitrate and nitrite using colorimetric Greiss reaction (17).
The concentration of NO in serum was determined by conversion
of nitrate (NO¯3) to nitrite (NO¯2) using elemental zinc and then
colorimetric measurement of nitrite (NO¯2) (µmol/L). We took 1
mL of blood, added 8 mg of elemental zinc solved in 0.4 mL of deionized water, after this we added 0.032 ml 5% CH3COOH (acetic
acid) and tilled 2 ml deionized water. We mixed the sample for 5 min
using vortex at room temperature and centrifuged it for 2.5 min at
700 rpm. We took 1 mL of supernatant and 1 mL of Greiss reagent
and mixed it for 10 min in vortex at room temperature. After 10 min
of mixing we have measured light absorption (optical density) with
spectrophotometer at 546 nm. The concentration of nitrate and ni-
Relationship between nonenzymatic antioxidant component and free radical nitric oxide in patients with schizophrenia
19
trite is sensed from a standard curve with known concentrations of
NaNO2 (1.56 µmol–100 µmol). As a blank test we used distilled
water in which we added Griess reagent.
Statistical analysis
The results were statistically analyzed using statistical software
SPSS version 15.0. Descriptive variables were presented in counted
means, SD and SEM values. For comparison of categorical variables
Pearson Chi-Square tests (with Yates’ Continuity Correction for all
2 · 2 tables) were used. When expected rates in cells were less than
five, Fischer’s exact test was used instead of Pearson Chi Square
Test. Two-tailed significance level of P < 0.05 were selected for all
tests. Spearman’s correlation coefficients were obtained in due to
small sample size, and potential violation of normality assumptions.
RESULTS
The total sample consisted of 50 patients suffering from Sch
with mean age (38.4 ± 1.77) and the average age of onset of illness
was 28 years (28.00 ± 1.094; X ± SEM) and 50 healthy controls with
mean age (34.56 ± 1.53). Results as to the social and demographic
data patients and their controls are summarized in Table 1.
Table 1 The characteristics of the patients and controls included in this study.
Control
SCHIZOPHRENIA
N
50
50
Age
38.4±1.77
34.56±1.53
Sex
15M/35F
18M/32F
SANS-Total (mean ±S.D)
23.82(±9.962)
SAPS-Total (mean±S.D.)
28.6(±9.794)
Duration of illness (mean±S.D)
32.5±5.00
Two groups of patients, with positive and negative psychopathological symptoms, were not significantly different for duration
of episodes before hospitalized (SD=34.21; 32.66 ± 5.78; X ± SEM,
SD=39.18; 32.13 ± 10.11; X ± SEM, p= 0.964).
Paired Samples Statistics showed a mean of NO between
group patients and control according to their mean values in Table 2. Variables 35 and 15 are continuous and statistically significant
(CI=13.31–27.29, t= 5.863, p= 0.0001).
Table 2 The characteristics of the patients and controls included in this study.
Paired Differences
T
Df
Sig. (2 tailed)
Std.
95% Confidence
Std.
Error
Interval of the
Mean Deviation
Mean
Difference
Lower
Upper
Levels of NO – 20.2545
24.43098
3.45506
13.31129
27.19771
5.862
49
0.000
levels of NO
0
controls
Pair 1 Levels of NO
35.8000 23.86310
3.37475
Levels of NO
15.5455 6.14903
0.86960
controls
The highest level of bilirubin is present when patients are hospitalized for the first time (Figure 1).
Figure 1 Average bilirubin level depending on the course of
illness for group patients.
Correlation between total bilirubin and nitric oxide for patients
with Sch was small (R2= 0.12758), while for patients with positive
psychotic symptoms that we received on the basis of the cumulative variance on the scale for the assessment of positive and negative symptoms (PANSS) the correlation is moderate (R2=0.3068).
Figure 2 Correlation between the levels of total bilirubin
and NO concentration in the blood of patients suffering
from schizophrenia.
Figure 3 Correlation between the levels of total bilirubin
and NO concentration in the blood of patients suffering
from schizophrenia with positive psychotic symptoms.
DISCUSSION
To date and to the author’s knowledge, the present study is the
one that specifically investigates correlations between serum levels
of nitric oxide and bilirubin in patients with schizophrenia (Sch) and
the hypothesis that this correlation exists in Sch remains speculative
and therefore, there have been no detailed studies to test this hypothesis. There are more data on the possible role of nitric oxide
and its potential to change in pathological conditions such as schizophrenia on the one hand, and bilirubin on the other hand. Bilirubin,
a potential antioxidant in patients with schizophrenia, is reduced to-
20
gether with the total antioxidant capacity. From the results obtained,
we can conclude that there are serious deregulation of oxidative
and antioxidative metabolism system during schizophrenia and increased oxidative stress and decreased bilirubin which is endowed
with a strong antioxidant activity, both of which may be relevant to
the pathophysiology of Sch which is quite consistent with the work
of Mancuso et al. (11) who explained this mechanism in some other
illnesses, such as atherosclerosis, liver disease and neurodegenerative disorders. Our results are consistent with the results of Huichun et al (18) who found increased levels of nitric oxide in patients
suffering from schizophrenia than those in the control group. The
research of Yilmaz et all. (19) showed that the total value of nitric
oxide was higher in patients than in the control group and there was
no correlation with total score on the scale for the assessment of
positive schizophrenic symptoms and frequency of hospitalization.
Given that overproduction of NO is typical in patients suffering from
schizophrenia, the excess NO could have serious pathophysiological implications, such as damage to the NMDA receptor-mediated
neurotransmission (20), impaired metabolism of dopamine and excessive oxyradical generation at the cell membrane, causing death,
lipid peroxidation and profound mitochondrial dysfunction (21).
Depletion of antioxidant status due to increased utilization with increased oxidative stress in patients with schizophrenia. It was proved
that schizophrenia disrupts homeostasis of glutathione, which is one
of the factors responsible for weakening of the antioxidant defense
that are endowed with antioxidant enzymes. Convergent evidence
suggests that oxidative mechanisms may play a role in schizophrenia. Plasma free radicals have been found in increased concentration, while albumin, uric acid and bilirubin decreased in patients with
schizophrenia (22). Plasma proteins, including albumin, bilirubin and
uric acid levels were lower in patients who were on haloperidol
(23), and among the first episode of schizophrenic patients. Some
studies (24) have shown that antipsychotic drugs have no significant
regulatory effect on antioxidant defense system. Our thoughts after
reports of a large number of scientific and research papers remain
on the fact that the differences reflect the heterogeneity of psychotic state respondents. Our findings of an increased concentration of
bilirubin during the first hospitalization is in contradiction with the results of Yao JK et all (23), who stated that the values of bilirubin were
lower in patients taking haloperidol, as well as in the patients within the first hospitalization. However, our results are consistent with
numerous studies that confirm the hypothesis that the antioxidant
capacity in patients with schizophrenia decreases with the progress
of the disease. We can expect higher bilirubin value during the first
hospitalization, but only if the patients who have the appearance of
clinical symptoms were hospitalized after shorter period, which may
not be the case with studies that are inconsistent with the foregoing. Chi-Un Pae et all (25) reported that the total plasma antioxidant
capacity was known less for patients suffering from schizophrenia
than in the control group, regardless of the clinical variables such as
relapse and treatment of disease. We can conclude that imbalance
between nitric oxide and bilirubin participates in the pathogenesis
basis of schizophrenia, especially in the first hospitalization in relation
of the course of illness. Established on these findings and theoretical
bases, new treatment strategies such as using antioxidant and nitric
oxide synthase inhibitors in treating schizophrenia may be effective
and safe further approach.
A. Memić et al.
CONCLUSION
Increased bilirubin consumption may be resulted from an increased oxidative stress which is accompanying sch. Future research
should analyze blood samples and compare values of NO and bilirubin depending on clinical symptoms, psychopharmacotherapy and
consist out of larger sample sizes.
Conflict of interest: none declared.
REFERENCES
1. Gonzalez-Liencres C, Tas C, Brown EC, Erdin S, Onur E, Cubukcoglu Z,, et al. Oxidative stress in schizophrenia: a case control study on the effects on social cognition
and neurocognition. BMC Psychiatry. 2014;14(1):268.
2. Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A. Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In vivo. 2004;18:377-390.
3. Yao JK, Reddy RD, van Kammen DP. Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs. 2001;15(4):287310.
4. Dawson TM, Snyder SH. Gases as biological messengers: nitric oxide and carbon
monoxide in the brain. J Neurosci. 1994;14(9):5147-59.
5. Giraldi-Guimarães A, Bittencourt-Navarrete RE, Mendez-Otero R. Expression of
neuronal nitric oxide synthase in the developing superficial layers of the rat superior
colliculus. Braz J Med Biol Res. 2004;37(6):869-77.
6. Calabrese V, Butterfield DA, Scapagnini G, Stella AM, Maines MD. Redox regulation
of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. Antioxid
Redox Signal. 2006;8:444-477.
7. Zoroglu SS, Herken H, Yurekli M, Uz Efkan, Tutkun H, Savas HA, et al. The possible
pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia.
J Psychiatr Res. 2002;36(5):309-15.
8. Akyol O, Herken H, Uz E, Fadillioglu E, Unal S, Sogut S, et al. The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients.
The possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol
Biol Psychiatry. 2002;26(5):995-1005.
9. Li HC, Chen QZ, Ma Y, Zhou JF. Imbalanced free radicals and antioxidant defense
systems in schizophrenia: A comparative study. J Zhejiang Univ Sci B. 2006;7(12):981986.
10. Cesare M, Giovambattista P, Vittorio C. Bilirubin: an endogenous scavenger of nitric
oxide and reactive nitrogen species. Redox Rep. 2006;11(5):207-13.
11. Mancuso C, Bonsignore A, Di Stasio E, Mordente A, Motterlini R. Bilirubin and S-nitrosothiols interaction: evidence for a possible role of bilirubin as a scavenger of
nitric oxide. Biochem Pharmacol. 2003;66(12):2355-63.
12. Vitek L, Lenicek M, Jirsa M, Novotna M, Novotny L, Eberova J. Serum bilirubin levels
and UGT1A1 promoter variations in patients with schizophrenia. Psychiatry Res.
2010;178:449–450.
13. Mancuso C. Heme oxygenase and its products in the nervous system. Antioxid Redox Signal. 2004;6(5):878-87.
14.Jansen T, Hortmann M, Oelze M, Opitz B, Steven S, Schell R et al. Conversion of
biliverdin to bilirubin by biliverdin reductase contributes to endothelial cell protection by heme oxygenase-1-evidence for direct and indirect antioxidant actions of
bilirubin. J Mol Cell Cardiol. 2010; 49(2):186-95.
15.Barone E, Trombino S, Cassano R, Sgambato A, De Paola B, Di Stasio E et al.
Characterization of the S-denitrosylating activity of bilirubin. J Cell Mol Med.
2009;13(8B):2365-75.
16.Jendrassik L. Grof P. Vereinfachte photometrische Methode zur Bestimmung des
Blutbilirubin, Biochem. 1938;297:81-89.
17.Grees LC, Wagner DA, Glogowski J. Analysis of nitrate, nitrite and 15N nitrate in
biological fluids. Anal Biochem. 1982;126:131-138.
18. Hui-chun L, Qiao-yhen C, Ying M, Jun-fu Z. Imbalanced free radicals and antioxidant
defense systems in schizophrenia: A comparative study. J Zhejiang Univ Science B.
2006;7(12):981-986.
Relationship between nonenzymatic antioxidant component and free radical nitric oxide in patients with schizophrenia
19.Yilmaz N, Herken H, Cicek HK, Celik A, Yürekli M, Akyol O. Increased levels of
Nitric oxide, Cortisol and Adrenomedullin in patients with chronic Schizophrenia.
Med Princ Pract. 2007; 16:137-141.
20. Clinton SM, Haroutunian V, Davis KL, Meador-Woodruff JH. Altered transcript expression of NMDA receptor associated postsynaptic proteins in the thalamus of
subjects with sch. Am J Psychiatry. 2003;160:1100-1109.
21. Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and
oxidative stress. Mol Psychiatry 2004;9:684-97.
22.Dadheech G, Mishra S, Gautam S, Sharma P. Evaluation of antioxidant deficit in
schizophrenia. Indian J Psychiatry. 2008;50(1):16-20.
23. Yao JK, Reddy R, van Kammen DP. Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatry Res. 2000;97(2-3):137-51.
24.Taenli F, Pirildar S, Akdeniz F, Uyanik BS, Ari Z. Serum nitric oxide metabolite
levels and the effect of antipsychotic therapy in schizophrenia. Arch Med Res.
2004;35(5):401-5.
21
25. Pae CU, Paik IH, Lee C, Lee SJ, Kim JJ, Lee CU. Decreased plasma antioxidants in
schizophrenia. Neuropsychobiology. 2004;50(1):54-6.
Reprint requests and correspondence:
Amra Memić, MD, MSc
Clinic of Psychiatry
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
E-mail: [email protected]
Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina!
Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini!
Original article
Medical Journal (2015) Vol. 21, No. 1, 22 - 26
Osteoporosis and physical activity
Osteoporoza i fizička aktivnost
Rubina Alimanović-Alagić1*, Mensur Vrcić2, Ramë Miftari3, Senad Alagić2, Senad Pešto4,
Elma Kučukalic-Selimović1
Clinic of Nuclear Medicine, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Faculty of Sport and Physical
Education, University of Sarajevo, Patriotske lige 41, 71000 Sarajevo, Bosnia and Herzegovina, 3Service of Nuclear Medicine, University Clinical Center of
Kosova, Prishtina, Kosova, 4Clinic of Emergency Medicine, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
Osteoporosis is a thinning of the bones that occurs over time
for most people. Building and maintaining bone mass requires a
combination of nutrients and physical activity. Building bone density in early childhood is the best way to prevent osteoporosis later. Risk factors are numerous and there is no unique cause of the
disorder. The aim of this study was to determine the influence of
sports, the occurrence of vitamin D deficiency and low calcium on
bone mineral density and occurrence of osteoporosis. Patients and
methods: the study involved a group of 286 patients diagnosed with
osteoporosis and osteopenia at the Clinic of Nuclear Medicine of
the Clinical Center University of Sarajevo (CCUS), age 30 to 65
over a 12 months period. The study was designed as prospective.
For each patient we did personal history and diagnostic procedure:
bone mineral density (BMD) at lumbar spine and proximal femur,
weight and body mass (BMI) presence of risk factors for osteoporosis, mineralogram and physical activity. Results of investigation:
low bone mineral density (BMD) is independent predictor of hip
fracture risk and spinal column or other fractures. BMD depends
on the value of minerals and vitamin D. Weight and body mass
(BMI) are associated with low bone mineral density and may affect the bone structure or bone degradation. Risk factors for the
prediction of osteoporosis and fractures have been less thoroughly studied in younger patients. In patients who are still actively involved in sports osteoporosis is uncommon, and occurs in 8% of
patients, while it occurs in 57% of patients lacking physical activity
and in 35% of patients with moderate physical activity. We evaluated the connection between weight and body mass index (BMI). Active sports, maintenance of body weight, varied nutrition, sufficient
intake of calcium and vitamin D, and sun exposure can increase
bone density and prevent fractures.
Osteoporoza je smanjenje mase koštanog tkiva koji se javlja tokom
vremena za većinu ljudi. Izgradnja i održavanje koštane mase zahtijeva
kombinaciju hranjivih tvari i fizičku aktivnost. Izgradnja gustoće kostiju u
ranom djetinjstvu je najbolji način za sprečavanje osteoporoze kasnije.
Faktori rizika su mnogobrojni, a nema jedinstvenog uzroka bolesti. Ciljevi
istraživanja: utvrditi uticaj bavljenja sportom, pojave sniženih vrijednosti
D vitamina i kalcija na mineralnu gustoću kostiju i pojavu osteoporoze.
Pacijent i metode rada: studija je uključivala grupu od 286 pacijenata sa
dijagnozom osteoporoze i osteopenije na Klinici za nuklearnu medicinu Kliničkog centra Univerziteta u Sarajevu, starosti 30-65 u periodu
od 12 mjeseci. Studija je bila prospektivna. Svakom pacijentu su uzeti
anamnestički podaci, te se pristupilo dijagnostičkoj proceduri: mjerenje mineralne gustoće kostiju (BMD) na lumbalnoj kičmi i proksimalnom
femuru, tjelesna težina i indeks tjelesne mase (BMI), deficijencija D vitamina i hipokalcemija, prisutnost faktora rizika za osteoporozu i tjelesno vježbanje-fizička aktivnost. Rezultati istraživanja: mineralna gustoća
kostiju (BMD) predstavljaju nezavisne prediktore rizika fraktura kuka
i kičmenog stuba ili drugih fraktura. BMD je u zavisnosti od vrijednosti minerala i vrijednosti vitamina D. Tjelesna težina i indeks tjelesne
mase (BMI) su povezani s niskom mineralnom gustoćom kostiju te mogu
utjecati na strukturu kostiju ili degradaciju istih. Kod mlađih pacijenata
pojava osteoporoze i prijeloma se manje temelji na prisustvu faktora
rizika. Pacijenti koji se još uvijek aktivno bave tjelesnim vježbanjem pojava
osteoporoze je mala, kod 8% pacijenata. Za razliku od pacijenata koji
nemaju fizičku aktivnost 57% ili se umjereno bave tjelesnim vježbanjem
osteoporoza se javlja u 35% slučajeva. Evaluirali smo povezanost između
tjelesne težine i indeksa tjelesne mase (BMI). Aktivno bavljenje fizičkim
aktivnostima, održavanje tjelesne težine, raznovrsna ishrana, dovoljno
unošenje kalcija i D vitamina, te izlaganje suncu mogu povećati gustoću
kostiju i spriječiti frakture.
Key words: bone mineral density, osteoporosis, BMI, physical activity, vitamin D deficiency
Ključne riječi: mineralna gustoća kostiju, osteoporoza, BMI, fizička
aktivnost, nedostatak vitamina D
INTRODUCTION
and hip, although any bone can be affected (1). The current opinion
is that childhood and adolescence are critical periods for building up
bone mineral density. It is also known that life style factors, such as
physical activity, may influence the accrual of bone mineral density
(2). Mechanical loading has been shown to be one of the best stimuli
to enhance not only bone mass but also structural skeletal adaptations, both independently contributing to bone strength (Figure 1).
The skeletal disease of bone thinning and compromised bone
strength, osteoporosis, continues to be a major public health issue
as the population ages. This disease is characterized by bone fragility
and an increased susceptibility to fractures, especially of the spine
23
Osteoporosis and physical activity
Figure 1 Osteoporosis.
Exercise prescription also includes a window of opportunity to
improve bone strength in the late pre- and early peri-pubertal period. Building and maintaining bone mass requires a combination of
nutrients and physical activity (3). Risk factors are numerous and
there is no single cause of the disorder (4). One of the best ways
to strengthen bones and prevent osteoporosis is by getting regular
exercise (5). Exercise, don’t just build muscle and endurance also
build and maintain the amount and thickness of bones (6).
Three types of exercise for osteoporosis are: 1. Weight-bearing, 2. Resistance and 3. Flexibility. All three types of exercise for
osteoporosis are needed to build healthy bones (Figure 2).
Vitamin D (1.25(OH)2D) is an important nutrient in the maintenance of bone health. The primary functions of vitamin D are
the regulation of intestinal calcium absorption and the stimulation
of bone resorption leading to the maintenance of serum calcium
concentration. Sources of vitamin D include sunlight, diet, and supplements (8). If vitamin D deficiency is not corrected, calcium continues to be pulled from the bone and rickets can occur in children,
while osteomalacia and osteoporosis can occur in adults. Sunlight is
the most common source of vitamin D (9).
The most common clinical tool to diagnose osteoporosis and
predict fracture risk is a bone mineral density (BMD) test. A measurement of bone density is often considered when it will help guide
decisions regarding treatment to prevent osteoporotic fractures (10).
Body mass index (BMI) is a predictor of fracture risk. BMI is a
reliable indicator of body fatness for most people and is used to
screen for weight categories that may lead to health problems (11).
Weight and body mass index are associated with low bone mineral
density and fractures in women aged 40 to 59 years (12).
Introduction Risk factors for the prediction of osteoporosis and
fractures have been less thoroughly studied in younger women. The
values of the recommended BMI are the same for both sex, it is 18.5
to 24.9 kg/m2 according to the World Health Organization Dexa
Scan: Left Femur for the European population.
Regular weight-bearing physical activity has been widely recommended for adult women and may be beneficial in preserving bone
mineral density (BMD).
Whilst exercise is recommended for optimum bone health in
adult women, there are few systematic reviews of the efficacy of walking as singular exercise therapy for postmenopausal bone loss (13).
Evidence shows that exercise may help build and maintain bone
density at any age (14). Studies have seen bone density increase
by doing regular resistance exercises, such as lifting weights, two or
three times a week. This type of weight bearing exercise appears
to stimulate bone formation, and the retention of calcium, in the
bones that are bearing the load. The force of muscles pulling against
bones stimulates this bone building process. So any exercise that
places force on a bone will strengthen that bone (15). Weight-bearing exercises are the most effective to build bones. These include
activities such as walking, stair climbing, running, hiking, and weight
lifting. Swimming and bicycling are not considered weight-bearing
exercises. Exercise also increases muscle strength, coordination, and
balance and decreases the likelihood of falls in the elderly (16).
The aim of this study was to determine the influence of sports,
the occurrence of vitamin D deficiency and low calcium on bone
mineral density with diagnosed osteoporosis.
MATERIALS AND METHODS
Figure 2 Exercise.
Calcium is an essential element in the human body and is necessary to many cell functions. It is a vital component of bone architecture and is required for deposition of bone mineral throughout life.
It is the levels of plasma calcium that dictate calcium balance (7).
The study involved a group of 286 patients with osteoporosis
and osteopenia at the Clinic of Nuclear Medicine Clinical Center
University of Sarajevo, age 30 to 65 over a 12 months period. For
each patient we did personal history and diagnostic procedure: bone
mineral density (BMD) at lumbar spine and proximal femur, weight
and body mass (BMI) presence of risk factors for osteoporosis, mineralogram and physical activity. BMD measurement was performed
for all subjects.
24
According to the World Health Organization (WHO) T-score
Means are as follows:
• T-score of -1.0 or above is normal bone density.
• T-score between -1.0 and -2.5 means you have low bone
density or osteopenia
• T-score of -2.5 or below is a diagnosis of osteoporosis.
Body Mass Index (BMI) is a number calculated from a person’s
weight and height. Body mass index (BMI) is a predictor of fracture
risk. Body Mass Index is a number calculated from a person’s weight
and height. BMI is a reliable indicator of body fatness for most people and is used to screen for weight categories that may lead to
health problems. The values of the recommended BMI are the same
for both sex, it is 18.5 to 24.9 kg /m2.
Patients were divided in three groups based on duration of their
physical activity:
Group I: Three times a week or more,
Group II: Once a week,
Group III: No physical activity
Serum calcium and D vitamin were measured using standard
methods. The normal adult value for calcium is 2.10-2.55 mmol/L.
Hypocalcemia is an electrolyte imbalance and is indicated by a
low level of calcium in the blood. The normal range of vitamin D
(25(OH)D) is 30–50 ng/ml.
R. Alimanović-Alagić et al.
Prevalence of osteoporosis in physical activity according to the
BMI.
I group: physical activity was registered in 58% (n=165) of patients,
diagnosed osteopenia in 95%, osteporosis in 5% of patients.
II group: moderate active was registered in 23% (n=65) patients,
diagnosed osteopenia in 68%, osteporosis in 32% of patients.
III group: lack of physical activity was registered in 19% (n=56) of
patients, diagnosed osteopenia in 11%, osteporosis in 89% of patients (Figures 4 and 5).
Figure 4 Physical activity.
RESULTS
The study included 286 patients, 189 women and 97 men, divided into three age groups: 30-40, 40-50 and 50-65 years (Table 1).
Table 1 Gender and age distribution.
n
%
Total
Gender
189
66%
Male
Female
97
34%
286
Age
100%
30-40
66
23%
40-50
109
38%
50-65
111
39%
In our study, osteopenia was diagnosed in 19% (n=54) of patients, osteoporosis of femur in 35% (n=100), osteoporosis of spine
in 46% (n=132) of patients (Figure 3).
Figure 5 Prevalence of osteoporosis according to the BMI
and III group physically active patients.
Calcium values ranged from 2 to about 2.3, depending on osteoporosis or osteopenia (Figure 6).
The values of vitamin D ranged from 14.1 to 42.13 depending
on the BMI, diet and physical activity (Figure 7).
Figure 6 Value of Calcium.
Figure 7 Value of vitamin D.
DISCUSSION
Figure 3 Pecentage of patients diagnosed as osteoporotic
using DXA spine and femur.
The study included 286 patienata: 189 women, 97 men divided
into three age groups: 30-40, 40-50 and 50-65 years. In our study,
osteopenia was diagnosed in 54 patients (19%), osteoporosis of femur in 100 patients (35%), and osteoporosis of spine in 132 patients (46%).
Osteopenia was diagnosed in 191 patients (67%), osteoporosis
of femur in 43 patients (15%), and osteoporosis of spine in 51 patient (18%).
25
Osteoporosis and physical activity
With regard to physical activity, 165 (58%) patients were active,
65 (23%) patients were moderately active and 56 (19%) patients
were not active.
Prevalence of osteoporosis at physical activity according to the
BMI was as follows: I group: physical activity was registered in 165
(58%) patients, osteopenia was diagnosed in 95%, and osteporosis
in 5% of patients. II group: moderate active was registered in 65
(23%) patients, osteopenia was diagnosed in 68%, and osteporosis
in 32% of patient. III group: lack of physical activity was registered in
56 (19%) patients, osteopenia was diagnosed in 11%, and osteporosis in 89% of patients.
BMI 17-19: there were 58% (n=165) of physically active patients, the frequency of osteopenia was registered in 95% (n=157)
while the occurrence of osteoporosis was registered in 5% (n=8) of
patients. BMI 23- 26: there were 23% (n=65) of moderately active
patients, the frequency of osteopenia was registered in 68% (n=44)
while the osteoporose was registered in 32% (n=21) of patients.
BMI 26-30: in (n=56) 19% of inactive patients occurrence of osteopenia was registered in 11% (n=7) of cases, and the occurrence of
osteoporosis in 89% (n=49) of patients.
In our study value of D vitamin was 14,1 to 42,12 ng/ml depending on the BMI, diet and physical activity. The calcium values
ranged from 2,0 to about 2.355 mmol/L, depending on osteoporosis or osteopenia.
A primary factor associated with risk of osteoporosis is the
maximal BMD of the skeleton (peak bone mass) developed during
childhood and early adult years (11). The age of bone mineralization
onset and the age of attainment of peak bone mass vary, according
to gender and the bone region being studied. Peak bone mass usually occurs before the third decade (14). Peak bone mass is dependent
primarily on genetic factors (70-80%), but it is also considerably influenced by physical activity and dietary calcium intake during adolescence (7,17). The age-related decrease of bone mass (regardless
of gonadal hormone levels) generally is starting some time after the
age of 50. The age-related bone loss is about 0.5% per year during
the sixth and seventh decades, but accelerates substantially with advancing ages. In women there is an increased acceleration of bone
loss at menopause (4,18).
The individuals who do not obtain enough calcium from foods
should take a supplement, less than the recommended 1000 mg daily. The normal range of Calcium is 2,10-2,55 mmol/L. Low forearm
bone mineral density (BMD) is a risk factor for sustaining a forearm fracture in both genders and it might be a predictor of a later
vertebral and/or hip fracture. The increased incidence results from
a combination of decreasing BMD and an increased propensity of
falling in older ages (19, 20). Most hip fractures occur in the very
elderly at an average age of 80 years. The greatest number (34.8%)
of osteoporotic fractures occurred in Europe (21). Epidemiological
observations suggest that sunlight exposure is an important determinant of hip fracture risk. Of the fractures due to osteoporosis,
hip fracture is associated with the highest long-term reductions in
quality of life, mortality and cost for society (22). The rate of hip
fractures is two to three times higher in women than men; however
the one year mortality following a hip fracture is nearly twice as high
for men as for women (23).
Normal, strong and healthy bones contain large amounts
of minerals, which make them strong. Peak bone mass is usually
achieved by age 30, therefore, physical activity and obtaining the
recommended doses of calcium and vitamin D in adolescence and
young adult will ensure peak bone mass development (24). In the
daily reference intake should be 800–2000 i.j. per day. The normal
range of vitamin D (25(OH)D) is 30–50 ng/ml (9, 25).
The amount of these bone minerals within our bones is referred
to as our bone mineral density (BMD). Our BMD is highest when we
are aged in our 20s, and then as we get older we gradually lose some
of the important minerals, causing our BMD to decline. If this loss
of minerals is excessive, our BMD will become very low, and we will
develop osteoporosis (26).
Characterized by weak and brittle bones, osteoporosis and its
precursor osteopenia affect 44 million patients bone fractures every year. Life Health care providers are vital to identify patients at
risk for bone loss and diagnose bone thinning so that prevention
and treatment strategies are effective. Prevention of falls with maintenance of bone health through adequate calcium, vitamin D, and
physical activity represent the base of the pyramid for all individuals,
including those with bone disease (27, 28). Peak bone mass is usually
achieved by age 30, therefore, physical activity and obtaining the
recommended doses of calcium and vitamin D in adolescence and
young adulthood will ensure peak bone mass development (29).
CONCLUSION
We concluded that the low BMI is a risk of substantial importance for all fractures that is largely independent of age and sex, but
dependent on BMD. The significance of BMI as a risk factor varies
based on the BMI level Patients with low BMI are at increased risk
of osteoporosis. To help reduce the risk of osteoporosis, patients
should be advised to maintain a normal weight. Significant association with serum level is use of multivitamins and physical activity.
Evidence show that exercise may help building and maintenance of
bone density at any age. Studies have seen bone density increase by
doing regular resistance exercises three times a week or more, such
as weight lifting. This type of weight bearing exercise appears to
stimulate bone formation, and the retention of calcium in the bones
bearing the load. A bone health through adequate intake of calcium,
vitamin D, and physical activity represent the base of the pyramid
for all individuals with bone disease.
Conflict of interest: none declared.
REFERENCES
1. Kanis J.A in: Osteoporosis. Blackwell Science, London. 1994:22-55.
2. Sarko J. Bone and mineral metabolism. Emerg Med Clin North Am. 2005;23(3):70321.
3. Marques EA, Mota J, Carvalho J. Exercise effects on bone mineral density in
older adults: a meta-analysis of randomized controlled trials. Age (Dordr).
2012;34(6):1493-515.
4. Holmberg AH, Johnell O, Nilsson PM, Nilsson J, Berglund G, Akesson K.. (2006).
Risk factors for fragility fracture in middle age. A prospective population-based
study of 33,000 men and women. Osteoporosis International. 17(7):1065-77.
5. Karlsson MK, Rosengren BE. Therapeutic and Prophylactic Effects of Sports and
Exercise on Osteoporosis and Fracture Risk. Dtsch Z Sportmed. 2012;63(1):9-12.
26
6. Martyn-St James M, Carroll S. Effects of different impact exercise modalities on
bone mineral density in premenopausal women: a meta-analysis. J Bone Miner Metab. 2010;28(3):251-67.
7. Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin
Nutr. 2004;80(6 Suppl):1725S–9S.
8. Cranney A, Weiler HA, O’Donnell S, Puil L. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. Am J Clin Nutr.
2008;88(2):513S–9S.
9. Stechschulte SA, Kirsner RS, Federman DG. Vitamin D: bone and beyond, rationale
and recommendations for supplementation. Am J Med. 2009;122(9):793–802.
10.Kuwabara A, Tanaka K, Tsugawa N, Nakase H, Tsuji H, Shide K, et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel
disease. Osteoporos Int. 2009;20(6):935–42.
11.Asomaning K, Bertone-Johnson ER, Nasca PC, Hooven F, Pekow PS. The association between body mass index and osteoporosis in patients referred for a bone
mineral density examination. J Womens Health (Larchmt). 2006;15(9):1028-34.
12.Morin S, Tsang JF, Leslie WD. Weight and body mass index predict bone mineral
density and fractures in women aged 40 to 59 years. Osteoporos Int. 2009;20:363–
70.
13. Martyn-St James M, Carroll S. High-intensity resistance training and postmenopausal bone loss: a meta-analysis. Osteoporos Int. 2006;17(8):1225-40.
14.American College of Sports Medicine. Physical activity and bone health. Medicine
and Science in Sports and Exercise 2004;36(11):1985-1996.
15.Khan K, McKay H, Kannus P, Bailey D, Wark J, Bennell K. In: Physical Activity and
bone health. Human Kinetics. 2001;111-114.
16. Shigematsu R, Okura T. A novel exercise for improving lower-extremity functional
fitness in the elderly. Aging Clin Exp Res. 2006;18(3):242-8.
17. Institute of Medicine. Vitamin D. In: Dietary reference intakes for calcium phosphorus, magnesium, vitamin, and fluoride. Washington, DC: National Academies Press.
1997;250–287.
18. Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N, et
al. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf ) Forthcoming. 2009.
19.Heinonen A. Physical activity, targeted bone loading and bone mineral density in
premenopausal women in. In: Physical activity and bone health. Human Kinetics.2001;129-142.
20.Martyn-St James M, Carroll S. Progressive high-intensity resistance training and
bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med. 2006;36(8):683-704.
21. Johnell O, Borgstrom F, Jonsson B, Kanis J. Latitude, socioeconomic prosperity, mo-
R. Alimanović-Alagić et al.
bile phones and hip fracture risk. Osteoporosis International. 2007;18(3):333.
22.Johnell O. The socioeconomic burden of fractures: today and in the 21st century.
Am J Med. 1997;103(2A):20S–25S.
23. Johnell O, Kanis JA. An estimate of the worldwide prevalence, mortality and disability associated with hip fracture. Osteoporos Int. 2004;15:897–902.
24. Stetzer E. Identifying Risk Factors for Osteoporosis in Young Women. The Internet
Journal of Allied Health Sciences and Practice. 2011;9:4.
25. Cranney A, Horsley T, O’Donnel S, Weiler H, Puil L, Ooi D, et al. Effectiveness and
safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep).
2007;(158):1-235.
26. Tanaka R, Ozawa J, Umehara T, Kito N, Yamasaki T, Enami A. Exercise intervention
to improve the bone mineral density and bone metabolic markers as risk factors for
fracture in Japanese subjects with osteoporosis: a systematic review and meta-analysis of randomised controlled trials. Journal of Physical Therapy Science. 2012;
24(12):1349-1353.
27.de Kam D, Smulders E, Weerdesteyn V, Smits-Engelsman BC. Exercise interventions to reduce fall-related fractures and their risk factors in individuals with low
bone density: a systematic review of randomized controlled trials. Osteoporosis
International. 2009;20(12): 2111-2125.
28.Holick MF. Vitamin D status: measurement, interpretation, and clinical application.
Ann Epidemiol.2009;19(2):73–8.
29. Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, et al.
Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a
meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551–
61.
Reprint requests and correspondence:
Rubina Alimanović-Alagić, MD, PhD
Clinic of Nuclear Medicine
Clinical Centre University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 298 386
Email: [email protected]
Original article
Medical Journal (2015) Vol. 21, No. 1, 27 - 29
Significance of bioelastic extramedullary bone
osteosynthesis in clinical practice
Značaj bioelastične ekstramedularne koštane
premosnice u kliničkoj praksi
Zoran Hadžiahmetović1*, Narcisa Vavra-Hadžiahmetović2
1
2
Clinic of Emergency Medicine, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina,
Clinic of Physical Medicine and Rehabilitation, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The authors of this study will show experimental development
followed by clinical application of bioelastic extramedullary osteosynthesis (BEO). The main reason for work on BEO developement
was the inability of proper bone fixation in small diaphysis in case
of proclaimed osteosynthesisa absence. In that regard, following the
computerized material estimation the basic task of the experimental
research was set, that was to determine the effect or reliability of
BEO as an extramedullary binder in simple and complex fractures of
small animals (13 dogs and 19 cats). By default the parameters of the
research showed a wide segmental bioelasticity of BEO reflected in
the prevention of shear, rotation, contraction and distraction. In 2006
this method was introduced as original surgical technique for the
chosen indicated field. Final results compared with other alternative
methods were in favor of BEO application. The bone osteosynthesis has shown its strong foundation in serious comminuted fractures,
necessary interphalangeal and metacarpophalangeal arthrodesis, and
in the installation of intercalary bone grafts in 12 applications (10 patients) at the Clinical Center University of Sarajevo (CCUS).
Autori će u radu prikazati eksperimentalni razvoj, a zatim i kliničku
aplikaciju bioelastične ekstramedularne osteosinteze (BEO) - premosnioce. Osnovni problem koji je uvjetovao rad na razvoju BEO jeste nemogućnost odgovarajuće fiksacije kosti kod malih dijafiza u situacijama
nedostatka proklamirane osteosinteze. U tom smislu nakon PC proračuna materijala koji je upotrebljen postavljen je osnovni zadatak eksperimentalnog istraživanja, a to je utvrditi efekat odnosno pouzdanost
BEO kao ekstramedularnog bindera kod jednostavnih i kompleksnih
prijeloma malih životinja (13 pasa i 19 mačaka). Prema zadanim parametrima istraživanja utvrđen je širok segmentni bioelasticitet BEO koji
se ogledao u prevenciji: striga, rotacije, kontrakcije i distrakcije. Metoda
je kao originalna operativna tehnika uvedena u kliničku praksu 2006.
godine u biranom indikacionom području. Konačni rezultati komparirani sa drugim alternativnim metodama idu u prilog primjene BEO.
Premosnica je pokazala svoje snažno uporište kod jakih kominutivnih
prijeloma, neophodnih interfalangealnih i metakarpofalangealnih artrodeza i pri ugradnji interkalarnih koštanih presadaka kostiju šake kod 12
aplikacija (10 pacijenata) u Kliničkom centru Univerziteta u Sarajevu.
Key words: bioelastic osteosynthesis, fractures, bone defects, arthrodesis
Ključne riječi: bioelastična osteosintreza, prijelom, koštani defekt,
artrodeza
INTRODUCTION
require use of special instruments and have a high purchase price.
With a view of achieving better bone elasticity and wide bridging
of a bone fracture computer calculation was used, specifically individual analysis of mechanical load of one and subsequently of two
K-wires of 12,0/24,0 gram weight, and Ø 2,0 mm, L= 150 mm
dimension. The force of Kg/N = 3/29,41, 5/49,03, 7/68.64 was
applied in the simulation. The analysis related to twisting deformation: static mo-ment (M) Ncm and achieved angle (α°), as well
as to deformation caused by twisting without longitudi-nal force
(KI/mm). Axial load (compression-distraction) of the K-wire, and
rigidness and elasticity of the structural model interconnection respectively were not measures given that they were in collision with
the specific characteristics of the experimental research. It was established that the minimum de-formation with twisting and bending
The main problem in the fixation of small bone fractures in
the locomotor surgical system is the selection of adequate fixation.
This is especially emphasized in case of small diaphysis defects.
The question is which bone implant or osteosynthesis is to be applied.
In case of a small plate and screws, frequent problems relate
to inadequate size, voluminous, rig-idness, use of special instruments and high implant prices. In case of Kirschner wire (K-wire)
and in-tramedullary and/or transcortical screw fixation, percutan
use causes frequent infections around wires, loose of fixation, fracture, bending, dislocation or spilling. External fixators are extremely
large and their use is limited to a narrow indicated area. They also
28
Z. Hadžiahmetović et al.
occurred with the creation of a structural binder consisting of two
K-wires arranged under the angle of 54° with four cerclage wires
on two levels in each main bone fragment (1).
This simulation presented basis for the experimental research
of bone wire complex on small an-imal bones (dogs and cats). In
that regard we simultaneously applied intramedullary and extramedullary bridging of the fracture with K-wire and cerclage. The
additional aim of the analysis was to determine the strength of
bond between the two interconnected K-wires and cerclage in a
routine procedure only in an extreme version, without additional
intramendullary support in simple and complex fractures.
Following very good initial results the further application was
exclusively exstramendullary and was called Extramedullary Fixation with Kirschner Wires and Cerclage (EFIKS). This research on
ani-mals was conducted in the period from 2001 to 2005. Over
that period 13 dogs and 19 cats with trauma fractures were surgically treated at the Cantonal Veterinary Station in Sarajevo. The
following parame-ters were monitored: fracture healing (radiography), implant fixation (specifically alenthesis – bone – soft tissues),
infection development, deformities, joint movements and everyday
activities of the animals (Figure 1). It was established that EFIKS
was: firm fractural osteosynthesis with wide segmental bioelasticity
in unstable fractures, good prevention from rotation, shear, angulations and distraction, with good adoption of fractural fragments,
and very cheap. Furthermore, the evident was a high level of osteosynthesis elasticity, specifically a direct correlativity of bioelasticity
with the established balance among the bone contact, size and dimension of the bone-position of implant (1).
A
B
Figure 1 Comminuted fracture of a dog femur (x-ray)
A. BEO after surgical procedure
B. BEO corrected fracture (2 months after the surgery)
In 2006 this method (sec.Hadžiahmetović) was introduced as
original in the clinical application for
surgical fixation of metacarpal bone fractures and phalanges at the
Clinic for Plastic and Reconstructive Surgery and in the Clinic for
Emergency Medicine of the CCUS (2,3,4,5).
Based on the presented results in the fracture treatment, the
new aim of the research related to
osteosynthesis development was set up, namely to determine the
following:
• The applicability of BEO in stabilization of intercalary (tricortical and cylindrical) bone grafting of phalangeal bone defects and
metacarpal bones;
• To which extent is BEO wildly uniform and provide better biochemical basis within the bone fu-sion (arthrodesis), and to which
extent is it more reliable in respect to intramedullary fixation with
K-wires;
• Whether the stabilization and final intercalary bone graft fusion
are in direct correlation with the implant selection (6,7).
MATERIALS AND METHODS
In the period from 2007 to 2012 ten (10) patients diagnosed
with bony defect in metacarpal or phalanges fractures were surgically treated at the Clinic for Plastic and Reconstructive Surgery and
the Clinic for Emergency Medicine of the CCUS. All cases related
to trauma substrate, except for two defects which occurred after
tumor extirpation, specifically the bone cyst extirpation (Table 1).
Table 1
1 Double phalange defect,
4 open defect *
No /Ost
Trauma/Tumor/
Arthrodesis
Bone graft
Cyst
1/1.
Phal.prox.pollicis
MTCP + IP
I liac bone (3 cortical )
(osteid osteoma)
2/2.*
Phal.prox.dig.IV,
MTCP + PIP
+
II meta carpal
V (trauma)
(cylindric )
3/1.
Phal.med.dig.III
PIP
Free fibula
(cyst )
(cylindric )
4/1.*
Phal.dist.indicis
DIP
I liac bone
(trauma)
(cortico-spongiosa )
5/1.*
Phal.prox.indicis
MTCP + PIP
I liac bone (2 cortical )
(trauma)
2/1.
Metacarpal.V
Free fibula
(trauma)
(cylindric )
6,7/2.
Phal.med.dig.IV
PIP + DIP
I liac bone
(trauma)
(cortico-spongiosa )
8/1.*
Metacarpal.
III
Radi al
(trauma)
(cortico-spongiosa )
9,10/2.
Phal.med. dig. III
PIP + DIP
I liac bone
(trauma)
(cortico-spongiosa )
The average size of the defects was 2.8cm /1.5-3.2cm/. In trauma defects all surgical treatments were performed approximately 5
days later. There were 7 men and 3 women with an average of 29
years.
The patients were monitored over the period of 3 to 6 months
following the surgery.
The proposed research parameters were: radiographic (bone
consolidation, position of intercalary graft, collapse, resorption,
reduction, finger rotation, bone infection), functional (volume of
movements, musculoskeletal strength according to Lovett scale,
determining finger volume on proposed and specific spots, daily activity test), structural stability (position of all BEO components and
their correlation with bone grafts).
RESULTS
Based on radiographic parameters all patients were determined
with complete fusion from 6 to 16 weeks without reduction, resorption, and graft or finger rotation.
Significance of bioelastic extramedullary bone osteosynthesis in clinical practice
Post operative bone infection was not registered in any of the
patients. Five (5) patients were subjected to a primary bone and soft
tissue defect treatment, and based on the antibiogram they were
treated with antibiotics pre and post operatively.
Figure 2 Aneurysmal bone cyst of middle phalanx of the
third finger. Substitution of phalanx with fibula graft, BEO,
proximal interphalangeal (PIP) and distal interphalangeal
(DIP) transient joint stiffness - the 2007 surgery (x-ray)
Figure 2A The same patient. Complete graft fusion on the
third finger (x-ray) Functional hand - 2015
By means of musculoskeletal strength according to Lovett scale
and manual muscular test respectively the hand function was given
grade 4 (good) and was achieved in all patients by 20th week, and
concerning the daily activities it was achieved after 16 weeks in 7 patients. There were no discrepancies in partial and total finger length.
In the examined period the structural stability of all BEO was regular.
DISCUSSION
The research results were compared with the results achieved
by Sabapathy et al. who attempted to achieve the fixation of intercranial graft only with K–wire in 15 patients, and in 20 exclusively
trauma phalangeal bone defects. They had 6 double phalange defects and 7 open defects with the average length of 3,3 cm /2,5
- 5,0 cm/ (8). The research parameters were identical and surgical
treatments were also conducted retrospectively.
Based on radiological parameter they achieved 16 fusions in 6
weeks, bone graft length resorptions of 20% and 15% which occurred in two terminal bone grafts; one patient had a range of motion of 0° to 40° at the pseudarthrosis level with reasonable stability;
one patient developed osteomyelitis and the infected bone graft was
removed after 3 months. The hand function and the rough muscular skeleton strength respectively as well as daily activities were
restored after 23 weeks. Structural stability was not restored in 3
patients who were diagnosed with lack of graft stabilization.
Bad selection of osteosynthetic material (implant) was recorded
in 15% of patients, which resulted in disturbed bone fusion (8).
29
CONCLUSION
The created BEO proved as a good choice in stabilization of
bone grafts and metacarpal bone phalanges grafts, and simple and
complex diaphyseal fractures of short and middle bones especially
of upper extremities. The implementation of the method is simple
and BEO is elastic enough to create large rigid diaphyseal bone segments. It satisfies all contemporary principles of „biological fixation“
of fractures and except for surgical cerclage set it does not require
purchasing of special instruments.
In certain cases it is necessary to prevent the bone lever phenomena, especially if the bone defect or fracture line is outside of
middle diaphysel segment or in a situation of inadequate contact
bracing. This can influence the need for additional use of cerclage
wires. However, reduction of micro movements can be achieved
with the increase of number and thickness of K-wires, especially if
stronger muscle activity is expected.
Conflict of interest: none declared.
REFERENCES
1. Hadžiahmetović Z, Krasni J. Osteosinteza tehnikom ekstramedularne fiksacije prijeloma Kirschner iglama i serklažom (EFIKS). Tr Glas. 2006; 4(3): 27- 30.
2. Hadžiahmetovi Z. Uvođenje novih dijagnostičkih i/ili terapeutskih procedura. Info
bilten, KCUS. 2006: (9 -10):19.
3. Hadžiahmetović Z. Početna klinička iskustva u liječenju dijafizarnih prijeloma malih
kostiju tehnikom originalne ekstramedularne osteosinteze. Med Arh. 2006; 60(6)
Supl.: 9-12.
4. Hadžiahmetović Z, Vavra – Hadžiahmetović N. Effects of Specific Forms of Extramedullary Fixation in Treatment of Diaphyseal Small Bone Fractures. HealthMED.
2008; 2(4): 219- 24.
5. Hadžiahmetović Z. Operativno liječenje prijeloma koštanih defekata originalnom ekstramedularnom osteosintetskom premosnicom. Club M Informator.
2012;4(16):64-66.
6. Hadžiahmetović Z. Biological extramedullary elastic osteosynthesis as a method of
choice in the replacement of the hand bone defect with intercalated bone grafts.
Folia Medica. 2012;47 (2 suppl):18.
7. Hadžiahmetović Z. Izbor osteosinteze pri nadomještanju koštanih defekata falangi
šake autolognim interkalarnim presadcima. Radovi Hrvatskog društva za znanost i
umjetnost, XII-XIII. 2010/2011;80-187.
8. Sabapathy SR, Venkatramani H, Giesen T, Ullah AS. Primary bone grafting with pedicled flap cover for dorsal combined injuries of the digits. Journal of Hand Surgery
(European Volume) 2008;33E:1:65-70.
Reprint requests and correspondence:
Zoran Hadžiahmetović, MD, PhD
Clinic of Emergency Medicine
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 297 824
Email: [email protected]
Original article
Medical Journal (2015) Vol. 21, No. 1, 30 - 33
Relevance of fine-needle aspiration cytology compared
to histopathology in differentiated thyroid carcinoma
Značaj nalaza citološke punkcije u poređenju sa
patohistološkom dijagnozom kod diferenciranih
karcinoma štitne žlijezde
Šejla Cerić*,Timur Cerić2, Miran Hadžiahmetović1, Selma Agić1,
Elma Kučukalić-Selimović1, Amela Begić1, Nermina Bešlić1, Sadat Pušina3
1
Clinic of Nuclear Medicine, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of Oncology, Clinical Center
University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 3Clinic of Oncology and Glandular Surgery, Clinical Center University of Sarajevo,
Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
Thyroid cancers are the most common malignant tumour of the
endocrine system, with an incidence that is growing every year. Thyroid
nodule with suspicious US features (hypoechoic, increased nodular vascularity, infiltrative margins, microcalcifications and size), abnormal cervical lymph nodule, and scyntigraphic signs (cold nodule) require further
diagnostics. The fine-needle aspiration (FNA) is the most accurate and
cost-effective method for evaluating thyroid nodules. Patients whose cytology results were malignant or suspicious for malignancey and patients
whose cytology results showed signs of marked atypia, are referred
to surgery. The aim of our study is to evaluate the FNA results and to
compare them to hystopathology in diferentiated thyroid carcinoma.
Our retrospective study included 65 patients who were referred to the
Clinic of Nuclear Medicine, Clinical Centre University of Sarajevo. All
patients underwent FNA and thyroid surgery and they were divided
into 5 groups based on the results of the FNA findings (National Cancer Institute Thyroid Fine-Needle Aspiration Guidelines Committee
IV). Based on the patohystological findings the results were divided in 2
groups (papillary and follicular thyroid cancer). Data is presented in the
form of tables and graphs, using classical methods of descriptive statistics, sensitivity and false-negative and positive rates and positive predictive value, depending on the nature and scale of the measurement data.
Sensitivity test (SN) was 67.0%, The positive predictive value (PPV) was
97.0%, false negative rate was 21,5 % and false postive 0%. Fine-needle
aspiration (FNA) biopsy of the thyroid gland is an accurate diagnostic test
used routinely in the initial evaluation of nodular thyroid disease. Results
from the study were comparable to those from literature with a special
reference to false negative results.
Karcinomi štitnjače su najčešći zloćudni tumori endokrinog
sistema, s učestalošću koja raste svake godine. Čvorovi štitne žlijezde sa sumnjivim karakteristikama na UZ-u (hipoehogene, povećane prokrvljenosti, sumnjive inflitrativne margine, mikrokalcifikati
i veličina), abnormalni limfni čvorovi i scintigrafskih znakova (hladni
čvorovi) zahtijevaju daljnju dijagnostiku. Citološka punkcija (FNA) je
najprecizniji i ekonomičan način za procjenu strukture čvorova štitnjače. Pacijenti čiji su citolološki rezultati bili maligni ili sumnjivi za
malignost i pacijenti čiji je citološki nalaz ukazivao na atipiju su upućeni na operaciju. Cilj našeg rada bio je ocijeniti rezultate FNA i
usporediti histopatologiju diferenciranih karcinoma štitnjače. U našoj
retrospektivnoj studiji bilo je 65 pacijenta koji su upućeni na Kliniku za nuklearnu medicinu, Kliničkog centra Univerziteta u Sarajevu.
Svi pacijenti su podvrgnuti FNA i operaciji štitnjače. Svi pacijenti su
podijeljeni u 5 skupina na temelju rezultata FNA nalaza (Nacionalni
Institut za karcinome štitnjače-Smjernice za aspiracionu punkciju IV).
Na temelju patohistoloških nalaza, rezultati su bili podijeljeni u 2 skupine (papillarni i folikularni karcinom štitnjače). Podaci su prikazani
u obliku tablica i grafova, korištene su klasične metode deskriptivne
statistike, osjetljivost i lažno-negativnih i pozitivne stope i pozitivne
prediktivne vrijednosti, ovisno o prirodi i opsegu mjerenja podataka.
Ispitivanje osjetljivosti (SN) je 67,0%, pozitivna prediktivna vrijednost
(PPV) je 97,0%, lažno negativnih stopa je 21,5%, a lažno pozitivna je
0%. Aspiraciona punkcija iglom (FNA) štitnjače je tačan dijagnostički
test koji se koristi rutinski u početnoj procjeni nodularne bolesti štitnjače. Rezultati ovog istraživanja su usporedivi sa onima iz literature,
ali poseban oprez treba posvetiti lažno negativnim rezultatima.
Key words: thyroid carcinoma, fine-needle aspiration, cytology, histopathology
Ključne riječi: karcinom štitnjače, citološka punkcija, citologija, histopatologija
INTRODUCTION
pending on the type of cell origin they are classified as: differentiated
(papillary and follicular), undifferentiated and rare tumours of the
thyroid gland (lymphoma, sarcoma, fibrosarcoma and metastatic
tumours). Papillary thyroid carcinoma is known to frequently metas-
Thyroid cancers are the most common malignant tumour of the
endocrine system, with an incidence growing every year (1). De-
Relevance of fine-needle aspiration cytology compared to histopathology in differentiated thyroid carcinoma
tasize to regional lymph nodes, whereas follicular thyroid carcinoma more frequently metastasizes to distant organs such as the lung,
bone, and brain.
A thyroid nodule is a palpable or not palpable-ultrasound (US)
detected lesion within thyroid gland (2). Generally, only nodules
larger than 1 cm should be evaluated, since they have a greater potential to be significant cancer. Thyroid nodule with suspicious US
features (hypoechoic, increased nodular vascularity, infiltrative margins, microcalcifications and size), abnormal cervical lymph nodule,
and scyntigraphic signs (cold nodule) require further diagnostics.
The next step is fine needle aspiration cytology (FNA). FNA is the
most accurate and cost-effective method for evaluating thyroid nodules. FNA results are divided into four categories: non-diagnostic,
malignant, indeterminate or suspicious for neoplasm, and benign.
The National Cancer Institute Thyroid Fine-Needle Aspiration State
of the Science Conference adds two additional categories: suspicious for malignancy (risk of malignancy 50–75%) and follicular lesion of undetermined significance (risk of malignancy 5–10%). The
conference further recommended that “neoplasm, either follicular
or Hurthle cell neoplasm” be substituted for “indeterminate” (risk
of malignancy 15–25%) (3). Routine FNA is not recommended for
subcentimeter nodules (4). These six diagnostic categories were
beneficial for further management: clinical follow-up or surgical
management (5).
Patients whose cytology results were malignant or suspicious
for malignancy and patients whose cytology results showed signs
of marked atypia, are refer to surgery. Some patients with nondiagnostic or benign cytology results but with suspicious US features are
also referred to surgery.
The aim of our study was to evaluate results of FNA and compare them to hystopathology in diferentiated thyroid carcinoma.
MATERIALS AND METHODS
Our retrospective study included 65 patients referred to the
Clinic of Nuclear Medicine, Clinical Centre University of Sarajevo.
All patients underwent FNA and thyroid surgery. They were all diagnosed with differentiated thyroid carcinoma after surgery with
hystopathology finding. Before surgery all patinets underwent FNA
for evaluation of disesase. FNAs were performed using pistol type
syringe holder guided by US. FNA results were correlated with histopathology findings and the sensitivity and positive predictive value
were calculated. The frequency of thyroid type cancer was investigated. All patients were divided into 5 groups based on the results
of FNA findings (National Cancer Institute Thyroid Fine-Needle Aspiration Guidelines Committee IV). Based on the patohystological
findings the results were divided in 2 groups (papillary and follicular
thyroid cancer).
The database was composed in Microsoft Office Excel 2010 and
data from paper documents were entered therein. After checking
the integrity of the data, the statistical analysis was performed in
IBM SPSS Statistics in. 22.0 Program for Mac. Data was presented
in the form of tables and graphs, using classical methods of descriptive statistics, sensitivity and false-negative and positive rates and
positive predictive value, depending on the nature and scale of the
measurement data.
31
RESULTS
Of the total number of patients (n = 65), 52 (80.0%) were female and 13 (20.0%) male.
Table 1 Gender structure to a group of subjects (n = 65).
Valid
Cumulative Frequency
Percent
percent
percent
female
52
80.0
80.0
80.0
13
20.0
20.0
100.0
Valid male
Total
65
100.0
100.0
Of the total number of patients (n = 65) the minimal age was
24, while the maximum amounted to 80. The average age was 53.55
years.
Table 2 Age (years) to a group of subjects (n = 65).
N Minimum Maximum Mean Std. Deviation Age
50
24
80
53.44
15.705
50
Valid N(listwise)
Of the total number of patients (n = 65) after FNA 1 result
(1.5%) did not meet the criteria, benign lesions were present in 14
patients (21.8%), while malignant lesions were present in 23 patients
(35.0%).
Table 3 Diagnostic results based on FNAB (fine needle aspi- ration biopsy) (n = 65).
Valid Cumulative
Frequency Percent percent
percent
Benign
14
21.5
21.5
21.5
Atypia of
7
10.8
10.8
32.3
Valid undetermined
significance
Neoplasm
23
35.4
35.4
67.7
Suspicious
20
30.8
30.8
98.5
for malignancy
Nondiagnostic
1
1.5
1.5
100.0
Total
65
100.0
100.0
Figure 1 Diagnostic results based on FNAB (fine needle
aspiration biopsy) (n = 65).
32
Of the total number of patients (n = 65), 37 patients (56.9%)
had papillary carcinoma of the thyroid gland, while 28 patients
(43.1%) had follicular carcinoma of the thyroid gland.
Table 4 Diagnostic results based on histological findings
(PHD) (n = 65).
Valid
Cumulative
Frequency Percent percent
percent
Ca papillare
37
56.9
56.9
56.9
Valid Ca folliculare
28
43.1
43.1
100.0
Total
65
100.0
100.0
Š. Cerić et al.
ter techology support is needed for better correlation between the
FNA and PHD.
Sensitivity test (SN) is defined as the ability of a test to identify people who actually have the disease. Sensitivity test (SN) was
67.0%, namely by means of the FNAB (fine needle aspiration biopsy) it was possible to detect 67.0% of patients who actually had
thyroid gland cancer. The positive predictive value (PPV) was 97.0%,
i.e., the probability that a patient with a positive FNA findings of
thyroid carcinoma really has the thyroid gland cancer is 97.0% . False
negative rate was 21,5 % ie. number of patients that have negative
FNA and positive PHD and false positive is 0% is patients that have
positive FNA and negative on surgery. Other results are comperable to those from litereature.
Table 6 Sensitivity and false negative rate and falase positive rate of FNA compared to PHD.
FEATURE
Sensitivity,
Positive predictive value, %
False-negative rate, %
False-positive rate, %
%
DEFINITION
67
Likelihood that patient who has disease has positive test results
97
Fraction of patients who have positive test (who have disease)
21.5 FNA negative; histology positive for cancer
0
FNA positive; histology negative for cancer
DISCUSSION
Figure 2 The diagnostic results based on histological findings (PHD) (n = 65).
The database was composed in Microsoft Office Excel 2010 and
data from paper documents was entered therein. After checking the
integrity of the data, the statistical analysis was performed in IBM
SPSS Statistics in. 22.0 Program for Mac. Data was presented in the
form of tables and graphs, using classical methods of descriptive
statistics, false-negative and positive rates and positive predicative
value, depending on the nature and scale of measurement data.
Table 5 Diagnostic accuracy of the FNAB (fine needle aspi- ration biopsy) findings in detecting thyroid cancer in rela- tion to the PHD (histopathologic findings) (N = 65).
FNA
Pap
Fol
8
6
Benign
14
Atypia of
5
2
7
undetermined
Valid significance
Neoplasm
16
7
23
Suspicious
8
12
20
for malignancy
Nondiagnostic
0
1
1
Total
65
37
28
This table contains a significant number of the FNA benign finding, 14 out of 65 (21,5%), diagnosed as malignacy after surgery. This
is of crucial interest in the study given that the finding was worse
than in the literature. The reason for that is a lack of specimen for
FNA, time elapsed from taking sample and analaysis performed at
pathology and use of less expensive fluids for fixation. Also, bet-
FNA is the most accurate and cost-effective method for evaluating thyroid nodules. In majority of cases the FNA diagnosis was in
correlation with final histopathology (6). The FNA has better sensitivity for recognition of malignant lesions in comparison to ultrasound or thyroid scintigraphy (7).
Of the total number of patients in our study (n = 65), 52 (80%)
were female and 13 (20%) patients were male, and the mean age
was 53.55 years, which is in correlation with majority of the published data (8).
One of the FNA limitations is usually a great number of inadequate samples. Published data shows that inadequate sample ranges
somewhere between 9-31% (9). In our study the inadequate sample
rate was 1.5%.
In the published data, the false-negative rate of FNA was 19%
and the false-positive rate was 6% (10). In our study the false negative rate was 21, 5% and false positive rate was 0% which is in correlation with the literature results. False negative results are usually
found in small thyroid nodules and in some inflammatory diseases or
degenerative changes in surrounding thyroid tissue. The false negative rate can be reduced by repeating FNA (11).
Of the total number of patients in our study (n = 65) diagnostic
results of FNA were as follows: benign lesions were present in 14
patients (21.5%), while malignant lesions were present in 23 patients,
atypia of undetermined significance was registered in 7 patients and
suspicious for malignancy in 20 patients. Diagnostic results based
on histological findings (PHD) showed that of the total number of
patients (n = 65), 37 patients (56.9%) had papillary carcinoma of the
thyroid gland, while 28 patients (43.1%) had follicular carcinoma of
the thyroid gland.
In our patients with benign FNA results surgery was performed
due to suspicious US features: pathological vascularisation, rapid enlargement in size of nodule, abnormal cervical lymph nodule and
Relevance of fine-needle aspiration cytology compared to histopathology in differentiated thyroid carcinoma
patients with compressive syndrome.
In most of the published studies sensitivity FNA ranges between
80% and 100%. This range in results is associated mainly with the
various systems of analyzing data. Also deciding factors for such a
wide range of sensitivity and specificity may be in the manner in
which cytologists categorise suspicious lesion or in their classification of false positive and false negative results.
In our study sensitivity test (SN) was 67.0%, meaning that by
means of FNA it was possible to detect 67.0% of patients who actually had the thyroid gland cancer. Sensitivity in our study was low
compared to other studies. That came as a result of a small number
of patients included in the study but also due to inadequate samples
and lack of qualified cytologist and inadequate technological support.
In published data a positive predictive value is estimated to be
34–100% (12). The positive predictive value (PPV) in our study was
97.0%, i.e., the probability that a patient with positive FNA findings of thyroid carcinoma actually has cancer of the thyroid gland is
97.0%. These results are also comparable to data from literature.
False-negative results relate to missed malignancy. False-negative rates generally vary from 1.5% to 11.5% (average, <5%), and
in our study it was 21.5% (13). The false-negative rate is defined as
the percentage of patients with “benign” cytology in whom malignant lesions are later confirmed on thyroidectomy. The frequency
of false-negative cytological diagnosis depends on the number of
patients who subsequently have surgery and histological review. In
most retrospective series, less than 10% of patients with a benign
cytological diagnosis subsequently have thyroid surgery, suggesting
that false-negative rates should be interpreted with some skepticism. Also FNA of small nodules are always in risk of having only
surrounding tissue of thyroid not the nodule.
False positive results means FNA finds malignancy but PHD is
negative. In our study it was 0%. In the literature, the false-positive
rates vary from 0% to 8% (average, 3%).
REFERENCES
1. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M et al., Cancer Incidence in Five Continents, Vol IX, 2007. IARC Scientific Publications, No. 160, Lyon,
IARC.
2. Marqusee E, Benson CB, Frates MC, Doubilet PM, Larsen PR, Cibas ES et al. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern
Med. 2000;133(9):696–700.
3. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph GD et al. Diagnostic
terminology and morphologic criteria for cytologic diagnosis of thyroidlesions: a
synopsis of the National Cancer Institute Thyroid Fine-NeedleAspiration State of
the Science Conference. Diagn Cytopathol. 2005;36(6):425–37.
4. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised
American Thyroid Association management guidelines for patients with thyroid
nodules and differentiated thyroid cancer.Thyroid. 2009;19(11):1167-214.
5. Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid
nodules: a study of 4703 patients with histologic and clinicalcorrelations. Cancer.
2007;111(5):306-15.
6. Sukumaran R, Kattoor J, Pillai R, Ramadas PT, Nayak N, Somanathan T et al. Fine
needle aspitarion cytology of thyroid lesions and its correlation with histopathology
in a serias of 248 patients. Indian J Surg Oncol. 2014;5(3):237-41.
7. Fon LJ, Deans GT, Lioe TF, Lawson JT, Briggs K, Spence RA. An audit of thyroid
surgery in a general surgical unit. Ann R Coll Surg Eng. 1996;78(3):192-6.
8. Sinna EA, Ezzat N. Diagnostic accuracy of fine needle aspiration cytology in thyroid
lesions. J Egypt Natl Canc Inst. 2012;24(2):63-70.
9. Sidawy MK, Del Vecchio DM, Knoll SM. Fine-needle aspiration of thyroid nodules:
correlation between cytology and histology and evaluation of discrepantcases. Cancer.1997;81(4):253-9.
10. Ravetto C1, Colombo L, Dottorini ME. Usefulness of fine-needle aspiration in the
diagnosis of thyroidcarcinoma: a retrospective study in 37,895 patients. Cancer.
2000;90(6):357-63.
11. Yeh MW, Demircan O, Ituarte P, Clark OH. False-negative fine-needle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid
carcinoma.Thyroid. 2004;14(3):207-15.
12. Cáp J, Ryska A, Rehorková P, Hovorková E, Kerekes Z, Pohnetalová D. Sensitivity
and specificity of the fine needle aspiration biopsy of the thyroid: clinicalpoint of
view. Clinic Endol (Oxf ). 1999, 51(4):509-15.
13. Hamburger JI. Diagnosis of thyroid nodules by fine needle biopsy: use and abuse. J
Clin Endocrinol Metab. 1994;79(2):335-9.
CONCLUSION
Fine-needle aspiration (FNA) biopsy of the thyroid gland is precise diagnostic test used routinely in the initial evaluation of nodular
thyroid disease. Results from this study showed high positive predictive value for FNA, but special caution should be paid to false negative results. These findings are usually found in small thyroid nodules
and in some inflammatory diseases or degenerative changes in surrounding thyroid tissue. The false negative rate can be reduced by
repeating FNA. Fine-needle aspiration (FNA) biopsy of the thyroid
gland should be considered as a part of integral diagnostic algorithm,
not as a solitary diagnostic method.
Conflict of interest: none declared.
33
Reprint requests and correspondence:
Šejla Cerić, MD, MSc
Clinic of Nuclear Medicine
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 298 485
Email: [email protected]
Original article
Medical Journal (2015) Vol. 21, No. 1, 34 - 37
Contemporary treatment of pathological pregnancies
in the first trimester
Savremeni tretman patoloških trudnoća
u prvom trimestru
Naima Imširija*, Lejla Imširija, Zulfo Godinjak, Sanjin Deković, Mohammad Abou El-Ardat
Clinic of Gynecology and Obsterics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
Pathological pregnancies in the first trimester and unwanted
pregnancies in general present a big clinical problem. It is necessary
to protect the health of the future mothers and their reproductive
ability. Classical methods (dilatation of the cervical canal, aspiration,
and curettage) are gradually withdrawing from the practice given that
„medical abortion“ in combination with mifepriston (a progesterone
receptor antagonist) and misoprostol (synthetic analogue of prostaglandin E1) has been accepted worldwide. Our Clinic conducted
a comprehensive study related to treatment of pathological pregnancies in the first trimester, and among the first ones in the region
pointed to the advantages of medical abortion over the classical approach. The study included 90 patients with pathological pregnancies
in the first trimester and it was established that medical pregnancy
termination was better, more efficient and with less complications
and side effects than the classical approach.
Patološke trudnoće u prvom trimestru i neželjene trudnoće uopšte, predstavljaju veliki klinički problem. Potrebno je
očuvati zdravlje budućih majki i njihovu reproduktivnu sposobnost. Klasične metode (dilatacija cervikalnog kanala, aspiracija i
kiretaža) polako izlaze iz prakse jer se u svijetu sve više koristi
„medikamentozni pobačaj“ i to kombinacija mifepristona (blokator progesteronskih receptora) i misoprostola (sintetski analog prostaglandina E1). Naša klinika je uradila obimnu kliničku
studiju tretmana patoloških trudnoća u prvom trimestru medikamentima, te prva na našim prostorima ukazala na prednosti
medikamentoznog pobačaja u odnosu na klasični pristup. Studija
je urađena na 90 pacijenatica sa patološkim trudnoćama u prvom trimestru, te je ustanovljeno da je medikamentozni prekid
trudnoće bolji, efikasniji i sa manje komplikacija i nus pojava od
klasičnog načina.
Key words: medikamentous abortion, misoprostol, mifepriston
Ključne riječi: medikamentozni abortus, misoprostol, mifepriston
INTRODUCTION
infection (and possible sterility) and injuries of genital and other organs during the intervention. Psychological aspects of abortion are
also important as well as dislike of women for surgical interventions,
which certainly include abortion.
An estimated 46 million abortions are performed globally each
year (1), although the latest data points to the fact that their number
is reducing and amounts to 41 million (2). Out of that total, 48%
relates to unsafe abortions performed by persons lacking the necessary skills, with unsafe abortion methods, and in an environment
lacking the minimal medical standards (3). The unsafe abortions
mainly occur in the countries in which abortions are prohibited or
limited to certain medical indications, and as such they always result
in a high rate of female morbidity and mortality. Unwanted pregnancies will occasionally occur regardless of adherence to adequate
contraception methods, and in such cases a legal option of pregnancy termination should exist at the request of the woman and under
the best possible conditions. Optimal contemporary abortion methods imply the instrumental methods and medical abortions conducted according to certain schemes and protocols depending on weeks
of gestation, available methods and some other conditions related
to women’s general health and local conditions. Medical abortion
appeared as an answer to the efforts to reduce the surgical abortion risks, mainly those related to anesthesia (mortality up to 0.1%),
MATERIALS AND METHODS
A prospective study was conducted at the Clinic of Gynecology and Obstetrics of the Clinical Center University of Sarajevo.
It included 90 patients with pathological pregnancies in the first trimester and was conducted over the period of two years. Patients
diagnosed with pathological pregnancy in the first trimester were
divided in three groups of 30 patients. The first 30 patients were
tested with 600 mg of mifepriston administered orally and subjected to ultrasound monitoring in order to determine if abortion occurred (complete or incomplete). If abortion was incomplete it was
completed surgically (vacuum aspiration). In the other 30 patients,
if they did not miscarriage within 48 hours, the 200 µg vaginal doze
of misoprostol was administered in four hour intervals, to a maximum of five doses in total. We monitored and recorded the amount
Contemporary treatment of pathological pregnancies in the first trimester
of bleeding, side effects (vomiting, diarrhea, temperature increase),
and the time elapsed from the administration of medical therapy to
abortion. The third group of 30 patients ended with vacuum aspiration and curettage, and they were subjected to ultrasound monitoring for possible complications (amount of bleeding, infections,
remaining fetal parts, etc.). That is a standard and the only method
currently applicable at our Clinic, and will serve as a control group.
The main demographic data is presented in tables. We analyzed the
arithmetic mean (x), standard deviation (s), standard error (Sx), and
the median applying the nonparametric median Chi-square test (x²test) with two independent samples. The test was used to prove if
these two samples belonged to the population with the same median. We applied the Yates correction. The aim of the study was to
demonstrate the success of new medical termination of pathological pregnancies in the first trimester.
RESULTS
Based on the analysis of indications for termination of pregnancy in the first trimester it was established that in 86.7% of Group
I patients pregnancy was terminated due to missed abortio, and in
13.3% due to blighted ovum. The chi-square test did not establish statistically significant difference in the frequency of indications within
the Group I subgroups, and in each of them pregnancy was terminated due to missed abortion, χ2=1.284; p=0.257 (Table 1).
Table 1 Indications for pregnancy termination.
INDICATIONS
SUBGROUP
TOTAL
IA
IB
IC
Missed
No.
25
25
28
78
%
83.3%
83.3%
93.3%
86.7%
Blighted
No.
5
5
2
12
%
16.7%
16.7%
6.7%
13.3%
Total
No.
30
30
30
90
%
100.0%
100.0%
100.0%
100.0%
Based on the analysis of the time elapsed from the application
of the medicine to miscarriage it was established that for the IA subgroup patients (patients treated only with mifepriston) that period
was 48.53±3.56 hours, and for the IB subgroup patients (patients
treated with both mifepriston and mizoprostol) 50,12±4,95 hours.
The ANOVA test showed that there was no statistically significant
difference between the IA (patients treated only with mifepriston)
and IB subgroup (patients treated with both mifepriston and mizoprostol) patients regarding the time needed for abortion, F=2.034;
p=0.159 (Table 2).
Table 2 Mean length of induced miscarriage.
LOWER UPPER
IA
30 48.53 3.56 0.65
47.20
49.86
36.00
54.00
IB
30 50.12 4.95 0.90
48.27
51.97
32.00
55.00
In patients from subgroup IA (patients treated only with mifepriston), due to mifepriston effects, miscarriage occurred within ap-
35
proximately 48,53h, and in subgroup IB (patients treated with both
mifepriston and mizoprostol) the effects of mifepriston occurred
within approximately 45,07 hours, and the effects of mizoprostol
within 3.96 hours (Table 3).
Table 3 Mean length of drug effects in the induction pro
cedure.
SUBGROUP MIFEPRISTON (H) MIZOPROSTOL (H) PREPIDIL GEL (H)
IA
48.53
0
0
IB
45.07
3.96
0
Due to mifepriston effects in subgroup IA (patients treated only
with mifepriston) 2 patients miscarried in less than 48 hours, 14 patients miscarried within 48 hours, whereas 14 patients miscarried in
over 48 hours. In subgroup IB (patients treated with both mifepriston and mizoprostol) due to the effects of mifepriston alone only 1
patient miscarried, while 29 patients miscarried due to joint effects
of mifepriston and mizoprostol (Table 4).
Table 4 Advanced effects of certain drugs in the induction
procedure in relation to a number of the examined sub group patients.
Table 8 shows the manner in which pregnancy was terminated,
and the outcome thereof. In the subgroup IA (patients treated only
with mifepriston) successful medical abortion was performed in 21
(70%) patients, and 9 (30%) patients were subjected to curettage
after unsuccessful medical induction. In the subgroup IB (patients
treated with both mifepriston and mizoprostol) successful medical
abortion was performed in 27 (90%) patients, and 3 (10%) patients
were subjected to curettage after unsuccessful medical induction.
In the IC group (patients in which abortion ended surgically) 30 curettages were performed, of which 6 patients were subjected to
repeated curettage. The Chi-square test showed that there was a
statistically significant difference in the method and success of abortion, and in that regard the IB group (patients treated with both
mifepriston and mizoprostol) had the best outcome, χ2=31.43;
p<0.05.
Table 5 Method and success of miscarriage.
Table 6 Correlation between the analyzed variables.
By application of the Pearson correlation the following has been
established:
36
•Time necessary for the successful induction in the subgroup IA
(patient treated only with mifepriston) is in a statistically negative
correlation with the cervix length (p=0.05), and with the gestation time (p=0.002), but in a positive correlation with parity
(p=0.001)
•Time necessary for the successful induction in the subgroup IB
(patients treated with both mifepriston and mizoprostol) is in a
negative correlation with the cervix length (p=0.031), gestation
time (p=0.026) and parity (p=0.036).
There was a better correlation between the induction and independent variables of the cervix length, gestation and parity in
the examined subgroup IB (patients treated with both mifepriston
and mizoprostol) in relation to the subgroup IA (patients treated
only with mifepriston).
The analysis of the side effects frequency within the Group I
subgroups showed that patients from the subgroup IC (patients in
which abortion ended surgically) had a statistically significant number of side effects (p=0.042). They mainly had frequent bleedings
and febrility (p<0,05), whereas nausea was equally presented in all
three subgroups (p=0.213). The lowest rate of side effects were
registered in the IB subgroup (patients treated with both mifepriston
and mizoprostol) (n=4) (Table 7).
Table 7 Frequency of side effects.
The analysis of the complication frequency in the Group I subgroups showed that patients from subgroup IC (patients in which
abortion ended surgically) had a statistically significant higher number of complications (p=0.047). Those patients frequently experienced rezidua post abortum and infections (p<0.05), with the lowest number of complications registered in IB group (patients treated
with both mifepriston and mizoprostol) (Table 8).
Table 8 Frequency of complications.
DISCUSSION
Contemporary methods of medical abortion are nowadays
available to women in many countries in various types and protocols. Invention of synergistic effects of antiprogestin (mifepristone)
and synthetic analogue prostaglandin E1 (misoprostole), on early
pregnancy termination and on second trimester pregnancy termination influenced development of a new, highly effective and safe
method of medical abortion. Nowadays, there are established
schemes of drugs administration in various gestation periods provided by the World Health Organization, based on numerous studies
conducted in this field. In France, medical abortion is approved even
up to seven weeks of gestation in home conditions. The Protocol
related to medical pregnancy termination in the period between
weeks 9 and 12 of pregnancy is still under consideration, and for
N. Imširija et al.
abortions in the second trimester there are several schemes in development. If unwanted pregnancy occurs, it is necessary to provide women with the opportunity to choose this new method of
medical abortion which has been the choice of approximately half
of the women in the countries in which it is available (4). The rate
of induced abortions (9/1000 women aged 15-49 in 2011) is low in
Finland. 92% of them are performed on grounds of social reasons.
Use of medical abortion (combination of mifepristone and misoprostol) has increased to nearly 90% of abortions, also in abortions
of 9-12 weeks of pregnancy. Intrauterine contraception, started at
the time of abortion, lowers the risk of future unplanned pregnancies (5). Surgical abortion by vacuum aspiration or dilatation and
curettage has been the method of choice for early pregnancy termination since the 1960s. Medical abortion became an alternative
method of first trimester pregnancy termination with the availability
of prostaglandins in the early 1970s and anti-progesterones in the
1980s. In the Cochrane Controlled Trials Register the investigation
was conducted in pregnant women with pathological pregnancy in
the first trimester. Patients were divided in groups depending on the
drug used and the manner of administration, and it was concluded
that the most successful method of medical abortion was the combination of mifepriston and mizoprostol. In the combined regimen,
the dose of mifepristone can be lowered to 200 mg without significantly decreasing the method effectiveness and vaginal mizoprostol
is more effective than oral or sublingual administration (6). Abortion
services are legally available in Ukraine although there are issues in
quality and access. Two studies conducted at six clinics in Ukraine
tried to explain the advantages, effectiveness and possibilities of
medical abortion by administration of mifepriston and misoprostol.
These two studies have shown a high level of success and acceptability in the application of medical abortion in the first trimester in
respect to the classical approach in Ukraine (7).
CONCLUSION
Contemporary methods of pregnancy termination by drugs are
safe, efficient and acceptable if the existing protocols are respected
and if all necessary drugs are available. Women accept this method
equally as the instrumental procedures of pregnancy termination,
considering it „natural“. Our study showed that the most efficient
protocol for medical termination of pathological pregnancies in the
first and second trimester involves combined oral application of 600
mg of mifepriston and vaginal application of 200 μg of misoprostol,
in a maximum of 5 dozes every 4 hours, with the smallest number of
side effects. We believe that this method of pregnancy termination
could increase in the overall number of early pregnancy terminations, especially in case of primigravida with pathological pregnancy
(blighted ovum, missed ab. foetus mortus in utero, anomaliae multiplices).
Conflict of interest: none declared.
REFERENCES
1. Alan Guttmacher Institute. Sharing responsibility: women, society and abortion
worldwide. New York: The Alan Guttmacher Institute: 1999.
37
Contemporary treatment of pathological pregnancies in the first trimester
2. Sedgh G, Henshaw S, Singh S, Lhman E, Shah IH. Induced abortion: rates and trends
worldwide. Lancet. 2007;370:1338-45.
3. Safe abortion: technical and policy guidance for health systems. Geneva: WHO;
2003.
4. Hamoda H, Ashok PW, Flett GM, Templeton A. A randomized trial of mifepristone
in combination with misoprostol administered sublingually or vaginally for medical
abortion at 13–20 weeks gestation. Hum Reprod. 2005;20:2348–54.
5. Update in current care guidelines: induced abortion. Duodecim. 2013;129(7):776-7.
6. Kulier R, Kapp N, Gülmezoglu AM, Hofmeyr GJ, Cheng L, Campana A. Medical
methods for first trimester abortion. Cochrane Database Syst Rev. 2011 Nov
9;(11):CD002855.
7. Raghavan S, Maistruk G, Shochet T, Bannikov V, Posohova S, Zhuk S, et al. Efficacy and acceptability of early mifepristone-misoprostol medical abortion in
Ukraine: results of two clinical trials. Eur J Contracept Reprod Health Care. 2013
Apr;18(2):112-9.
Reprint requests and correspondence:
Naima Imširija, MD, PhD
Clinic of Gynecology and Obstetrics
Clinical Center University of Sarajevo
Patriotske lige 81
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 250 250
Email: [email protected]
Bosnia and Herzegovina versions of Guidelines for Patients!
Bosanskohercegovačka verzija Vodiča za pacijente!
Original article
Medical Journal (2015) Vol. 21, No. 1, 38 - 42
Alternative approach to supracricoid partial
laryngectomy
Alternativni pristup tehnici suprakrikoidne parcijalne
laringektomije
Predrag Špirić*, Sanja Špirić, Dmitar Travar, Slobodan Spremo, Mirjana Gnjatić
Ear, Nose and Troath Clinic, University Hospital Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The aim of this study was to present surgical modifications of
supracricoid partial laryngectomy (SCPL) together with all advantages that we brought with it. Background: SCPL is a valuable surgical
technique with the organ preservation aim. First time described by
Austrian surgeons Majer and Rieder in 1959 remained more or less
the same. Major drawbacks of this technique are long-term decannulation with swallowing problem. Oncologic outcomes were proven
by different independent studies. Material and methods: we analyzed
a total of 16 patients in 6 year period with a diagnosis of advanced
T3, T4 laryngeal cancer or recurrence treated with a suggested technique of SCPL. Another inclusion criteria were ECOG lower than 1
(Karnofsky 80 and higher), one healthy crico-arythenoid joint. Results: during the 6 year period we treated 16 patients with advanced
laryngeal cancer. Mean age was 59,5. In all patients we performed
modified SCPL without preliminary trachostomy and reconstructed
with cricohyoidopexy (CHP) or cricohyoidoepiglottopexy (CHEP).
One of the patients was successfully operated as cricoglossopexy
(CGP). No active suction was applied. Nasogastric tube feeding was
maintained six day average. Patients stayed 9,18/7,4* day average in
hospital. Conclusion: SCPL can be performed without preliminary
tracheostomy. Patient’s breathing is established immediately after the
operation and swallowing in a few days. This makes modified SCPL
highly desirable for surgeons as well as for the patients. Surgical technique is simplified if compared with traditional one, can be easily reproduced what makes it teachable and consequently acceptable in
a surgical routine in laryngeal surgery. Patients with infection were
excluded
Cilj ove studije je da prikaže modifikaciju suprakrikoidne
parcijalne laringektomije(SCPL) zajedno sa svim prednostima
koje ta modifikacija donosi. Uvod: SCPL je značajna poštedna
hirurška tehnika. Prvi put su je opisali Austrijski hirurzi Majer i
Rieder 1959 i od tada nije imala značajnih izmjena. Glavni nedostaci ove tehnike su dugotrajan postupak dekanilmana i problemi sa gutanjem. Onkološki rezultati ove tehnike su dokazani
mnogobrojnim nezavisnim studijama. Materijal i metode: ovim
ispitivanjem je obuhvaćeno 16 pacijenata u periodu od 6 godina,
sa dijagnozom uznapredovalog T3 i T4 ili recidiva carcinoma
larinksa koje smo liječili predloženom tehnikom. Ostali inkluzioni kriterijumi su bili ECOG 1(Karnofsky skor 80 i više) jedan
funkcionalan krikoaritenoidni zglob. Rezultati: u šestogodišnjem
periodu liječili smo 16 pacijenata sa dijagnozom uznapredovalog karcinoma larinksa. Prosječna starost pacijenata je bila 59,5
godina. Svi su liječeni modifikovanom tehnikom SCPL bez preliminarne traheotomije sa krikoidopeksijom (CHP) ili krikohioidoepiglotopeksijom (CHEP). Kod jednog pacijenta je urađena
rekonstrukcija po tipu krikoglosopeksije (CGP). Nismo primjenjivali sukcionu drenažu. Nazogastrična sonda je korištena prosječno 6 dana. Prosječna hospitalizacija je bila 9,18/7,4 dana. Zaključci: SCPL se može izvesti bez preliminarne traheotomije. Kod
pacijenata se spontano disanje uspostavlja neposredno nakon
ekstubacije a akt gutanja kroz nekoliko dana. To ovu tehniku čini
krajnje poželjnom kako za hirurga tako i za pacijente. Predložena
tehnika je pojednostavljena, lako se uči i samim tim je prihvatljiva
kao dio hirurške rutine u hirurgiji larinksa.
Key words: laryngeal cancer, surgery, supracricoid partial laryngectomy, modification
Ključne riječi: karcinom larinksa, hirurgija, suprakrikoidna parcijalna laringektomija, modifikacija
INTRODUCTION
have a wide palette of procedures depends on the surgeon’s skills
and affinity. Also, radiation and chemotherapy can be applied. All
surgical techniques and chemo-radiotherapy administered in the advanced stages of the disease, unfortunately, often failed. In those
cases, total laryngectomy remains the key tool for fighting such tumors. On the other hand, total laryngectomy is a mutilating procedure which undermines patient’s demands and expectations in three
dimensions. First, it is the technique that sacrifices natural breathing,
Supracricoid partial laryngectomy (SCPL) is established as a
surgical substitute to total laryngectomy for T3 and T4a advanced
tumors or extended relapsed tumors. This technique was invented
and presented by Majer in 1959 and later, Piquet in 1974 (1,2). It was
intended for the treatment of a different kind of laryngeal tumors
from early stages to very advanced ones. In early tumor stages, we
39
Alternative approach to supracricoid partial laryngectomy
which makes patient fight with tracheotomy breathing problems
such as cold or warm air, dry or moist air, foreign body and water
aspiration risk during everyday activities, and smell disturbance due
to exclusion of nose in a breathing process. Secondly, it is the technique that sacrifices voice that puts the patient in large scale of communication problems. Third, it carries esthetically an unacceptable
postoperative appearance. Also, it undermines different scopes of
living such, jogging, taking a shower, sexual activities, etc. From this
point of view, SCPL is a technique of great value for surgeon and
patient. Of course indication must be negotiable between patient
and surgeon because of the higher risk of relapsed disease than total
laryngectomy (3). We use SCPL only as a “substitute” technique for
total laryngectomy. There is an almost single demand, one functional
arytenoid (cricoarythenoid joint). The aim of this study is to present
a modification of SCPL and its advantages in comparison to one
standard.
MATERIALS AND METHODS
This operating procedure was performed on 16 patients in
the six year period (2006-2012). Patient inclusion criteria were advanced laryngeal cancer of stage III and IV (T3-T4a) or recurrence.
All patients we previously indicated for total laryngectomy. Two
preconditions had to be fulfilled, one functional crycoarythenoid
joint and limited subglottic extension up to 1 cm distance from the
lower edge of the true vocal cord. All patients were examined by
endo-video-laryngoscopy and CT scans. The neck was additionally
examined by ultrasound. Distant metastases were justified by chest
plain radiographs and abdominal ultrasound.
Surgical technique:
All surgeries were performed under general inhalation anesthesia without preliminary tracheostomy. A vertical skin incision was
made from jugular notch to, approximately 2 cm, above the level of
the hyoid bone (Fig 1).
Figure 1 Vertical skin incision.
Strap muscles were retracted and larynx was opened verticaly
by oscillating saw. This approach gave us a clear vision of tumor
extent (Figure 2).
Figure 2 Extent of the tumor.
After opening the larynx we removed the tumor with up to 1cm
margin starting with a side of the healthy cricoarythenoid joint. After
that we removed complete laryngeal framework on the other side
of the level cricoid to a supraglotic level in accordance with tumor
extent. Sometimes even the hyoid bone was resected (Figure 3).
Figure 3 Surgical site after tumor removal.
We reconstructed lateral walls with remnants of pharyngeal
mucosa and carefully covered nude arytenoid cartilage as well as
post-cricoid region. We used 3-0 resorbable suture. It is extremely
important to maintain the wide pharyngeal space opened by attaching the mucosa to lateral wall. Also, we have to avoid excess of mucosa in post-cricoid level. At that moment we put the nasogastric
feeding tube in place. Then we proceeded to second important step.
We suspended The base of the tongue after resection and fixed it to
the hyoid bone with a few stitches of 2-0 resorbable suture. This is
going toprevent the base of the tongue to press on the reconstructed area in order to avoid respiratory insufficiency (Figure 4).
40
Predrag Špirić et al.
RESULTS
Figure 4 Surgical site after reconstruction.
The next step was closure of the wound by approximation of
all available mucosa on lateral pharyngeal walls. Then third important step is termino-terminal (cricohyoido-(epiglotto) pexy) anastomosis. We used resorbable suture size 1 in fashion without loop
over cricoid or hyoid bone. It is mandatory in order to maintain
respiratory space. Usually we put three stitches that went through
upper-anterior part of perichondrium of cricoid and lower posterior part of the periosteum of the hyoid bone. It means that mucosa
from the base of the tongue goes on anterior part of cricoid perichondrium and, at that point, meets cricotracheal mucosa. By this
kind of reconstruction, we get sufficient air space for breathing and
fast mucosal healing (Figure 5).
Figure 5 Cricohyoidopexy.
The second layer was soft tissue of pharyngeal muscles and
parts of subdermal structures sutured with 2-0 resorbable suture.
After that we put deep stitches of skin with 2-0 silk suture. At the
end we put two silk stitches 1-0 through the skin and the perioseum of mandibular and sternal bone in order to minimize voluntary
movement of the head backwards. Then the patient was extubated
and sent to the ward with standard care.
We treated 16 patients with diagnosis of squamous cell carcinoma of the larynx. Two of them were females while others were
male. Four patients developed recurrences after surgical intervention from previous disease and 12 were primary tumors of various
stages. Location and staging were presented in Table 1.
Table 1 Region and stage.
Cases
Region
Stage
TNM
Supraglottic
R
R
1
2
S upraglottic
R
R
3
Supraglottic
IVa
T3N2aMx
Supraglottic
IVa
T4aN2aMx
4
5
Supraglottic
IVa
T4N0Mx
6
Supraglottic
III
T3N0Mx
Supraglottic
III
T3N0Mx
7
8
Supraglottic
IVa
T4aN2aMx
9
Supraglottic
IVa
T4aN0Mx
Supraglottic
IVa
T4aN0Mx
10
11
Supraglottic
IVa
T3N0Mx
12
Glottic
IVa
T3N0Mx
Glottic
R
T3N0Mx
13
14
Glottic
R
R
15
Supraglotic
III
R
Glottic
III
T3N0Mx
16
Table 2 Surgical intervention.
Cases
Reconstruction
Dissection
1
CGP
0
2
CHP
0
CHP
Selective
3
4
CHP
Radical modified
5
CHEP
0
CHEP
0
6
7
CHP
0
8
CHP
Radical modified
CHEP
0
9
10
CHP
0
CHP
Selective
11
CHEP
Selective
12
13
CHP
Radical modified
CHP
0
14
CHP
0
15
16
CHEP
0
41
Alternative approach to supracricoid partial laryngectomy
From this table is obvious that all patients had advanced laryngeal
cancer of stage III to IVa mostly in supraglottic region. We operated
them by modifying the technique of SCPL without a tracheostomy.
Author performed cricohyoidopexy (CHP) in ten cases, cricohyoepiglottopexy (CHEP) in five cases and after the removal of hyoid
bone in one case we performed cricogottopexy (CGP). This kind
of reconstruction is not yet established as standard reconstruction
procedure, although article was presented at a German ENT annual
meeting in 2014 by Ahmed El Batawi et all as successful procedure.
In six patient, selective or radical modified dissection was performed
as additional procedure. In all operated patients we did not use active suction drains. Results of surgical intervention were displayed in
Table 2.
In all our patients SCPL was performed without preliminary
tracheostomy. All patients were breathing sufficiently after extubation while nasogastric tube remained in position for enteral feeding.
One patient underwent tracheostomy due insufficient breathing six
hours after the operation. He was decannulated 7 days after the
operation. A nasogastric feeding tube was in place for six day in
average. It means that all patients established oral feeding during
the hospital stay. Two wound infections had conservative treatment
for 17/26 days. The average hospital stay was 9,18 days or 7,4 if
we count patients without complications. Postoperative outcomes
were presented in Table 3.
Table 3 Postoperative outcome.
Cases Decannulation
in days
Nasogastric
tube in days
Complications Hospital stay
in days
1
0
5
0
6
2
0
5
0
6
3
0
4
0
8
4
0
5
0
7
5
0
5
0
8
6
0
15
0
8
7
0
7
Inflammation
17
8
7
7
Inflammation
26
9
0
5
0
7
10
0
7
0
7
11
0
6
0
8
12
0
5
0
8
13
0
5
0
8
14
0
5
0
8
15
0
6
0
8
16
0
5
0
7
6 (average)
12,5%
9,18 (7,4*)
(average)
DISCUSSION
Organ preservation intervention, no matter surgical or chemoradiation, is a goal which should be achieved in the treatment of
advanced laryngeal cancer. In general, SCPL from the beginning was
kind of controversial. It was always in competition with total laryngectomy to prove safety as well as functionality (4). This procedure
was invented in an attempt to sacrifice part of swallowing function
in order to spare two other functions, natural breathing and voice.
After 1990 it is established as oncologically safe procedure, although
hard to teach and reproduce (5). One of our reasons for making
modification of this technique was to facilitate it’s reproducibility.
At the same moment we wanted to ease patient’s postoperative
course. Decannulation is frustrating and long lasting process, sometime impossible, and this is disappointing for patient and surgeon
(6,7). We operated cases with stage III and IV as a substitute for
total laryngectomy. Patients with early stages of disease, we operated with other surgical techniques. By our opinion and experience
SCPL should be used for advanced stages of laryngeal cancer exclusively while other techniques have advantages in comparison with
SCPL when used in early stages of disease. Some authors express
the same opinion (8), of course, other authors have different experience and used SCPL for a wide range of laryngeal cancer stages.
Also, it is a very convenient technique for recurrences, no matter
after surgical or chemoradiation therapy. We prefer CHP in reconstruction because we found out that epiglottis is often a liability for
breathing afterwards because it goes in reconstruction to low and
cover part of air space. From the other side, it is not essential for
airway protection during swallowing as arythenoid fold with active
cricoarythenoid joint seems to play key role in this process. When
our technique is used, neck dissection is performed through a
new skin incision as procedure by itself which makes two completely
divided space compartments. We found it superior than the usual
apron neck incision, which unite this two procedures because there
is less possibility for infection spread from one surgical site to another. With a modified technique of SCPL process of decannulation is
completely avoided which lowered morbidity with absolute patient
satisfaction. Most of the authors stressed long-term decannulation
as a major problem of SCPL(7).
We start oral feeding very early at day three or four and remove nasogastric tube at day six on average. Other authors frequently stress
swallowing problem (9). Of course, there is slight discomfort and
coughing due to minor aspiration of liquids during the swallowing
process but no pulmonary complications were observed. This is the
reason we start solid or semisolid food first and pure liquids later
with different neck positions to ease swallowing. We had two complications of local wound infection without the need for additional
surgery intervention. Our hospital stay was 7,4 days at average
for patient without complications which is comparable with other
institutions (10). Patients could be rejected from the hospital earlier
regarding health condition, but our policy was to stay in hospital
until stitches are removed.
CONCLUSION
The modified technique of SCPL is safe, repeatable and teachable procedure. It is performed without preliminary tracheostomy
with all advantages of this situation. Swallowing process goes much
easier and faster than with usual SCPL technique.
Conflict of interest: none declared.
42
REFERENCES
1. Mayer EH, Rieder W. Technique de layngectomie permettant de conserver la
perméabilité respiratoire (La cricohiodopexie). Ann Otolaryngol Chir Cervicofac.
1959;76:677-81.
2. Piquet JJ, Desaulty A, Decroix G. Crico-hyoido-epiglotto-pexy. Surgical technic and
functional results. Ann Otolaryngol Chir Cervicofac. 1974;91(12):681–6.
3. De Virgilio A, Fusconi M, Gallo A, Greco A, Kim SH, Conte M, Alessi S, Tombolini
M, de Vincentiis M. The oncologic radicality of supracricoid partial laryngectomy
with cricohyoidopexy in the treatment of advanced N0-N1 laryngeal squamous cell
carcinoma. Laryngoscope. 2012; 122 (4): 826-33.
4. Sperry SM, Rassekh CH, Laccourreye O, Weinstein GS. Supracricoid partial laryngectomy for primary and recurrent laryngeal cancer. JAMA Otolaryngol Head Neck
Surg. 2013;139(11): 1226-35.
5. Sánchez-Cuadrado I1, Castro A, Bernáldez R, Del Palacio A, Gavilán J. Oncologic
outcomes after supracricoid partial laryngectomy. Otolaryngol Head Neck Surg.
2011 Jun; 144 (6): 910-4.
6. Clayburgh DR1, Graville DJ, Palmer AD, Schindler JS. Factors associated with supracricoid laryngectomy functional outcomes. Head Neck. 2013 Oct; 35 (10): 1397403.
7. Gonçalves AJ, Bertelli AA, Malavasi TR, Kikuchi W, Rodrigues AN, Menezes MB.
Results after supracricoid horizontal partial laryngectomy. Auris Nasus Larynx.
2010;37(1):84-8.
8. Soudry E, Marmor Y, Hazan A, Marx S, Sadov R, Feinmesser R. Supracricoid partial
laryngectomy: an alternative to total laryngectomy for locally advanced laryngeal
cancers. J Laryngol Otol. 2008;122(11):1219-23.
Predrag Špirić et al.
9. Webster KT, Samlan RA, Jones B, Bunton K, Tufano RP. Supracricoid partial laryngectomy: swallowing, voice, and speech outcomes. Ann Otol Rhinol Laryngol.
2010;119(1):10-6.
10.Lewin JS, Hutcheson KA, Barringer DA, May AH, Roberts DB, Holsinger FC, Diaz
EM Jr. Functional analysis of swallowing outcomes after supracricoid partial laryngectomy. Head Neck. 2008;30(5):559-66.
Reprint requests and correspondence:
Predrag Spiric, MD, PhD
Ear, Nose and Troath Clinic
University Hospital Banja Luka
12 beba 1, 78000 Banja Luka
Bosnia and Herzegovina
Phone: +38765613520
Fax:+38751342644
Email: [email protected]
Professional article
Medical Journal (2015) Vol. 21, No. 1, 43 - 46
Sarcopenia
Sarkopenija
Ksenija Miladinović*
Clinic of Physical and Rehabilitation Medicine, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
Introduction: there has not been a generally accepted definition
for sarcopenia, nor determining parameters, which inhibits investigation and production of means for the treatment. A review of the
literature was undertaken to point to its definition, etiology and
treatment. Etiology is associated with an imbalance of positive and
negative regulators of muscle. Possible determination parameters
are: muscle mass, muscle strength, muscle power, speed walk. Treatment is currently based on adequate non-acid diet with sufficient
protein intake, adequate intake of vitamin D, B12 and folic acid, as well
as on individually adjusted exercise program, preferably resistance
training. Pharmacological agents are under investigation. Conclusion:
the views around a single definition and the determining parameters
of sarcopenia should be harmonized as soon as possible, and until
then apply a treatment that is available.
Uvod: sarkopenija još nije dobila općeprihvaćenu definiciju,
niti determinirajuće parametre, što inhibira istraživanja i proizvodnju lijekova. Pretraživanje literature imalo je za cilj da ukaže
na definiciju, etiologiju i tretman sarkopenije. Etiologija se dovodi
u vezu sa disbalansom pozitivnih i negativnih regulatora mišića.
Mogući parametri determinacije su: mišićna masa, mišićna snaga,
mišićna moć, brzina hoda.Tretman se za sada zasniva na odgovarajućoj neacidnoj dijeti sa dovoljnim unosom proteina, dovoljnom unosu D, B12 vitamina i folne kiseline, kao i individualno
prilagodjenom programu vježbi, po mogućnosti sa otporom. Farmakološka sredstva su u fazi ispitivanja. Zaključak: treba što prije usaglasiti stavove oko jedinstvene definicije i determinirajućih
parametara sarkopenije, a do tada primjenjivati tretman koji je na
raspolaganju.
Key words: sarcopenia, definition, treatment
Ključne riječi: sarkopenija, definicija, tretman
INTRODUCTION
EWGSOP (European Working Group on Sarcopenia in Older People) “Sarcopenia is a syndrome characterized by progressive and generalized loss of muscle strength with the risk of consequences such as
physical disability, poor quality of life and death” When the cause is aging per se speaks of “primary sarcopenia“, and when is present chronic
disease, malnutrition or inactivity speaks of “secondary sarcopenia”
IWGS (International Working Group on Sarcopenia) “Sarcopenia
is defined as the age-associated loss of muscle mass and function. Its
causes are multifactorial and may include inactivity, altered endocrine
function, chronic disease, inflammation, insulin resistance and nutritional
deficits. Although cachexia can be a component of sarcopenia, they are
two different states” (3).
Sarcopenia should be distinguished from “weaknesses”. The clinical
term “weakness” or “fragility” is a well-recognized syndrome and is defined as a condition that is seen especially in older people, and is characterized by small functional potential, rapid fatigue, mood disorders,
accelerated osteoporosis, reduced muscle mass and strength, and great
susceptibility to the occurrence of various diseases. These patients are
prone to sudden deterioration and death, therefore, is one of the greatest challenges of geriatric medicine. There is also the term “Sarcopenic
thickness” which denotes a group of people with sarcopenia, and with
a high percentage of body fat. This group has a particularly high risk of
complications such as chronic inflammation and insulin resistance (4).
While clinical widely recognized, the problem of universal defini-
Sarcopenia is a conceptual term which refers to the loss of skeletal muscle mass and a loss of its function. In the age between 20 and
80 years starts reduction in size and number of muscle fibers in the
percentage of about 30%, especially in the appendicular skeleton part.
Consequently with advanced age declines muscular strength and muscular endurance, especially in the lower body, more than muscle mass.
It is estimated that the percentage decline of isometric strength of knee
extensor, associated with age, is between 55 and 76% (1).
The term sarcopenia was introduced in 1989 and since then the
definition of this condition experienced numerous modifications. First
it was based on the biogerontological concept, then on the clinical condition which focuses on the influence of muscle deficit to function, as
well as on the possible role of external factors for the occurrence of
this syndrome, such as lifestyle, diet and concomitant diseases (2). The
current operational definitions of sarcopenia are:
ESPEN-SIG (the European Society for Clinical Nutrition and Metabolism Special Interest Groups) “Sarcopenia is a condition characterized
by loss of muscle mass and muscle strength. Although primarily is a disease of elderly people, its occurrence can be associated with other conditions that are not seen only in elderly, such as inactivity, malnutrition,
or cachexia. As osteopenia it can be seen in people with inflammatory
diseases”.
44
tions of sarcopenia remains unresolved. Moreover, there are no generally accepted guidelines that determine the favorable or unfavorable
characteristics of its clinical significance in human studies. This presents
a problem for the development of pharmacological interventions that
alter natural course of the disease. Even numerous potential drugs
were identified as a result of a good understanding of the functional and
structural changes that are seen on the molecular level in sarcopenia,
there is still no legal permission for their production. Why? There are no
commonly accepted parameters that could define the disease, characterize its progress, and provide measurement results in the application
of some interventions that would satisfy regulatory requirements.
Since 2005, in parallel with the new attempts to define sarcopenia there are some suggestions for the use of simple tests to screen
and identify patients with sarcopenia. Moreover, some of these measurements are recommended for diagnostic criteria of arcopenia and
weakness syndrome. The latest is that 2011. International Working
Group for sarcopenia (5) presented four recommendations for the
identification of sarcopenia in clinical practice, and these are: 1) assessment of the reduced physical abilities (or weakness), 2) consideration
of sarcopenia in immobile patients or those who cannot get up from the
wheelchair without assistance, 3) evaluation of the usual habitual walk
on four meters distance 4) patients with habitual gait with a speed of
less than 1m/s should be considered for quantitatively measuring body
composition (DEXA, CT, MRI).
ETIOLOGY OF SARCOPENIA
The causes of sarcopenia are multifactorial. Muscle has a number
of positive and negative regulators that influence its maintenance and
health. Positive regulators are: 1) Anabolic hormones (insulin, androgens); 2) Growth factors (GH, IGF-1, HGF, FGF); 3) Vitamin D; 4)
Physical activity (has a positive effect on muscle mass and muscle performance); 5) Sufficient protein intake (leucine, aromatic amino acids).
Negative regulators are: 1) Catabolic hormones (glucagon, corticoids);
2) Inflammatory factors (cytokines); 3) Myostatin; 4) The processes associated with aging (hormonal changes, anabolic resistance, obesity/
chronic low level inflammation, osteoporosis, muscle remodeling, i.e.
reduced activation of satellite cells in the muscle (Figure 1) and reduced
ratio between muscle fibers of type I and type II). Besides the mentioned factors that contribute to the reduction of muscle mass and increase in intramuscular fat, must be taken into account and increased
sedentary lifestyles and multiple medications, which come with aging (6).
K. Miladinović
POSSIBLE PARAMETERS FOR DETERMINING SARCOPENIA
Muscle mass
Muscle mass is well characterized parameter that can be objectified by radiological methods. Decrease in muscle mass more
than 2 SD according to T score, considered to be the domain of
sarcopenia. Loss of muscle mass is associated with high risk for development of chronic metabolic diseases, such as Diabetes mellitus
type 2. However, increase in muscle mass does not always mean the
improvement of physical function, which is similar to osteoporosis,
i.e. an increase in bone mass does not necessarily mean that the risk
of fractures is reduced.
Various unsuitable methods were used to measure muscle mass,
which are no longer in use. Thus, due to imprecision anthropometric
measurements are less used. To obtain a complete picture of body
composition requires a four-component model that includes water,
proteins, minerals and fatty tissue. Currently used radiological methods are: DEXA densitometry (Figure 2), computerized tomography
(CT) (Figure 3) and magnetic resonance imaging (MRI) (Figure 4).
Figure 2 DEXA display of
muscles (downloaded at
www.84daybodychallenge.com).
Figure 3 CT display of older man thigh. Downloaded at
www.ars.usda.gov.
Lack of DEXA densitometry is that it cannot isolate intramuscular
fat. As a lack for CT it can be considered a large dose of radiation.
MRI remains the most appropriate of the muscle mass measuring methods, because as CT has the accurate reproduction of
muscle and fat tissue, and radiation is minimal.
Muscle strength
Figure 1 Reduced activation of satelite cells
(www.anti-agingfirewalls.com).
Muscle strength is a better predictor of muscle function in the
general population of muscle mass. It is defined as the maximum
capacity in the production of muscle force. It is associated with the
loss of lean tissue, and reduced activity of satellite cells and altered
relationships between fibrils of type I and type II, and in older men
and women. According to the new research, muscular strength is a
predictor of mortality. In the study of Health, Aging and Body Structure, small muscle strength was strictly associated with mortality, regardless of the small muscle mass (7). The gold standard to measure
muscle strength is isokinetic dynamometry. However, it requires the
45
Sarcopenia
Figure 4 MRI display of younger and older man thigh. Downloaded at www.eatmore2weighless.com.
use of expensive equipment, and its use is limited.
The maximum power that can be generated in one maximum
contraction is designated as one repetition maximum (1-RM). Early
research related to 1-RM date back to 1955, and from 1990 this
“unit” is used in research as a measure of muscle strength (Hoeger,
Hopkins and Hale, 1990). 1-RM is obtained using specific equipment
for older people, designed for exercises with the generic type of
resistance, and it represents a reliable alternative that correlates
well with the assessment of muscle strength obtained by using the
dynamometer. The lack of use of 1-RM is that the absolute value of
1-RM are not comparable between different sets of equipment.
As a measure of muscle strength is increasingly in use hand grip. For
the measurement of grip there are two smaller dynamometer in use:
Jamar dynamometer (Figure 5) and Martin vigorimeter (Figure 6),
which has the advantage of being suitable for patients with arthritis,
since it has three sizes of rubber balls. It is recommended to take the
best of three test repetitions and for the left and right hand. However, variations in the clinical practice are large, so that a comparison
with the results obtained in studies very difficult. It is an interesting
study of Cooper and associates in 2010, because it was first made
transparent meta-analysis of the relationship between objectively
measured physical ability (hand grip, speed walking, sit-stand up test
and standing balance) and mortality in the elderly. Conclusion of 13
examined studies (44 638 participants) is that mortality is reduced
with each kilogram of increasing grip strength (8). It was also concluded that the walking speed, ability to rise from a chair and standing balance are associated with mortality in the elderly population
(over 70 years old), while the hand grip is associated with mortality
in younger population as well (under 60 years).
Muscular power
Muscular power defined as the maximum rate of muscle work
per time unite, seems more sensitive parameter for determination
of the physiological changes associated with aging, compared to
the muscle strength. This was confirmed by studies that have raised
the muscle power as a strong predictor of physical ability in older people (9). Other studies have attempted to explain the causes
of reduced muscle power and led in connection with the biological
processes of aging, especially with neuromuscular impairments activation, rigidity of tendons, speed of contraction and changes in
muscle architecture (10). Measurement of peak muscle power in
the elderly is objectively gained by feet pressure or knee extension
at high speed training with resistance. Since this requires expensive
equipment this measurement is too expensive as a benchmark for
Figure 5 Martin vigorimeter
Figure 6 Jamar dynamometer
sarcopenia in clinical practice. Therefore, in clinical practice has been
introduced a simple test sit-stand up for 30 seconds to determine
the average and peak muscle power. The objection to this proposal
is that this is not precisely measure for studies that deal with therapeutic agents. As for the other parameters, patients with arthritis
are not eligible for the determination of muscle power.
Muscle fatigue
Muscle fatigue is defined as the inability of muscles to produce
or maintain a level of power required for a given operating speed.
Muscle fatigue itself has its own central and peripheral component.
However, there is little published research that associate muscle fatigue and sarcopenia.
Walking speed
Most commonly used distance for testing the walking speed
is 4m, and the current reference speed is 0.8 m/s by the recommendation of EWGSOP and ESPEN-SIG, or 1 m/s by the recommendation of IWGS. In clinical practice walking speed, sit-stand up
test and standing balance are often measured in the context of the
Short Physical Performance Battery (BKFI/PPBS) (11). It is generally
accepted that the total BKFI score less than 10/48 (there are 12
sections, each scored 0-4) indicates a functional impairment in the
elderly population and that strictly predicts the loss of ability to walk
400 m distance.
All above mentioned parameters are not generally accepted by
all scientific, professional and regulatory bodies, and also proposals
for their reference values are different. The best reviews of the current situation in the field of sarcopenia are given by Cooper with
associates and Rizolli with associates in 2013 (3,4).
TREATMENT OF SARCOPENIA
The current treatment for sarcopenia includes:
1) The correct and adequate nutrition (especially adequate intake of proteins)
2) Sufficient intake of vitamin D
3) Individually adjusted physical activity, if possible, exercise with resistance
4) Pharmacological treatment is under investigation (angiotensin II
converting enzyme, inhibitors of chronic inflammation and myostatin
produced positive results to the current phase of testing). Hormones
have not shown good effects (4).
46
K. Miladinović
DISCUSSION
REFERENCES
Exercise plays an important role in building and maintaining bone
and muscle strength. It also helps to reduce falls by improving balance and aids rehabilitation from fractures. Muscles and bones respond and strengthen when they are ‘stressed’. This can be achieved
by weight bearing or impact exercises. After a program of resistance
training is introduced, research shows that motor neuron firing and
protein synthesis (both of which are needed in building muscle
mass) increase even in the elderly (12,13). These changes indicate it
is possible to rebuild muscle strength even at an advanced age. Aerobic exercise also appears to aid in the fight against sarcopenia (14).
Adequate nutrition intake plays a major role in treating sarcopenia. Research has shown older adults may need more protein per
kilogram than their younger counterparts to maintain proper levels
that reinforce muscle mass (15,16). Protein intake of 1.0-1.2 g/kg
of body weight per day is probably optimum for older adults. This
theory, coupled with the fact that older adults tend to take in fewer
calories in general, may lead to pronounced protein deficiency as
well as deficiency of other important nutrients. Therefore, maintaining adequate protein intake as well as adequate caloric intake
is an important facet of the treatment of this disease. Diets rich in
acid producing foods (meat and cereal grains) and low in non-acid
producing foods (fruits and vegetables) have been shown to have
negative effects on muscle mass. As mentioned above, protein is important, but a diet high in meat and cereal grains should be balanced
with a diet high in fruits and vegetable (nonacid-producing foods) in
order to be effective in treating sarcopenia. An adequate nutritional
intake and an optimal dietary acid-base balance are important elements of any strategy to preserve muscle mass and strength during
aging (17).
There is a moderate inverse relationship between vitamin D status and muscle strength. Chronic ingestion of acid-producing diets
appears to have a negative impact on muscle performance, and decreases in vitamin B12 and folic acid intake may also impair muscle
function through their action on homocysteine (17).
1. Doherty TJ. Aging and Sarcopenia (review). J Appl Physiol. 2003;95(4):1717-27.
2. Malafarina V, Uriz-Otano F, Iniesta R, Gil-Guerrero L. Sarcopenia in the elderly:
diagnosis, physiopathology and treatment. Maturitas. 2012;71(2):109-14.
3. Cooper C, Fielding R, Visser M, van Loon LJ, Rolland Y, Orwoll E, et al. Tools in the
Assessment of Sarcopenia. Calcif Tissue Int. 2013;93(3):201-10.
4. Rizzoli R, Reginster JY, Arnal JF, Bautmans I, Beaudart C, Bischoff-Ferrari H, et al.
Quality of Life in Sarcopenia and Frailty. Calcif Tissue Int. 2013;93(2):101-20.
5. Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, et al. Sarcopenia:
an undiagnosed condition in older adults. Current consensus definition, prevalence,
etiology, and consequences. International Working Group on Sarcopenia. J Am
Med Dir Assoc. 2011;12(4):249-56.
6. Faulkner JA, Larkin LM, Claflin DR, Brooks SV. Age-related changes in the structure
and function of skeletal muscles. Clin Exp Pharmacol Physiol. 2007;34:1091-96.
7. Asher L, Aresu M, Falaschetti E, Mindell J. Most older pedestrians are unable to
cross the road in time. Age Ageing. 2012;41:690-694.
8. Fried LP, Xue QL, Cappola AR, Ferrucci L, Chaves P, Varadhan R, et al. Nonlinear
multysistem physiological dysregulation associated with frailty in older women. J
Gerontol A Biol Sci Med Sci. 2009;64(10):1049-57.
9. Waters DL, Baumgartner RN, Garry PJ, Vellas B. Advantages in dietary, exercises
related, and therapeutic interventions to prevent and treat sarcopenia in adult patients. Clin Interv Aging. 2010;5:259-70.
10.Breen L, Phillips SM. Skeletal muscle protein metabolism in the elderly: interventions to counteract the “anabolic resistence” of ageing. Nutr Metab. 2011;8:68.
11. Romero-Ortuno R. The frailty instruments for primary care of the survey of health,
ageing and retirement in Europe predicts mortality similarly to a frailty index based
on comprehensive geriatric assessment. Geriatr Gerontol Int. 2013;13(2):497-50.
12. Roth SM, Ferrel RF, Hurley BF. Strength training for the prevention and treatment of
sarcopenia. J Nutr Health Aging. 2000;4(3):143-55.
13.Hasten DL, Pak-Loduca J, Obert KA, Yarasheski KE. Resistance exercise acutely
increases MHC and mixed muscle protein synthesis rates in 78-84 and 23-32 yr
olds. Am J Physiol Endocrinol Metab. 2000;278(4):E620-6.
14.Sheffield-Moore M, Yeckel CW, Volpi E, Wolf SE, Morio B, Chinkes DL et al.
Post-exercise metablolism in older and younger men following moderate aerobic
exercise. Am J Physiol Endocrinol Metab. 2004;287(3):E513-22.
15.Campbell WW, Crim MC, Dallal GE, Young VR, Evans WJ. Increased protein requirements in elderly people: data and retrospective reassessments. Am J Clin Nutr.
1994;60(4):501-9.
16. Campbell WW, Evans WJ. Protein requirements of elderly people. Eur J Clin Nutr.
1996;50 Suppl 1S180-3.
17. Mithal A, Bonjour J-P, Boonen S, Burckhardt P, Degens H, El Hajj Fuleihan G, et al.
Impact of nutrition on muscle strength and performance in older adults. Osteoporos Int. 2013;24(5):1555-66.
CONCLUSION
Although there has been some progress, remains the need for
unique consensus for defining and diagnosing of sarcopenia, as well
as for specifying the parameters for the assessment of the results in
the application of new potential means for its prevention and treatment. The question is whether the means potentially affect the muscle mass and muscle strength, considering that both parameters are
in most current definitions of sarcopenia, and besides, both are essential in prevention of disability, occurrence of weakness, and even
mortality. To obtain legal permission for their production primarily
there is need for clear, generally accepted definition of anatomical
and physiological assessment of muscle mass and muscle strength. In
the meantime we must recognize sarcopenia in clinical practice, and
treat it with current interventions that are available, i.e. individualy
adjusted exercise programme, preferably resistance training, optimal dietary acid-base balance and adequate supplementation with
vitamin D, B12 and folic acid.
Conflict of interest: none declared.
Reprint requests and correspondence:
Ksenija Miladinović, MD
Clinic of Physical and Rehabilitation Medicine
University Clinical Centre
Bolnička 25, 71000 Sarajevo
Bosnia and Herzegovina
Email: [email protected]
Professional article
Medical Journal (2015) Vol. 21, No. 1, 47 - 50
Major trauma care at Clinic of Emergency Medicine of
the Clinical Center University of Sarajevo
Zbrinjavanje traume major na Klinici za urgentnu
medicinu Kliničkog centra Univerziteta u Sarajevu
Gjulera Dedović Halilbegović1*, Zoran Hadžiahmetović1, Adnana Talić-Tanović2, Samra
Halilović1, Lejla Aldžuz3
Clinic of Emergency Medicine, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Central Sterilization Unit,
Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 3General Hospital “Prim. dr. Abdulah Nakaš”, Kranjčevićeva 12,
71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
Major trauma covers all serious, life-threatening injuries that usually
occur in traffic accidents, due to falls from a height, and as a result of
cold weapon or firearm activities. With the goal of reducing mortality
and disability in these injuries, it is necessary to establish a harmonized
system in prehospital trauma and in hospitalization of traumatized
patients. For the purpose of survival, the most important thing is the
establishment and maintenance of vital functions and surgical management of injuries aimed towards preventing the occurrence of irreversible shock. The first operating period is the acute or intention period
covering the first three hours from the arrival of the injured person to
the hospital facility where he/she can receive a surgical treatment. It
implies treatment of critically injured patients, where the implemented
reanimation measures cannot prevent an unfavourable course, without
surgical intervention. The main goal of this research was to determine
if the survival of critically traumatized patients depended on the quality
and promptness of urgent medical and necessary surgical intervention.
It is assumed that the injured patients with heavy bleeding in certain
organs have the highest survival rate if surgically treated within three
hours from the moment of injury. The survey covers injured patients
admitted to the Clinic of Emergency Medicine of the Clinical Centre
University of Sarajevo (CCUS) during 2009 and 2010 with signs of vital
function disorders. The study included all patients with life threatening
injuries regardless of the injury mechanism, the injured organ or gender,
patients over 15 years of age (due to use of a specific scoring system??),
who sustained injuries within the Sarajevo Canton (with transportation
time of up to 30 minutes), and who at admission had signs of hemodynamic instability or clinical and radiological verification of life threatening traumatic substrate. The study excluded patients with lethal exitus
occurring immediately after the reception and patients in which the
vital surgery recommendation was not determined upon the reception.
The study group consisted of 60 critically injured patients recommended for urgent surgery. The primary or the intention group (GI) consisted of 30 patients who were surgically treated in the first operating
period. The secondary group (GII) consisted of 30 patients who were
surgically treated 3 hours later. This research has proven the assumption that surgical treatment in the first three hours following the injury
provides higher survival rate with faster general condition stabilization
and minimum post-traumatic sequelae.
Major trauma obuhvata sve teške, po život opasne, povrede koje
najčešće nastaju u saobraćajnim udesima, kod padova sa visine, te kod
djelovanja hladnog ili vatrenog oružja. Da bi se smanjio mortalitet i invaliditet kod ovih povreda, potrebno je uspostaviti usaglašen trauma
sistem u prehospitalnom i hospitalnom zbrinjavanju traumatiziranih
pacijenata. Za preživljavanje najvažnije je uspostavljanje i održavanje
vitalnih funkcija te hirurško zbrinjavanje povrede.Prvi operacijski period je akutni ili intencioni period koji obuhvata prva tri sata od dolaska povrijeđenog u bolničku ustanovu gdje se može pružiti potrebni
operativni tretman. Podrazumjeva zbrinjavanje vitalno ugroženih, kod
kojih sprovedene mjere reanimacije ne mogu spriječiti nepovoljan tok,
bez hirurške intervencije. Glavni cilj ovog istraživanja je utvrditi da li
je preživljavanje životno ugroženih traumatiziranih pacijenata ovisio od
kvaliteta i brzine pružanja urgentne medicinske i neophodne hirurške
intervencije. Predpostavka je da povrijeđeni pacijenti sa obilnim krvarenjem u nekom od organskih sistema imaju najviše šanse za preživljavanjem ako se operativni tretman učini unutar tri sata od nastanka
povrede. Istraživanje obuhvata povrijeđene pacijente koji su primljeni
Na Kliniku urgentne medicine (KUM) Kliničkog centra Univerziteta u
Sarajevu (KCUS) u toku 2009. i 2010. godine sa znacima poremećaja
vitalnih funkcija. U studiju su uključeni svi povrijeđeni životno ugroženi
pacijenti bez obzira na mehanizam povrede, na organski sistem koji
je povrijeđen, spol, koji su stariji od 15.g. (zbog korištenja specifičnog
sistema skorovanja), kod kojih je povreda nastala unutar sarajevskog
Kantona (sa vremenom transporta do 30 minuta), a na prijemu su bili
prisutni znaci hemodinamske nestabilnosti ili sa kliničkom i radiološkom verifikacijom traumatskog supstrata koji ugrožava život. Iz studije
su isključeni pacijenti kod kojih je nastupio letalni egzitus neposredno
nakon prijema i kod kojih na prijemu nije bila postavljena vitalna indikacija za operaciju. Ispitivanu skupinu sačinjava 60 povrijeđenih, životno
ugroženih pacijenata kod kojih je postavljena indikacija za hitnu operaciju. Primarnu ili intencionu grupu (IG) čini 30 pacijenata koji su operativno zbrinuti u prvom operacionom periodu. U drugoj, sekundarnoj
grupi (IIG) se nalazi 30 pacijenata koji su operativno tretirani nakon 3
sata. Ovim ispitivanjem je dokazano da pretpostavka stoji jer operativnim zbrinjavanjem u prva tri sata od povrede postiže se veći stepen
preživljavanja uz bržu stabilizaciju opšteg stanja sa minimalnim posttraumatskim sekvelama
Key words: major trauma, trauma system, the first operating period
Ključne riječi: major trauma, trauma sistem, prvi operacijski period
48
INTRODUCTION
Major trauma is a severe, life-threatening injury, which can affect
multiple organ systems or regions, but only one body. It usually occurs
in traffic accidents, falls from a heights, or as a result of cold weapon or firearm activities. According to the World Health Organization
data, an estimated 5 million people worldwide died from injuries in
2000 - a mortality rate of 83.7 per 100 000 population (1). Mortality
caused by physical injuries is in third place, immediately after cardiovascular and malignant diseases, but in first place in terms of importance, given that the most vital age is at risk. In the major trauma care
the first operating period is extremely important. This is the acute or
intention period which covers the first three hours from the arrival of
the injured person to the hospital facility where he/she can receive
surgical treatment. It implies taking care of critically injured patients,
from whom implemented reanimation measures cannot prevent an
unfavorable course without surgical intervention.
In order to prevent the permanent growth of this condition it is necessary to take a number of preventive measures in all spheres of life;
from the construction of modern roads and control of weapon possession, to combat against all forms of addictions, which will reduce
criminal activities, often resulting in severe, penetrating injuries.
On the other hand, in order to reduce mortality and disability, it is
imperative to establish a unique trauma system in prehospital and
hospital care of traumatized patients.
The trauma system is the organized, coordinated provision of full
medical care to all of those injured in specific geographical areas integrated with local public health care (5).
For the purpose of survival the most important thing is the establishment and maintenance of vital functions. Priority is given to
the control of cardiac and respiratory functions, as well as shock prevention. This period can not exceed one hour. This “golden hour of
shock” should not be exceeded. The extension of this period leads to
shock prolongation and development of irreversible ischemic changes
(8,9).
Treatment of injuries categorized as major trauma at the Clinic of Emergency Medicine of the Clinical Center University of Sarajevo
Clinic of Emergency Medicine of the CCUS covers the space of
2200 square meters. The dispensary diagnostic unit is comprised of
the CPR cabinet and the operating and stationary block so that patients can promptly be provided with essential diagnostics and surgical
treatments at one place. The circular intersection is also provided.
Through inside halls, the Clinic is connected to the DIP building, The
Central Medical Block, The Institute of Radiology, The Department
of Orthopaedics and The Traumatology and Techno-economic block.
There is a heliport at a distance of about 200 meters from the Clinic
of Emergency Medicine. Connection with other clinics is maintained
by phones, pagers, and via radio networks with ER.
Injured patients are received and triaged in the surgical dispensary
by the emergency medicine specialists. Life threatening traumatized
patients are transported to the KPR cabinet. If need be, and upon
request of the emergency physician, it is necessary to immediately
include the anaesthesiologist with the anaesthetists, general surgeon
and traumatologist present at the Clinic (working days from 2 am and
24 hours on weekends). If required, surgeons of other profiles from
G. Dedović Halilbegović et al.
the respective CCUS clinics can also be engaged. All the injured treated at the Clinic of Emergency Medicine are referred in accordance
with the ABCD Protocol. Diagnosis and initial reanimation is carried
out simultaneously with constant monitoring of vital parameters.
The role of the ER surgeon is to recognize and recommend surgical treatment based on the level of urgency. In cases of massive
bleeding the surgeon should recommend a life saving surgery without
prior diagnosis, and necessary consultation with other surgical profiles
is made in the operating theatre “ad tabula”. The consilium decides
about the further referral of the patient which can be either to the
operating theatre or to the intensive care unit.
The main goal of this research was to determine if the survival of
critically traumatized patients depended on the quality and promptness of urgent medical and necessary surgical intervention. It is assumed that the injured patients with heavy bleeding in certain organs
have the highest survival rate if surgically treated within three hours
from the moment of injury.
MATERIALS AND METHODS
The study was conducted as a retrospective-prospective, comparative analytical study which included injured patients admitted to Clinic
of Urgent Medicine of the CCUS during 2009 and 2010 with signs of
vital function disorders. The data was obtained from patient records,
original memorandums stored in the database, history of illnesses and
surgical lists. All the injured patients treated at the Clinic of Emergency
Medicine have been referred in accordance with the ABCD Protocol. In
order to achieve objectivity in assessing the injury severity and the expected survival, the following scoring systems were used: Physiological
/ GCS, RTS /, Anatomical / AIS, ISS / and Combined / TRISS /.
The study included all patients with life threatening injuries regardless of
the injury mechanism, the injured organ or gender, and patients over 15
years of age (due to the use of a specific scoring system), who sustained
injuries within the Sarajevo Canton (with transportation time up to 30
minutes), and who at the reception had signs of hemodynamic instability or clinical and radiological verification of life threatening traumatic
substrate.
The study excluded patients with lethal exitus occurring immediately after the admission and in which vital surgery recommendation
was not determined upon the admission. The study group consists of
60 critically injured patients randomly selected for urgent surgery. The
primary or intention group (GI) consisted of 30 patients who were surgically treated in the first operating period. The secondary group (GII)
consisted of 30 patients surgically treated after 3 hours.
RESULTS
Table 1 Age structure of critically traumatized patients.
Age
15- 24
25- 34
35- 44
45- 54
55- 64
65 +
Total
Primary group(GI)
No
%
10
33
11
37
4
12
2
7
3
10
1
3
30
100
Secondary groups(GII)
No
%
9
30
7
23
5
17
4
13
2
7
3
10
30
100
Major trauma care at Clinic of Emergency Medicine of the Clinical Center University of Sarajevo
49
Table 2 Type of injury according to the organ systems
involvment (comprehensiveness).
Primary group(GI)
No
%
Polytrauma
15
50
Multiple trauma
7
23
Isolated trauma
8
27
Total
30
100
Secondary groups(GII)
No
%
18
60
2
7
10
33
30
100
Table 3 Leading trauma based on the organ systems (location
of injury).
The organic systems Primary group(GI)
No
%
Head
18
60
Thorax
14
47
Abdomen
16
53
Secondary groups(GII)
No
%
17
57
15
50
16
53
Table 4 Time spent at Clinic of Emergency Medicine.
Time spent in CUM
less than 60 min
60-120 min
120 > min
Total
Primary group(GI)
No
%
11
37
5
17
14
46
30
100
Secondary groups(GII)
No
%
7
23
13
44
10
33
30
100
Table 5 The expected survival according to the TRISS.
TRISS Ps
Primary group(GI)
No
%
61
18
Less than 50%
7
2
50-60%
13
4
61-70%
3
1
71-80%
3
1
81-90%
13
4
More than 90%
100
30
Total
Secondary groups(GII)
No
%
63
19
7
2
3
1
0
0
10
3
17
5
100
30
Table 6 Distribution based on surgical blocks where emergency surgery took place.
Surgical block (SB)
SB at Clinic of
Emergency Medicine
SB at COB
SB at Clinic of
Neurosurgery
Primary group(GI)
No
%
Secondary groups(GII)
No
%
22
58
7
21
15
39
19
56
1
3
8
23
Figure 1 Beginning of operating period (in minutes)
from the arrival at Clinic of Emergency Medicine.
Figure 2 The outcome of treatment in relation to operating period.
DISCUSSION
Life-threatening injuries are usually attributed to men (82%) up to
35 years of age. A high percentage of injuries relates to traffic accidents (46%) with the prevalence of multiple trauma (55%) but also injuries inflicted by cold weapons and firearms (41%) with isolated (30%)
or multiple trauma (15%).
The data corresponds to epidemiological studies in the world literature (3,10,11). According to the Trauma Committee of the American Association of Surgeons (ACS) 34.7% of severe, life-threatening
injuries result from road traffic accidents (12).
In a majority of patients, head and abdomen were leading traumas
with blunt injury symptoms requiring several diagnostic procedures
and involvement of different profile surgeons. In the outpatient diagnostic block of the Clinic of Emergency Medicine, the majority of
patients were kept up to 120 minutes. In the 2010 study conducted at
Athens General Hospital, it was established that each additional diagnostic procedure subtracts 30 minutes (13) and the length of stay in
the Emergency suit was 121 + 100 (21-221) minutes (14).
In the vast majority of patients the Injury Severity Score (ISS) was
> 25, and in over 60% of respondents the estimated survival was under 50% according to the TRISS method. In his doctoral thesis Akšamija G, found that 66,2% of polytrauma patients had ISS> 25, while life
expectancy with an estimated TRISS <50% was attributed to 22.8% of
polytrauma patients (15).
Out of the total number of injuries, 57% were treated at the Central Operating Block (COB), but a majority of patients who were surgically treated in the first period, underwent surgical treatment at the
Operating Block (OB) of the Clinic of Emergency Medicine (58%). After endopleural drainage performed at the Clinic of Emergency Medicine, 30% of patients from the GI group continued their operative
treatment at COB, and 13% of patients underwent abdomen surgery
at the Clinic of Emergency Medicine.
In 50% of injured patients the intention operating period began in
the first 60 minutes following their arrival to the Clinic of Emergency
Medicine. Those were patients with ISS> 25, and with TRISS <50 in
61% of them. 37% of injured patients were retained at the Clinic of
Emergency Medicine for up to 60 minutes, and within that period 47%
of them were subjected to endopleuralna drainage.
Emergency operations in the second group of patients started
150-180 minutes following their arrival at the Clinic of Emergency
Medicine (+ 30 minutes for transportation from the place of accident),
and in 47% of them in the interval of 3 hours and 30 minutes after the
injury. It can be explained that the aforementioned interval “was used”
50
for additional specialist examinations and subsequently recommended
diagnostic procedure for 21% of patients surgically treated at Operation Block of the Clinic of Emergency Medicine. Furthermore it can
be explained that the interval was used for the admission and triage at
PIT of the Clinic of Emergency Medicine due to required reanimation
during the agreement of the Admission Advisory Board, or for the
transportation of injured patients to COB and their reception by other
teams (anesthesiologist and surgeon), given that 56% of patients from
the GII were surgically treated at COB. 23% of the injured patients
were surgically treated in the period from 3 to 48 hours after the injury, which can be explained by their serious condition requiring a longer
stabilization period, or the presence of a small amount of free fluid or
small hematoma, which during the additional control showed signs of
growth. It can also be explained by a possible subsequent rupture of
parenchymal abdominal organ after the so-called, free interval, despite
the fact that based on the initial diagnosis findings, parenchymal organs
were intact, or by hollow organ injuries with gradual development of
the acute abdomen, or by craniotomy for the purpose of decompression and external ventricular drainage.
The type of injury, based on which organ systems were impacted
(with the prevalence of multiple traumas in both groups) and the lead
trauma (head or abdomen), influenced the time of the surgical procedures in the groups. However, given that there was no significant
difference between the observed groups, the results in both groups
are without significant deviations. For the same reason, the expected
survival according to the TRISS method did not show any deviations
between the groups, given that both groups involved those injured
with vital function disorders (values of severity in both groups were
above 25 (ISS> 25)) (16), who were divided to two groups based on
the operating period. Table 6 shows that operating block, where the
patient was surgically treated, significantly influenced the time of the
surgery. In the examined period the COB was located in the premises
of the old surgery and patients were transported by ambulance.
It can be concluded that the time of surgery influenced the outcome of the treatment, given that there was statistically significant difference recorded in the treatment outcome, with the largest number
of survivors from both groups, and given that there was no significant
deviation between the observed groups in the estimated expected
survival.
In relation to those cases where the patients were surgically treated in the first operational period, the subsequent surgical treatment
was accompanied with more serious postoperative complications,
including mortality, with visibly more difficult, longer and slower postoperative course and recovery (17).
Survival, quality of recovery, and return of these patients to normal life, primarily depend on fast and accurate diagnosis and high quality of medical treatment.
G. Dedović Halilbegović et al.
ing injuries to be treated within three hours of the injury, it is necessary
to establish a consolidated trauma system in prehospital and hospital
care of traumatized patients. Surgical treatment and further recovery
should be centralized at the Clinic of Emergency Medicine with a multidisciplinary approach developed through the trauma system, which
ensures that decisions about the life-threatened, traumatized patient
are made by Trauma headed by the Trauma leader involved in the
medical care from the very beginning.
Conflict of interest: none declared.
REFERENCES
1. Palmer C. Major trauma and the injury severity score-where should we set the bar?
Annu Proc Assoc Adv Automot Med. 2007;51:13-29.
2. Peden M et al. WHO. World Health Report 2003.
3. Sabistion CD.Textbook of surgery. The Biological basis of Modern Surgical Practice.
15th ed. Philadelphia. Ann Surg. 1997; 226(5): 662.
4. Hadžiahmetović Z. Principi primarnog zbrinjavanja i dijagnostika kod životno
ugroženih pacijenata, Vaša apoteka (vodič kroz farmaciju i medicinu). 2007;(5):16-18.
5. Hadžiahmetović Z. Trauma sistem.Sarajevo: Institut za naučnoistraživački rad i razvoj KCUS, 2013.
6. Gavrankapetanović F i saradnici. Politrauma. Sarajevo. 2004;22-34,57-80,93-1.
7. Newgard C, Schimcker R, Hedges J, Trickett J, Davis D, Bulger E, et al. Emergency
medical services intervals and survival in trauma: assessment of the “golden hour”
in a North American prospective cohort. Ann Emerg Med. 2010;55(3):235-46.
8. Hadžiahmetović Z, Mašić I, Nikšić D. Transformacija sistema zbrinjavanja politraumatiziranih pacijenata u Bosni i Hercegovini, Med. Arh. 2003;57(5-6):317-319.
9. Gavrankapetanović I, Gavrankapetanović F, Lazović M, Hadžiahmetović Z, Hajir Y,
Kulenović F, i saradnici. Zbrinjavanje politraumatiziranih - naša iskustva. Med Arh.
2003;57 (4,supl.1);16.
10.American College of Surgeons. Committee on Trauma. Injury prevention. ACS
2003.
11.Tscherne H, Regel G. Trauma Management. Tscherne Unfallchirurgie. Berlin:
Springer. 1997; (1):5-13; (2):15-22; (9): 225-37; (11):257-97.
12. American College of Surgeons. National Trauma Data Bank. Annual Report 2007.
ACS 2007.
13.Wurmb TE, Frühwald P, Hopfner W, Keil T, Kredel M, Brederlau J, et al. Wholebody multislice computed tomography as the primary and solid diagnostic tool in
patient with multiple injuries: the focus on time. J Trauma. 2009;66(3):658-65.
14. Markopoulou A, Argyriou G, Charalampidis E, Koufopoulou A, Nestor A, Nanas S,
et al. Time-to-treatment for critically ill-polytrauma patients in Emergency Department. Health Science Journal. 2013;7(1):81-89.
15.Akšamija G. Korelativnost postojećeg organizacijskog modela zbrinjavanja na
konačni ishod liječenja politraumatiziranih pacojenata u KCUS; Doktorska disertacija; Med.Fakultet; Sarajevo, 2010.
16. Dedović Halilbegović G. Značaj hirurškog tretmana u prvom operacionom periodu
za preživljavanje životno ugrožen–traumatiziranih pacijenata;Magistarski rad;Med.
Fakultet;Sarajevo, 2014.
17.Eid H, Barss P, Adam S, Torab F, Lunsjo K, Grivna M, et al. Factors affectin anatomical region of injury, severity, and mortality for road trauma in a high-income
developing country: lessons for prevention. Injury. 2009;40(7):703-7.
CONCLUSION
Survival of patients with signs of major trauma depends on the
general condition before the injury, age, but also to a large extent on
the quality of the offered emergency medical assistance, promptness
of the patient’s stabilization and necessary diagnostic procedures and
the time passed between the injury and urgent surgical treatment. In
order to enable the majority of traumatized patients with life threaten-
Reprint requests and correspondence:
Gjulera Dedović Halilbegović, MD
Clinic of Emergency Medicine
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Email: [email protected]
Medical Journal (2015) Vol. 21, No. 1, 51 - 53
Professional article
Outcome of the surgical repair of high and
intermediate anorectal malformations in children
Osnovni test u određivanju fertilnog kapaciteta
adolescenata
Sejdi Statovci*, Nexhmi Hyseni, Islam Rashiti, Murat Berisha, Antigona Hasani,
Butrint Xhiha, Ali Aliu
Clinic of Pediatric Surgery, University Clinical Centre of Kosovo, Prishtina, Kosovo
*Corresponding author
ABSTRACT
Introduction: anorectal malformations (ARM) include a variety of
congenital defects of the anus, anal canal and rectum, ranging from
the simple anal membrane to very complex anomalies which are very
often associated with other congenital anomalies. Posterior sagittal
anorectoplasty (PSARP) is widely accepted as standard treatment
procedure for all types of ARM. The aim of this study was to analyze
the outcome of the treatment of patients with high type anorectal
malformations including complications, voluntary bowel movements,
postoperative constipation and soiling. Materials and methods: this
study focused on 43 patients with high and intermediate anorectal malformations diagnosed and treated at our clinic in the period
from 2005 to 2014 in the framework of a combined retrospective
and prospective analysis of a total of 76 patients with anorectal malformations. 43 patients were analyzed in various aspects, including
the type of defects, surgical techniques used for their treatment,
functional outcome of the treatment, complications and mortality
rate. Results: out of 43 patients analyzed in this study 32 were male
(74.42%) and 11 female (25.58%). The most common malformations
INTRODUCTION
Anorectal malformations include a wide spectrum of clinical
presentation ranging from simple defects with no need for colostomy to a very complicated anomalies requiring complex and staged
management. Their estimated incidence is 1 per 4000–5000 live
birth (1,2,3). ARM used to be classified into low, intermediate, or
high type (Wingspread classification), depending on whether the
terminal bowel is located below, within, or above the levator sling
(4). Actually, the Krickenbeck classification of ARM is used widely.
This classification determines criteria for classification based on the
fistula location and also determines a standard method for postoperative assessment of the treatment outcome (3,4). Associated
malformations of other organ systems are identified in 30-70% of
children with ARM (5,6). Associated anomalies, their type, number
of affected organs in the same patient are very important for the
related to those without fistula in 17 patients (39.53%), followed by
rectourethral fistula in 14 patients (32.56%) and vestibular fistula in 6
patients (13.95%), classified as intermediate defects. There was one
case with rectal atresia (2.33%) and one case with cloacal malformation (2.33%). 1 patient died prior to any surgical treatment, 2 patients
with intermediate malformations (4.65%) were treated in one stage
without colostomy while in 40 patients (93.02%) colostomy was performed after birth. PSARP was the procedure of choice in 96.77% of
patients to whom the surgical treatment was completed. Constipation was present in 28.13% of all patients. In patients over 3 years of
age voluntary bowel movements were present in 51.72% while totally
incontinent was present in 13.79%. Mortality rate was 13.95% (N=6).
Conclusion: treatment of ARMs is a challenging problem, especially
those of high type, because of a high percentage of children that suffer from fecal incontinence which may happen even after an excellent
surgical treatment.
Key words: anorectal malformations, anal stenosis, colostomy, bowel management
survival rate and prognosis of treatment. Associated anomalies can
be twice more frequent in patients with higher anomalies than in
those with lower lesions (7). Very important decision to be made in
a neonate with ARM is whether the patient needs a colostomy or
not. Surgical treatment of low type anomalies can be done at neonatal age with a single act without colostomy, while high type anomalies require surgical treatment in three stages beginning with colostomy. Although various pediatric surgeons have reported treatment
of high type anomalies with a single act without colostomy (8,9),
posterior sagittal approach (PSARP), introduced by Alberto Pena,
has became widely accepted as the standard approach for all types
of imperforate anus (3,10). This approach allowed surgeons to see
directly the complex anatomy and relations of the rectum and genitourinary system and also made them possible to repair these defects under direct vision.
A new laparoscopically assisted anorectal pull-through (LAARP)
52
for the repair of high-type ARMs was described by Georgeson et
al. (11). It is a less invasive procedure when compared with those
operations that would have previously required a laparotomy such
as a rectobladder neck fistula and rectoprostatic fistula (12).
Despite all advances in operative techniques and improvements
of survival rate of these patients, there is a high incidence of postoperative fecal incontinence and constipation that occur even after an
excellent surgical repair. These complications are manageable by additional procedures such as the bowel management protocol, continent appendicostomy and sometimes redo operations (13,14,15).
MATERIALS AND METHODS
This study focused on 43 patients with high and intermediate
anorectal malformations diagnosed and treated at the University
Clinical Centre of Kosovo in the period from 2005 to 2014 in the
framework of a combined retrospective and prospective analysis of
a total of 76 patients with anorectal malformations. Patient records
and databases of the Clinic of Pediatric Surgery and Clinic of Neonatology were used to obtain necessary data. Operated patients were
invited for evaluation of their postoperative functional outcome.
According to X-ray images and intraoperative findings we classified
ARMs into high, intermediate and low according to Wingspread
classification. All patients with low ARMs were excluded from this
study. We have also used Krickenbeck classification of ARM for defining the type of malformations and for evaluation of postoperative
functional outcome. Voluntary bowel movements (VBM) and soiling
were evaluated in a group of 29 patients at toilet training age (over
3 years of age). Postoperative constipation was analyzed in a group
of 32 patients starting as early as possible in life, from the moment
the parents reported the occurrence of constipation.
S. Statovci et al.
The most common malformations were those without fistula in
17 patients (39.53%). Rectourethral fistula was found in 14 patients
(32.56%). Out of that number 10 patients had rectourethral prostatic
fistula and 4 other patients had rectourethral bulbar fistula. Vestibular fistula was classified as intermediate lesion in 6 patients (13.95%).
Rectal atresia as a rare malformation was diagnosed in 1 male patient
(2.33%) while in females there was 1 case of cloacal malformation
(2.33%). All types of high ARMs according to Krickenbeck classification are shown in Table 1.
Table 1 Types of high and intermediate ARMs according to
Krickenbeck classification.
MALE
FEMALE
TOTAL
high interm. high interm.
N
N
N
N
N
%
Recto-urethral fist. prostatic
10
10 23.26
Recto-urethral fistula bulbar
4
4
9.30
Recto-vesical fistula
4
4
9.30
Vestibular fistula
6
6
13.95
1
1
2.33
Cloaca
8
5
4
17 39.53
No fistula
1
1
2.33
Rectal atresia
Total
23
9
7
4
43
100
Surgical treatment was performed in 33 patients. Out of that number, 3 patients (9.09%) with intermediate lesions were treated primarily at first stage without colostomy whereas in 30 patients (90.91%)
surgical treatment consisted of three stages including the colostomy
creation after birth, definitive repair and colostomy closure. LAARP
was used in the treatment of 1 patient (3.03%) whereas 32 other patients (96.97%) were treated using PSARP as the procedure of choice
(Figure 2).
RESULTS
Male-female ratio of the patients with high ARMs in this study
was 2.9 : 1. High ARMs were found in 23 males (53.49%) and 5
females (11.63%), while intermediate ARMs were found in 9 males
(20.93%) and 6 females (13.95%) (Figure 1).
Figure 2 Operative techniques used in the treatment of
high ARMs.
Figure 1 Distribution of high and intermediate ARMs in
male and female patients.
In total of 8 surgically treated patients postoperative complications
occurred in 7 patients (16.67%). Five of them (11.90%) underwent
redo operations as a result of postoperative complications. Functional
outcomes were analyzed in 32 patients following the surgical treatment. Constipation of grade 2 and grade 3 was present in 28.13%
of analyzed patients (N-9). Voluntary bowel movements (VBM) and
Outcome of the surgical repair of high and intermediate anorectal malformations in children
soiling were evaluated in 29 patients over 3 years of age. VBM were
present in 15 patients (51.72%), whereas 11 patients (36.36%) still
had soiling. Therefore only 4 patients (13.79%) were considered continent. In total, soiling was present in 25 patients (86.21%).
Due to poor outcome after final treatment, five patients (15.63%)
underwent redo operations. Overall mortality rate of patients with
high ARMs was 13.95% (N=6).
DISCUSSION
As shown in Figure 1, high and intermediate type lesions were
more frequent in male than in female patients which seem to be
similar to the literature (6). The most common type in this study
was ARM without fistula which was found in 17 patients (39.53%).
12 of them were classified as high type defects and 5 others as intermediate. In female patients there were 4 cases without fistula and all
of them were classified as high type. In the reports of M. Levitt and
A. Pena the incidence of ARM without fistula was 5% (16), which
was less than in our study. The second most common malformation in our study was recto-urethral fistula registered in 14 patients
(32.56%). It was the most common malformation in male patients
presented in 10 patients with rectoprostatic fistula and 4 patients
with rectobulbar fistula. At this point, our study matches Alberto
Pena’s reports from 1995. In his series recto-urethral fistula was the
most common lesion in male patients (17). This study involved only
one case of rectal atresia (1.32%) and one cloaca (1.32%) with 5 cm
long common channel, so we considered it as high type lesion.
As mentioned before, a very important decision to be made in
a neonate with ARM is whether the patient needs a colostomy and
staged treatment or primary treatment without colostomy at first
stage. Out of 43 patients with high ARMs we opted for one stage
treatment without colostomy in 3 patients. This group consisted of
two female patients with vestibular fistula and one male patient without fistula. In this regard there are reports in the literature related to
the treatment of high ARMs at first stage without colostomy (8,9).
93.02% of patients (N=40) underwent staged surgical treatment including the formation of a divided colostomy, definitive repair of
ARM and the colostomy closure. In all cases we performed divided
colostomy at the level of sigmoid colon. We avoided loop colostomies because they were found to be associated with a higher total
incidence of complications than divided colostomies (18,19,20). In
total, surgical treatment was completed in 33 patients. A group of
10 other patients to whom the surgical treatment was not completed consists of 5 patients who died after colostomy, 3 patients with
colostomy waiting for definitive repair and 2 patients with colostomy who did not return to our clinic for further treatment.
PSARP is widely accepted as the standard procedure in patients
with high and intermediate type of ARMs (10,21). It was also the
standard operative technique for us, and therefore we used it in
the treatment of 96.97% of patients in this study (N=32), including
3 patients treated at first stage without colostomy and 29 patients
with colostomy. Only one patient with colostomy, with rectovesical
fistula, was surgically treated with LAARP (1.54%) (Figure 2).
Postoperative complications occurred in 7 patients (16.67%) as
follows: postoperative adhesive ileus after colostomy in 1 patient,
prolapse of rectal mucosa in 1 patient, prolapse of colostomy in 2
53
patients, wound dehiscence at the sight of colostomy in 1 patient,
postoperative anal and urethral stenosis in 1 patient, and partial
wound dehiscence in 1 patient. Laparotomy was performed in case
with adhesive ileums, colostomy revision was performed in 3 patients, and redo anoplasty in 1 patient. Patient with anal and urethral
stenosis was treated successfully with dilations of urethra and anus.
One patient with partial wound dehiscence after PSARP was treated
conservatively and wound was healed by secondary intention.
Out of 33 patients with finalized surgical treatment 1 patient
who was operated in first stage with PSARP died 10 days after the
operation due to sepsis and complications thereof. Consequently,
functional outcome was evaluated in 32 patients. Postoperative constipation was present in 28.13% of analyzed patients (N-9). Constipation of grade 2 (needs for laxatives) was present in 5 patients,
whereas constipation of grade 3 (resistant to diet and laxatives) was
present in 4 patients who were treated with enemas.
29 patients at toilette training age (over 3 years of age) were
evaluated for VBM and soiling using Krickenbeck criteria for assessment of postoperative outcome (4). VBM were present in 15
patients (51.72%) whereas 11 patients (36.36%) still had soiling.
Therefore only 4 patients (13.79%) were considered continent. In
total, soiling was present in 25 patients (86.21%) including 14 patients (48.28%) without VBM and 11 above mentioned patients with
VBM but also soiling. Occasional soiling (grade 1) was registered in
2 patients (6.90%), everyday soling with no social problems (grade
2) was registered in 6 patients (20.69%), and finally constant soiling
(grade 3) was present in 17 patients (58.62%).
14 patients included in this study underwent bowel management
procedures with daily enemas which produced successful outcome
in 9 patients, whereas 5 patients needed two enemas daily to remain
completely clean.
Posterior sagittal approach including posterior plication of muscle complex and re-establishing of anorectal angle was also the
procedure of choice in redo operations in 5 patients with poor
functional outcome. The group of patients to whom redo PSARP
was performed consists of 3 patients with vestibular fistula, 1 patient with rectourethral prostatic fistula and the patient treated with
LAARP because of rectovesical fistula. Decision for redo operation
in 3 patients (9.38%) was made due to fecal incontinence which occurred as a result of incorrect anorectal angle and misplaced anus
and rectum, and in 2 patients (6.25%) due to chronic and severe
constipation, megarectum and overflow incontinence. In one patient
with severe constipation and megarectum developed after vestibular
fistula repair, posterior sagittal anorectoplasty was a part of abdomino-perineal approach, combined with laparotomy and resection of
megarectum, which provided excellent results. In four patients with
redo PSARP we recorded the improvement of functional outcome
but in the fifth patient, with poor developed muscle complex, results
were not satisfying. Usage of PSARP in redo operations was reported by many authors (22,23).
6 neonatal patients died during this study (13.95%). 1 patient
died prior to any surgical treatment. Another patient died after
PSARP without colostomy, 3 patients after colostomy and the last
one (with associated long gap esophageal atresia) died after colostomy and gastrostomy. Pneumonia, cardio respiratory failure, acute
renal failure, sepsis and complications thereof were the causes of
deaths.
54
CONCLUSION
Treatment of high ARMs is a challenging problem. It is associated
with high percentage of children suffering from fecal incontinence
even after an excellent surgical treatment. Bowel management protocol, when applied accurately, is very important in improving the
quality of life of operated patients with ARM because it offers better
opportunities for integration of the children in daily activities. Redo
operations must be considered in patients with constant soiling and
cases with megarectum. Correction of incorrect anorectal angle in
patients with well-developed muscle complex can give good results
and significantly improve the patients’ quality of life.
Conflict of interest: none declared.
REFERENCES
1. Upadhyaya VD, Gangopadhyay AN, Srivastava P, Hasan Z, Sharma SP. Evolution
of management of anorectal malformation through the ages. Internet J Surg.
2008;17:1.
2. Levitt MA, Peña A. Imperforate anus and cloacal malformations. In: Holcomb III
GW, Murphy JP, editors. Ashcraft’s Pediatric Surgery. 5th ed. Philadelphia, PA: Saunders Elsevier. 2010:468-90.
3. Gangopadhyay AN, Pandey V. Anorectal malformations. J Indian Assoc Pediatr Surg.
2015;20(1):10-5.
4. Holschneider A, Hutson J, Pena A, et al. Preliminary report on the International
Conference for the Development of Standards for the Treatment of Anorectal
Malformations. Journal of Pediatric Surgery. 2005;40:1521-1526.
5. Peña A, Hong A (2000) Advances in the management of anorectal malformations.
Am J Surg. 180:370–376.
6. Endo MHayashi AIshihara M, et al. Analysis of 1992 patients with anorectal malformations over the past two decades in Japan. J Pediatr Surg. 1999;34435- 441
7. Mittal A, et al. Associated anomalies with anorectal malformation. Indian J Pediatr.
2004;71:509–514.
8. Albanese CT, Jennings RW, Lopoo JB: One-stage correction of high imperforate
anus in the male neonate. J Pediatr Surg. 1999;34(5):834-836
9. Liu G, Yuan J, Geng J, Wang C, Li T. The treatment of high and intermediate anorectal malformations: one stage or three procedures? J Pediatr Surg. 2004;39(10):146671.
10.De vries, Pena A. Posterior sagittal anorectoplasty. Journal of paediatric surgery.
2001: 17(5):638-643.
11.Georgeson KE, Inge TH, Albanese CT. Laparoscopically assisted anorectal pullthrough for high imperforate anus — A new technique. J Pediatr Surg .2000;35:92730.
12.Bischoff A, Levitt MA, Peña A. Laparoscopy and its use in the repair of anorectal
malformations. J Pediatr Surg. 2011;46:1609-17.
S. Statovci et al.
13. Bischoff A, Levitt M. A, Peña A. Bowel management for the treatment of pediatric
fecal incontinence. Pediatr Surg Int. 2009;25(12):1027–1042.
14. Har AF, Rescorla FJ, Croffie JM. Quality of life in pediatric patients with unremitting
constipation pre and post Malone Antegrade Continence Enema (MACE) procedure. J Pediatr Surg. 2013;48(8):1733-7.
15. Brain AJ, Kiely EM. Psterior saggital anorectoplasty for reoperation in children with
anorectal malformations. Brit J Surg. 2001;76(1):57-59.
16. Levitt MA, Peña A. Anorectal malformations. Orphanet Journal of Rare Diseases.
2007; 2:33.
17. Peña A. Anorectal Malformations. Semin Pediatr Surg. 1995;4:35-47.
18.Peña, A., Levitt, M.A. Imperforate Anus. Pediatric Gastrointestinal and Liver Disease, 3rd edition. 2006;749-755.
19.Oda O, Davies D, Colapinto K, Gerstle JT. Loop versus divided colostomy for the
management of anorectal malformations. J Pediatr Surg. 2014;49(1):87-90;
20.Van den Hondel D, Sloots C, Meeussen C, Wijnen R. To split or not to split: colostomy complications for anorectal malformations or hirschsprung disease: a single center experience and a systematic review of the literature. Eur J Pediatr Surg.
2014;24(1):61-9.
21. Rintala RJ. Anorectal malformations—management and outcome. Seminars in fetal
& neonatal. 1996;1(3,):219–230.
22.Pena A. Posterior saggital anorectoplasty as a secondary operation for the treatment of faecal incontinence. J Pediatr Surg. 2001;18(6):762-773.
23.Dewan PA, Hrabovszky Z, Mathew M. Redo anorectoplasty in the management
of anorectal anomaly patients. Australian and New Zealand Journal of Surgery.
2000;70 (supple l), A109.
Reprint requests and correspondence:
Sejdi Statovci, MD
Clinic of Pediatric Surgery
University Clinical Centre of Kosovo
Prishtina 10000
Kosovo
Email: [email protected]
Review article
Medical Journal (2015) Vol. 21, No. 1, 55 - 58
European sterilization standards in the Clinical Center
University of Sarajevo
Evropski standardi sterilizacije u Kliničkom centru
Univerziteta u Sarajevu
Adnana Talić-Tanović*, Aida Pitić, Mahir Trnka, Azra Muzurović
Central Sterilization Unit, Clinical Centre University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
Sterilization is the process related to elimination or destruction of
all microorganisms including their spores. Central sterilization is a unit
functioning within surgical disciplines of the Clinical Center University
of Sarajevo. It has become operational in 2001 in a newly built area
of the Central Medical Block, covering the space of 940 m2. The organization of Central sterilization in one place has been an economic
solution. The quality of sterile material is reliable, there is a better
control, and less staff is engaged. Sterilization involves reprocessing of
surgical instruments and equipment for all operating theatres and departments of the Clinical Center, preparation of sterile surgical laundry, transport of sterile materials and their distribution to operating
theatres at several locations. The aim of this article is to present the
function and importance of Central Sterilization of the Clinical Centre University of Sarajevo. Proper reprocessing of medical equipment
for repeated use, specifically mechanical cleaning, disinfection and
sterilization, presents an important measure for preventing hospital
infections. The sterilization technique using saturated stream under
pressure is the most reliable and as such is used in the CCUS. Each
sterilization step is controlled and recorded.
Sterilizacija je proces pri kome se vrši eliminacija ili destrukcija svih mikroorganizama uključujući i sporogene oblike. Centralna sterilizacija je organizaciona jedinica u sastavu hirurških
disciplina Kliničkog centara Univerziteta u Sarajevu. Sa radom
je počela 2001. godine u novosagrađenom prostoru Centralnog
medicinskog bloka. Površina je 940 m2. Organizovanje Centralne
sterilizacije na jednom mjestu je ekonomično rješenje. Kvalitet
sterilnog materijala je pouzdan, bolja je kontrola, a angažovano je
manje osoblja. Djelatnost je reprocesiranje hirurških instrumenata i pribora za sve operacione sale i odjeljenja Kliničkog centra,
priprema sterilnog operacijskog veša, transport sterilnog materijala i distribucija prema operacijskim salama koje se nalaze na više
lokacija. Cilj rada je prikazivanje rada i zanačaja Centralne sterilizacije Kliničkog centra Univerziteta u Sarajevu. Pravilno repocesiranje medicinske opreme za višekratnu upotrebu tj. mehaničko
čiščenje dezinfekcija i sterilizacija predstavlja značajnu mjeru za
prevenciju bolničkih infekcija. Najpouzdaniji način sterilizacije je
zasićenom parom pod pritiskom što koristimo u KCU Sarajevo.
Svaki korak sterilizacije je kontrolisan i dokumentovan.
Key words: central sterilization, surgical instruments, medical materials
Ključne riječi: centralna sterilizacija, hirurški instrumenti,
medicinski materijal
INTRODUCTION
rary planning principles and comprises three separate parts. In accordance with the existing standards the Central sterilization of the
CCUS is organized in three completely separated sectors depending
on purity of the processed materials. The first sector (impure) is
used for processing of contaminated materials which following the
disinfection enter the second sector (clean sector) through washing
and disinfection machines. The third sector is sterile and sterile materials are kept therein. There must be a physical barrier between
the sectors preventing the staff ’s entry. Staff in the Central sterilization wears surgical gowns (1,2).
Often forgotten and neglected, the central sterilization is an independent and unavoidable part of the hospital’s every day functioning. Although it is (unjustly) linked with the surgical work, its role
is much wider. The central sterilization is certainly the central part of
the basic hospital functioning. Except for cleaning, disinfection, ster-
Sterilization is a health care unit not receiving adequate attention. It primarily has a preventive role in combating infections and is
therefore important in treatment of hospitalized patients but also in
treatment of other users of health care protection. Bruch and Bruch
(1971) suggest the use of definition according to which sterilization
is the process by which living organisms are removed or killed to the
extent that they are no longer detectable in standard culture media
in which they previously have been found to proliferate, namely the
microorganisms no longer grow thereon.
Central sterilization is an organizational unit functioning within surgical disciplines of the CCUS. It has become operational in
2001 in a newly built area of the Central Medical Block, covering the
space of 940 m2. The space is organized in line with all contempo-
56
ilization and sterile packing of instruments, materials and equipment
for the operating theatre needs, the central sterilization is also used
for preparation of materials, equipment and instruments necessary
for every day functioning of literally all hospital departments and
dispensaries.
Organization of the central sterilization in one space has been
an economic solution. Quality of sterile material is reliable, there is
a better control, and less staff is engaged.
A. Talić-Tanović et al.
of microorganisms from the living tissue in order to prevent their
development or for limitation and treatment of already existing infection. From the aforementioned definitions it can be concluded
that asepsis is a working requirement in certain medical disciplines
achieved by sterilization of inanimate objects and materials getting in
touch with the living tissues. Disinfection can be defined as the procedure for destruction, inhibition or removal of vegetative forms of microorganisms, not necessarily the bacterial spores. Not all the existing
microorganisms should be destroyed by disinfection. It is sufficient to
reduce them to the level not harmful to human health or the quality
of groceries (2,4,5).
Figure 1 Interior of Central Sterilization Unit.
Function
Reprocessing of surgical instruments and equipment for all operating theatres and departments of the CCUS, preparation and
sterilization of the surgical laundry for operating theatres, processing
and sterilization of the spongious bone for the need of the Clinic of
Orthopedics and Traumatology, transport of the materials for sterilization, specifically transport and distribution of sterile materials to
the operating theatres at several locations.
Sterilization for medical and pharmaceutical purposes can be defined as the procedure which in a bottom line guarantees that no
more than one microorganism to one million will survive in the overall number of sterilized units of the final product. Sterilization is the
procedure or process for elimination of all types and forms of microorganisms, including bacterial spores to the extent that they are no
longer detectable in standard culture media in which they previously
have been found to proliferate, namely the microorganisms no longer
grow thereon. Thus, sterile means deprived of each and every life
category. This is the definition we always use to emphasize the difference between sterilization and disinfection (1,3,4).
The processing of reusable instruments and devices is conducted in automatic washing and disinfection facilities. For the purpose
of sterilization water purification is necessary for removing chemical hardness. Water demineralization is the procedure for complete
removal of minerals dissolved in the water. Depending on the purification phase requirements for water, quality is different. Ideally, demineralized water should be used in all purification phases, specifically
high quality water with minimum amount of particles and dissolved
minerals. Drinking water can be used for the initial washing, but the
water for final washing should be of high quality. Sensitive instruments
and equipment should always be washed, sterilized and transported
in the appropriate transporting baskets with holders in order to prevent their damage during processing and handling.
Asepsis is the state of being free from live microorganisms (without germs). Antisepsis is the procedure for destruction and removal
Figure 2 Interior of Central Sterilization Unit.
Preparing of instruments
There is a strictly established procedure in the medical materials-instruments sterilization cycle. Each step is of crucial importance,
and any mistake can lead to contamination and make the procedure
useless. On the other hand, life and health of patients and staff are
jeopardized and increase of financial expense can occur. Therefore,
each step in the sterilization cycle must be controlled in many ways,
recorded and monitored; and the final goal is to get a safely sterilized
product, specifically a guarantee of assured quality (4,5)
Transportation
After use, the instruments and other reprocessed materials are
transported to the central sterilization service in closed systems (trolleys and containers) where further treatments for safe and repeated
use are performed.
Cleaning/disinfection
The used instruments are placed in a special department of the
central sterilization service where a series of cleaning and disinfection
procedures take place (manual and automatic depending on the material the instrument is made of, but also of its characteristics). The
majority of impurity and microorganisms are removed by adequate
cleaning procedures. Cleaning is a precondition for successful sterilization, or in other words, sterilization does not stand for replacement of cleaning (1,4,5).
Each instrument treated in the central sterilization service, after
completed cleaning and disinfection, is a subject of thorough inspection. The aim of the inspection is not the washing quality control
(which is the case if it relates to manual washing. There are series of
57
European sterilization standards in the Clinical Center University of Sarajevo
tests for manual and automatic washing with a view of controlling impurity invisible to the naked eye) but the control of instrument functionality instead. Articular parts and scissor sharpness are subject to
control, meaning that each instrument must be functional in order to
be reused. It is wrong to check instruments in the operating theatre
or during surgical interventions. A disfunctional instrument makes
the work more difficult, it can cause complications, and adequate replacement can not be provided on time. Therefore, the inspection
conducted in the central sterilization service provides for timely replacement of the disfunctional instrument, namely it prevents possible complications in the operating theatre (1,6)
Packaging
Packaging implies providing adequate types of package for appropriate materials. The aim of the packaging is primarily to provide
adequate protection to the packed materials; sterile barrier system;
aseptic opening; in other words to ensure that the packaging technique and choice of materials provide high protection quality for the
sterile product.
Sterilization
There are numerous sterilization techniques. In health care institutions the most frequent sterilization method is by using saturated
steam under pressure (steam sterilizer). Regardless of the type of
sterilization it should provide safety for staff and patients.
Sterile storage
Secure a place for storage of sterilized materials (adequate microclimate conditions; humidity, temperature).
Transportation to users
In closed systems (trolley, containers) – transport packing.
Use
Accurate use of sterilized materials (aseptic opening and handling
of materials). Only a wrong step in opening can result in material
contamination before the use.
Problems which determined our plans and our vision
Sterilization is the heart of hospital and it should not stop beating!
It implies improvement of work quality not only in central sterilizations but also drawing attention to the importance of the central type
sterilization units. The importance of the education is for staff to be
thinking about the importance of respecting legal procedures, protocols, and to be familiarized with the existing norms and standards.
In time when the world is in constant fight against infections, when
increasing attention is being given to methods and measures of prevention, sterilization and disinfection are at the very top of the list as
a primary tool in that struggle.
The standards set up in the Central sterilization must be in accordance with the existing standards of the European Committee for
Standardization (EN and ISO). They are a relevant category, which
means that in time and with development of new technologies they
can be expanded and updated. Our goal is continuous monitoring of
the mentioned standards and their evaluation.
Societal development results in the expansion of numerous disease pathogen agents, of which new are discovered every day, but
measures for their repression have also been taken. Sterilization is a
method of choice in the control of currently known disease agents. It
is not self-sufficient, but, i.e. when we talk about instruments, it largely depends on previously conducted cleaning and disinfection procedures. The goal is to direct all available resources to the same aim, and
that is to get a safely sterilized product. The nurse in charge of sterile
materials must keep records on all procedures in sterilization and in
distribution of sterile materials (date, department).
Biological survaillance of sterilization is the most important control of the sterilization function, the only method of controling the
success of sterilization. Biological indicators (Bacillus Stearothermophilus spores – for sterilization in the autoclave and Bacillus Subtilis
spores – dry heat and ethylene oxide sterilization) are to be placed
in the sterilization chamber not reachable by steam. After completed
sterilization a package with biological material is sent to a microbiological laboratory to establish if microorganisms were destroyed or
not.
More contemporary biological indicators, besides the indicator
band with spores also have the growth medium, and the analysis can
be made in the sterilization unit with a portable incubator which enables result reading within 24-48 hours, which is much faster than to
wait for results from the microbiological laboratory (three or more
days). The new generation of biological indicators can be read in 1-3
hours. Destroyed spores confirm the success of sterilization. Systems
for speedy reading of biological indicators have removed the only
flaw of biological control – waiting for the results. After three hours
we can issue the material with absolute certainty in its sterility. European rules recommend biological survaillance of each autoclave filling
(1,2,7)
Possible mistakes occur as a consequence of the sterilization
theory ignorance, ignorance about specific sterilizer functioning, sterilizer overburdening, improper set preparations, lack of equipment
maintenance, short sterilization process, and efforts to speed up the
sterilization process. In case of more significant defects on certain
vital parts of the central sterilization equipment, there is an alternative
sterilization at certain locations such as Clinic for Urgent Medicine,
Clinic of Orthopedics and Traumatology, Vascular Clinic, which in
such cases should take responsibility for sterilization (1,7).
CONCLUSION
Nowadays, organization of sterilization at one place is the world
standard. It enables the use of different sterilization possibilities.
Quality is more reliable. Less staff is engaged. Quality of work in
those units is provided by qualified staff conducting the standard
procedures. It is very important that employees are hard working,
honest, which means that they are ready to admit committed mistakes, and that they have a high degree of self control given that
the patient’s destiny depends on that. The respect for the central
sterilization department has rapidly increased by development of
58
technology, which has been the biggest change in medical practice
in the past few years. The sterilization process carries enormous
responsibility of the entire institution, especially its employees. The
entire documentation must be kept neatly and be officially verified
by the institution. One must bear in mind that, in case of accidents,
this documentation can be used in the court proceedings. There
are no exemptions for the sterility issues. Sterilization is the letter
A in the medical alphabet! Each patient has the right to get a product which is safely treated to its final goal – to be used as sterile!
Sterilization is the heart of hospital, which can beat properly only
if all working criteria have been respected; if employees in the central sterilization service work as a team, if they are familiarized with
norms and standards, if they are continuously educated, and have
high degree of self-conscience. Modern sterilization should be the
extended hand of the operating theatre.
A. Talić-Tanović et al.
4. Rutala WA, Weber DJ. New disinfection and sterilization methods. Emerg Inf Dis.
2001;7:348-53.
5. Švrakić S, Šemić E, Pindžo M. Vodič za sestre i tehničare instrumentare. Ministarstvo
zdravstva Kantona Sarajevo, Sarajevo, 2010.
6. Buchrieser V, Miorini T. Osnovna skripta za reprocesiranje medicinskih instrumenata i pribora, 2009.
7. Kalenić S, et al. Medicinska mikrobiologija, 1. izd., Zagreb: Medicinska naklada,
2013.
Conflict of interest: none declared.
REFERENCES
1. Bojič-Turčić V. Sterilizacija i dezinfekcija u medicine. Medicinska naklada, Zagreb,
1994.
2. Block, SS. Disinfection, Sterilization and Preservation; 5th Edition (2000) Lippincott
Williams & Wilkins; Philadelphia.
3. Zuhlsdorf B, Floss H, Martiny H. Efficacy of 10 different cleaning processes in a
washer-disinfector for flexible endoscopes. J Hosp Infect. 2004;56(4):305-11.
Reprint requests and correspondence:
Adnana Talić-Tanović, MD, PhD
Central Sterilization Unit
Clinical Centre University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 297 600
Email: [email protected]
Review article
Medical Journal (2015) Vol. 21, No. 1, 59 - 62
Carbapenem resistant Enterobacteriaceae - increasing
issue for global healthcare
Enterobakterije otporne na karbapeneme - rastući
problem za globalnu zdravstvenu zaštitu
Amela Dedeić-Ljubović*
Department of Clinical Microbiology, Clinical Centre University of Sarajevo, Bolnička 25, 71 000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The emergence and global spread of carbapenemase-producing
Enterobacteriaceae is of great concern to health services worldwide.
These β-lactamases hydrolyses almost all β-lactams, are plasmid-encoded and easily transferable among bacterial species. They are
mostly of the KPC, VIM, IMP, NDM and OXA-48 types. Infections
caused by these bacteria have limited treatment options and have
been associated with high mortality rates. Carbapenemase producers are mainly identified among Klebsiella pneumoniae, Escherichia coli,
and still mostly in hospital settings and rarely in the community. The
types of carbapenemase vary among countries, partially depending
on the migration of population between the regions and the possible
reservoirs of each carbapenemase. This review described the epidemiology of carbapenemases produced by enterobacteria highlighting
the troublesome situation and the need to detect and screen these
enzymes to prevent and control their dissemination.
Pojava i globalno širenje enterobakterija koje produkuju karbapenemaze je od velikog značaja za zdravstvene ustanove širom svijeta.
Ove β-laktamaze hidroliziraju gotovo sve β-laktame, plazmidskog su
porijekla i lako se prenose među bakterijskim vrstama. Uglavnom
su KPC, VIM, IMP, NDM i OXA-48 tipa. Infekcije uzrokovane ovim
bakterijama su praćene ograničenim terapijskim mogućnostima i povezane su sa visokom stopom smrtnosti. Karbapenemaza producirajući sojevi su uglavnom dokazani među izolatima Klebsiella pneumoniae
i Escherichia coli, uglavnom u bolničkoj, rjeđe u vanbolničkoj sredini.
Tipovi karbapenemaza variraju od zemlje do zemlje, što djelomično
zavisi od migracije stanovništva između regija i mogućeg rezervoara
istih. Ovaj pregled opisuje epidemiologiju karbapenemaza producirajućih enterobakterija naglašavajući zabrinjavajuće stanje i potrebu
detekcije i praćenja istih kako bi se preveniralo i kontrolisalo njihovo
širenje.
Key words: carbapenemases, Enterobacteriaceae, KPC, NDM,
OXA-48
Ključne riječi: karbapenemaze, enterobak terije, KPC, NDM,
OXA-48
INTRODUCTION
others are plasmid encoded (KPC, IMI-2, GES, derivatives), but all
effectively hydrolyze carbapenems and are partially inhibited by
clavulanic acid (4).
KPCs (acronym for K. pneumoniae carbapenemase) are the
most frequently encountered enzymes in this group (5). Since the
first report of this enzyme in 1996 isolated from a clinical Klebsiella
pneumonia strain in North Carolina, USA (8), the KPC producers
have spread around the world and are becoming a major clinical
and public health concern (9). Several KPC clones are disseminating
harboring different multilocus sequence type, β-lactamase content
and plasmids. However the blaKPC genes are flanked by a same
transposon Tn4401 located on conjugative plasmids and are horizontally transferred (10).
This gives to this enzyme an extraordinary spreading capacity
(11). They have been detected more often in Klebsiella spp. (5), but
have also been reported in other Enterobacteriaceae (12). Thirteen
variants of KPC are known so far; KPC2 and KPC3 are the most
frequent worldwide variants (13). The mortality rate due to infection with a KPC producer ranged from 25% to 69% (14). Single or
Carbapenemases are an increasing concern for global healthcare due to their association with resistance to β-lactam antibiotics,
and to other classes of antibiotics such as aminoglycosides, fluoroquinolones and cotrimoxazole (1). Thus they reduce the possibility
of treating infections due to multidrug-resistant strains (2). The first
description of carbapenemase-producing enterobacteria (NmcA)
was in 1993 (3). Since then, large varieties of carbapenemases have
been identified belonging to three molecular classes: the Ambler
class A, B and D β-lactamases (4). They have become epidemiologically important in different parts of the world including Mediterranean countries, in recent years (2, 5, 6). Their enzymes are carried
either on chromosome or acquired via plasmids (7).
Class A carbapenemases
A variety of class A carbapenemases have been described:
some are chromosome encoded (NmcA, Sme, IMI-1, SFC-1) and
60
sporadic hospital outbreaks caused by KPCs isolated from various
species were reported (15, 16, 17). KPC-2 is clearly the most prevalent variant in Europe (9).
Class B carbapenemases
Class B metallo-β-lactamases (MBLs) are mostly of the Verona
integron-encoded metallo- β- lactamase (VIM) and IMP types and,
more recently, of the New Delhi metallo-β-lactamases-1 (NDM-1)
type. MBLs can hydrolyze all β-lactams except monobactam (e.g.
aztreonam). Their activity is inhibited by EDTA but not by clavulanic acid (18). The death rates associated with MBL producers are
high (18% to 67%) (19). Italy was the first Mediterranean country
to report acquired metallo-β-lactamases, with sporadic isolates of
VIM-4-producing K. pneumoniae and Enterobacter cloacae (20). Since
then, single or sporadic hospital outbreaks caused by VIM-1 like
enzymes have been described from various regions in this country
(21, 22). However, such VIM-producing Enterobacteriaceae have not
undergone wide dissemination, unlike the one observed in Greece
during the same period (23). Endemicity of VIM- and IMP-producing Klebsiella pneumoniae strains has now been noted in Greece (18).
Most recently reported NDM-1 enzyme is spreading rapidly
worldwide notably in Central and South America which represented
the last zone without description of this enzyme (24, 25). NDM-1
was initially identified in E. coli and K. pneumoniae in a patient returning to Sweden from India in 2008 (26). Most of the outbreaks
indicated a link with the Indian subcontinent, and in some cases with
the Balkan countries (27) and the Middle East (28).
Contrary to other carbapenemase genes, blaNDM-1 is not associated with a single clone. Thus NDM-1 has been identified mostly
in non-clonally related E. coli and K. pneumoniae and to a lesser extent in other enterobacterial species. These enzymes are encoded
on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. The strains harboring
NDM are broadly resistant to many other drug classes in addition
to β-lactams, and carry a diversity of other resistance mechanisms,
which leaves few treatment options (tigecycline or colistin). NDM-1
producers have been reported in the environment and in the community (29). They have been identified in Enterobacteriaceae species
around the world highlighting the ability of this gene to disseminate
in bacteria (30). Moreover NDM-1 has been identified in E. coli
ST131, a well-known source of community infections (31).
A. Dedeić-Ljubović
to temocillin is interesting to detect this enzyme (33). OXA-48 was
initially identified in K. pneumoniae isolate from Turkey in 2001 (34).
Since then, OXA-48 producing strains have been extensively
reported as sources of nosocomial outbreaks in many part of the
world notably in Mediterranean countries (35-38).
Moreover this enzyme has been found in different Enterobacteriaceae, such as Citrobacter freundii (39). Providencia rettgeri, and
Enterobacter cloacae (35) and even in E. coli (40,41). The death rates
associated with MBL producers are unknown.
Occurrence of carbapenemase-producing Enterobacteriaceae according
to ECDS
39 national experts (NEs) from Europe rated the occurrence
and spread of CPE for their respective country in 2013. 37 of the
NEs declared that they were fully aware of the current epidemiology of CPE in their country. Three NEs (representing Iceland, Montenegro and the Former Yugoslav Republic of Macedonia) reported
no case of CPE in their country. Sporadic cases, single or sporadic
hospital outbreaks were reported by NEs from 21 countries. For 11
countries, regional or national spread was reported, whereas NEs
of three countries (Greece, Italy and Malta) reported that CPE are
regularly isolated from patients in most hospitals, corresponding to
an endemic situation (figure 1). Thirty-three of the NEs indicated
that Klebsiella pneumoniae was the most frequent Enterobacteriaceae species harbouring carbapenemases in their country. IMP, KPC,
NDM, OXA-48 and VIM are the five most common carbapenemases in Enterobacteriaceae and thirty three of the NEs reported that
one or more of these most common carbapenemases could be
isolated in their country. In five countries (Bosnia and Herzegovina,
Estonia, Montenegro, Serbia and the Former Yugoslav Republic of
Macedonia), these data were not available (42).
Class D carbapenemases
Class D β-lactamases, also named OXAs for oxacillinases include 232 enzymes with few variants, possessing the same carbapenemase activity Initially OXA β-lactamases were reported from P.
aeruginosa but until now, these carbapenemases have been detected
in many other Gram-negative bacteria, including Enterobacteriaceae
(13, 32).
OXA-48 represents the main enzyme isolated around the world.
This enzyme hydrolyses penicillins but has a weakly activity against
carbapenems or extended-spectrum cepholosporins (third generation cephalosporin, aztreonam). Its activity is not inhibited by EDTA
or clavulanic acid tazobactam and sulbactam, whereas its activity
may be inhibited by NaCl in vitro (32). Its high level of resistance
Figure 1 Occurrence of carbapenemase-producing Enterobacteriaceae in 38 European countries based on self-assessment by the national experts (European Centre for Disease
Prevention and Control. Carbapenemase-producing bacteria in Europe:
interim results from the European Survey on carbapenemase-producing
Enterobacteriaceae (EuSCAPE) project. Stockholm: ECDC; 2013.)
Strategies for detection
Preventing the spread of carbapenemase producers relies on
the accurate detection of colonized patients at an early stage of
Carbapenem resistant Enterobacteriaceae - increasing issue for global healthcare
hospitalization or on admission/discharge either to the hospital or
to a specific unit. The accurate and rapid laboratory identification
of carbapenem-resistant isolates is important to prevent spread of
such multidrug resistant strains and to avoid therapeutic failures.
Screening should include as a minimum ‘at-risk’ patients, such as
those in intensive care units, transplant recipients and the immunocompromised, and those transferred from any foreign hospital (unknown prevalence of carbapenemase producer carriage) or from
non-foreign hospitals but known to face a high risk of carriage of
carbapenemase producers. Since the reservoir of Enterobacteriaceae is mostly the intestinal flora, stools and rectal swabs are the most
suitable specimens for performing such screening. Identification of
the carbapenemase genes relies mostly on molecular techniques,
whereas detection of carriers is possible by using screening culture
media. This strategy may help prevent development of nosocomial outbreaks caused by carbapenemase producers, particularly K.
pneumoniae. Screened patients should be kept in strict isolation before obtaining results of the screening (at least 24–48 hours) (5).
CONCLUSION
Plasmid-acquired carbapenemases in Enterobacteriaceae, which
were first discovered in Europe in the 1990s, are now increasingly
being identified at an alarming rate. They are mostly of the KPC,
VIM, NDM and OXA-48 types. Carbapenemase producers are mainly identified among Klebsiella pneumoniae and Escherichia coli, and
still mostly in hospital settings and rarely in the community. Their
prevalence in Europe varies significantly from high (Greece and Italy)
to low (Nordic countries). The types of carbapenemase vary among
countries, partially depending on the cultural/population exchange
relationship between the European countries and the possible reservoirs of each carbapenemase.
Rapid identification of colonized or infected patients, early and
accurate detection, the reinforcement of infection control measures
with restriction of the usage of carbapenems, is crucial in controlling
the spread of these multidrug resistant organisms.
Conflict of interest: none declared.
REFERENCES
1. Souli M, Galani I, Giamarellou H. Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill. 2008;13:pii 19045.
2. Giamarellou H, Poulakou G. Multidrug-resistant Gram-negative infections: what are
the treatment options? Drugs. 2009;69:1879 -901.
3. Naas T, Nordmann P. Analysis Analysis of a carbapenem-hydrolyzing class A beta-lactamase from Enterobacter cloacae and of its LysR-type regulatory protein. Proc Natl
Acad Sci USA. 1994;91:7693-7.
4. Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases. Clin Microbiol
Rev. 2007;20:440-58.
5. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011;17:1791-8.
6. Walsh TR. Emerging carbapenemases: a global perspective. Int J Antimicrob Agents.
2010; 36: 8–14.
7. Nahid F, Khan AA, Rehman S, Zahra R. Prevalence of metallo-β-lactamase
NDM-1-producing multi-drug resistant bacteria at two Pakistani hospitals and implications for public health. J Infect Public Health. 2013;6:487-93.
8. Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD,
61
Alberti S, Bush K, Tenover FC. Novel carbapenem-hydrolyzing β-lactamase, KPC1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents
Chemother. 2001;45:1151-61.
9. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009;9:228-36.
10. Cuzon G, Naas T, Truong H, Villegas MV, Wisell KT, Carmeli Y, et al. Worldwide diversity of Klebsiella pneumoniae that produce beta-lactamase blaKPC-2 gene. Emerg
Infect Dis. 2010;16:1349-56.
11.Naas T, Cuzon G, Villegas MV, Lartigue MF, Quinn JP, Nordmann P. Genetic structures at the origin of acquisition of the beta-lactamase blaKPC gene. Antimicrob.
Agents Chemother 2008;52:1257-63.
12.Deshpande LM, Rhomberg PR, Sader HS, Jones RN. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in
the United States Medical Centers: report from the MYSTIC Program (1999–2005).
Diagn Microbiol Infect Dis. 2006;56:367-72.
13.Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in
Gram-negative bacterial pathogens. Int J Med Microbiol. 2010;300:371-9.
14. Robustillo RA, Díaz-Agero PC, Sanchez ST, Ruiz-Garbajosa P, Pita López MJ, Monge
V. Emergence and outbreak of carbapenemase-producing KPC-3 Klebsiella pneumoniae in Spain, September 2009 to February 2010: control measures. Euro Surveill.
2012; 17(7). pii: 20086.
15. Gómez-Gil MR, Pano-Pardo JR, Romero-Gomez MP, Gasior M, Lorenzo M, Quiles I,
Mingorance J. Detection of KPC-2-producing Citrobacter freundii isolates in Spain. J
Antimicrob Chemother. 2010;65:2695-7.
16.Oteo J, Saez D, Bautista V, Fernández-Romero S, Hernández-Molina JM, PérezVázquez M, et al. Spanish Collaborating Group for the Antibiotic Resistance Surveillance Program. Carbapenemase-Producing Enterobacteriaceae in Spain in 2012.
Antimicrob Agents Chemother. 2013;57:6344-47.
17.Cuzon G, Naas T, Demachy MC, Nordmann P. Nosocomial outbreak of Klebsiella
pneumoniae harbouring blaKPC-3 in France subsequent to a patient transfer from
Italy. Int J Antimicrob Agents. 2012;39:448-9.
18. Walsh TR, Toleman MA, Poirel L, Nordmannn P. Metallo-β-lactamases: the quiet before the storm? Clin Microbiol Rev. 2005;18:306-25.
19. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, et al. Prospective observational study of the impact of VIM-1 metallo-β-lactamase on the
outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob
Agents Chemother. 2009;53:1868-73.
20.Luzzaro F, Docquier JD, Colinon C, Endimiani A, Lombardi G, Amicosante G, et
al. Emergence in Klebsiella pneumoniae and Enterobacter cloacae clinical isolates of
the VIM-4 metallo-β-lactamase encoded by a conjugative plasmid. Antimicrob Agents
Chemother. 2004;48:648-50.
21.Aschbacher R, Doumith M, Livermore DM, Larcher C, Woodford N. Linkage of
acquired quinolone resistance (qnrS1) and metallo-β-lactamase (blaVIM-1) genes in
multiple species of Enterobacteriaceae from Bolzano, Italy. J Antimicrob Chemother.
2008;61:515-23.
22. Aschbacher R, Pagani L, Doumith M, Pike R, Woodford N, Spoladore G, et al. Metallo-β-lactamases among Enterobacteriaceae from routine samples in an Italian tertiary-care hospital and long-term care facilities during 2008. Clin Microbiol Infect.
2011;17:181-9.
23. Canton R, Akóva M, Carmeli Y, Giske CG, Glupczynski Y, Gniadkowski M, et al. European Network on Carbapenemases. Rapid evolution and spread of carbapenemases
among Enterobacteriaceae in Europe. Clin Microbiol Infect. 2012;18:413-31.
24. Pasteran F, Albornoz E, Faccone D, Gomez S, Valenzuela C, Morales M, et al. Emergence of NDM-1-producing Klebsiella pneumoniae in Guatemala. J Antimicrob
Chemother. 2012;67:1795-7.
25.Escobar Pérez JA, Olarte Escobar NM, Castro-Carozo B, Valderrama Marquez IA,
Garzon Aguilar MI, Martinez de la Barrera L, et al. Outbreak of NDM-1-producing
Klebsiella pneumonia in a neonatal unit in Colombia. Antimicrob Agents Chemother.
2013;57:1957-60.
26. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence
type 14 from India. Antimicrob Agents Chemother. 2009;53:5046-54.
27.Livermore DM, Walsh TR, Toleman M, Woodford N. Balkan NDM-1: escape or
transplant? Lancet Infect Dis. 2011;11:164.
62
28.Poirel L, Fortineau N, Nordmann P. International transfer of NDM-1- producing Klebsiella pneumoniae from Iraq to France. Antimicrob Agents Chemother.
2011;55:1821-2.
29.Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al.
Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a
molecular, biological, and epidemiological study. Lancet Infect Dis. 2010; 10: 597-602.
30.Nordmann P, Poirel L, Walsh TR, Livermore DM. The emerging NDM carbapenemases. Trends Microbiol. 2011;19:588-95.
31.Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, Demarty R, Alonso MP, Caniça
MM, et al. Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J Antimicrob Chemother. 2008;61:273-81.
32.Peirano G, Schreckenberger PC, Pitout JD. Characteristics of NDM-1-producing
Escherichia coli isolates that belong to the successful and virulent clone ST131. Antimicrob Agents Chemother. 2011;55:2986-8.
33. Nordmann P, Dortet L, Poirel L. Carbapenem resistance in Enterobacteriaceae: here
is the storm! Trends Mol Med. 2012;18:263-72.
34. Woodford N, Pike R, Meunier D, Loy R, Hill R, Hopkins KL. In vitro activity of temocillin against multidrug-resistant clinical isolates of Escherichia coli, Klebsiella spp. and
Enterobacter spp., and evaluation of high-level temocillin resistance as a diagnostic
marker for OXA-48 carbapenemase. J Antimicrob Chemother. 2013 Sep 29. [Epub
ahead of print].
35. Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004;
48:15-22.
36.Carrër A, Poirel L, Eraksoy H, Cagatay AA, Badur S, Nordmann P. Spread of
OXA-48-positive carbapenem resistant Klebsiella pneumoniae isolates in Istanbul,
Turkey. Antimicrob. Agents Chemother. 2008;52: 2950-54.
37.Poirel L, Ros A, Carrër A, Fortineau N, Carricajo A, Berthelot P, Nordmann P.
Cross-border transmission of OXA-48-producing Enterobacter cloacae from Morocco to France. J Antimicrob Chemother. 2011;66:1181-2.
38. Cuzon G, Ouanich J, Gondret R, Naas T, Nordmann P. Outbreak of OXA-48-positive carbapenem-resistant Klebsiella pneumoniae isolates in France. Antimicrob
Agents Chemother. 2011;55:2420-3.
A. Dedeić-Ljubović
39.Potron A, Poirel L, Rondinaud E, Nordmann P. Intercontinental spread of OXA-48
beta-lactamase-producing Enterobacteriaceae over a 11-year period, 2001 to 2011.
Euro Surveill. 2013;18: pii 20549.
40. Nazic H, Poirel L, Nordmann P. Further identification of plasmid mediated quinolone
resistance determinant in Enterobacteriaceae in Turkey. Antimicrob Agents Chemother. 2005; 49:2146–47.
41. Gulmez D, Woodford N, Palepou MF et al. Carbapenem-resistantEscherichia coli
and Klebsiella pneumoniae isolates from Turkey with OXA-48-like carbapenemases
and outer membrane protein loss. IntJ Antimicrob Agents. 2008;31:523-26.
42. Kilic A, Aktas Z, Bedir O et al. Identification and characterization ofOXA-48 producing, carbapenem-resistant Enterobacteriaceae isolates in Turkey. Ann Clin Lab Sci.
2011;41:161-6.
43.European Centre for Disease Prevention and Control. Carbapenemase-producing
bacteria inEurope: interim results from the European Survey on carbapenemase-producing Enterobacteriaceae (EuSCAPE) project. Stockholm: ECDC; 2013.
Reprint requests and correspondence:
Amela Dedeić-Ljubović, MD, PhD
Department of Clinical Microbilogy
Clinical Centre University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Tel/fax: +387 33; 29 85 25
Email: [email protected]
Case report
Medical Journal (2015) Vol. 21, No. 1, 63 - 66
Recurrent aphthous ulceracions as an initial clinical
and patohistological biomarker of Crohn’s disease
Rekurentne aftozne ulceracije kao inicijalni klinički
i patohistološki biomarker Crohnove bolesti
Amira Dedić1*, Mersiha Avdić-Saračević2, Ljiljana Kesić3, Mia Hodžić1, Alma Kantardžić
Department of Paradontology and Oral Medicine, Faculty of Dentistry University of Sarajevo, Bolnička 4a, 71000 Sarajevo, Bosnia and Herzegovina,
Departmant of Periodontology, New Mowasat Hospital, Kuwait,
3
Dental Clinic, Department of Oral Medicine and Paradontology, Faculty of Medicine University of Niš, Republic of Serbia
1
2
*Corresponding author
ABSTRACT
SAŽETAK
We present a case of a six-year old patient with recurrent aphthous ulcerations (RAU) that has persisted since the birth. RAU manifests itself through a combined presence of small round aphthous
ulcers with a diameter varying from several mm to 2x5 cm located
on the mucosa of the cheeks and tongue. The diagnostic procedure
focused on determining the systematic etiological logical factor for the
purpose of excluding systematic and autoimmune diseases. The biopsy
or patohistological analysis confirmed the clinical diagnosis of Crohn’s
disease. The interdisciplinary diagnostics of the RAU and Crohn’s disease points to the correlation of the exact clinical diagnosis confirmed
by the patohistological analysis of the oral mucosa and mucosa of the
colon. A multidisciplinary cooperation is thus recommended in case of
all patients suffering from RAU.
U radu smo prikazali slučaj šestogodišnjeg pacijenta sa
rekurentnim aftoznim ulceracijama koje perzistiraju od rođenja. RAU se očituje kombiniranim prisustvom malih aftoznih ulceracija okruglog oblika od nekoliko mm u promjeru do velikih
veličine 2 x 5 cm, na sluznici obraza i jezika. Dijagnostička procedura je išla u pravcu određivanja sistemskog etiološkog faktora u cilju isključenja sistemskih i autoimunih bolesti. Biopsija
tj. patohistološki nalaz potvrdio je kliničku dijagnozu Crohnove
bolesti. Interdisciplinarna dijagnostika RAU i Crohnove bolesti ukazuje na korelaciju egzaktne kliničke dijagnoze potvrđene
patohistološkim nalazom oralne sluznice i sluznice kolona. Stoga
se kod svih pacijenata sa RAU preporučuje multidisciplinarna
saradnja.
Key words: recurrent aphthous ulceration, Crohn’s disease, heliobacter pylori, biopsy, patohistological analysis
Ključne riječi: rekurentna aftozna ulceracija, Crohnova bolest, heliobacter pylori, biopsija, patohistološki nalaz
INTRODUCTION
best documented is the genetic component. According to some studies, hereditary factors have an impact of 40% in the cases of patients
suffering from RAU (5, 6, 7). According to Ship et al. the probability
that a child will develop RAU, if both parents are prone to RAU, exceeds 90% (8). In cases where parents are not prone to RAU, this
probability amounts to 20%. Another piece of evidence on the hereditary nature of the disturbance is offered by studies in which a
specific HLA antigen was discovered in patients suffering from RAU,
especially in cases of certain ethnic groups (9).
Recent researches have applied sophisticated immunological tests
emphasizing more and more the role of lymphocyte toxicity (10),
cell-mediated cytotoxicity, depending on the potentials and errors
in subpopulations of lymphocytes (11, 12). Burnett and Wray have
proven that serums and monocytes cause a greater cytolysis in patients suffering from RAU than in the control groups of respondents
(13). Thomas et al. have shown increased cytotoxicity of T-lymphocytes for epithelious cells in patients suffering from RAU (10). Works
of Pedersen et al. and other authors have demonstrated changes in
the ratio of CD4 and CD8 lymphocytes or disturbance of the func-
Recurrent aphthous ulcerations (RAU) constitute a T-lymphocytes-mediated disease with a still unknown anti-gene(1). It is a clinically single entity with variable manifestations (2). RAU is a non-inflammatory disease of non-keratinized oral mucosae. The clinical
term of recurrent aphthous ulcerations describes the unpredictable
occurrence and remissions, and the frequency is related to hereditary
factors, which may be seen based on the anamnesis (3).
In an epidemiological research based on a representative sample
of 6000 respondents of the Bosnia and Herzegovina population , the
incidence of aphtae was 1.1%. That means that around 45,000 persons in Bosnia and Herzegovina have at least one oral mucosa aphtae
at this moment. The research has shown that every fifth person or every second 20-year old anywhere in the world suffers from aphthous
lesions (4).
Although the role of genetics, local, systematic, microbe-related and immunological factors in the etiology of RAU is known, the
pathogenesis still remains unknown. Out of all etiological factors, the
64
tion of numerous cytokines in the mucosa tissue (14, 15). Patients
suffering from HIV, especially those with a number of CD4 cells reduced to under 100/mm3 are more prone to occurrence of reversible aphthae (9).
Hematological disturbances, sideropenic anemia, lack of folic acid
and, vitamin B12 are well known causes of RAU, with a prevalence of
20%, although the results vary from study to study (16, 17).
In their study Brailo et al. have shown a strong link between RAU
and dyspeptic disturbances. The authors point out that after the exclusion of hematological deficiencies (Fe, folic acid and vitamin B12) a
patient suffering from RAU needs to be sent to a gastroenterological
examination, and an infection caused by H. pylori needs to be excluded. The reasons given by the authors are contained in the findings of
the study that point to a high frequency of infections caused by H.
pylori in case of 11.7% of respondents and remission of RAU after
the eradication therapy in case of 62.5% of respondents (2).
The research by Gallo et al. shows to which extent psychological
stress can influence the occurrence of RAU as a trigger or modifying
factor, but not as a cause, since no direct correlation has been established (18). Albanidou-Farmaki et al. concluded that stress may be
one of the etiological factors in the occurrence of RAU, since levels
of salivary and serum cortisol and level of anxiety were considerably
higher than in the control group (19).
A. Dedić et al.
The lesions in the oral cavity, both symptomatic and asymptomatic, occur in case of 6 to 20% of patients suffering from Crohn’s
disease (9). According to Ljušković, frequent oral changes in the case
of Crohn’s disease constitute its first stage. This is followed by the intestinal disease. Characteristic oral changes in case of Crohn’s disease
occur on the buccal mucosa and lips. Curves and ulcerations are also
visible. Granular changes on the gingiva and angular heilitis may also
occur (26).
Clinical and patohistological correlations
The patohistological RAU analysis result points to a localized inflammation and necrosis of the oral mucosa. The perivascular mononuclear infiltration is increased, including vascular abnormalities and
edema. The infiltrate may reach deep into the corium where numerous blood vessels are visible with pathological changes indicating vasculitis (27). According to Radović, vasculitis is an inflammatory change
of blood vessels diagnosed by means of a biopsy in order to determine the level of activity of the disease and possibly the existence of
changes that might precede a malignant disease (28).
The dynamics of diagnostic procedures in patients suffering from
RAU
Crohn’s disease
Crohn’s disease is a chronic granulomatous disease of unknown
etiology that attacks any part of the gastrointestinal tract, including
also the oral cavity, but most frequently the terminal ileum. The disease is characterized by a transmural inflammation of the intestine
wall. The clinical description of Crohn’s disease is characterized by
the following symptoms: abdominal pain, elevated temperature and
diarrhea. The earliest changes are aphthous lesions in the digestion
system (20). Extraoral manifestations are: aphthous ulcerations, skin
lesions (erythema multiforme), arthritis, hepatitis, uveitis, iritis (21).
Bishop et al. reported that patients with Crohn’s disease have oral
granulomatous lesions as the initial manifestation of the disease, approximately a year before radiological changes in case of the terminal
ileum. The oral patohistological analysis result is compatible with the
appearance of lesion in case of Crohn’s disease in any part (22, 23).
In case of Crohn’s disease ulcerations on the small and large intestines
are macroscopically visible in the area of thickened mucosa or other
line curve ulceration (9).
More recent epidemiological data point to the existence of two
types of Crohn’s disease: non-perforating type that develops slowly
and repeats rarely, and perforating or aggressive type that develops
fast. Crohn’s disease includes all age groups of both sexes (24).
Impaired absorption of vital nutrients (Ca, Fe and folic acid) that
are absorbed in the duodenum and strong diarrhea lead to a misbalance in electrolytes and reduced value of albumin. A lack of iron and
folic acid leads to anemia and leukocytosis.
One of the first characteristics of an inflammatory intestine disease is a superinfection by the Candida albicans as a reaction to the
bacteriostatic effect of sulfasalazine or damaged ability of neutrophils
to destroy this fungus that has the ability to create granulomas (25). In
patogenetical terms, it is an immune disturbance, where the secretion
of IgA is progressively reduced with the increase in pain intensity.
Figure 1 Major aphthous ulceration (lip)
Figure 2 Major aphthous ulceration (buccal mucosa)
Recurrent aphthous ulceracions as an initial clinical and patohistological biomarker of Crohn’s disease
65
from the literature and research conducted so far, the clinical and
patohistological diagnosis has confirmed that RAU can be the initial
symptom of ulcerous colitis and Crohn’s disease.
DISCUSSION
Figure 3 Major aphthous ulceration (tongue)
CASE REPORT
A six-year old patient reported to the Department of Paradontology and Oral Medicine of the Faculty of Dentistry in Sarajevo due
to ulcerations on the oral mucosa and tongue that has persisted since
the birth. Based on the anamnesis given by his mother, ulcerations
are continuous and painful. Stress has been excluded as a factor given
that the boy is an excellent and exemplary student. Based on a clinical
examination we have confirmed round aphthous ulcerations on the
non-keratinized mucosa of the minor and major type with a reactive
demarcation zone to the healthy mucosa. The patient feels pain without lymphadenopathy. As part of the therapy protocol we prescribed
a symptomatic therapy (vitamins, orobases, topical corticosteroids,
vitamin and mineral complexes), which did not produce any results
for the epithelization and recidivism. This made us engaged in further
diagnostic procedures and possible systematic etiology of RAU. We
referred the patient to the Pediatric Clinic, Department of Gastroenterology of the Clinical Center University of Sarajevo due to suspicion related to inflammatory intestinal diseases. All laboratory and
biochemical parameters were within reference values. However, the
result showed the presence of Heliobacter pylori IgG 20,2 U/ml.
Given that this finding pointed to patogenetical changes in the
gastrointestinal system, the patient was sent to a colonoscopy. The
colonoscopy showed an ulceration of 55 cm in size. A pH biopsy was
conducted in a specific location of the ulceration. The clinical finding
was confirmed by the patohistological finding with a definite exact
diagnosis of Crohn’s disease.
Prior to the colon biopsy, the patient with ulcerations, who did
not respond to numerous therapy modalities, was referred to the
Maxillofacial Surgery Department of CCUS for a biopsy of the aphthous ulceration on the mucosa of the cheek and tongue. The patohistological finding of oral mucosa matched and confirmed the clinical finding of RAU. After the colon biopsy and confirmation of the
Crohn’s disease diagnosis, the patient was prescribed corticosteroids,
which resulted in an improvement of the systematic condition and epithelization of RAU. The therapy prescribed by the gastroenterologist
included: PRONISON tbl. a 5 mg (4 + 4 + 0); RANIBOS tbl. a 150 mg
(1/2 + 0 + 1).
Following all diagnostic procedures and comparisons with data
Recurring aphthous ulcerations of RAU constitute an autoimmune
disease. It is characterized by round or oval ulcerations (of the
recurring ulcus type) – they are solitary or mutually confluent in a larger
number, of different size with a red rim due to reactive inflammation
and bottom covered by fibrin deposits. Our case relates to a six-year
old boy in which case RAU became chronic, with the presence of
recurring aphthous ulcerations. In the period following the arrival to
our clinic recurring aphthous ulcerations did not react to numerous
therapeutic procedures. This was intriguing as a medical phenomenon
and we immediately referred the patient to all diagnostic procedures
in order to obtain etiologically defined systematic factors and an exact
diagnosis. Hematological deficiencies (sideropenia, lack of folic acid
and vitamin B12) are frequent findings in patients suffering from RAU.
This is also confirmed by the findings of Barnadas et al. (16) that have
confirmed the mentioned deficiencies in 26.2% of patients diagnosed
with RAU. However, such findings have not been confirmed in the
case of our patient.
Thongprasom et al. (17) have described the lack of folic acid
in even 47.83% of patients with RAU. Weusten and van de Wiel
have described three cases of refracternal RAU that fully regressed
after a substitution treatment with vitamin B12 (29). In this study
the sideropenic anemia was found in 9 (13.2%) respondents. After
a substitution therapy with iron, RAU regressed in 4 (44.4%)
respondents. In our case the results related to folic acid and vitamin
B12 could not be connected with RAU, since there were within
reference values. The patient was sent to the laboratory for immune
diagnostics of infective diseases, where the value of Heliobacter
pylori, type IgG was confirmed, with a positive reference value of 20.2
U/ml. This finding is in compliance with the research (30).
H. pylori is a pathogen that has an important role in the occurrence
of gastric ulcerations, but its role in the development of aphthous
ulcerations is still unclear. Due to histological similarity between
gastric and oral ulcerations, numerous studies have been conducted
with thepurpose of exploring the role of that microorganism in
the occurrence of RAU. According to Riggio et al. (31) H. pylori
can be isolated from lesions in 11% of patients with RAU, whereas
according to Birek et al. it may be isolated from lesions in as many as
71.8% of patients (30). In our case, H. pylori was isolated, which is
in compliance with the research conducted by Riggio and Birek (30,
31). Accordingly, it may be concluded that the infection caused by
H. pylori may be a predisposition factor in a certain number of RAU
cases.
Taking into account the fact described in literature (2, 3, 9,
27, 32, 33), that recurring aphthous ulcerations may be initial or
accompanying finding in case of Morbus Crohn, our diagnostic
procedures were based accordingly. We excluded the Behcet
syndrome, Reiter syndrome, IgA deficiency and nutritive deficiency.
However, the clinical finding of persistent aphthous ulcerations in our
case was a clinical and human imperative to make all efforts in order
to have an exact diagnosis of either exclusion or confirmation of M.
66
CrohnThe literature confirms that RAU is more frequent in women
(2, 6, 34). Given that our case involved only one patient, we cannot
coment this. However, the age and persistence of RAU in the case of
the six-year old boy present a new data for the literature related to
diagnostic, clinical and patohistological procedures.
The important piece of information that around 10–15% of
patients have atypical symptoms of extraintestinal disease in the form
of recurring aphthous ulcerations and extraoral complications (35) is
in compliance with the findings related to our patient. Nobody from
the family suffered from Crohn’s disease, so the data on hereditary
defect of permeability is not important in this case. A colonoscopy
was performed on the mucosa of the rectum, sigmoid colon in the
area of colon descendens, on a length of 55 cm shallow ulceration
with fibrin bottom, from where a biopsy was taken, including a
clinical finding of aphthous ulceration from the buccal mucosa and
mucosa of the tongue, which were compatible. However, the biopsy
of patohistological verification of the buccal mucosa and mucosa of
the tongue corresponded to inflammatory changes, which pointed
to a chronic inflammation, corresponding to the pH finding of oral
mucosae. These procedures confirmed the diagnosis of Crohn’s
disease. Oral aphthous ulcerations of RAU are the initial findings for
the detection of inflammatory intestinal diseases and Crohn’s disease.
CONCLUSION
Based on the presented clinical case of RAU, there are certain
clinical dilemmas such as: (i) are oral ulcerations the initial symptom
of Crohn’s disease?, (ii) are repeated aphthous ulcerations an expression of Crohn’s disease?, (iii) do repeated aphthous ulcerations
co-indicate finding of Crohn’s disease?
The clinical and patohistological diagnostics confirm that recurrent aphthous ulcerations of RAU are the initial symptom of Crohn’s
disease. Dental medicine and gastroenterology are related because
they focus on digestive tract, and interdisciplinary cooperation is a
clinical imperative. Therefore, it is necessary to follow clinical and
patohistological diagnostic procedures.
Conflict of interest: none declared.
REFERENCES
1. Picek P, Andabak –Rogulj A, Vučićević-Boras V, Brailo V, Cigić L, Canjuga I, et al. Serumski
i salivarni parametri kod oboljelih od rekurentnih aftoznih ulceracija. Acta Stomatol Croat.
2012;46(1):43–49.
2. Brailo V, Vučević-Boras V, Cekić-Arambašin A. Rekurentne aftozne ulceracije: Analiza predisponirajućih čimbenika u 68 bolesnika. Liječ Vjesn. 2007;129:4–7.
3. Topić B. Diferencijalna dijagnoza i terapija bolesti oralnih sluznica. Sarajevo–Zagreb:
Stomatološki fakultet; 2004.
4. Đukanović D, Đajić D, Stanić S, Kovačević K. Bolesti usta: Oboljenja mekih tkiva usne duplje
/ Oralna medicina - atlas. Beograd: Stomatološki fakultet Univerziteta u Beogradu; 2001.
5. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, Häyrinen-Immonen R.
Reccurent aphthous ulcers today: a review of the growing knowledge. Int J Oral Maxillofac
Surg. 2004;33:221–34.
6. Shashy RG, Ridley MB. Aphthous ulcers: A difficult clinical entity. Am J Otolaryngol.
2000;21(6):389–93.
7. Greenberg MS, Pinto A. Etiology and management of reccurent aphthous stomatitis. Curr
Infect Dis Rep. 2003;5(3):194–198.
8. Ship II. Epidemiological aspects of recurrent aphthous ulcerations. Oral Surg Oral Med
Oral Pathol. 1972;33:400–6.
A. Dedić et al.
9. Greenberg MS. Burketova Oralna medicina: Dijagnoza i liječenje, 10th edition. Zagreb:
Medicinska naklada; 2006.
10. Thomas DW, Bagg J, Walker DM. Characterization of the effector cells responsible for
the in vitro cytotoxicity of blood leucocytes from aphthous ulcer patients for oral epithelial
cells. Gut. 1990;31:294.
11. Hoover CI, Olson JA, Greenspan JA. Humoral responses and cross-reactivity to viridians
streptococci in recurrent aphthous ulceration. J Dent Res. 1986;65:1101.
12. Greenspan JS, Gadol N, Olson JA, Hoover CI, Jacobsen PL, Shillitoe EJ, et al. Lymphocyte
function in recurrent aphthous ulceration. J Oral Pathol. 1985;14:592.
13. Burnetti PR, Wray D. Tyler effects of serum and mononuclear leukocytes on oral epithelial
cells in recurrent aphthous stomatitis. Clin Immunol Immunopathol. 1985;34:197.
14.Pedersen A. Psychologic stress and recurrent aphthous ulceration. J Oral Pathol Med.
1989;18(2):119-22.
15. Buño IJ1, Huff JC, Weston WL, Cook DT, Brice SL. Elevated levels of interferon gamma,
tumor necrosis factor alpha, interleukins 2,4,5, but not interleukin 10, are present in recurrent aphthous stomatitis. Arch Dermatol. 1998;134:827-31.
16. Barnadas MA, Remacha A, Condomines J, de Moragas JM. Hematologic deficiencies in
patients with recurrent oral aphthae. Med Clin (Barc). 1997;109(3):85–7.
17. Thongprasom K, Youngnak P, Aneksuk V. Hematologic abnormalities in recurrent oral ulceration. Southeast Asian J Trop Med Pub Health. 2002;33(4):872–7.
18. Gallo Cde B, Mimura MA, Sugaya NN. Psychological stress and recurrent aphthous stomatitis. Clinics (Sao Paulo). 2009;64(7):645–8.
19. Albanidou-Farmaki E, Poulopoulos AK, Epivatianos A, Farmakis K, Karamouzis M, Antoniades D. Increased anxiety level and high salivary and serum cortisol concentrations in
patients with recurrent aphthous stomatitis. The Tohoku journal of experimental medicine.
2008;214(4):291–6.
20. Vrhovac B, Jakšić B, Reiner Ž, Vucelić B. Interna medicina 2. Zagreb: Naprijed; 1991.
21.Topić B. Stomatološka praksa i bolesti pojedinih organskih sustava. Sarajevo-Zagreb:
Stomatološki fakultet Univerziteta u Sarajevu i Medicinska naklada; 2008.
22. Šimić D. Bolesti sluznica: multidisciplinarni pristup. Zagreb: Medicinska naklada; 2012.
23. Bishop RP, Brewster AC, Antonioloi DA. Crohn’s disease of the mouth. J Gastroenterol.
1972;62:302-6.
24. Achkar E, Farmer RG, Flesher B, editors. Clinical gastroenterology. 2nd ed. Philadelphia:
Lea and Febiger; 1992.
25. Curran FT, Youngs DJ, Allan RN. Candidacidal activity of Crohn’s disease neutrophils. Gut.
1991;32:55-60.
26. Ljušković B. Parodontologija i oralna medicina. Beograd: Vojna knjiga; 2009.
27. Dedić A. Autoimune bolesti: Praktikum. Sarajevo: Stomatološki fakultet Univerziteta u Sarajevu; 2010.
28. Radović S, Dorić M, Tomić-Ćuk I, Babić M, Kuskunović S. Dijagnostičke procedure u patologiji. Sarajevo: Medicinski fakultet Univerziteta u Sarajevu; 2012.
29. Weusten BLAM, van de Wiel A. Aphthous ulcers and vitamin B12 deficiency. The Netherlands Journal of Medicine. 1998;53(4):172–175.
30. Birek C, Grandhi R, McNeill K, Singer D, Ficarra G, Bowden G. Detection of Helicobacter
pylori in oral aphthous ulcers. J Oral Pathol Med. 1999;28(5):197–203.
31. Riggio MP, Lennon A, Wray D. Detection of Helicobacter pylori DNA in recurrent aphthous stomatitis tissue by PCR. J Oral Pathol Med. 2000;29(10):507–13.
32. Cekić-Arambašin A, Vidas I, Topić B, Alajbeg I, Vučićević-Boras V, Biočina-Lukenda D, et
al. Oralna medicina. Zagreb: Školska knjiga; 2005.
33. Siegel MA, Jacobson JJ. Inflammatory bowel diseases and the oral cavity. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 1999;87:12-4.
34.Rodu B. Oral mucosal ulcers: Diagnosis and management. J Am Dent Assoc.
1992;123(10):83–6.
35. Halme L, Meurman JH, Laine P, von Smitten K, Syrjänen S, Lindqvist C, et al. Oral findings in patients with active or inactive Crohn’s disease. Oral Surg Oral Med Oral Pathol.
1993;76:175-81.
Reprint requests and correspondence:
Amira Dedić, MD, PhD
Department of Periodontology and Oral Medicine
Faculty of Dentistry , University of Sarajevo
Bolnička 4a, 71000 Sarajevo, Bosnia and Herzegovina
Phone: +387 33 214 249
Email: [email protected]; [email protected]
Case report
Medical Journal (2015) Vol. 21, No. 1, 67 - 69
Heroin overdose caused by intranasal administration
(sniffing) causes coma, rhabdomyolysis, acute kidney
failure and diffuse hepatopathy
Predoziranje heroinom intranazalnim putem
(šmrkanjem) uzrokuje komu, rabdomiolizu sa
posljedičnom akutnom renalnom insuficijencijom i
difuznom hepatopatijom
Amina Godinjak*, Amer Iglica, Selma Jusufović, Anes Ajanović, Ira Tančica, Adis Kukuljac,
Senad Pešto2
Medical Intensive Care Unit, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic of Emergency Medicine, Clinical
Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The occurence of rhabdomyolysis with consequent renal failure and diffuse hepatopathy should rise a high index of suspicion
of drug overdose, even in the absence of obvoius intravenous drug
abuse. Admission to the intensive care unit is associated with a
mortality of 22% in the absence of acute kidney injury, and 59% if
renal impairment occurs. It is very rare for overdose to occur after
intranasal administration of heroin. We present a case of a 31- year
old male, admitted to our Intensive Care Unit with clinical presentation of coma, rhabdomyolysis, acute kidney failure and diffuse
hepatopathy after heroin overdose caused by intranasal administration (snifing).
Pojava rabdomiolize sa posljedičnom renalnom insuficijencijom i
znacima difuzne hepatopatije treba probuditi visok indeks sumnje na
predoziranje drogom, čak i u odsustvu očiglednih znakova intravenskog
korištenja droge. Prijem u Jedinicu intenzivne njege je povezan s mortalitetom od 22% u nedostatku akutne renalne insuficijencije, a 59% ako
dođe do akutne renalne insuficijencije. Vrlo rijetko dolazi do predoziranja nakon intranzalnog uzimanja (šmrkanja) heroina. Predstavit ćemo
slučaj 31-godišnjeg muškarca koji je primljen u Jedinicu internističke intenzivne terapije pod kliničkom slikom kome, rabdomiolize, akutne renalne insuficijencije i difuzne hepatopatije nakon predoziranja heroinom
intranazalnim putem (ušmrkavanjem).
Key words: heroin overdose, coma, rhabdomyolysis, acute kidney
failure
Ključne riječi: predoziranje heroinom, koma, rabdomioliza, akutna
renalna insuficijencija
INTRODUCTION
ants, the strength of the drug reduces, with the effect that if steps
are missed, the purity of the drug reaching the end user is higher
than they are used to, and because they are unable to tolerate the
increase an overdose ensues (4).
Bosnia and Herzegovina has a strategic location on the Balkan
route which connects drug production centres in Asia and the markets in western Europe. As such it become a regional traffic centre
for international trafficking of narcotics in Europe. At least 60 tonnes
of heroin are smuggled annually via the Balkan route. At least 10
tonnes of heroin pass through BiH and its police seize barely 10
kilograms per year. The purity of seized drugs is not investigated at
the moment in Bosnia and Herzegovina. Furthermore, there is an
increasing number of synthetic new drugs, so-called „magic dragon“,
„crocodile“ — homemade synthetic opiates stronger than heroin,
made from petrol, red phosphorus and codeine. These synthetic
opiates have a structure nearly identical to heroin, and are reported
Even though overdose is a known complication of intravenous
heroin abuse, it is very rare in case of heroin sniffing. Worldwide,
the UN estimates that there are more than 50 million regular users
of heroin, cocaine and synthetic drugs (1). In 2009, it was estimated
that the number of intravenous drug users in Bosnia and Herzegovina could be as many as 15000 (2). The European Monitoring Centre
for Drugs and Drug Addiction reports that the retail price of heroin
in most European countries varies between €35-40 per gram (3).
The patient in our study revealed that he usually pays 10-20 KM
(5-10 €) for one dose of heroin of unknown purity. The average
purity of street heroin varies between 30% and 50%. The variation
of purity has led to people suffering from overdoses as a result of
the heroin missing a stage on its journey from port to end user, as
each set of hands that the drug passes through adds further adulter-
68
to cause liver and muscle damage. Further studies are needed to
investigate the full effect of these new drugs. Currently there are no
available screening tests for these new drugs in the Clinical Center
University of Sarajevo.
CASE REPORT
A 31-year-old man was found in coma at his house and brought
by emergency ambulance to the Emergency Medical Center and
hospitalized at the Medical Intensive Care Unit ( JIIT). He had a history drug abuse, including prescription drugs (Lexillium, Tramadol)
and ultimately he confessed „recreational“ sniffing of heroin. A day
prior to the admission, he was at a party where he had taken an
undetermined amount of heroin of unknown quality which resulted
in unconsciousnes upon returning home. He was in coma for at least
12 hours before his mother called an ambulance. The patient did
not regain consciousness after receiving intravenous Naloxone (2
ampules) in the Emergency Medical Center.
He has lived with his mother since the age of 6, without father.
He had no significant medical or surgical history. He was of strong
muscular built, given that weight-lifting and boxing were his hoobby
for the past five years.
Physical examination showed deep coma (GCS 3/15) with
contracted pupils. He had no signs of venepuncture on his body.
Apart from swelling and edema of his feet and two necrotic cutaneous lesions on lateral sides of his ankles, physical examination
was not significant. His body temperature was 39,4oC upon admission, rising to the maximum of 40,0oC six hours after admission.
Blood pressure was 109/76 (87) mmHg, heart rate 135/min and
respiratory rate 35/min on admission. Acid-base status revealed
slight hyperchloremic metabolic acidosis (pH 7,30; pCO2 4,7; pO2
9.7; HCO3 16,7; Base excess -8,5; anion gap 5,5 and sO2 93.0%).
Laboratory data revealed an elevated leucocyte (Le) count of 14,5
x109/L, elevated potassium (K) level of 5,5 mmol/L, decreased calcium (Ca) level of 2,04 mmol/L, increased levels of: creatinine 275
mmol/L, urea 14,6 mmol/L, creatine kinase (CK) 32860 U/L, lactic
dehydrogenase (LDH) 2388 U/L, aspartate aminotransferase (AST)
1067 U/L, alanine aminotransferase (ALT) 779 U/L, and C-reactive
protein (CRP) 53,0 mg/L. There was an increase in INR 1,62 and
activated partial thromboplastin time (APTT) 43,1 s. His toxicology
results were positive for benziodiazepines, morphine and heroin.
Immediately after admission, the patient was intubated, and placed
on mechanical ventilation. He was treated with IV hydration, antibiotics, and anticoagulant with dose adjustment with regard to creatinine clearance.
A second laboratory test 12 hours after admission showed decreased Ca level 1,74 mmol/L, and even more increased levels of:
creatinine 330 mmol/L, urea 18,6 mmol/L, CK 39600 U/L, LDH
3072 U/L, AST 1248 U/L, ALT 865 U/L, CRP 153,7 mg/L, INR
1,53 and APTT 60,6 s. Troponin level increased to maximum of
11,3 ng/mL 24 hours after admission. An electrocardiogram (ECG)
showed sinus tachycardia with a ventricular rate of 143/min, without signs of acute ischemia or myocardial lesion. Results of a computed tomographic (CT) scan of the patient’s head were normal
upon admission and 24 hours after admission. Lumbar puncture
results were normal and cerebrospinal liquor was sterile.
A. Godinjak et al.
A diagnosis of heroin overdose, rhabdomyolysis and consequent acute renal failure and diffuse hepatopathy was established.
The day after the admission, the patient was afebrile and started
improving. On the third day he regained conciousness and after
completing criteria for extubation, he was extubated. His laboratory parameters improved, with steady fall in Le to 6,85 x109/L,
K 3,9 mmol/L, CK 4727 U/L, LDH 1065 U/L, AST 246 U/L, ALT
297 U/L, and CRP 96,9 mg/L, INR 1,02 and APTT 36,1 s. At this
stage (fifth day of hospitalization), he was transferred to the Clinic
of Nephrology due to continued elevated levels of creatinine 272
mmol/L and urea 17,5 mmol/L. After conservative treatment, he
fully recovered and was released from hospital.
DISCUSSION
The onset of heroin’s effects depends on the route of
administration. Intravenous injection is the fastest route of drug
administration, causing blood concentrations to rise the most
quickly, followed by smoking, suppository (anal or vaginal insertion),
insufflation (snorting), and ingestion (swallowing).
To insufflate
(snif) heroin, a user crushes the heroin into a fine powder and then
gently inhales it (sometimes with a straw or a rolled up banknote, as
with cocaine) into the nose, where heroin is absorbed through the
soft tissue in the mucous membrane of the sinus cavity and straight
into the bloodstream. This method is sometimes preferred by users
who do not want to prepare and administer heroin for injection or
smoking, but still experience a fast onset.
The motherof our patient found a home-made set for sniffing
including a mirror and a rolled piece of paper. Only one study so far
described cases of fatal heroin overdose associated with non-parental
administration including sniffing (5). It is very rare for overdose to
occur after intranasal administration of heroin. Rhabdomyolysis after
intravenous administration has been reported but the occurrence of
rhabdomyolisis after heroin insufflation (sniffing) is very uncommon.
Rhabdomyolysis may often be present with or without muscle
swelling or limb compression or no symptoms at all, even in conscious
patients. Toxic or allergic reactions to heroin are probably more
important causes of rhabdomyolysis than limb compression.
Release of the muscle tissue components into the bloodstream
causes disturbances in electrolytes, which can lead to nausea, vomiting,
confusion, coma or abnormal heart rate and rhythm. Damage to the
kidneys may give rise to decreased or absent urine production, usually
12 to 24 hours after the initial muscle damage. Our patient had 975
ml of diuresis in the first 12 hours after admission and over 2000 ml in
the next 24 hours. Swelling of the damaged muscle occasionally leads
to the compartment syndrome—compression of surrounding tissues,
such as nerves and blood vessels, in the same fascial compartment—
leading to the loss of blood supply and damage or loss of function in
the part(s) of the body supplied by these structures. Symptoms of this
complication include pain or reduced sensation in the affected limb (6).
The most reliable test in the diagnosis of rhabdomyolysis is the
level of creatine kinase (CK) in the blood. This enzyme is released
by damaged muscle, and levels above 5 times the upper limit of
normal indicate rhabdomyolysis. Depending on the extent of the
rhabdomyolysis, concentrations up to 100,000 U/l are not unusual.
(7).
Heroin overdose caused by intranasal administration (sniffing) causes coma, rhabdomyolysis, acute kidney failure and diffuse hepatopathy CK concentrations rise steadily for 12 hours after the original
muscle injury, remain elevated for 1–3 days and then fall gradually (8).
Initial and peak CK levels have a linear relationship with the risk of
acute renal failure: the higher the CK, the more likely it is that kidney
damage will occur(9).
In our study, the maximum rise of CK was 39600 U/L and it
occured 24 hours after admission.
There is no specific concentration of CK above which renal
impairment definitely occurs; concentrations below 20,000 U/l are
unlikely to be associated with a risk of renal impairment, unless there
are other contributing risk factors. The transaminases, enzymes
abundant in both liver and muscle tissue, are also usually increased;
this can lead to the condition being confused with acute liver injury,
at least in the early stages. The incidence of actual acute liver injury is
25% in patients with non-traumatic rhabdomyolysis; the mechanism
for this is uncertain (11). Our patient had all the parameters of diffuse
hepatopathy, which was most probably connected to rhabdomyolisis.
Low calcium levels may be present at the initial stage due to binding
of free calcium to damaged muscle cells. Also, other markers of
muscle damage, such as aldolase, troponin, carbonic anhydrase type
3 and fatty acid-binding protein (FABP), can also be present. Our
patient had high troponin level without ECG signs of acute miocardial
ischemia or lesion.
The main goal of the treatment is to treat shock and preserve
kidney function. Initially this is done through the administration of
generous amounts of intravenous fluids, usually isotonic saline (0.9%
sodium chloride solution). Amounts of 6 to 12 liters in the first 24
hours are recommended. The rate of fluid administration may be
altered to achieve a high urine output (200–300 ml/h in adults) unless
there are other reasons why this might lead to complications, such as
a history of heart failure (12).
The prognosis depends on the underlying cause and whether
any complications occur. Rhabdomyolysis complicated by acute
kidney impairment may have a mortality rate of 20%. Admission to
the intensive care unit is associated with a mortality of 22% in the
absence of acute kidney injury, and 59% if renal impairment occurs
(13). Our patient recovered fully after the conservative treatmen and
was eventually released form the hospital in good condition.
REFERENCES
1. “World Drugs Trade”. BBC News. www.bbc.co.uk. Retrieved 2012-07-20.
2. UNICEF Bosnia and Herzegovina ‘Report on behavioural and biological surveillance
among injection drug users in Bosnia and Herzegovina, 2009: A respondent-driven
sampling survey’, UNICEF/UNDP 2010, Sarajevo/Banja Luka.
3. European Monitoring Centre for Drugs and Drug Addiction. „Annual report: the
state of the drugs problem in Europe.“ Luxembourg: Office for Official Publications
of the European Communities. 2008. p. 70.
4. Bell, B. “BBC News - Afghan opium crop failure ‘led to UK heroin shortage’”. www.
bbc.co.uk. Retrieved 2012-11-03.
5. Thiblin I, Eksborg S, Petersson A, Fugelstad A, Rajs J. Fatal intoxication as a consequence of intranasal administration (snorting) or pulmonary inhalation (smoking) of
heroin. Forensic Sci Int. 2004;139(2-3):241-7.
6. Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. American Family Physician.
2002;65 (5):907–12.
7. Vanholder R, Sever MS, Erek E, Lameire N. Rhabdomyolysis. Journal of the American Society of Nephrology. 2000;11(8):1553–61.
8. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis –
an overview for clinicians. Critical Care. 2005;9(2):158–69.
9. Brancaccio P, Lippi G, Maffulli N. Biochemical markers of muscular damage. Clinical
Chemistry and Laboratory Medicine. 2010;48(6):757–67.
10. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis –
an overview for clinicians. Critical Care. 2005;9 (2):158–69.
11.Greaves I, Porter K, Smith JE. Consensus statement on the early management of
crush injury and prevention of crush syndrome. Journal of the Royal Army Medical
Corps. 2003;149(4):255–9.
12.Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. New England
Journal of Medicine. 2009;361(1):62–72.
CONCLUSION
The occurence of rhabdomyolysis with consequent renal failure
and diffuse hepatopathy should rise a high index of suspicion of drug
overdose, even in the absence of obvoius intravenous drug abuse,
with or without muscle swelling or a history of limb compression.
In such cases routine screening of narcotics in urine is advocated.
Awareness of different drug administration routes as well as all complications of drug overdose will assist in the diagnosis and prompt
treatment, thus reducing the morbidity and mortality.
Conflict of interest: none declared.
69
Reprint requests and correspondence:
Amina Godinjak, MD
Medical Intensive Care Unit
Clinical Center University of Sarajevo
Bolnička 25, 71000 Sarajevo
Bosnia and Hercegovina
Email: [email protected]
Case report
Medical Journal (2015) Vol. 21, No. 1, 70 - 72
Long term survival of unoperated patient with the left
ventricular pseudoaneurysm
Višegodišnje preživljavanje neoperirane bolesnice s
psudouneurizmom lijevog ventrikula srca
Zlatko Šantić1*, Slobodan Kožul2, Katica Mustapić-Šantić1
Polyclinic “Sunce”, Obilazna cesta 6, 88220 Široki Brijeg, Bosnia and Herzegovina,
Department of Clinical Radiology, Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina.
1
2
*Corresponding author
ABSTRACT
SAŽETAK
This paper presents a 82 year old female patient with the left ventricular pseudoaneurysm (PA), which most likely occurred as complication of an acute myocardial infarction (MI) 15 years ago. She was
treated with medications. Methods: we performed transthoracic
echocardiography (TTE) and computerized tomography (CT) of the
abdomen. Random PA was found. The survival of our patients was
compared to other non-surgically treated patients with PA, and the attention was drawn to differences in echocardiographic presentation of
the actual heart aneurysm and PA. Results: based on the available data
the above mentioned patient could be considered as the LV pseudoaneurysm patient with the longest survival, receiving medicamentous
treatment.
Prikazana je 82-godišnja bolesnica s pseudoaneurizmom
lijevog ventrikula srca (PA), koja je nastala najvjerojatnije kao
rana komplikacija akutnog infarkta srca (MI) preležanog prije 15
godine. Liječena je medikamentozno. Metode: urađena je transtorakalna ehokardiografija (TTE) i kompjuterizirana tomografija (CT) abdomena. Slučajno je nađena PA. Preživljavanje naše
bolesnice je uspoređeno s drugim neoperiranim bolesnicima s
PA, te je ukazano na razlike u ehokardiografskom prikazu prave
aneurizme srca i PA. Rezultati: prema dostupnim podacima prikazana gospođa bi bila bolesnica s najdužim preživljavanjem s
PA, liječena medikamentozno.
Key words: pseudoaneurysm, survival, echocardiography, CT
Ključne riječi: pseudoaneurizma, preživljavanje, ehokardiografija,
CT
INTRODUCTION
CASE REPORT
A heart rupture (HR) is a heavy complication of myocardial
infarction (MI). According to majority of studies, the incidence is
around 1%, mortality due to rupture of the free wall is 80%, and rupture of interventricular septum is 41% (1). The incidence of HR was
higher before the era of thrombolytic therapy, PCI, and increased use
of beta-blockers, ACE inhibitors, antiplatelets, statins, and it is now
around 6% (1).
LV pseudoaneurysm is a severe complication that occurs after the
rupture of the free wall of adherent pericardium. The incidence is
uncertain due to high mortality, short survival, and small number of
patients. Most often it occurs after MI, in 55 % of patients, and after
cardiac intervention, 33 % of patients, after blunt trauma of the heart,
7%, and endocarditis, 5 % (2).
Due to cardiac tamponade and high mortality, cardio surgical treatment was indicated. Survival of the majority of non-surgically treated patients with PA is short, burdened by heart failure, arrhythmias,
thromboembolism and sudden death. Fewer patients live longer and
patients who lived 10 and 12 years afterwards have been presented
(3,4,5,6).
A 82 year old female patient was treated at Department of Internal Medicine of the Clinical Hospital Mostar 15 years ago as acute
Figure 1 ECG: atrial fibrillation, scar inferior, persistent ST
segment elevation in V5 and V6, with negative T wave.
Long term survival of unoperated patient with the left ventricular pseudoaneurysm inferolateral MI, in addition she had diabetes mellitus and arterial hypertension. During the hospitalization the echocardiogram was not
performed, and ECG recording at discharge showed sinus rhythm,
80/min, q in II, III, aVF, V5, and V6 leads, with persistent ST segment
elevation of 1mm in leads V5 and V6, with a negative T wave in I,
aVL, V5 and V6. ECG of the patient is shown in Figure 1.
In 2005 she was surgically treated for the ascending colon cancer. The follow-up CT of January 2011 showed wide pericardial
outflow and calcification, enlargement of the left ventricle, diameter of 57.8 x 48.4 mm (Figure 2). Figure 3 shows larger thrombus
(35.1x18mm) in the present expansion of the left ventricule (LV),
and Figure 4 shows that the described changes were associated with
posterior LV wall.
Figure 2 Calcification extensions of LV and thrombus.
Figure 3 Contrast and thrombus in calcified LV enlargement.
Figure 4 Posterior localization of PA on the side CT imaging.
71
Subsequently, in February 2011, the echocardiography was performed. The procedure was rather difficult due to the reduced and
deformed thorax (kyphoscoliosis). It was performed with a sector
probe of 2.0 MHz. Findings showed dilatation of the left ventricle,
LVIDd 59mm, with a large akinetic inferior wall of the cavity (Figures
5 and 6), size 50 mm, with calcified rim (Figure 7), in communication with the LV through the hole, width of 20,6 mm. Doppler flow
measurement through the hole in the extension of the LV obtained
spectrum corresponding to low blood flow velocities in systole and
diastole, due to wide PA hole (Figure 8).
Figure 5 Pseudoaneurysm of Figure 6 Pseudoaneurysm,
inferior wall, apical view of apical four chambers view.
two cavities.
Figure 7 Calcified wall and
pseudoaneurysm cavity,
atypical section.
Figure 8 The flow through
the rupture in systole and
diastole.
Global myocardial contractility was reduced, in the basal and
middle segment of the inferior wall akinesis, reduced LV systolic
function, ejection fraction (EF) Simpson about 36%. Moderate mitral
regurgitation was expressed, with Vmax 3.64 m/s. The left atrium in
diastole 53mm. TR1 +, ACT and pulmonary 87ms.
It was concluded that the finding corresponded to LV pseudoaneurysm inferior wall.
The X-ray images of the heart and lungs during hospitalization
in 1999: the lungs without infiltrative changes. Fully dilated heart,
weakened tone myocards, frenicocostal sinuses free.
Follow-up examination: except for even larger expansion infarction,
without other changes. She suffered from heart failure, atrial fibrillation, hypotension, diabetes, kyphoscoliosis of the thoracolumbal
spine, chronic iron deficiency anemia, and duodenal ulcer. Given all
the mentioned diagnoses, she was not ready for additional examinations and intervention. The patient was not surgically treated and
she died in October 2014.
DISCUSSION
The report describes a patient who survived inferolateral region
MI, 15 years ago. During the first two days of hospitalization her
condition was very bad. She frequently had chest pain, shortness of
breath, weakness, and heavy breathing. Until the echocardiography
72
was performed, and given the state of the patients in the first days
of infarction and the persistent ST segment elevation in leads V5
and V6 (Figure 2), and PA findings, an early myocardial rupture was
suspected. It was only 12 years after MI that she was diagnosed with
heart PA.
LV free wall rupture in MI is a heavy complication, and it makes
85% of all ruptures occurring in the first week, of which 40-50% in
the first 48 hours (2). Due to cardiac tamponade and high mortality
cardiac surgery is indicated, with mortality rate from 13 to 35.7%
(3). The risk of PA rupture is about 30-45%, and it is an indication
for urgent cardiac surgery. The mortality rate of patients with nonsurgically treated PA is 48-55% as compared to 19-35% of those
underwent surgical treatment (7).
Jose Lopez - Sendone et al. (1) thoroughly analyzed the incidence
and factors associated with rupture of the heart, through the Global
Registry of Acute Coronary Events (GRACE) in the period from
January 2000 to December 2007 in 60198 of patients with acute
coronary syndrome. The incidence of HR was 0.9% for STEMI, 0.17%
for non-STEMI and 0.25 % for unstable angina. Hospital mortality was
58% compared to 4.5% of patients with no HR. Mortality in free wall
rupture was 80%, and 41% in septal rupture. Of the total of 273
patients with HR, 0.2% had a rupture of the free wall and septum
rupture of 0.26% (1).
Patients who do not undergo cardiac surgery, can live for
several years (3,4,5,6). Some are almost asymptomatic, others with
signs of hypotension, heart failure, arrhythmias, thromboembolism.
According to a metaanalyses out of 107 patients who were operated,
25 died (23 %) within three days after surgery. The average survival
of the other 82 patients who were operated was 46 weeks. The
total of 31 patients was treated conservatively and 15 of them (48
%) died in less than seven days. The remaining 16 patients lived for
approximately 156 weeks. Among the patients who were surgically
treated, 12 lived for at least one year, five lived for at least 5 years and
2 patients for at least 10 years (8).
Morreno et al. showed that the risk of PA rupture in their patients
was not too high. For four years they followed 10 patients with PA.
One woman was surgically treated, nine received medicamentous
treatment, and there was no lethal outcome. They specified a relatively
high risk of ischemic stroke, 32.5%, in the follow-up period (5).
Prolonged survival of unoperated patients may be due to a very
narrow PA hole, small PA, reduced LV systolic function, and creation
of a large thrombus within PA.
Our patient lived 15 years after MI which probably caused the PA in
the first attack. Based on these facts she could be considered the PA
registered patient with the longest survival rate (3).
The diagnosis of PA was established on the basis of the
echocardiographic examination, contrast CT angiography of the
left ventricle. Sometimes it is difficult to distinguish between heart
aneurysm and pseudoaneurysm. And for PA it is important to look
for cavities connected to a narrow hole cavity, LV 0.25 to 0.50 the
diameter of the cavity, and the ratio of actual aneurysm 0.9-1.0. PA
is three times more localized in the inferior or posterolateral wall,
while the right aneurysm in 80-90% of patients is localized in apical
or anterolateral wall (9). Thrombus is often located in PA cavity. If
the hole is very narrow high flow spectra, can be found. Unlike the
heart aneurysm, PA has no endocardium and myocardium. There are
only adherent pericardium, hemopericardium and often thrombus.
Z. Šantić et al.
PA is very prone to rupture and cardiac tamponade, a rare aneurysm.
Patients with PA should receive anticoagulant therapy, given the high
risk of thromboembolism.
In a series of 290 patients with PA, Frances et al. showed that
they all had electrocardiographical abnormalities, usually non-specific
changes in the ST segment, and only 20 % of patients had ST segment
elevation (8).
CONCLUSION
Pseudoaneurysm of the left ventricle is a rare but very severe
heart complication. Due to high risk of rupture, majority of patients are subjected to emergency cardiac intervention. Given that
postoperative mortality is relatively high, they often have significant
comorbidity, and that in some cases non-surgically treated patients
live for years, it is necessary to individually assess whether a patient
should be treated surgically or conservatively.
This paper presents a 82 year old female patient with unoperated PA, who lived 15 years after acute inferolateral MI, probably occurred after an early myocardial rupture. According to the available
data she is the PA diagnosed patient with the longest survival.
Conflict of interest: none declared.
REFERENCES
1. López-Sendón J, Gurfinkel EP, Lopez de Sa E, Agnelli G, Gore JM, Steg PG, et al.
Factors related to heart rupture in acute coronary syndromes in the Global Registry
of Acute Coronary Events. Eur Heart J. 2010;31(12):1449-56.
2. Kostić MB, Tomić M, Boričić N, Nedeljković O, Tasić M, Tomašević M et al. Pseudoanurizma leve komore. Srce i krvni sudovi. 2012;31(1):34-37.
3. Kocatürk H, Karaman A, Bayram E, Ҫolak M. Left Ventricular Pseudoaneurysm: A
Four Year Folow-Up With Medical Therapy. N Engl J Med. 2011;28:59-61.
4. Takx RAP, Fink C, Henzler T. Incidental left ventricular pseudoaneurysm discovered
5 years after myocardial infarction. OMICS J Radiology. 2013;2(5).
5. Moreno R, Gardillo E, Zamorano J, Almeria C, Garcia-Rubira JC, Fernandez-Ortiz
A, et al. Long term outcame of patients with postinafarction left ventricular pseudoanurism. Heart. 2003;89(10):1144-6.
6. Mao CT, Li MF, Kao YC, Cherng WJ, Hung MJ. Long-term survival of a patient with
asymptomatic left ventricular pseudoaneurysm after acute myocardial infarction. J
Inter Med Taiwan. 2012;23:442-48.
7. Letonja M, Letonja MS. With computed tomography confirmed anterolateral left
ventricular pseudoaneurysm in patient with dilatative alcoholic cardiomyopathi. Radiol Oncol. 2011;45(3):180-3.
8. Frances C, Romero A, Grady D . Left ventricular pseudoaneurysm. J Am Coll Cardiol. 1998;32(3):557-61.
9. Patra S, Dhadake SD, Agrawal N, Manjunath CN. Giant left ventricular pseudoaneurysm folowing acute inferior wall myocardial infarction presenting with acute left
ventricular failure: a rare complication. BMJ Case Rep. 2013.
Reprint requests and correspondence:
Zlatko Šantić, MD, PhD P
Polyclinic “ Sunce “
Obilazna cesta 6
88220 Široki Brijeg
Bosnia and Herzegowina
Phone and Fax: + 387 39 705 767
Email: [email protected]
Instructions to authors
73
INSTRUCTIONS TO AUTHORS
Journal “Medical Journal” publishes original research articles, professional, review and educative articles, case reports, criticism, reports,
and Bosnian/Croatian/Serbian language.
Authors take responsibility for all the statements and attitudes in their articles. If article was written by several authors, it is necessary to
provide full contact details (telephone numbers and email addresses) of the corresponding author for the cooperation during preparation
of the text to be published.
Authors should indicate whether the procedures carried out on humans were in accordance with the ethical standards of medical deontology and Declaration of Helsinki.
Articles that contain results of animal studies will only be accepted for publication if it is made clear that ethics standard were applied.
Measurements should be expressed in units, according to the rules of the SI System.
Manuscript submission should be sent to Editorial Board and addressed to:
“MEDICINSKI ŽURNAL”
Institut za naučnoistraživački rad i razvoj Kliničkog centra Univerziteta u Sarajevu
Bolnička 25
71000 Sarajevo
Bosna i Hercegovina
e-mail: [email protected]; [email protected]
COVER LETTER
Apart from the manuscript, the authors should enclose a cover letter, with the signed statements of all authors, to the Editorial Board of
“Medical Journal” stating that:
1.
the work has not been published or accepted for publication previously in another journal,
2.
the work is in accordance with the ethical committee standards,
3.
the work, accepted for publication, becomes ownership of “Medical Journal”.
PREPARATION OF MANUSCRIPT
disk (Word Windows), or e-mail.
Spacing: 1,5: left margin: 2,5 cm; right margin: 2,5 cm; top and bottom margin: 2,5 cm.
program in which they are prepared. Articles are written in-extenso in English.
The manuscript should be submitted on a good quality CD disc, or by e-mail, together with two printed copies (if it is possible). Sent CD
disks will not be returned to the authors.
ARTICLE CONTAINS:
TITLE OF THE ARTICLE IN ENGLISH LANGUAGE
TITLE OF THE ARTICLE IN BOSNIAN/SERBIAN/CROATIAN (B/S/C) LANGUAGE
First name and last name of author and co-authors
Name and address of institution in which author/co-authors are employed (same for all authors) in B/S/C and English language as well
as the address of corresponding author at the end of the paper.
Summary in B/S/C language with the precise translation in English. Abstract of approximately 200-250 words should concisely describe
the contents of the article.
Key words
ARTICLE BODY
The main body of the article should be systematically ordered under the following headings:
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
74
-
CONCLUSION
REFERENCES
INTRODUCTION
Introduction is a concise, short part of the article, and it contains purpose of the article relating to other published articles with the same
topic. It is necessary to quote the main problem, aim of investigation, and/or main hypothesis which is investigated.
MATERIALS AND METHODS
protocol and type of clinical investigation, place and period of investigation. Main characteristics of investigation should be described (randomization, double-blind test, cross test, placebo test), standard values for tests, time framework (prospective, retrospective study), selection
and number of patients – criteria for inclusion and exclusion from the study.
RESULTS
and directly incorporated in the text, at the exact place, with ordinal number and concise heading. Table should have at least two columns
DISCUSSION
Discussion is concise and refers to own results, in comparison with the other authors’ results. Citation of references should follow Vancou-
CONCLUSION
Conclusion should be concise and should contain most important facts, which were obtained during investigation and its eventual clinical
REFERENCES – Instructions for writing references
References should follow the format of the requirements of Vancouver rules.
number in parenthesis at the end of the sentence according to the order of entering. Every further referring to the same reference, number
numbers in the order of entering in the text (entering reference number). Journal’s title is abbreviated using Index Medicus abbreviations.
It is very important to properly design references according to instructions that may be downloaded from addresses National Library of
Medicine Citing Medicine http://www.ncbi.nlm.nih.gov/books/bv.fcg?rid=citmed.TOC&depth=2,
or International Committee of Medical Journal Editors Uniform Requirements for Manuscripts Submitted to Biomedical Journals:
Sample References http://www.nlm.nih.gov/bsd/uniform_requirements.html.
Instructions to authors
75
UPUTSTVA AUTORIMA
Časopis “Medicinski žurnal” objavljuje originalne naučne radove, stručne, pregledne i edukativne, prikaze slučajeva, recenzije, saopćenja,
stručne obavijesti i drugo iz područja svih medicinskih disciplina. Rad in-extenso (cjelokupan) piše se na engleskom jeziku, uz sažetak i naslov
rada koji uz engleski trebaju biti napisani i na našim jezicima (bosanski, hrvatski i srpski). Autori su odgovorni za sve navode i stavove u njihovim radovima. Ukoliko je rad pisalo više autora, potrebno je navesti tačnu adresu (uz telefonski broj i e-mail adresu) onog autora s kojim
će uredništvo sarađivati pri uređenju teksta za objavljivanje.
Ukoliko su u radu prikazana istraživanja na ljudima, mora se navesti da su provedena u skladu s načelima medicinske deontologije i Deklaracije
iz Helsinkija.
Ukoliko su u radu prikazana istraživanja na životinjama, mora se navesti da su provedena u skladu s etičkim načelima. Prilikom navođenja
mjernih jedinica, treba poštovati pravila navedena u SI sistemu.
Radovi se šalju Redakciji na adresu:
“MEDICINSKI ŽURNAL”
Institut za naučnoistraživački rad i razvoj Kliničkog centra Univerziteta u Sarajevu
Bolnička 25
71000 Sarajevo
Bosna i Hercegovina
e-mail: [email protected]; [email protected]
POPRATNO PISMO
Uz svoj rad, autori su dužni Redakciji “Medicinskog žurnala” dostaviti popratno pismo, koje sadržava vlastoručno potpisanu izjavu svih autora:
1.
da navedeni rad nije objavljen ili primljen za objavljivanje u nekom drugom časopisu,
2.
da je istraživanje odobrila Etička komisija,
3.
da prihvaćeni rad postaje vlasništvo “Medicinskog žurnala”.
OPSEG I OBLIK RUKOPISA
Windows), ili e-mail.
Prored: 1,5: lijeva margina: 2,5 cm; desna margina: 2,5 cm; gornja i donja margina: 2,5 cm.
obavezno napisati na engleskom jeziku, a sažetak i naslov još i na našem jeziku.
Rad se dostavlja na CD-u, i/ili e-mailom, uz dva štampana primjerka (ako je moguće). CD se ne vraća.
RAD SADRŽI:
NASLOV RADA NA ENGLESKOM JEZIKU
NASLOV RADA NA NAŠEM JEZIKU
Ime i prezime autora i koautora
Naziv i puna adresa institucije u kojoj je autor-koautor/i zaposlen/i (jednako za sve autore), na engleskom jeziku, te na kraju rada navedena
adresa kontakt-autora.
Sažetak na našem jeziku, kao i na engleskom - max. 200–250 riječi, s najznačajnijim činjenicama i podatcima iz kojih se može dobiti uvid u
kompletan rad.
Ključne riječi - Key words, na našem jeziku i na engleskom, ukupno do pet riječi, navode se ispod Sažetka, odnosno Abstracta.
SADRŽAJ
Sadržaj rada mora biti sistematično i strukturno pripremljen i podijeljen u poglavlja i to:
UVOD
MATERIJAL I METODE
REZULTATI
DISKUSIJA
ZAKLJUČAK
LITERATURA
76
UVOD
Uvod je kratak, koncizan dio rada i u njemu se navodi svrha rada u odnosu na druge objavljene radove sa istom tematikom. Potrebno je
navesti glavni problem, cilj istraživanja i/ili glavnu hipotezu koja se provjerava.
MATERIJAL I METODE
literaturi. U kliničko-epidemiološkim studijama opisuju se: uzorak, protokol i tip kliničkog istraživanja, mjesto i vrijeme istraživanja. Potrebno je opisati glavne karakteristike istraživanja (npr. randomizacija, dvostruko slijepi pokus, unakrsno testiranje, testiranje s placebom itd.),
standardne vrijednosti za testove, vremenski odnos (prospektivna, retrospektivna studija), izbor i broj ispitanika – kriterije za uključivanje i
isključivanje u istraživanje.
REZULTATI
ose u tekst gdje im je mjesto, s rednim brojem i konciznim naslovom.Tabela treba imati najmanje dva stupca s obrazloženjem što prikazuje;
DISKUSIJA
Piše se koncizno i odnosi se prvenstveno na vlastite rezultate, a potom se nastavlja upoređivanje vlastitih rezultata s rezultatima drugih
autora, pri čemu se citiranje literature navodi po važećim Vankuverskim pravilima. Diskusija se završava potvrdom zadatog cilja ili hipoteze,
odnosno njihovim negiranjem.
ZAKLJUČAK
Treba da bude kratak, da sadrži najbitnije činjenice do kojih se došlo u radu tokom istraživanja i njihovu eventualnu kliničku primjenu, kao i
LITERATURA - Upute za citiranje - pisanje literature
Literatura se obavezno citira po Vankuverskim pravilima.
Svaku tvrdnju, saznanje ili misao treba potvrditi referencom. Reference u tekstu treba označiti po redoslijedu unošenja arapskim brojevima
u zagradi na kraju rečenice. Ukoliko se kasnije u tekstu pozivamo na istu referencu, navodimo broj koji je referenca dobila prilikom prvog
unošenja/pominjanja u tekstu. Literatura se popisuje na kraju rada, rednim brojevima pod kojim su reference unesene u tekst (ulazni broj
reference), a naslov časopisa se skraćuje po pravilima koje određuje Index Medicus. Ukoliko je citirani rad napisalo više autora, navodi se
prvih šest i doda “et al.”.
Vrlo je važno ispravno oblikovati reference prema uputama koje se mogu preuzeti na adresama National Library of Medicine Citing Medicine http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=citmed.TOC&depth=2 , ili International Committee of Medical Journal Editors Uniform
Requirements for Manuscripts Submitted to Biomedical Journals:
Sample References http://www.nlm.nih.gov/bsd/uniform_requirements.html.
Prijedlog mreže Primarne Perkutane Koronarne Intervencije
za Bosnu i Hercegovinu!
Prijedlog mreže Primarne Perkutane Koronarne Intervencije
za Federaciju Bosne i Hercegovine!