TRAUMA 2016 / 2 by KAREPUBLISHING

ISSN 1306 - 696X

TURKISH JOURNAL of TRAUMA & EMERGENCY SURGERY Ulusal Travma ve Acil Cerrahi Dergisi

Volume 22 | Number 2 | March 2016

www.tjtes.org

TURKISH JOURNAL of TRAUMA & EMERGENCY SURGERY Ulusal Travma ve Acil Cerrahi Dergisi Editor-in-Chief Recep Güloğlu Editors Kaya Sarıbeyoğlu (Managing Editor) M. Mahir Özmen Hakan Yanar Former Editors Ömer Türel, Cemalettin Ertekin, Korhan Taviloğlu Section Editors Anaesthesiology & ICU Güniz Meyancı Köksal, Mert Şentürk Cardiac Surgery Münacettin Ceviz, Murat Güvener Neurosurgery Ahmet Deniz Belen, Mehmet Yaşar Kaynar Ophtalmology Cem Mocan, Halil Ateş Ortopedics and Traumatology Mahmut Nedim Doral, Mehmet Can Ünlü Plastic and Reconstructive Surgery Ufuk Emekli, Figen Özgür Pediatric Surgery Aydın Yagmurlu, Ebru Yeşildağ Thoracic Surgery Alper Toker, Akif Turna Urology Ali Atan, Öner Şanlı Vascular Surgery Cüneyt Köksoy, Mehmet Kurtoğlu

www.tjtes.org

THE TURKISH ASSOCIATION OF TRAUMA AND EMERGENCY SURGERY ULUSAL TRAVMA VE ACİL CERRAHİ DERNEĞİ President (Başkan) Vice President (2. Başkan) Secretary General (Genel Sekreter) Treasurer (Sayman) Members (Yönetim Kurulu Üyeleri)

Kaya Sarıbeyoğlu M. Mahir Özmen Hakan Yanar Ali Fuat Kaan Gök Gürhan Çelik Osman Şimşek Orhan Alimoğlu

CORRESPONDENCE İLETİŞİM Ulusal Travma ve Acil Cerrahi Derneği Şehremini Mah., Köprülü Mehmet Paşa Sok. Dadaşoğlu Apt., No: 25/1, 34104 Şehremini, İstanbul, Turkey

Tel: +90 212 - 588 62 46 Fax (Faks): +90 212 - 586 18 04 e-mail (e-posta): travma@travma.org.tr Web: www.travma.org.tr

ISSUED BY THE TURKISH ASSOCIATION OF TRAUMA AND EMERGENCY SURGERY ULUSAL TRAVMA VE ACİL CERRAHİ DERNEĞİ YAYIN ORGANI Owner (Ulusal Travma ve Acil Cerrahi Derneği adına Sahibi) Editorial Director (Yazı İşleri Müdürü) Managing Editor (Yayın Koordinatörü) Amblem Correspondence address (Yazışma adresi) Tel Fax (Faks)

Kaya Sarıbeyoğlu Kaya Sarıbeyoğlu M. Mahir Özmen Metin Ertem Ulusal Travma ve Acil Cerrahi Dergisi Sekreterliği Şehremini Mah., Köprülü Mehmet Paşa Sok., Dadaşoğlu Apt., No: 25/1, 34104 Şehremini, İstanbul +90 212 - 531 12 46 - 588 62 46 +90 212 - 586 18 04

p-ISSN 1306-696x • e-ISSN 1307-7945 • Included in Index Medicus, Medline; EMBASE, Excerpta Medica; Science Citation Index-Expanded (SCI-E), Index Copernicus, DOAJ, EBSCO, and Turkish Medical Index (Index Medicus, Medline; EMBASE, Excerpta Medica; Science Citation Index-Expanded (SCI-E), Index Copernicus, DOAJ, EBSCO ve TÜBİTAK ULAKBİM Türk Tıp Dizini’nde yer almaktadır.) Publisher (Yayımcı): KARE Yayıncılık (KARE Publishing) • www.kareyayincilik.com • Design (Tasarım): Ali Cangül • Graphics (Grafikler): Edibe Çomaktekin • Linguistic Editor (İngilizce Editörü): Merve Şenol • Redaction (Redaksiyon): Erman Aytaç • Online Manuscript & Web Management (Online Dergi & Web): LookUs • Press (Baskı): Yıldırım Matbaacılık • Press date (Basım tarihi): March (Mart) 2016 • This publication is printed on paper that meets the international standard ISO 9706: 1994 (Bu dergide kullanılan kağıt ISO 9706: 1994 standardına uygundur.)

KARE www.tjtes.org

INFORMATION FOR THE AUTHORS The Turkish Journal of Trauma and Emergency Surgery (TJTES) is an official publication of the Turkish Association of Trauma and Emergency Surgery. It is a peer-reviewed periodical that considers for publication clinical and experimental studies, case reports, technical contributions, and letters to the editor. Six issues are published annually.

tion, called “Upload Your Files”.

As from 2001, the journal is indexed in Index Medicus and Medline, as from 2005 in Excerpta Medica and EMBASE, as from 2007 in Science Citation Index Expanded (SCI-E) and Journal Citation Reports / Science Edition, and as from 2008 in Index Copernicus. For the five-year term of 2001-2006, our impact factor in SCI-E indexed journals is 0.5. It is cited as ‘Ulus Travma Acil Cerrahi Derg’ in PUBMED.

Figures, illustrations and tables: All figures and tables should be numbered in the order of appearance in the text. The desired position of figures and tables should be indicated in the text. Legends should be included in the relevant part of the main text and those for photomicrographs and slide preparations should indicate the magnification and the stain used. Color pictures and figures will be published if they are definitely required and with the understanding that the authors are prepared to bear the costs. Line drawings should be professionally prepared. For recognizable photographs, signed releases of the patient or of his/her legal representatives should be enclosed; otherwise, patient names or eyes must be blocked out to prevent identification.

Submission of a manuscript by electronic means implies: that the work has not been published before (except in the form of an abstract or as part of a published lecture, review, or thesis); that it is not under consideration for publication elsewhere; and that its publication in the Turkish Journal of Trauma and Emergency Surgery is approved by all co-authors. The author(s) transfer(s) the copyright to the Turkish Association of Trauma and Emergency Surgery to be effective if and when the manuscript is accepted for publication. The author(s) guarantee(s) that the manuscript will not be published elsewhere in any other language without the consent of the Association. If the manuscript has been presented at a meeting, this should be stated together with the name of the meeting, date, and the place. Manuscripts may be submitted in Turkish or in English. All submissions are initially reviewed by the editor, and then are sent to reviewers. All manuscripts are subject to editing and, if necessary, will be returned to the authors for answered responses to outstanding questions or for addition of any missing information to be added. For accuracy and clarity, a detailed manuscript editing is undertaken for all manuscripts accepted for publication. Final galley proofs are sent to the authors for approval. Unless specifically indicated otherwise at the time of submission, rejected manuscripts will not be returned to the authors, including accompanying materials. TJTES is indexed in Science Citation Index-Expanded (SCI-E), Index Medicus, Medline, EMBASE, Excerpta Medica, and the Turkish Medical Index of TUBITAK-ULAKBIM. Priority of publications is given to original studies; therefore, selection criteria are more refined for reviews and case reports. Open Access Policy: Full text access is free. There is no charge for publication or downloading the full text of printed material. Manuscript submission: TJTES accepts only on-line submission via the official web site (please click, www.travma.org.tr/en) and refuses printed manuscript submissions by mail. All submissions are made by the on-line submission system called Journal Agent, by clicking the icon “Online manuscript submission” at the above mentioned web site homepage. The system includes directions at each step but for further information you may visit the web site (http://www.travma.org/en/ journal/). Manuscript preparation: Manuscripts should have double-line spacing, leaving sufficient margin on both sides. The font size (12 points) and style (Times New Roman) of the main text should be uniformly taken into account. All pages of the main text should be numbered consecutively. Cover letter, manuscript title, author names and institutions and correspondence address, abstract in Turkish (for Turkish authors only), and title and abstract in English are uploaded to the Journal Agent system in the relevant steps. The main text includes Introduction, Materials and Methods, Results, Discussion, Acknowledgments, References, Tables and Figure Legends. The cover letter must contain a brief statement that the manuscript has been read and approved by all authors, that it has not been submitted to, or is not under consideration for publication in, another journal. It should contain the names and signatures of all authors. The cover letter is uploaded at the 10th step of the “Submit New Manuscript” sec-

Abstract: The abstract should be structured and serve as an informative guide for the methods and results sections of the study. It must be prepared with the following subtitles: Background, Methods, Results and Conclusions. Abstracts should not exceed 200 words.

References: All references should be numbered in the order of mention in the text. All reference figures in the text should be given in brackets without changing the font size. References should only include articles that have been published or accepted for publication. Reference format should conform to the “Uniform requirements for manuscripts submitted to biomedical journals” (http://www.icmje.org) and its updated versions (February 2006). Journal titles should be abbreviated according to Index Medicus. Journal references should provide inclusive page numbers. All authors, if six or fewer, should be listed; otherwise the first six should be listed, followed by “et al.” should be written. The style and punctuation of the references should follow the formats below: Journal article: Velmahos GC, Kamel E, Chan LS, Hanpeter D, Asensio JA, Murray JA, et al. Complex repair for the management of duodenal injuries. Am Surg 1999;65:972-5. Chapter in book: Jurkovich GJ. Duodenum and pancreas. In: Mattox KL, Feliciano DV, Moore EE, editors. Trauma. 4th ed. New York: McGraw-Hill; 2000. p. 735-62. Our journal has succeeded in being included in several indexes, in this context, we have included a search engine in our web site (www. travma.org.tr) so that you can access full-text articles of the previous issues and cite the published articles in your studies. Review articles: Only reviews written by distinguished authors based on the editor’s invitation will be considered and evaluated. Review articles must include the title, summary, text, and references sections. Any accompanying tables, graphics, and figures should be prepared as mentioned above. Case reports: A limited number of case reports are published in each issue of the journal. The presented case(s) should be educative and of interest to the readers, and should reflect an exclusive rarity. Case reports should contain the title, summary, and the case, discussion, and references sections. These reports may consist of maximum five authors. Letters to the Editor: “Letters to the Editor” are only published electronically and they do not appear in the printed version of TJTES and PUBMED. The editors do not issue an acceptance document as an original article for the ‘’letters to the editor. The letters should not exceed 500 words. The letter must clearly list the title, authors, publication date, issue number, and inclusive page numbers of the publication for which opinions are released. Informed consent - Ethics: Manuscripts reporting the results of experimental studies on human subjects must include a statement that informed consent was obtained after the nature of the procedure(s) had been fully explained. Manuscripts describing investigations in animals must clearly indicate the steps taken to eliminate pain and suffering. Authors are advised to comply with internationally accepted guidelines, stating such compliance in their manuscripts and to include the approval by the local institutional human research committee.

YAZARLARA BİLGİ Ulusal Travma ve Acil Cerrahi Dergisi, Ulusal Travma ve Acil Cerrahi Derneği’nin yayın organıdır. Travma ve acil cerrahi hastalıklar konularında bilimsel birikime katkısı olan klinik ve deneysel çalışmaları, editöryel yazıları, klinik olgu sunumlarını ve bu konulardaki teknik katkılar ile son gelişmeleri yayınlar. Dergi iki ayda bir yayınlanır. Ulusal Travma ve Acil Cerrahi Dergisi, 2001 yılından itibaren Index Medicus ve Medline’da, 2005 yılından itibaren Excerpta Medica / EMBASE indekslerinde, 2007 yılından itibaren Science Citation Index-Expanded (SCI-E) ile Journal Citation Reports / Science Edition uluslararası indekslerinde ve 2008 yılından itibaren Index Copernicus indeksinde yer almaktadır. 2001-2006 yılları arasındaki 5 yıllık dönemde SCI-E kapsamındaki dergilerdeki İmpakt faktörümüz 0,5 olmuştur. Dergide araştırma yazılarına öncelik verilmekte, bu nedenle derleme veya olgu sunumu türündeki yazılarda seçim ölçütleri daha dar tutulmaktadır. PUBMED’de dergi “Ulus Travma Acil Cerrahi Derg” kısaltması ile yer almaktadır. Dergiye yazı teslimi, çalışmanın daha önce yayınlanmadığı (özet ya da bir sunu, inceleme, ya da tezin bir parçası şeklinde yayınlanması dışında), başka bir yerde yayınlanmasının düşünülmediği ve Ulusal Travma ve Acil Cerrahi Dergisi’nde yayınlanmasının tüm yazarlar tarafından uygun bulunduğu anlamına gelmektedir. Yazar(lar), çalışmanın yayınlanmasının kabulünden başlayarak, yazıya ait her hakkı Ulusal Travma ve Acil Cerrahi Derneği’ne devretmektedir(ler). Yazar(lar), izin almaksızın çalışmayı başka bir dilde ya da yerde yayınlamayacaklarını kabul eder(ler). Gönderilen yazı daha önce herhangi bir toplantıda sunulmuş ise, toplantı adı, tarihi ve düzenlendiği şehir belirtilmelidir. Dergide Türkçe ve İngilizce yazılmış makaleler yayınlanabilir. Tüm yazılar önce editör tarafından ön değerlendirmeye alınır; daha sonra incelenmesi için danışma kurulu üyelerine gönderilir. Tüm yazılarda editöryel değerlendirme ve düzeltmeye başvurulur; gerektiğinde, yazarlardan bazı soruları yanıtlanması ve eksikleri tamamlanması istenebilir. Dergide yayınlanmasına karar verilen yazılar “manuscript editing” sürecine alınır; bu aşamada tüm bilgilerin doğruluğu için ayrıntılı kontrol ve denetimden geçirilir; yayın öncesi şekline getirilerek yazarların kontrolüne ve onayına sunulur. Editörün, kabul edilmeyen yazıların bütününü ya da bir bölümünü (tablo, resim, vs.) iade etme zorunluluğu yoktur. Açık Erişim İlkesi: Tam metinlere erişim ücretsizdir. Yayınlanan basılı materyali tam metni indirmek için herhangi bir ücret alınmaz. Yazıların hazırlanması: Tüm yazılı metinler 12 punto büyüklükte “Times New Roman” yazı karakterinde iki satır aralıklı olarak yazılmalıdır. Sayfada her iki tarafta uygun miktarda boşluk bırakılmalı ve ana metindeki sayfalar numaralandırılmalıdır. Journal Agent sisteminde, başvuru mektubu, başlık, yazarlar ve kurumları, iletişim adresi, Türkçe özet ve yazının İngilizce başlığı ve özeti ilgili aşamalarda yüklenecektir. İngilizce yazılan çalışmalara da Türkçe özet eklenmesi gerekmektedir. Yazının ana metnindeyse şu sıra kullanılacaktır: Giriş, Gereç ve Yöntem, Bulgular, Tartışma, Teşekkür, Kaynaklar, Tablolar ve Şekiller. Başvuru mektubu: Bu mektupta yazının tüm yazarlar tarafından okunduğu, onaylandığı ve orijinal bir çalışma ürünü olduğu ifade edilmeli ve yazar isimlerinin yanında imzaları bulunmalıdır. Başvuru mektubu ayrı bir dosya olarak, Journal Agent sisteminin “Yeni Makale Gönder” bölümünde, 10. aşamada yer alan dosya yükleme aşamasında yollanmalıdır. Başlık sayfası: Yazının başlığı, yazarların adı, soyadı ve ünvanları, çalışmanın yapıldığı kurumun adı ve şehri, eğer varsa çalışmayı destekleyen fon ve kuruluşların açık adları bu sayfada yer almalıdır. Bu sayfaya ayrıca “yazışmadan sorumlu” yazarın isim, açık adres, telefon, faks, mobil telefon ve e-posta bilgileri eklenmelidir. Özet: Çalışmanın gereç ve yöntemini ve bulgularını tanıtıcı olmalıdır. Türkçe özet, Amaç, Gereç ve Yöntem, Bulgular, Sonuç ve Anahtar Sözcükler başlıklarını; İngilizce özet Background, Methods, Results, Conclusion ve Key words başlıklarını içermelidir. İngilizce olarak hazırlanan çalışmalarda da Türkçe özet yer almalıdır. Özetler başlıklar hariç 190210 sözcük olmalıdır. Tablo, şekil, grafik ve resimler: Şekillere ait numara ve açıklayıcı bilgiler ana metinde ilgili bölüme yazılmalıdır. Mikroskobik şekillerde resmi açıklayıcı bilgilere ek olarak, büyütme oranı ve kullanılan boyama tekniği de belirtilmelidir. Yazarlara ait olmayan, başka kaynaklarca daha önce yayınlanmış tüm resim, şekil ve tablolar için yayın hakkına sahip kişiler-

den izin alınmalı ve izin belgesi dergi editörlüğüne ayrıca açıklamasıyla birlikte gönderilmelidir. Hastaların görüntülendiği fotoğraflara, hastanın ve/veya velisinin imzaladığı bir izin belgesi eşlik etmeli veya fotoğrafta hastanın yüzü tanınmayacak şekilde kapatılmış olmalıdır. Renkli resim ve şekillerin basımı için karar hakemler ve editöre aittir. Yazarlar renkli baskının hazırlık aşamasındaki tutarını ödemeyi kabul etmelidirler. Kaynaklar: Metin içindeki kullanım sırasına göre düzenlenmelidir. Makale içinde geçen kaynak numaraları köşeli parantezle ve küçültülmeden belirtilmelidir. Kaynak listesinde yalnızca yayınlanmış ya da yayınlanması kabul edilmiş çalışmalar yer almalıdır. Kaynak bildirme “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” (http:// www.icmje.org) adlı kılavuzun en son güncellenmiş şekline (Şubat 2006) uymalıdır. Dergi adları Index Medicus’a uygun şekilde kısaltılmalıdır. Altı ya da daha az sayıda olduğunda tüm yazar adları verilmeli, daha çok yazar durumunda altıncı yazarın arkasından “et al.” ya da “ve ark.” eklenmelidir. Kaynakların dizilme şekli ve noktalamalar aşağıdaki örneklere uygun olmalıdır: Dergi metni için örnek: Velmahos GC, Kamel E, Chan LS, Hanpeter D, Asensio JA, Murray JA, et al. Complex repair for the management of duodenal injuries. Am Surg 1999;65:972-5. Kitaptan bölüm için örnek: Jurkovich GJ. Duodenum and pancreas. In: Mattox KL, Feliciano DV, Moore EE, editors. Trauma. 4th ed. New York: McGraw-Hill; 2000. p. 735-62. Sizlerin çalışmalarınızda kaynak olarak yararlanabilmeniz için www.travma.org.tr adresli web sayfamızda eski yayınlara tam metin olarak ulaşabileceğiniz bir arama motoru vardır. Derleme yazıları: Bu tür makaleler editörler kurulu tarafından gerek olduğunda, konu hakkında birikimi olan ve bu birikimi literatüre de yansımış kişilerden talep edilecek ve dergi yazım kurallarına uygunluğu saptandıktan sonra değerlendirmeye alınacaktır. Derleme makaleleri; başlık, Türkçe özet, İngilizce başlık ve özet, alt başlıklarla bölümlendirilmiş metin ile kaynakları içermelidir. Tablo, şekil, grafik veya resim varsa yukarıda belirtildiği şekilde gönderilmelidir. Olgu sunumları: Derginin her sayısında sınırlı sayıda olgu sunumuna yer verilmektedir. Olgu bildirilerinin kabulünde, az görülürlük, eğitici olma, ilginç olma önemli ölçüt değerlerdir. Ayrıca bu tür yazıların olabildiğince kısa hazırlanması gerekir. Olgu sunumları başlık, Türkçe özet, İngilizce başlık ve özet, olgu sunumu, tartışma ve kaynaklar bölümlerinden oluşmalıdır. Bu tür çalışmalarda en fazla 5 yazara yer verilmesine özen gösterilmelidir. Editöre mektuplar: Editöre mektuplar basılı dergide ve PUBMED’de yer almamakta, ancak derginin web sitesinde yayınlanmaktadır. Bu mektuplar için dergi yönetimi tarafından yayın belgesi verilmemektedir. Daha önce basılmış yazılarla ilgili görüş, katkı, eleştiriler ya da farklı bir konu üzerindeki deneyim ve düşünceler için editöre mektup yazılabilir. Bu tür yazılar 500 sözcüğü geçmemeli ve tıbbi etik kurallara uygun olarak kaleme alınmış olmalıdır. Mektup basılmış bir yazı hakkında ise, söz konusu yayına ait yıl, sayı, sayfa numaraları, yazı başlığı ve yazarların adları belirtilmelidir. Mektup bir konuda deneyim, düşünce hakkında ise verilen bilgiler doğrultusunda dergi kurallarına uyumlu olarak kaynaklar da belirtilmelidir. Bilgilendirerek onay alma - Etik: Deneysel çalışmaların sonuçlarını bildiren yazılarda, çalışmanın yapıldığı gönüllü ya da hastalara uygulanacak prosedür(lerin) özelliği tümüyle anlatıldıktan sonra, onaylarının alındığını gösterir bir cümle bulunmalıdır. Yazarlar, bu tür bir çalışma söz konusu olduğunda, uluslararası alanda kabul edilen kılavuzlara ve T.C. Sağlık Bakanlığı tarafından getirilen yönetmelik ve yazılarda belirtilen hükümlere uyulduğunu belirtmeli ve kurumdan aldıkları Etik Komitesi onayını göndermelidir. Hayvanlar üzerinde yapılan çalışmalarda ağrı, acı ve rahatsızlık verilmemesi için neler yapıldığı açık bir şekilde belirtilmelidir. Yazı gönderme - Yazıların gönderilmesi: Ulusal Travma ve Acil Cerrahi Dergisi yalnızca www.travma.org.tr adresindeki internet sitesinden on-line olarak gönderilen yazıları kabul etmekte, posta yoluyla yollanan yazıları değerlendirmeye almamaktadır. Tüm yazılar ilgili adresteki “Online Makale Gönderme” ikonuna tıklandığında ulaşılan Journal Agent sisteminden yollanmaktadır. Sistem her aşamada kullanıcıyı bilgilendiren özelliktedir.

TURKISH JOURNAL OF TRAUMA & EMERGENCY SURGERY ULUSAL TRAVMA VE ACİL CERRAHİ DERGİSİ Vol. - Cilt 22

Number - Sayı 2 March - Mart 2016

Contents - İçindekiler Deneysel Çalışma - Experimental Experimental Studies - DeneyselStudy Çalışma 115-120 Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis Alkalen fosfataz bağırsak izomeraz enziminin akut mezenterik iskemi tanısındaki rolü Lapsekili E, Menteş Ö, Balkan M, Günal A, Yaman H, Kozak O, Peker Y 121-126 Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury Sepsis nedenli akut böbrek hasarında agomelatinin etkilerinin değerlendirilmesi Başol N, Erbaş O, Çavuşoğlu T, Meral A, Ateş U 127-133 Effects of different recruitment maneuvers on bacterial translocation and ventilator-induced lung injury Farklı yeniden kazandırma manevralarının bakteri translokasyonu ve ventilatör ilişkili akciğer hasarına etkisi Ergin Özcan P, Akıncı Öİ, Edipoğlu İ, Şentürk E, Baylan S, Cağatay AA, Türköz KH, Esen F, Telci L, Çakar N 134-138 Neuroprotective effects of adalimumab on rats with experimental peripheral nerve injury: An electron microscopic and biochemical study Deneysel periferik sinir hasarı yapılan sıçanlarda adalimumabın nöroprotektif etkileri: Elektron mikroskobik ve biyokimyasal bir çalışma Polat E, Dağlıoğlu E, Menekşe G, Dike MS, Özdöl Ç, Türk CÇ, Yıldırım AE, Alagöz F, Dalgıç A, Belen D

Original Articles - Orijinal Çalışma 139-144 Is every intussusception treatment an emergency intervention or surgery? Her intususepsiyon tedavisi acil girişim veya cerrahi midir? Güney LH, Fakıoğlu E, Acer T, Ötgün İ, Arslan EE, Sağnak Akıllı M, Hiçsönmez A 145-149 Work-related injuries sustained by emergency medical technicians and paramedics in Turkey Türkiye’de acil tıp teknisyenleri ve paramediklerin karşılaştıkları iş kazaları Gülen B, Serinken M, Hatipoğlu C, Özaşır D, Sönmez E, Kaya G, Akpınar G 150-154 Can outcome of pancreatic pseudocysts be predicted? Proposal for a new scoring system Pankreatik psödokistin sonuçları tahmin edilebilir mi? Yeni bir skorlama sistemi önerisi Şenol K, Akgül Ö, Gündoğdu SB, Aydoğan İ, Tez M, Çoşkun F, Tihan DN 155-162 Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis: An analysis of 3392 cases Basit ve perfore apandisitlerde temel laboratuvar testlerinin tanısal değeri: 3392 olgu analizi Sevinç MM, Kınacı E, Çakar E, Bayrak S, Özakay A, Aren A, Sarı S 163-168 Neutrophil-lymphocyte ratio and mean platelet volume can be a predictor for severity of acute appendicitis Nötrofil-lenfosit oranı ve ortalama trombosit hacminin akut apandisitin şiddetini belirlemedeki rolü Yardımcı S, Uğurlu MÜ, Coşkun M, Attaallah W, Yeğen ŞC 169-174 High velocity missile-related colorectal injuries: In-theatre application of injury scores and their effects on ostomy rates Yüksek kinetik enerjili parça tesirine bağlı kolorektal yaralanmalar: Cerrahi esnasında skorlama sistemlerinin uygulanması ve ostomi oranları üzerine etkisi Kaymak Ş, Ünlü A, Harlak A, Ersöz N, Şenocak R, Coşkun AK, Zeybek N, Lapsekili E, Kozak O Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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TURKISH JOURNAL OF TRAUMA & EMERGENCY SURGERY ULUSAL TRAVMA VE ACİL CERRAHİ DERGİSİ Vol. - Cilt 22

Number - Sayı 2 March - Mart 2016

Contents - İçindekiler

175-183 Views of emergency physicians working in university and state hospitals in Turkey regarding the use of analgesics in patients with acute abdominal pain Türkiye’de üniversite ve eğitim araştırma hastanelerinde çalışan acil tıp hekimlerinin akut karın ağrısında analjezik kullanım sıklığı ve bunu etkileyen faktörler Özen Ö, Kıyan S 184-191 Intramedullary nailing of adult isolated diaphyseal radius fractures Yetişkin izole radius kırıklarında intramedüller çivi tedavisi Köse A, Aydın A, Ezirmik N, Topal M, Can CE, Yılar S

Case Reports - Olgu Sunumu 192-194 Triple gastric peptic ulcer perforation Üçlü gastrik peptik ülser perforasyonu Radojkovic M, Mihajlovic S, Stojanovic M, Stanojevic G, Damnjanovic Z 195-198 Should warm fresh whole blood be the first choice in acute massive hemorrhage in emergency conditions? Sıcak taze tam kan masif kanamalı acil durumlarda ilk seçenek olmalı mıdır? Kendigelen P, Kamalak Z, Abat D 199-201 A case of delayed carotid cavernous fistula after facial gunshot injury presented as loss of vision with symptom resolution after endovascular closure procedure Yüz bölgesine ateşli silah yaralanması sonrası görme kaybı ile başvuran ve endovasküler tedavi sonrası semptomları düzelen gecikmiş karotikokavernöz fistül olgusu Alagöz F, Yılmaz F, Sönmez BM, Yıldırım AE, Karakılıç ME 202-204 A different approach to simultaneously injured ulnar and radial arteries: Translocation of an arterial segment Birlikte yaralanmış ulnar ve radial arter onarımına farklı bir yaklaşım: Arteriyel segment translokasyonu Başbuğ HS, Bitargil M, Özışık K

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EXPERIMENTAL STUDY

Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis Emin Lapsekili, M.D.,1 Öner Menteş, M.D.,1 Müjdat Balkan, M.D.,1 Armağan Günal, M.D.,2 Halil Yaman, M.D.,3 Orhan Kozak, M.D.,1 Yusuf Peker, M.D.1 1

Department of General Surgery, Gülhane Military Medical Academy, Ankara-Turkey

Department of Pathology, Gülhane Military Medical Academy, Ankara-Turkey

Department of Biochemistry,Gülhane Military Medical Academy, Ankara-Turkey

ABSTRACT BACKGROUND: The aim of the present study was to investigate the diagnostic value of alkaline phosphatase (ALP) intestineisomerase, plasma lactate dehydrogenase (LDH), and D-dimer levels in acute mesenteric ischemia. METHODS: Thirty Wistar rats were divided into 5 groups of 6 rats each. In Group 1, blood samples were obtained to determine normal parameter levels. In the sham group, Group 2, blood samples were obtained following laparotomy. In Group 3, blood samples were obtained 2 hours after ligation. In Groups 4 and 5, blood samples were obtained at 4 and 6 hours after ligation, respectively. Ischemic damage was assessed using a pathological scoring system. Blood samples were analyzed for hourly changes in parameters. RESULTS: No statistically significant difference in D-dimer levels was found between ischemia groups (p=0.337). A statistically significant difference in LDH levels was found between the control group, Group 1, and Group 4 (p=0.018). ALP intestine-isomerase enzyme levels were not statistically significant in other groups (p=0.077). CONCLUSION: Findings indicate that plasma LDH levels higher than 1900 IU/L may be a useful marker in the early diagnosis of acute mesenteric obstruction. However, ALP intestine-isomerase enzyme and D-dimer plasma levels were not found to contribute to the diagnosis. Keywords: Acute mesenteric ischemia; ALP intestine-isomerase; D-dimer; LDH.

INTRODUCTION Mesenteric ischemia is a clinical condition involving decreased or totally obstructed flow of blood to the intestines, manifesting as either acute or chronic.[1] Acute mesenteric ischemia (AMI) is seen in 1–2% of all acute abdomen emergencies. However, difficulties in diagnosis may lead to increased mortality.[2] The AMI mortality rate has remained the same for years, in spite of developments Address for correspondence: Emin Lapsekili, M.D. Gülhane Askeri Tıp Akademisi, Genel Cerrahi Anabilim Dalı Harp Cerrahisi Bilim Dalı, Etlik, Ankara, Turkey Tel: +90 312 - 304 17 23 E-mail: lapsekiliemin@yahoo.com Qucik Response Code

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in diagnostic methods.[3] It has been well documented in clinical studies that AMI has a mortality rate of 50–70%.[4] It has been reported in a majority of reviewed studies that the most significant contributing factor to the mortality rate is late diagnosis. AMI is most commonly encountered in the geriatric population. High index of suspicion plays a strong role in quick diagnosis of AMI in patients with abdominal pain and contradictory physical examination findings with clinical symptoms. Another important clue for diagnosis is that 95% of patients with embolism-induced AMI have a history of heart disease.[1] There are radiological alternatives in AMI diagnosis. In addition to radiological instruments, biochemical markers may aid in early diagnosis, including aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), amylase, lactate, potassium, pH, leukocytes and Ddimer.[5] In addition, level of lactate dehydrogenase (LDH) enzyme, converting pyruvate to lactate, is used in diagnosis. While specificity of LDH in diagnosis of intestinal ischemia is known, LDH may also be increased in many other clinical conditions, such as myocardial infarction. 115

Lapsekili et al. Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis

In the present experimental study, the role of alkaline phosphatase (ALP) intestine-isomerase levels in diagnosis of AMI was examined.

MATERIALS AND METHODS The present study was supported by the Research Foundation of the Gülhane Military Medical Academy and was approved by the research and animal ethics committees. Thirty female albino Wistar rats were randomly divided into 5 groups of 6 rats each. In Group 1, blood samples were obtained to determine normal levels of plasma LDH, D-dimer, and ALP intestine-isomerase after anesthesia. Blood samples were obtained from the sham group, Group 2, after laparotomy. In Group 3, blood samples were obtained 2 hours after ligation. In Groups 4 and 5, blood samples were collected at 4 and 6 hours after ligation, respectively. Ischemic damage was graded with pathological scoring system of the dissected jejunum. All blood samples were analyzed hourly for changes in serum LDH, D-dimer, and ALP intestine-isomerase. Induction of anesthesia was performed using 50 mg/kg intramuscular ketamine sodium (Ketalar®; Eczacıbaşı, İstanbul, Turkey) and 25 mg/kg intramuscular ∝ xylazine hydrochloride (Rompun Flk®; Bayer, İstanbul, Turkey). In the 12 hours leading up to surgery, rats consumed only tap water. Superior mesenteric artery ligation was performed with 4/0 polypropylene (Prolene®; Ethicon Inc., Somerville, NJ, USA) at the aforementioned time intervals.

Pathological Examination Removed jejunum samples were dissected at the anti-mesenteric side of the intestine and left for fixation in 10% formaldehyde solution for 12 hours. Following fixation, all jejunum samples were sliced horizontally. After routine pathological tissue follow-up procedures, 5 γm-thick sections prepared from tissue specimens were embedded in paraffin blocks using a microtome. All specimens were stained with hematoxylin-eosin and microscopically examined with 100x magnification to determine ischemic intestinal damage grading using Park’s scoring system (Table 1).[6]

Biochemical Examination Blood samples were collected in routine biochemical tubes, and serum was separated by centrifuge at 4000 rpm for 10 minutes. Tubes were divided into 2 groups, 1 of which was placed in an Olympus AU2700 auto-analysis machine for spectrophotometric LDH measurements. The other was kept in -70°C until all samples were processed, at which time, they were placed in a Sebia machine that utilized agarose gel electrophoresis and ALP intestine-isomerase enzyme levels of all samples were measured. Blood samples kept in citrate tubes were centrifuged at 3000 rpm for 10 minutes to separate serum for D-dimer measure116

Table 1. Park’s pathological scoring system Score Pathology 0 Normal 1

Desquamation on mucosal cells without necrosis

Mucosal villus necrosis with crypts saved

Mucosal villus necrosis with cryptic involvement

Innermost muscular tissue necrosis or thinning of

muscular tissue with mucosal necrosis

Transmural necrosis

ments. Plasma D-dimer levels were determined with immunoturbidimetry on STA Compact® machine with kit (Diagnostica Stago Inc., Parsippany, NJ, USA).

Statistical Analysis Data were analyzed using SPPS software (version 15.0; SPSS Inc., Chicago, IL, USA). Kolmogorov-Smirnov test was used to analyze distribution of variables. LDH and D-dimer variables were found to be normally distributed, and Mann-Whitney U test was applied. Values of ALP intestine-isomerase enzyme were skewed, and Kruskal-Wallis test was used to analyze differences in enzyme levels among ischemic and nonischemic groups. Chi-square test was used to compare pathologic scores of ischemic and nonischemic groups. Receiver operating characteristic (ROC) curve was used to compare efficiency of the 3 enzyme parameters by plotting sensitivity vs 1-specificity for several possible decision levels. All p values of enzyme parameters less than .05 were considered statistically significant.

RESULTS No mortality was observed. Following pathological examination, intestinal ischemia levels were compared with the nonischemic control (Group 1) and sham (Group 2) groups, using chi-square test. Statistically significant differences were found between these groups and the ischemia groups (p=0.001). Distribution of Park’s scores is presented in Figure 1. Grade 1–2 mucosal ischemic properties were found in Group 3 (of 2nd hour ischemia; Fig. 2a, b). Grade 2–3 and 4 ischemic damage were found in ischemic Groups 4 and 5 (Fig. 2c, d). No statistically significant relationship was determined among ischemic Groups 3, 4, and 5, regarding pathological damage (p=0.345). No significant difference was found in D-dimer enzyme levels among ischemic Groups 3, 4, and 5 (p=0.337). Statistically significant difference was found in serum LDH levels of Groups 1 and 4 (p=0.018). No statistically significant difference in ALP intestine-isomerase enzyme level was found among the groups (p=0.077). Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Lapsekili et al. Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis

DISCUSSION

Recently, the most important tool in AMI diagnosis was digital subtraction angiography (DSA), with a sensitivity rate of 88%.[7] However, difficulties in clinical practice and the invasive nature of the DSA procedure are difficult to manage in emergency situations. This procedure is now being replaced by thin-slice computed tomography (CT) and CT-aided angiography. With use of these diagnostic tools, acute abdomen disorders are easier to rule out, and presence of intestinal wall ischemia can also be evaluated.[8]

0 Control

Sham

2. hours

4. hours

6. hours

Figure 1. Distribution of Parkâ&#x20AC;&#x2122;s scores among groups.

As sham and control groups (Groups 1 and 2) were considered nonischemic, and Groups 3, 4, and 5 were considered ischemic, differences in inter-LDH levels were statistically significant (p=0.038). However, differences in D-dimer and ALP intestinal enzyme levels between the ischemic and nonischemic groups were not statistically significant (p=0.161 and p=0.082, respectively). Differences in LDH levels of the nonischemic and ischemic groups were statistically significant, with ROC curves over the 1900 IU/L threshold, resulting in 94% sensitivity and 41% specificity.

Mesenteric ischemia is a condition characterized by inflammation and injury of the small intestine, resulting from inadequate blood supply.[9,10] Many studies point to late diagnosis as the primary cause of mortality. Early diagnosis of AMI is therefore vital in lowering rates of mortality and postoperative morbidity. There is high incidence of AMI in geriatric patients. Differential diagnosis of AMI is very important in patients suffering from acute abdominal pain with contradicting physical examination symptomatology and patient history. AMI resulting from embolism is common in patients with history of heart disease,[1] and Luther et al. reported total mortality rate of 67% with delayed diagnosis and surgical treatment as the primary causes.[10] Abdominal pain with

(a)

(b)

(c)

(d)

Figure 2. (a) Shedding in Parks Score 1, damaged intestinal mucosal cells without necrosis (H-E x100). (b) Intestinal villus damage in Parks Score 2, intestinal damage with saved crypts (H-E x100). (c) Mucosal villus necrosis with cryptic involvement in Parks Score 3, intestinal damage (H-E x100). (d) Parks Score 4, intestinal damage with innermost part of muscular tissue necrosis or thinning in muscular tissue with mucosal necrosis (H-E x100).

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Lapsekili et al. Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis

effects on kidneys could lead to high serum amylase levels responsible for intestinal inflammation. Approximately 50% of patients had metabolic acidosis as late intestinal ischemic finding, while 25% had hyperamylasemia.[16]

ROC Curve 1.0

In an experimental study, Zhang et al. demonstrated that biochemical markers of ALT, AST, ALP, GGT, and LDH rose after 3 hours of ischemic period.[17] Karaağaç et al. showed in an experimental study that IL-1ß, IL-6, and TNF-α levels rose in the 2nd and 4th hour after ischemic period.[18] In an experimental study of mesenteric artery ischemia conducted by Gunduz et al., ischemia-modified albumin was found to be significantly increased at the 2nd and 4th hour after ischemic period, though future research is warranted.[19]

Sensitivity

0.8

0.6

0.4

0.2

0.0

0.2

0.4

0.6

0.8

1.0

1-Specificity

Figure 3. The ROC curve of LDH comparring of ischemic and nonischemic groups to determine AMI diagnosis.

inadequate physical exam findings and previous heart disease history is common in the geriatric population, suggesting that AMI may not always present with unique symptoms. Unfortunately, no gold standard early diagnostic tool is currently available. The present study was designed to examine the previously unstudied role of ALP intestine-isomerase in the early diagnosis of AMI. Radiological findings are more important than laboratory markers in the diagnosis of AMI, and radiological studies now tend toward CT and spiral CT in place of DSA. Kirkpatrick et al.[11] reported diagnostic CT sensitivity of 96% and specificity of 94%, while Taourel et al.[12] reported sensitivity of 95% and specificity of lower than 30%. Meanwhile, a multi-institutional study reported a specificity near 100% with multislice CT, overcoming the 88% specificity rate achieved by the prior gold standard diagnostic tool, DSA.[13,14] The most common biochemical pathologies in AMI patients are hemoconcentration, leukocytosis, and high anion-gap metabolic acidosis. In previous initial biochemical assessments of serum amylase, aspartate aminotransferase, LDH, and creatine phosphokinase, levels had not reached sensitivity and specificity rates sufficient to aid in diagnosis of AMI. Hyperphosphatemia and hyperkalemia are late findings, usually accompanying intestinal necrosis.[15] Hypovolemia and its

In an experimental study conducted by Uncu et al., ALT, AST, ALP, LDH, creatine kinase, and phosphorus levels rose in the first hour after the ischemic period, but none of those parameters were sufficiently specific for diagnosis of AMI.[20] In an experimental study conducted by Gönüllü et al., peritoneal lavage fluid samples of arterial occlusion were analyzed for pH and potassium levels, then compared with blood pH levels. It was demonstrated that within the first 30 and 60 minutes, pH levels of the lavage fluid dropped, and potassium levels rose, a finding that could be of early diagnostic importance. [21] In a similar study conducted by Ljungdahl et al., using an experimental pig model, it was reported that superficial intestinal mucosa pH levels dropped from 7.28 to 6.76, with high superior mesenteric vein lactate levels.[22] Sonnino et al. found strong statistical correlation between intestinal ischemia and levels of fatty acid-binding proteins in peritoneal fluid normally found only in intestinal mucosa villus tips, not in the circulatory system.[23] Diagnostic use of inert Xenon (Xe54) gas is promising in early diagnosis of AMI— when dissolved in salt and injected into the peritoneal cavity, it is absorbed with passive diffusion into the intestine. While tissues with normal perfusion can clean this gas easily, ischemic tissues cannot.[24] Lange et al. reported rise in level of lactate as the best serum marker in acute abdomen diagnosis, with 100% sensitivity and 42% specificity.[25] In the present study, serum LDH levels were found to be statistically significant when control and fourth-hour ischemia groups were compared, while intergroup comparisons showed no statistically significant difference in enzyme levels. When LDH serum levels were compared among the nonisch-

Table 2. Mean values of ischemic and nonischemic groups Pathology

LDH (IU/L)a

D-dimer (ng/ml)b

IALP (%)c

Non-ischemic

2758.67

319.58

12.08

Ischemic

4947.28

180.06

17.78

P value: a(0.036), b(0.161), c(0.082). LDH: Lactate dehydrogenase. IALP: Intestinal alkaline phosphatase.

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Lapsekili et al. Role of alkaline phosphatase intestine-isomerase in acute mesenteric ischemia diagnosis

emic control (Group 1) and sham (Group 2) groups, and the ischemic groups (Groups 3, 4, and 5), LDH serum levels in the ischemic groups were found to be statistically significant, with 94% sensitivity and 41% specificity (p=0.038) (Figure 3).

levels above 1900 IU/L may be a useful marker in the early diagnosis of acute mesenteric obstruction, while ALP intestinal isomerase enzyme and D-dimer plasma levels did not contribute to the diagnosis of acute mesenteric ischemia.

D-dimer is a marker that rises in most thrombolytic cases as a byproduct of fibrin degradation.[26] Most surgical trauma and tissue degradation results in coagulation and activation of the fibrinolytic system. Therefore, D-dimer sensitivity and specificity in surgical practice is quite low.[27] Studies that report D-dimer measurement results make important contributions to diagnostic methods.[5] In an experimental study of mesenteric artery ligation in rats, Altinyollar et al. found increased D-dimer levels with statistical significance when the data of the sham group was compared to that of the seventh-hour ischemia group.[28] Acosta-Mérida et al. reported that 6 patients treated for AMI had significantly higher D-dimer results, compared to the 8 who had not undergone treatment.[29,30] A similar study conducted by Kulacoglu et al. reported a significant rise in D-dimer levels of the sixth-hour ischemia group.[31]

Conflict of interest: None declared.

In the present study, similar levels of D-dimer were found in the ischemic rat model and the control and sham groups (avg.=235 ng/mL). The authors hypothesize that in early-term ischemia, rise in degradation products may not cause increase in D-dimer level (discouraging its use in early diagnosis, compared to its possible use in late diagnosis). The authors suggest that normal levels of D-dimer at an early stage cannot rule out diagnosis of ischemia. High index of suspicion with immediate attempts at early diagnosis and emergency angiography for thrombolytic treatment should not be delayed in cases of AMI.[32] ALP intestine-isomerase enzyme is present in high concentrations in intestinal epithelial cells, and is responsible for calcium absorption and transport of fatty acids.[33] In the present study, the physiological role of a possible increase or decrease of ALP intestine-isomerase enzymes in intestinal ischemia was examined, and the potential of enzyme measurement to be used in AMI diagnosis was assessed. No statistically significant results were found with regard to difference in enzyme levels, either intergroup or between the ischemic and nonischemic groups. However, in qualitative analysis, the rise in enzyme levels concurrent with the period of ischemia was noteworthy. Future studies with larger groups are warranted to evaluate ALP intestinal isomerase levels in diagnosis of AMI. In the present experimental study, no significant difference in ALP intestinal isomerase enzyme levels were found between the ischemic and nonischemic groups, while differences in LDH levels were statistically significant (p=0.036; Table 2). A gradual increase in LDH levels was determined in the ischemic groups, beginning at the first hour and continuing throughout the ischemic period. In conclusion, the present findings suggest that LDH plasma Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

REFERENCES 1. Adams JT. Abdominal wall, omentum, mesentery and retroperitoneum. In: Schwartz SI, Shires TG, Spencer FC, editors. Principles of surgery. 6th ed. New York: Mc Graw Hill Co; 1994. p. 1495–504. 2. Yasuhara H. Acute mesenteric ischemia: the challenge of gastroenterology. Surg Today 2005;35:185–95. 3. Turnage RH, Badgwell B. Abdominal wall, umblicus, peritoneum, mesenteries, omentum and retroperitoneum. In: Townsend CM Jr, Beauchamp D, Evers BM, Mattox KL, editors. Sabiston textbook of surgery. 18th ed., Philadelphia: Saunders; 2008. p. 1129–54. 4. Luther B, Moussazadeh K, Müller BT, Franke C, Harms JM, Ernst S, et al. The acute mesenteric ischemia - not understood or incurable?. [Article in German] Zentralbl Chir 2002;127:674–84. [Abstract] 5. Kurt Y, Akin ML, Demirbas S, Uluutku AH, Gulderen M, Avsar K, et al. D-dimer in the early diagnosis of acute mesenteric ischemia secondary to arterial occlusion in rats. Eur Surg Res 2005;37:216–9. 6. Park PO, Haglund U, Bulkley GB, Fält K. The sequence of development of intestinal tissue injury after strangulation ischemia and reperfusion. Surgery 1990;107:574–80. 7. Klein HM, Lensing R, Klosterhalfen B, Töns C, Günther RW. Diagnostic imaging of mesenteric infarction. Radiology 1995;197:79–82. 8. Wiesner W, Hauser A, Steinbrich W. Accuracy of multidetector row computed tomography for the diagnosis of acute bowel ischemia in a nonselected study population. Eur Radiol 2004;14:2347–56. 9. Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of the intestines. Curr Probl Surg 1978;15:1–85. 10. Luther B, Moussazadeh K, Müller BT, Franke C, Harms JM, Ernst S, et al. The acute mesenteric ischemia - not understood or incurable?. [Article in German] Zentralbl Chir 2002;127:674–84. [Abstract] 11. Kirkpatrick ID, Kroeker MA, Greenberg HM. Biphasic CT with mesenteric CT angiography in the evaluation of acute mesenteric ischemia: initial experience. Radiology 2003;229:91–8. 12. Taourel PG, Deneuville M, Pradel JA, Régent D, Bruel JM. Acute mesenteric ischemia: diagnosis with contrast-enhanced CT. Radiology 1996;199:632–6. 13. Yikilmaz A, Karahan OI, Senol S, Tuna IS, Akyildiz HY. Value of multislice computed tomography in the diagnosis of acute mesenteric ischemia. Eur J Radiol 2011;80:297–302. 14. Wolf EL, Sprayregen S, Bakal CW. Radiology in intestinal ischemia. Plain film, contrast, and other imaging studies. Surg Clin North Am 1992;72:107–24. 15. May LD, Berenson MM. Value of serum inorganic phosphate in the diagnosis of ischemic bowel disease. Am J Surg 1983;146:266–8. 16. Tsai CJ, Kuo YC, Chen PC, Wu CS. The spectrum of acute intestinal vascular failure: a collective review of 43 cases in Taiwan. Br J Clin Pract 1990;44:603–8. 17. Zhang FX, Zhang CM, Hu L. The effect of examination of enzymes in serum to diagnosis of acute mesenteric ischemia in rabbit. [Article in Chinese] Zhonghua Wai Ke Za Zhi 2005;43:430-2. [Abstract] 18. Karaağaç H, Zeybek N, Peker Y, Yağcı G, Şengül A, Günhan Ö, et al. Diagnostic value of plasma cytokine levels in acute mesenteric ischemia: an experimental study. Gulhane Med J 2007;49: 216–21. 19. Gunduz A, Turkmen S, Turedi S, Mentese A, Yulug E, Ulusoy H, et al. Time-dependent variations in ischemia-modified albumin levels in mes-

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sis. [Article in German] Zentralbl Chir 1998;123:230–4. [Abstract] 27. Owings JT, Gosselin RC, Anderson JT, Battistella FD, Bagley M, Larkin EC. Practical utility of the D-dimer assay for excluding thromboembolism in severely injured trauma patients. J Trauma 2001;51:425–30. 28. Altinyollar H, Boyabatli M, Berberoğlu U. D-dimer as a marker for early diagnosis of acute mesenteric ischemia. Thromb Res 2006;117:463–7. 29. Acosta-Mérida MA, Marchena-Gómez J, Cruz-Benavides F, HernándezNavarro J, Roque-Castellano C, Rodríguez-Méndez A, et al. Predictive factors of massive intestinal necrosis in acute mesenteric ischemia. [Article in Spanish] Cir Esp 2007;81:144–9. [Abstract] 30. Acosta S, Björck M. Acute thrombo-embolic occlusion of the superior mesenteric artery: a prospective study in a well defined population. Eur J Vasc Endovasc Surg 2003;26:179–83. 31. Kulacoglu H1, Kocaerkek Z, Moran M, Kulah B, Atay C, Kulacoglu S, et al. Diagnostic value of blood D-dimer level in acute mesenteric ischaemia in the rat: an experimental study. Asian J Surg 2005;28:131–5. 32. Doğtaş A, Solak O, Topçu Ö, Duman M. Selective Intra-arterial Thrombolytic Treatment of the Acute Thromboembolism of the Superior Mesenteric Artery. C.U. Journal of Medicine 2005;27:79–82. 33. Calbreath FD. Clinical chemistry a fundamental textbook. Philadelphia: W.B. Saunders Company. 1992. p. 186–90.

DENEYSEL ÇALIŞMA - ÖZET OLGU SUNUMU

Alkalen fosfataz bağırsak izomeraz enziminin akut mezenterik iskemi tanısındaki rolü Dr. Emin Lapsekili,1 Dr. Öner Menteş,1 Dr. Müjdat Balkan,1 Dr. Armağan Günal,2 Dr. Halil Yaman,3 Dr. Orhan Kozak,1 Dr. Yusuf Peker1 1 2 3

Gülhane Askeri Tıp Akademisi, Genel Cerrahi Anabilim Dalı, Ankara Gülhane Askeri Tıp Akademisi, Patoloji Anabilim Dalı, Ankara Gülhane Askeri Tıp Akademisi, Biyokimya Anabilim Dalı, Ankara

AMAÇ: Çalışmamızdaki amacımız, akut mezenterik iskeminin erken tanısında alkalen fosfataz (ALP) bağırsak izomeraz enzim düzeyleri ile birlikte LDH ve D-dimer düzeylerinin değerini belirlemektir. GEREÇ VE YÖNTEM: Otuz adet wistar cinsi sıçan her grupta altı sıçan olmak üzere beş gruba ayrıldı. Birinci grup kontrol grubu: Normal sıçandaki ALP-bağırsak izomeraz, LDH ve D-dimer düzeylerini belirlemek için girişim yapılmadan sadece kan alınan grup. İkinci grup sham: Sadece laparotomi yapılarak kan örneği alınan grup. Üçüncü grup: Superior mezenterik arter ligasyonu sonrasındaki ikinci saatte kan örneği alınan grup. Dördüncü ve beşinci grup; sırasıyla ligasyon sonrası dördüncü ve altıncı saatlerde kan örneği alınan grup. Bağırsaktaki iskemik hasar patolojik olarak sınıflandırıldı. Tüm kan örnekleri parametrelerdeki saatlik değişimlerini saptamak amacıyla biyokimyasal olarak değerlendirildi. BULGULAR: İskemi grupları arasında D-dimer sonuçları belirgin olarak anlamlı bulunmadı (p=0.337). LDH seviyeleri birinci ve dördüncü deney grubu arasında anlamlı bulundu (p=0.018). ALP-bağırsak izomeraz enzim düzeyleri tüm diğer gruplar arasında anlamlı değildi (p=0.077). TARTIŞMA: Bulgularımız ALP-bağırsak izomeraz enzimi ve D-dimer düzeylerinin, akut mezenterik iskeminin erken döneminde, tanısal olarak değerli olmamasına rağmen 1900 IU/L üzerindeki LDH düzeylerinin kullanışlı bir tanısal belirteç olabileceğini göstermektedir. Anahtar sözcükler: Akut mezenterik iskemi; ALP-bağırsak izomeraz; D-dimer; LDH. Ulus Travma Acil Cerrahi Derg 2016;22(2):115–120

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doi: 10.5505/tjtes.2015.49475

Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

EXPERIMENTAL STUDY

Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury Nurşah Başol, M.D.,1 Oytun Erbaş, M.D.,2 Türker Çavuşoğlu, M.D.,3 Ayfer Meral, M.D.,4 Utku Ateş, M.D.5 1

Department of Emergency Medicine, Gaziosmanpaşa University Faculty of Medicine, Tokat-Turkey

Department of Physiology, İstanbul Bilim University Faculty of Medicine, İstanbul-Turkey

Department of Histology and Embryology, Ege University Faculty of Medicine, İzmir-Turkey

Department of Biochemistry, Dumlupınar University Evliya Çelebi Training and Research Hospital, Kütahya-Turkey

Department of Histology and Embryology, İstanbul Bilim University Faculty of Medicine, İstanbul-Turkey

ABSTRACT BACKGROUND: Sepsis-related acute kidney injury (AKI) is a serious complication of sepsis. Problems persist regarding early diagnosis and treatment of AKI. The aim of the present study was to evaluate the efficacy of agomelatine, which is primarily known for its positive effects on depressive and anxiety disorders in sepsis-related AKI. METHODS: Sepsis model was created with cecal ligation puncture (CLP). Rats were separated into 4 groups of 8 each: the control group, the sham-operated group, the CLP+saline group, and the CLP+agomelatine group. Agomelatine was administered intraperitoneally in doses of 20 mg/kg. RESULTS: In the agomelatine group, reductions were observed in levels of tumor necrosis factor α (TNF-α), malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine, as well as in histological kidney scores, compared to the non-treated group. In addition, it was demonstrated that agomelatine treatment had positive effect on sepsis-induced morphological damage to renal and tubular tissues. CONCLUSION: Agomelatine showed strong efficacy in sepsis-related AKI, demonstrated with histological and biochemical results in an experimental model. It is believed that antioxidant and pro-inflammatory effects of agomelatine are responsible for the improvement in kidneys. Keywords: Acute kidney injury; agomelatine; cecal ligation puncture; sepsis.

INTRODUCTION Sepsis is a complex clinical syndrome with high rates of morbidity and mortality.[1] According to criteria of the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM), the elementary definition of sepsis is “a complex immune reaction against a microorganism.”[2] Sepsis is associated with multiple organ dysfunctions.[3] Renal functions are particularly affected in the early stages of sepsis.[4] Acute kidney injury (AKI) is a common and serious Address for correspondence: Nurşah Başol, M.D. Gaziosmanpaşa Üniversitesi Tıp Fakültesi Hastanesi, Acil Tıp Anabilim Dalı, 60000 Tokat, Turkey Tel: +90 356 - 212 95 00 / 3418 E-mail: drnursahbs@hotmail.com Qucik Response Code

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complication that increases mortality and is characterized by rapid kidney failure due to micro- and macro-hemodynamic impairment and immune toxicity in kidney tissue cells.[5,6] Pathophysiology of AKI is not clear, though multifactorial mechanisms containing ischemia–reperfusion injury, direct inflammatory injury, coagulation, endothelial cell dysfunction, and apoptosis are generally considered to be causes.[7] Agomelatine, N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, is specified for the treatment of major depression, with dual effects on sleep problems and depressive disorders.[8] It is a synthetic drug, an agonist of melatonin receptors (MT1 and MT2) and an antagonist of serotonin receptor (5-HT2C).[9–11] Oxidative stress, which plays a key role in pathogenesis of sepsis, is a leading cause of organ dysfunction in particular. [12] Melatonin at high doses is known for its strong antioxidant and anti-inflammatory activity.[13] In several experimental studies, beneficial effects of melatonin have been demonstrated with sepsis models.[13–16] Although the exact mechanism is not clear, it is thought that the antioxidant, anti-apoptotic, anti-inflammatory, and immunomodulating effects of melato121

Başol et al. Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury

nin are responsible for good effects on sepsis.[14] In addition, reports have indicated protective effects of melatonin on renal functions.[17–19] However, exact pathophysiology of sepsisrelated AKI remains unclear and, in spite of new treatment options, AKI continues to occur with high mortality.[20] The aim of the present study was to research effects of agomelatine, a melatonin analogue, on sepsis-induced AKI. Cecal ligation puncture (CLP) was performed on rats to create an animal model of sepsis, and agomelatine effects on renal functions were evaluated with biochemical and histopathological testing.

MATERIALS AND METHODS Animals Used in the present study were 42 male Sprague Dawley mature albino rats, each weighing 200–220 g. They were fed ad libitum and housed in pairs in steel cages in a temperaturecontrolled environment (22±2°C) with light/dark cycle of 12 hours each. Protocol was approved by the committee for animal research and the study strictly conformed to the animal experiment guidelines of the Committee for Human Care.

Drugs All drugs were freshly prepared. Agomelatine (Valdoxan®, Servier Laboratories Ltd., Slough, UK) was dissolved in saline. Saline (0.9% NaCl) was used as control solution. All solutions were administered intraperitoneally (IP) in a volume of 1 mL/ kg body weight.

Experimental Design Rats were separated at random into 2 initial groups, and CLP was performed on 26 rats to induce a sepsis model. Ten rats (7 rats in the CLP+saline group and 3 in the CLP+agomelatine group) died in the first 24 hours after surgical procedure and were excluded from the study. No mortality occurred in the sham-operated group. Study groups were designed as follows: Group 1: Normal (non-operated and orally fed control, n=8) Group 2: Sham-operated (n=8) Group 3: CLP and 1 ml/kg 0.9 NaCl (saline) IP (n=8) Group 4: CLP and 20 mg/kg agomelatine IP (n=8) Rats were anesthetized IP with injection of combination 80 mg/kg ketamine hydrochloride (Alfamine®; Alfasan International BV., Woerden, Holland) and 7 mg/kg xylazine hydrochloride (Alfazyne®; Alfasan International BV, Woerden, Holland). Under aseptic conditions, 3-cm midline laparotomy was performed to expose the cecum with the adjoining intestine. The cecum was ligated tightly with a 3.0 silk suture at its base under the ileocecal valve and punctured once with a 22-gauge needle. The cecum was then gently squeezed to extrude a small amount of feces from the perforation site. The cecum 122

was returned to the peritoneal cavity, and the laparotomy incision was closed with 4-0 polyglactin 910 sutures. Following surgery, the animals were permitted a period to recover before being placed in their cages. In the sham group, under aseptic conditions, only laparotomy was performed; the cecum was neither ligated nor punctured. Rats were considered septic 5 hours after CLP.[21] Treatments were performed within the first hour of surgical procedure. The study was concluded after 24 hours. The rats were euthanized with an overdose of pentobarbital sodium, and blood samples were collected by cardiac puncture for biochemical analysis.

Determination of BUN and Creatinine Levels Blood urea nitrogen (BUN) and creatinine concentrations were determined spectrophotometrically, using an automated system of analysis. BUN and creatinine concentrations were expressed as mg/dL.

Determination of Plasma TNF-α Levels Plasma TNF-α levels were measured using commercially available ELISA enzyme-linked immunosorbent assay kit (Quansys Biosciences, Logan, UT, USA). Plasma samples were diluted 1:2, and TNF-α was determined in duplicate, according to manufacturer’s guide. Detection limit for TNF-α assay was <2 pg/mL.

Determination of Lipid Peroxidation Lipid peroxidation was determined in plasma samples by measuring malondialdehyde (MDA) levels as thiobarbituric acidreactive substances (TBARS).[22] Briefly, trichloroacetic acid and TBARS reagent were added to the plasma samples, then mixed and incubated at 100°C for 60 minutes. After cooling on ice, the samples were centrifuged at 3000 rpm for 20 minutes, and the absorbance of the supernatant was read at 535 nM. MDA levels were expressed as nM, and tetraethoxypropane was used for calibration.

Histopathological Studies of Kidney For histological and immunohistochemical studies, all animals were IP anesthetized with 40 mg/kg ketamine and 4 mg/kg xylazine, and were perfused with 200 mL of 4% formaldehyde in 0.1 M phosphate-buffered saline. Formalin-fixed kidney sections (4 μm) were stained with hematoxylin and eosin. All sections were photographed with Olympus C-5050 digital camera mounted on Olympus BX51 microscope. Morphological evaluation was performed by computerized image analysis system (Image-Pro Express 1.4.5; Media Cybernetics, Inc., Rockville, MD, USA) on 10 microscopic fields per section, examined with ×20 magnification by an observer blinded to the study group. Kidney sections from all groups were evaluated semi-quantitatively to determine extent of tubular epithelial necrosis, Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Başol et al. Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury

Table 1. Malondialdehyde, TNF-α, BUN and creatinine levels Normal group Sham-operated group CLP + saline group

CLP + 20 mg/kg agomelatine group

Malondialdehyde (nM)

65.3±3.2

71.2±3.5

218.9±7.5** 212.5±6.5##

TNF-α (pg/mL)

21.07±1.9

22.8±2.14

274.5±7.9** 119.9±5.8##

Plasma BUN content (mg/dL)

24.7±1.2

21.6±1.5

55.01±3.2** 37.8±3.6#

Plasma creatinine content (mg/dL)

0.35±0.02

0.37±0.03

0.79±0.03* 0.56±0.05#

Results are presented as mean ± SEM. *p<0.01, **p<0.000 (different from normal and sham-operated groups), ##p<0.000, #p<0.05 (different from CLP + saline Group). TNF-a: Tumor necrosis factor alpha; BUN: Blood urea nitrogen; CLP: Cecal ligation and puncture.

luminal necrotic debris, tubular dilatation, hemorrhage, and interstitial inflammation, rated as follows: 0-5% = score 0; 6-20% = score 1; 21-40% = score 2; 41-60% = score 3; 6180% = score 4; and 81-100% = score 5.[23,24]

Statistical Analysis Data are presented as mean±standard error of the mean (SEM). Data analyses were performed using SPSS software for Windows (version 15.0; SPSS Inc., Chicago, IL, USA). Data were analyzed with non-parametric Mann-Whitney U test, and p values of 0.05 or less were considered statistically significant.

RESULTS Serum TNF-α, MDA, BUN, and creatinine levels of all groups

are shown in Table 1. MDA is a predictor of lipid peroxidation, and in cases of sepsis, high levels indicate oxidative stress. Plasma MDA levels were markedly elevated in the CLP+saline group, compared to the normal and sham-operated groups (p<0.000). A significant decrease was observed in the CLP+agomelatine group, compared to the CLP+saline group (p<0.000). No differences were observed between the normal and sham-operated groups. TNF-α, which causes harmful effects of inflammation, is a pro-inflammatory cytokine that can be used to determine severity of sepsis as organ dysfunction. In the present study, plasma TNF-α was also found to be significantly higher in the CLP+saline group, compared to the normal and sham-operated groups (p<0.000). A significant decrease in TNF-α was

(a)

(b)

(c)

(d)

Figure 1. Kidney histolopathology. (a) Kidney from normal group, H&E x10 magnification, renal tubuls (T), (b) sham group showed minimal histopathological alteration, (c) CLP+saline group showed severe histopathological alteration related to tubular injury (TI). (d) CLP+agomelatine group showed decrease in tubular injury.

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Table 2. Changes in histopathological kidney injury scores Normal group Sham-operated group CLP + saline group

CLP + 20 mg/kg agomelatine group

Tubularepithelial necrosis

0.5±0.18† 3.3±0.18** 2.1±0.22##

Luminal necrotic debris

0.62±0.18† 2.5±0.32** 1.37±0.32#

Tubular dilatation

0.37±0.19† 3.1±0.22** 1.8±0.35#

Hemorrhage

0 0.5±0.18† 3.0±0.3** 1.9±0.22##

Interstitial inflammation

0.6±0.26† 3.25±0.5** 1.75±0.36#

Results are presented as mean ± SEM. †p<0.05 (different from normal group), **p<0.000 (different from normal and sham-operated groups), #p<0.05, ##p<0.01 (different from CLP + saline group). CLP: Cecal ligation and puncture.

also observed in the CLP+agomelatine group (p<0.000). No differences were observed between the normal and shamoperated groups. AKI was assessed by measurement of BUN and creatinine levels. BUN levels were compared among the 4 groups, with the highest in the CLP+saline group. BUN was significantly lower in the CLP+agomelatine group, compared to the CLP+saline group (p<0.05). Creatinine levels were markedly increased in the CLP+saline group, compared to the normal and sham groups (p<0.01). In the CLP+agomelatine group, a significant decrease was observed in creatinine levels, compared to the CLP+saline group (p<0.05). No difference in BUN or creatinine levels was observed in the normal or sham groups. Histopathology of kidney tissue in all groups is shown in Fig. 1. Alteration of kidney tissue in sham group was minimal. Histopathological indicators of AKI (tubular epithelial necrosis, luminal necrotic debris, tubular dilatation, hemorrhage, and interstitial inflammation) were observed in the CLP+saline group. Tubular injury was observed in the CLP+agomelatine group, though to a lesser extent than in the CLP+saline group. Mean±SD of kidney tissue tubular epithelial necrosis scores were (0.5±0.18), (3.3±0.18), and (2.1±0.22); scores for luminal necrotic debris were (0.62±0.18), (2.5±0.32), and (1.37±0.32); scores for tubular dilatation were (0.37±0.19), (3.1±0.22), and (1.8±0.35); scores for hemorrhage were (0.5±0.18), (3.0±0.3), and (1.9±0.22), and scores for interstitial inflammation were (0.6±0.26), (3.25±0.5), and (1.75±0.36) in the sham, CIP+saline, and CIP+agomelatine groups, respectively (Table 2). A marked increase in tubular epithelial necrosis, luminal necrotic debris, tubular dilatation, hemorrhage, and interstitial inflammation was observed in the sham group, compared to the normal group (p<0.05). Scores of all histological parameters in the CLP+saline group were higher than those in the sham and normal groups (p<0.000). There was a significant decrease in scores of all histological parameters in the CLP+agomelatine group, compared to the CLP+saline group (p=<0.05 for luminal necrotic debris scores, tubular dilatation scores, and interstitial inflammation scores; p=<0.01 for tubular epithelial necrosis scores and hemorrhage scores). 124

DISCUSSION The curative effect of agomelatine on the kidney was demonstrated in the present study with biochemical and histological parameters in an experimental model of sepsis-induced AKI. AKI occurs in nearly half of all septic patients and is associated with increased mortality.[25] It has been suggested that AKI in sepsis is correlated with important destructive effects. While detection of acute lung injury is not easy in early stages, the authors suggested that it can indicate severity of sepsis.[26] Increased levels of BUN and creatinine were used to define AKI. Craciun et al. reported that creatinine is a predictor of glomerular filtration rate, which, though influenced by factors such as gender and age, can be used to detect AKI. It was also reported that BUN can indicate kidney function, but is less specific than creatinine. The authors suggested that high levels of BUN can reflect mortality of sepsis.[27] In the present study, in addition to BUN and creatinine levels, histopathological changes in renal and tubular tissues were used to determine renal injury. Olguner et al. reported that an association between high kidney injury scores and sepsis has been histologically demonstrated.[28] For example, the histological kidney score was found to be higher in the sepsis group than in the sham group of a study by Koca et al. These parameters were also used to evaluate an agent in AKI.[29] In the present study, histological findings were similarly used in the diagnosis stage, as well as to evaluate effects of agomelatine on AKI. Certain mechanisms are believed to contribute to the pathogenesis of AKI, which has yet to be clearly understood. In the present study, TNF-α levels were higher in the sepsis group than in the normal and sham groups. Luo et al. demonstrated that pro-inflammatory cytokines such as TNF-α increase with sepsis-related AKI. The authors suggested that the inflammation largely contributed to the pathogenesis of AKI. [30] Similarly, Chancharoenthana and et al. demonstrated that hypercytokinemia plays a more distinct role in sepsis-related AKI than in non-sepsis related AKI.[31] It has been determined that oxidative stress plays an important role in sepsis-related AKI.[32] The results of the present Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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study support this conclusion. MDA, the end-product of lipid peroxidation, was higher in the sepsis group than in the normal and sham groups.

study, the authors suspect that agomelatine is more effective than melatonin, due to its impact on the kynurenine pathway in cases of sepsis-related AKI.

TNF-α, MDA, BUN, and creatinine levels were used to evaluate the effect of agomelatine on sepsis-induced AKI. Histological investigations and scores to determine kidney injury were used for further assessment. Levels of TNF-α, MDA, BUN, and creatinine were reduced, as were histological kidney injury scores, in the AKI group treated with agomelatine, compared to the AKI group that was not. Put simply, decrease in BUN and creatinine can indicate the positive effect of agomelatine on renal function. This suggestion is supported with histopathological kidney investigations.

Conclusion

Agomelatine is a melatonin analogue, known to be more potent than melatonin in antidepressant models.[33] The effect of agomelatine on inflammation was studied by Molteni et al.[34] Pro-inflammatory cytokines were found to be reduced in rats treated with agomelatine, a finding similar to that of the present study. The authors reported that agomelatine modified the expression of enzymes involved in the kynurenine pathway. It has been suggested that the kynurenine pathway is aggravated in cases of septic shock.[35] Agomelatine may have effects beneficial to this pathway, in addition to its antioxidant and pro-inflammatory effects on sepsis-related AKI.

REFERENCES

The efficacy of melatonin in sepsis models has been documented.[13,14,16] Shang et al. reported that use of melatonin as a therapeutic agent in endotoxemic rats decreased incidence of acute lung injury by reducing lipid peroxidation, neutrophil infiltration, TNF-α release, and IL-10 production. It has been demonstrated that melatonin affects sepsis by reducing inflammation and inhibiting nuclear factor κB (NF-κB) activation.[16] Srinivasan noted that Gitto et al. demonstrated positive effects of melatonin on oxidative stress in newborns with sepsis, utilizing MDA, 4-HDA concentration, and nitrate level. Melatonin was recommended because of its immunomodulatory, antioxidant, and anti-apoptotic effects on sepsis caused by multiple organ failure.[14] Similarly, in a study by Lowes et al., melatonin was administered to rats with sepsis induced by lipopolysaccharide/peptidoglycan G (LPS/Pep G) in an acute model, and it was reported that melatonin protected mitochondria from oxidative stress and inflammation.[13] In addition to those using sepsis models, other studies have demonstrated beneficial effects of melatonin on renal damage as ischemia-reperfusion injury or acute renal failure.[11,18,36] Agomelatine has generally been studied in relation to depressive and anxiety disorders, and, to the best of our knowledge, the present study is the first to research its effects on sepsis-related AKI. Agomelatine has effects similar to those of melatonin, due to its melatonergic receptors. Hence, the mechanism responsible for these beneficial effects is generally attributed to the antioxidant and anti-inflammatory effects of melatonin. Though it is outside the scope of the present Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Results of the present study indicate that pro-inflammatory and antioxidant mechanisms play important roles in the pathogenesis of sepsis-induced AKI. While the mechanism is not entirely clear, the present data suggest that agomelatine may have beneficial effects on kidneys. Further studies are needed before agomelatine can be suggested as treatment of sepsis-related AKI. Conflict of interest: None declared.

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DENEYSEL ÇALIŞMA - ÖZET OLGU SUNUMU

Sepsis nedenli akut böbrek hasarında agomelatinin etkilerinin değerlendirilmesi Dr. Nurşah Başol,1 Dr. Oytun Erbaş,2 Dr. Türker Çavuşoğlu,3 Dr. Ayfer Meral,4 Dr. Utku Ateş5 Gaziosmanpaşa Üniversitesi Tıp Fakültesi, Acil Tıp Anabilim Dalı, Tokat İstanbul Bilim Üniversitesi Tıp Fakültesi, Fizyoloji Anabilim Dalı, İstanbul 3 Ege Üniversitesi Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı, İzmir 4 Dumlupınar Üniversitesi Evliya Çelebi Eğitim ve Araştırma Hastanesi, Biyokimya Anabilim Dalı, Kütahya 5 İstanbul Bilim Üniversitesi Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı, İstanbul 1 2

AMAÇ: Sepsis nedenli akut böbrek hasarı sepsisin önemli komplikasyonlarından biridir. Sepsisin erken dönemlerinde gelişir ve mortaliteyi artırır. Hem erken tanı sürecinde hem de tedavi aşamasında hala problemler vardır. Bu çalışmanın amacı, genellikle anksiyete ve depresyonda kullanılan agomelatinin sepsis nedenli akut böbrek hasarındaki olası etkilerinin değerlendirilmesidir. GEREÇ VE YÖNTEM: Sepsis modeli çekal ligasyon ve delme (CLP) tekniği ile oluşturuldu. Sıçanlar her biri sekizerli dört gruba ayrıldı. İlk grup normal, ikinci grup sham grubu olarak belirlendi. Üçüncü grup sepsis modeli oluşturulup sadece salin verilen grup, dördüncü grup ise sepsis modelini takiben agomelatin uygulanan grup olarak belirlendi. Yirmi dört saatin sonunda böbrek doku örnekleri ve kanlar alınarak histopatolojik ve biyokimyasal yöntemlerle analizleri yapıldı. BULGULAR: Çalışmada agomelatine uygulanan grupta sadece salin uygulanan gruba göre TNF-α, MDA, BUN, kreatin ve histolojik böbrek skorlaması daha düşük olarak bulundu. Aynı zamanda, histopatolojik değerlendirmede agomelatin tedavisinin böbrek dokularında sepsisin oluşturduğu hasarlanmayı düzelttiği görüldü. TARTIŞMA: Bu çalışmada, agomelatinin sepsis nedenli akut böbrek hasarında faydalı olduğu savunulmaktadır. Bu hem biyokimyasal hem de histolojik değerlendirmeler ile gösterilmiştir. Agomelatinin anti-oksidan ve proenflamatuvar etkilerinin böbreklerdeki bu düzelmeden sorumlu olduğu düşünülmektedir. Anahtar sözcükler: Agomelatin; akut böbrek hasarı; CLP; sepsis. Ulus Travma Acil Cerrahi Derg 2016;22(2):121–126

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doi: 10.5505/tjtes.2015.29499

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EXPERIMENTAL STUDY

Effects of different recruitment maneuvers on bacterial translocation and ventilator- induced lung injury Perihan Ergin Özcan, M.D.,1 Özkan İbrahim Akıncı, M.D.,1 İpek Edipoğlu, M.D.,1 Evren Şentürk, M.D.,1 Sevil Baylan, M.D.,1 Atahan Arif Cağatay, M.D.,2 Kemal H Türköz, M.D.,3 Figen Esen, M.D.,1 Lütfi Telci, M.D.,1 Nahit Çakar, M.D.1 1

Department of Anesthesiology, İstanbul University İstanbul Faculty of Medicine, İstanbul-Turkey

Department of Infectious Diseases and Clinical Microbiology, İstanbul University İstanbul Faculty of Medicine, İstanbul-Turkey

Department of Pathology, Marmara University Faculty of Medicine, İstanbul-Turkey

ABSTRACT BACKGROUND: Investigated in the present study were the effects of various recruitment maneuvers (RMs) using the same inflation pressure-time product on bacterial translocation from lung to blood, and ventilator-induced lung injury (VILI). METHODS: Tracheotomy was performed on anesthetized rats, and ventilation was initiated using pressure-controlled mode. Subsequently, Pseudomonas aeruginosa was inoculated through the tracheotomy tube and ventilated for 30 minutes before rats were randomly separated into 4 groups. Group 1 underwent sustained inflation (SI), Group 2 underwent low-pressure SI, Group 3 underwent modified sigh, and Group 4 was a control group. Blood cultures were taken at baseline, 15 minutes after randomization (after each RM for the first hour), and finally at 75 minutes after the last RM. The rats were euthanized and the lungs were extirpated. The left lung was taken for measurement of wet:dry weight ratio, and the right lung was used for pathologic evaluation. RESULTS: Positive blood cultures were found to be higher in Group 3 at early study periods. Total pathological scores were also higher in Group 3. CONCLUSION: Higher severity of ventilator-induced lung injury occurred in the modified sigh group, evidenced by bacterial translocation and results of histopathological evaluation. Keywords: Bacterial translocation; mechanical ventilation; recruitment maneuver; SIGH; ventilator-induced lung injury.

INTRODUCTION Mechanical ventilation is the most important supportive therapeutic option in cases of acute respiratory distress syndrome (ARDS). However, it is well known, based on experimental and human studies, that mechanical ventilation may cause ventilator-induced lung injury (VILI).[1] Different recruitment maneuvers (RMs) are important adjuncts of mechanical ventilation in clinical practice, used to Address for correspondence: Evren Şentürk, M.D. İstanbul Üniversitesi İstanbul Tıp Fakültesi, Anesteziyoloji Anabilim Dalı, 34093 Çapa, İstanbul, Turkey Tel: +90 212 - 631 87 67 E-mail: evrensenturk2@yahoo.com Qucik Response Code

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enhance oxygenation by opening collapsed sections of the lung. Due to the tendency of unstable alveoli to collapse, it is thought that RMs are likely to reduce VILI that occurs due to repeated opening and closing during ventilation. However, RMs have side effects, and may induce hyperinflation and lung injury.[2] Therefore, to evaluate RMs for efficiency and related risks, optimal pressure level, applicable time period, and applicable rate should be discussed. RMs can be performed in different ways. Sustained inflation (SI) is applied to raise static airway pressure to a fixed level for a fixed time period. Inflation pressure applied in several RM-related studies has ranged between 30 and 60 cmH2O, with the time periods ranging from 3 seconds to 3 minutes. These studies have suggested that the magnitude of airway pressure and duration of pressure elevation play major roles in the success of an RM.[3–5] Respiratory effects of different RMs have also been studied.[6] Bacterial translocation from the lungs to the bloodstream has been used as a marker of VILI in a number of experimental 127

Ergin Özcan et al. Effects of different recruitment maneuvers on bacterial translocation and ventilator- induced lung injury

studies.[7–10] Repeated collapse and reopening of the alveoli, inflammation, and high ventilation pressures and volumes have been shown to cause VILI.[11,12] Examined in the present study were the effects of different RMs with identical inflation pressure-time products on bacterial translocation from the lungs to the bloodstream, oxygenation, morphologic changes, and wet:dry weight ratio of the lungs. The authors hypothesized that the level of pressure applied was not the only factor triggering VILI, and that the frequency and timing of pressure also had significant impacts on its occurrence.

MATERIALS AND METHODS The study was conducted following approval of protocol from the Institutional Animal Investigation Committee. Care and handling of the animals were in accordance with European Community guidelines. Thirty-two male Sprague Dawley rats (each weighing 250–300 g) were used. Sample size was calculated in accordance with a previous study.[10] Significance level of 5% (α=0.05) and probability of 80% (β=0.20), used to detect a difference of at least 80% increase in bacterial translocation, indicated an appropriate sample size of n=7 subjects.

Animal Preparation Rats were anesthetized with inhaled mixture of 1–3% isoflurane, 60% O2, and 40% air, with subsequent intraperitoneal injection of 50 mg/kg ketamine. Following surgical tracheotomy, the rats were kept under pressure-controlled ventilation with Servo 300 ventilator (Siemens AG, Solna, Sweden). Ventilation parameters: (i) peak inspiratory pressure (PIP) of 10 cmH2O (ii) positive end-expiratory pressure (PEEP) of 0 cmH2O (iii) respiratory rate of 60 breaths/minute (iv) inspired fraction of oxygen (FiO2) of 1.0 (v) inspiratory-to-expiratory time ratio (I/E) of 1/2 Intraperitoneal ketamine (50 mg/kg) and vecuronium bromide (0.5 mg/kg) were also used for maintenance of anesthesia and muscle relaxation. The carotid artery was cannulated using 24-gauge Insyte-W catheter (Becton Dickinson Infusion Therapy Systems Inc., Sandy, UT, USA) in aseptic conditions. Blood pressure was monitored using Mercury disposable transducer (Mennen Medical, Inc., Southampton, PA, USA), and blood samples were obtained for blood gas analyses and blood cultures. Rectal body temperatures were continuously monitored, and normothermia was maintained using heating lamp and pad.

Bacterial Preparation Regarding preparation of the bacterial solution, Pseudomonas aeruginosa (ATCC 27853) were thawed and cultured over128

night, incubated in brain-heart infusion broth (Becton Dickinson Diagnostics, Inc., Sparks, MD, USA) in 37°C to obtain stationary-phase microorganisms. A tube containing an inoculum of 1x105 colony-forming units/mL of Pseudomonas aeruginosa was individually prepared for each rat on every study day and kept on ice until used.

Experiment Protocol After completion of monitorization, rats were ventilated with baseline ventilator settings for 15 minutes in order to achieve stabilization. Baseline ventilator parameters (tidal volume [VT], PIP, mean airway pressure [MawP], PEEP) and hemodynamic parameters (mean arterial pressure [MAP], heart rate [HR]) were recorded. Blood samples were obtained for baseline blood gas analyses and blood culture. Colloid solution (hydroxyethyl starch 450/0.7, 6%; Eczacıbaşı Baxter, İstanbul, Turkey) was infused to replace blood loss after each blood draw. Blood pressure was kept within normal range by saline infusion. After first blood samples were obtained, 500 μL of saline containing 105cfu/mL Pseudomonas aeruginosa was instilled through the tracheostomy tube, and 5 mL of air was injected to distribute the bacteria through the lungs. PEEP level was increased to 3 cmH2O, and all rats were ventilated for 30 minutes prior to being randomly separated into 4 groups, as follows: • Group 1 (Pressure group): SI of 40 cmH2O PEEP - 20 sec, 4 times/h • Group 2 (Time group): Low-pressure SI of 20 cmH2O PEEP - 40 sec, 4 times/h • Group 3 (Modified sigh group): Modified sigh of 40 cmH2O PIP - 3 cmH2O PEEP for 1 minute, f: 60/minute, I/E:1/2, 4 times/h • Group 4 (Control group): 10 cmH2O PIP - 3 cmH2O PEEP In all groups, ventilator settings between RMs were maintained at baseline (PIP: 10 cmH2O; PEEP: 3 cmH2O; f:60/min; FiO2: %100; I/E:1/2). Inflating pressure-time product (the product of the pressure value over the time it is applied) was equal in the 3 RMs (Fig.1). The method applied in Group 3 was not completely in line with sigh. For this reason, in order to establish an equal product in all groups, high PIP (40 cmH2O) was imposed at a frequency level of 60/minute for 1 minute. Because of this, the RM of Group 3 is described as “modified sigh.”

Microbiologic Evaluation Blood cultures were incubated at 37°C overnight and kept in the incubator for at least 10 days. Blood cultures were analyzed to determine whether culture positivity had been obtained each day, regardless of turbidity or opacity. Bacteremia was defined as ≥1 colony of Pseudomonas aeruginosa appearing in 100 µL of blood sample cultured on agar plate. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Ergin Özcan et al. Effects of different recruitment maneuvers on bacterial translocation and ventilator- induced lung injury

PIP cmH2O Group 3

Group 1

Group 4

Group 2

10 3 20 sec

40 sec

60 sec

1 breath / sec

Figure 1. Inflation pressure-time product of groups. Group 1 (Pressure) = 40 cmH2O x 20 sec x 4 times/h= 3200 inflation pressure-time product Group 2 (Time) = 20 cmH2O x 40 sec x 4 times/h= 3200 inflation pressure-time product Group 3 (Modified sigh) = 40 cmH2O x 20 sec x 4 times/h= 3200 inflation pressure-time product (f:60/min, I/E: 1/2, inspiratory time period 20 sec in each sigh) Group 4 (Control group)

Isolated strains were identified using standard microbiological methods. Pseudomonas aeruginosa strains were identified by the presence of large colonies, grape-like odor, oxidasepositive colonies, the ability to grow at 42°C, and characteristic pigmentation. Once isolated strains were identified, E-test strips (AB Biodisk Na Inc., Solna, Sweden) were used to determine whether susceptibility pattern was similar to that of Pseudomonas aeruginosa.

Morphological Evaluation

peribronchial lymphocytic infiltration, intra-alveolar hemorrhage, intra-alveolar macrophage infiltration, interstitial mononuclear cell infiltration, interstitial polymorphonuclear leukocyte infiltration; 0 = none, 1 = focal and rare, 2 = widespread, 3 = whole-lung involvement). Six blood cultures were taken: at baseline, 15 minutes after RM, and 75 minutes after final maneuver. In addition, ventilator variables and hemodynamic parameters were recorded simultaneously. Blood gas analyses were performed at baseline and at experiment conclusion, when the final blood culture was taken. Schematic diagram of the experiment is shown in Fig. 2. Primary outcome was evaluation of bacterial translocation, and secondary outcomes concerned oxygenation, morphologic changes, and wet:dry weight.

The rats were euthanized using intra-arterial sodium thiopental (120 mg/kg), the thorax was opened under aseptic conditions, and the lungs were extirpated with the heart. The left lung was used for the measurement of wet:dry weight. Microbalances were used to determine wet weight; the lung was then kept in an incubator at 100°C for 24 hours and weighed again to determine dry weight.

Statistical Analysis

The right lung was sent to the pathology laboratory in 10% formalin. A pathologist blinded to the study groups performed histological examination. The lung was serially sectioned in caudal-to-coronal fashion from the apex to the base and embedded in paraffin blocks. Following routine dehydration and clearing processes, 3–4 µm sections from each paraffin block were taken and stained with hematoxylin and eosin. All fields of slides were read. Sections were evaluated with grading scale of 0 to 3 for 6 parameters (perivascular edema,

Morphologic evaluation scores, and pH, PaO2, PaCO2, MawP, and MAP values are reported as mean±SD. Intergroup comparisons were performed using Kruskal-Wallis one-way analysis of variance. Dunn’s multiple comparisons test was used for post-hoc analysis when p<0.05. Wilcoxon Mann-Whitney U test was used for intragroup analysis. Chi-square test was used to compare positive blood cultures among groups. Kaplan-Meier curves and log-rank test were used to analyze bacterial translocation. In all analyses, p<0.05 was considered statistically significant.

1st blood culture Blood gas analyses

2nd blood culture

3th blood culture

4th blood culture

5th blood culture

Last blood culture Blood gas analyses

Stabilization 15 min Induction of anesthesia

P. aeruginosa

30 min

15 min 1st RM

2nd RM

15 min 3rd RM

15 min

60 min

4rd RM

Figure 2. Schematic diagram of experimental protocol.

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blood cultures were present in Group 4. In Fig. 3, the KaplanMeier curve shows percentage of positive blood cultures in terms of time in each group (p=0.0012, log-rank test).

RESULTS Blood Cultures All rats survived until the end of the experiment. Positive blood cultures were observed 15 minutes after the first maneuver in 1 rat Group 1, 2 rats in Group 2, and 5 rats in Group 3 (Table 1). In Group 3, positive blood cultures were observed in all rats after the third maneuver. Group 4 and Group 3 culture results differed at all times except baseline. Blood culture results obtained following third RM revealed that the number of positive cultures in Group 3 was significantly different than in Group 2 (OR: 0.02; 95% CI: 0.0009 to 0.55, p=0.007) and Group 4 (OR: 0.003; 95% CI: 0.0000 to 0.19, p=0.0002). By the end of the experiment, all blood cultures were positive in Groups 1, 2, and 3, but no positive

Blood Gas Analysis, and Hemodynamic and Mechanical Ventilation Variables Baseline pH, PaO2, PaCO2, MawP, and MAP were similar in all groups (Table 2). When baseline and end-of-experiment values were compared, PaO2 was lower in Groups 1, 2, and 3, though the difference was significant only in Group 3 (p=0.004). By the end of the experiment, the PaO2 value in Group 4 was significantly higher than that in Groups 1, 2, and 3. In addition, PaCO2 was decreased in all experimental groups. However, no significant differences between baseline and final PaCO2 values were observed.

Table 1. Time course of positive blood culture results

Baseline 1st RM

2nd RM

3rd RM

4th RM

75 min after last RM

Group 1 (n=8)

Group 2 (n=8)

2† 5

Group 3 (n=8)

Group 4 (n=8)

0* 0* 0†≠ 0§ 0

RM: Recruitment maneuver. *p<0.05, significantly different from Group3; †p<0.05, significantly different from Group3; ≠p<0.05, significantly different from Group1; § p<0.05, significantly different from Groups1, 2, and 3.

Table 2. Oxygenation, and hemodynamic and mechanical ventilation variables

Group 1

Group 2

Group 3

Group 4

pH Baseline

7.42±0.05 7.41±0.04 7.41±0.03 7.41±0.02

7.45±0.04* 7.44±0.004 7.38±0.05 7.41±0.03

End of experiment

PaO2 (mmHg) Baseline

End of experiment

263.12±130 221.0±40.5 243.0±50.7 254.0±31.8 226.7±61* 189.0±55.8* 166.6±30.2*† 310.0±51.4

PaCO2 (mmHg) Baseline

36.2±6.3 35.2±3.8 32.2±4.6 32.1±4.8

32.2±6.2

End of experiment

31.9±3.2

30.3±4.5

29.0±2.8

MAP (mmHg) Baseline

96.2±8.3 94.0±16.2 90.6±7.5 91.5±12.9

60.2±8.5*† 61.6±12.4*† 53.6±8.1*† 80.6±8.8

End of experiment

MawP (cmH2O) Baseline

4.8±0.6 4.5±1.2 4.4±1.6 4.1±0.7

5.6±0.6

End of experiment

5.6±0.7

5.7±0.6

5.3±1.2

VT (mL) Baseline

8.12±1.2 8.0±1.3 8.12±1.5 8.8±0.8

8.8±0.8

End of experiment

8.6±0.7

8.3±1.8

8.1±1.1

MAP: Mean arterial pressure; MawP: Mean airway pressure; VT: Tidal volume. *p<0.05, significantly different from Group 4; †p<0.005, significantly different from baseline.

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Percent of positive blood culture (%)

100

were seen in Group 3. Intra-alveolar hemorrhage, intra-alveolar macrophage, and polymorphonuclear leukocyte infiltration were significantly different among the groups (p<0.05).

Group 1 Group 2 Group 3

Group 4

DISCUSSION

60 40 20

Time (min)

100

150

Figure 3. Kaplan-Meier curve showing percentage of positive blood cultures according to time. Group 1: Pressure group; Group 2: time group; Group 3: modified sigh group; Group 4: control group.

In addition, MAP was monitored continuously throughout the experiment, though only 6 MAP values for each rat were included in statistical analysis. Compared to baseline values, MAP had decreased in all groups by the end of the experiment. These decreases were statistically significant in Groups 1, 2, and 3, but not in the control group. A total of 4 mL blood was obtained for blood gas analyses and blood cultures throughout the study, and the same amount of colloid was used to replace blood loss. The amounts of NaCl used during the study period were 4.9±1.6 mL in Group 1, 4.5±1.6 mL in Group 2, 5.5±1.6 mL in Group 3, and 3.4±1.3 mL in Group 4. Wet:dry weight ratio was higher in Group 3 (5.3±0.7), compared to Group 1 (4.5±1.5), Group 2 (4.6±2.1), and Group 4 (4.6±0.3), though the differences were not statistically significant.

Histology Results The right lung was evaluated for 6 pathological changes (Table 3). One of the most striking results was that the highest scores

Primary findings were as follows: 1. RMs had positive blood cultures. 2. Modified sigh had negative effect on bacterial translocation, histopathology, and oxygenation. Investigated in the present study were the influences of different RMs with the same inflation pressure-time product on bacterial translocation from the lungs to the bloodstream, and the modified sigh group was found to be at highest risk. Many experimental studies have shown that bacteria translocate from the lungs to the bloodstream via mechanical ventilation.[7–10] Mechanical ventilation strategies associated with high VT and high airway pressure can produce microvascular injury in the lungs, leading to pulmonary edema, which results in lymphatic flow acceleration that allows bacteria to enter systemic circulation.[13,14] Deterioration of mucociliary activity caused by mechanical ventilation can also facilitate passage of bacteria by disrupting bacterial clearance. The bacteria may be forced to spread out of the airway due to the physical impact of positive pressure, which is reported to be more significant in small animals.[1] The highest rate of bacterial translocation via repeated RMs was observed in the modified sigh group. This rate, observed particularly in the early stages, indicated that repetitive opening and closing can cause more severe lung injury than exposure to high pressure or prolonged exposure to pressure. In an experimental study, Tschumperlin et al. demonstrated that repeated intermittent distention in alveolar cell culture leads to more inflammatory mediator secretion than fixed continuous distension.[15] During histopathologic examination in the present study, intra-alveolar hemorrhage and intra-alveolar macrophage infiltration were found to be more significant in the modified sigh group. Though not statistically significant, other histopathologic parameters indicating lung injury were also found to be higher in the modified sigh group.

Table 3. Quantitative pathology scores of groups

Group 1

Group 2

Group 3

Group 4

Perivascular edema

0.33±0.50 0.50±0.70 0.80±0.78 0.25±0.50 0.44

Peribronchial lymphocyte infiltration

1.55±1.01

1.40±0.69

2.00±0.66

0.75±0.50

Intra-alveolar hemorrhage

0.88±0.33

1.10±0.73

1.60±0.84

0.50±0.57† 0.04

Intra-alveolar macrophage

0.33±0.70* 0.60±0.69 1.50±0.84 0.50±1.00* 0.02

Interstitial mononuclear cell infiltration

2.00±0.86

2.20±0.91

2.30±0.67

1.00±0.00† 0.052

Interstitial PNL infiltration

1.55±1.01

1.80±0.78

2.40±0.69

1.00±0.81† 0.048

0.06

Total 1.11±0.98α 1.26±0.95α 1.76±0.90 0.66±0.63α <0.0001 PNL: Polymorphonuclear leukocytes; *p<0.05, significantly different from Group 3; αp<0.0001, significantly different from Group 3; †p<0.05, significantly different from Group 3.

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In the 3 experimental groups, different numbers of positive blood cultures were observed after the first maneuver. This early bacteremia supports the hypothesis that application of mechanical ventilation can cause susceptibility to bacteremia. Lin et al. similarly reported that translocation of the instilled bacteria can lead to positive blood culture in spite of preventive artificial ventilation strategies (VT: 7 mL/kg; PEEP: 5 cmH2O).[16] As mentioned in the methodology of the present study, there was an interval of 1 hour between the initiation of mechanical ventilation and sampling of the first positive blood culture. This interval apparently provided the necessary time for translocation. In a previous study conducted by the present study group, an RM (45 cmH2O/30 sec) had been applied every 15 minutes for 2 hours on rats that had been administered intratracheal Pseudomonas aeruginosa, and positive blood culture was not detected.[9] However, in the present study, the rats were administered mechanical ventilation for 45 minutes prior to the first RM. This interval may have allowed bacteria to spread across the alveoli. Due to several environmental factors, reduced bacterial lag time increasing the number of bacteria may also have played a role in the translocation. Another important difference is that mechanical ventilation frequency was 60/minute, and decrease in PaCO2 values was observed at the end of the study, compared to the baseline values. Cakar et al. used mechanical ventilation with a frequency rate of 30/minute, and PaCO2 increased in the RM group. Stretch injury due to mechanical ventilation could have been avoided by hypercapnic acidosis, and no growth may have been noticed in blood cultures, a suspicion that has been supported in the literature.[17,18] A third difference between previous studies and the present is that, despite fluid resuscitation, MAP decreased, compared to baseline, in all groups except for the control group by the end of the study. It is thought that hypotension due to impaired circulation and repetitive opening and closing may have made the modified sigh group more susceptible to lung injury. That the highest rate of oxygenation deterioration, the earliest and most pronounced growth on blood culture, and the highest, though still not significant, wet:dry ratio were observed in the modified sigh group has led the authors to suspect that the mechanism somehow causes increased damage to lungs, in spite of inflation pressure-time product and baseline ventilation parameters being identical to those of the other RMs. Though the 3 experimental groups were exposed to high pressure for the same amount of time, the method was different. PIP of 40 cmH2O and PEEP of 3 cmH2O caused repetitive opening and closing in the modified sigh group for 1 minute. It is thought that, because high levels of pressure elicit opening, the repetitive opening and closing result in damage to the alveoli. While duration of exposure to high pressure was the same, a constant level of pressure was applied with no variation in the pressure and time groups. Compared to the time group, growth was observed earlier and in 132

greater amounts in the pressure group, though there was no statistically significant difference. However, the literature supports that of these 2 important RM components, pressure has more impact than time.[19–21] Many interesting points have been made in the “pressure vs time” debate. Pressure and time are primary factors in recruitment and derecruitment of the alveoli. Based on the mathematical model developed by Bates and Irwin, alveoli not only have critical opening and closing pressure, but duration of opening and closing changes in acutely injured lungs.[22] Several limitations affected the present study. First, such differentiations between the time and the pressure groups were not made, because volumetric measurements were not taken. Second, results of 40 cmH2O/40 sec and 20 cmH2O/20 sec groups were not compared with 40 cmH2O/20 sec and 20 cmH2O/40 sec groups. Third, the same maneuvers used in an ARDS model may have produced different results. In conclusion, all RMs eventually resulted in bacteremia. Higher severity of VILI occurred in the modified sigh group, evidenced by bacterial translocation and histopathological evaluation, despite it having the same inflation pressure-time product as the other RM groups.

Acknowledgments This study was performed in the experimental laboratory founded by Prof. Dr. Kutay AKPIR at İstanbul University’s Department of Anesthesiology and Intensive Care. In addition, the authors thank Fatma Vildan Adali for assistance with all randomization procedures. Conflict of interest: None declared.

REFERENCES 1. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294–323. 2. Kacmarek RM, Kallet RH. Respiratory controversies in the critical care setting. Should recruitment maneuvers be used in the management of ALI and ARDS? Respir Care 2007;52:62235. 3. Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky AS. Safety and efficacy of a sustained inflation for alveolar recruitment in adults with respiratory failure. Intensive Care Med 1999;25:1297–301. 4. Grasso S, Mascia L, Del Turco M, Malacarne P, Giunta F, Brochard L, et al. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002;96:795–802. 5. Barbas CSV, Silva E, Garrido A, Assunção M, Hoelz C, Meyer EC, et al. Recruitment maneuvers with different pressure control levels inARDS patients (abstract). Am J Respir Crit Care Med 2001;163:767. 6. Constantin JM, Jaber S, Futier E, Cayot-Constantin S, Verny-Pic M, Jung B, et al. Respiratory effects of different recruitment maneuvers in acute respiratory distress syndrome. Crit Care 2008;12:50. 7. Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini JJ. Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs. Crit Care Med 1997;25:1733–43.

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Ergin Özcan et al. Effects of different recruitment maneuvers on bacterial translocation and ventilator- induced lung injury 8. Verbrugge SJ, Sorm V, van’t Veen A, Mouton JW, Gommers D, Lachmann B. Lung over inflation without positive end-expiratory pressure promotes bacteremia after experimental Klebsiella pneumoniae inoculation. Intensive Care Med 1998;24:172–7. 9. Cakar N, Akinci O, Tugrul S, Ozcan PE, Esen F, Eraksoy H, et al. Recruitment maneuver: does it promote bacterial translocation? Crit Care Med 2002;30:2103–6. 10. Ozcan PE, Cakar N, Tugrul S, Akinci O, Cagatay A, Yilmazbayhan D, et al. The effects of airway pressure and inspiratory time on bacterial translocation. Anesth Analg 2007;104:391–6. 11. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997;99:944–52. 12. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347– 54. 13. Dreyfuss D, Soler P, Saumon G. Mechanical ventilation-induced pulmonary edema. Interaction with previous lung alterations. Am J Respir Crit Care Med 1995;151:1568–75. 14. Brigham KL. Mechanisms of lung injury. Clin Chest Med 1982;3:9–24. 15. Tschumperlin DJ, Oswari J, Margulies AS. Deformation-induced injury

of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am J Respir Crit Care Med 2000;162(2 Pt 1):357–62. 16. Lin CY, Zhang H, Cheng KC, Slutsky AS. Mechanical ventilation may increase susceptibility to the development of bacteremia. Crit Care Med 2003;31:1429–34. 17. Contreras M, Ansari B, Curley G, Higgins BD, Hassett P, O’Toole D, et al. Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism. Crit Care Med 2012;40:2622– 30. 18. Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG. Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med 2008;36:3135–44. 19. Albert SP, DiRocco J, Allen GB, Bates JH, Lafollette R, Kubiak BD, et al. The role of time and pressure on alveolar recruitment. J Appl Physiol (1985) 2009;106:757–65. 20. Arnal JM, Paquet J, Wysocki M, Demory D, Donati S, Granier I, et al. Optimal duration of a sustained inflation recruitment maneuver in ARDS patients. Intensive Care Med 2011;37:1588–94. 21. Marini JJ. Recruitment by sustained inflation: time for a change. Intensive Care Med 2011;37:1572–4. 22. Bates JH, Irvin CG. Time dependence of recruitment and derecruitment in the lung: a theoretical model. J Appl Physiol (1985) 2002;93:705–13.

DENEYSEL ÇALIŞMA - ÖZET OLGU SUNUMU

Farklı yeniden kazandırma manevralarının bakteri translokasyonu ve ventilatör ilişkili akciğer hasarına etkisi Dr. Perihan Ergin Özcan,1 Dr. Özkan İbrahim Akıncı,1 Dr. İpek Edipoğlu,1 Dr. Evren Şentürk,1 Dr. Sevil Baylan,1 Dr. Atahan Arif Çağatay,2 Dr. Kemal H Türköz,3 Dr. Figen Esen,1 Dr. Lütfi Telci,1 Dr. Nahit Çakar1 1 2 3

İstanbul Üniversitesi İstanbul Tıp Fakültesi, Anesteziyoloji Anabilim Dalı, İstanbul İstanbul Üniversitesi İstanbul Tıp Fakültesi, İnfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, İstanbul Marmara Üniversitesi Tıp Fakültesi, Patoloji Anabilim Dalı, İstanbul

AMAÇ: Bu çalışmada, aynı basınç-zaman ürünlü farklı yeniden kazandırma manevralarının akciğerden kana bakteri geçişine ve ventilatör ilişkili akciğer hasarına etkisi araştırıldı. GEREÇ VE YÖNTEM: Sıçanlara anestezi uygulandıktan sonra trakeotomi açıldı ve basınç kontrollü ventilasyon modunda ventilasyona başlandı. Ardından Pseudomonas aeruginosa içeren solüsyon trakeotomi kanulünden verilip, ventilasyona bu şekilde 30 dakika devam edildikten sonra sıçanlar rastgele dört gruba ayrıldı. Grup 1: “Sustained inflation” (SI); Grup 2: Düşük basınç SI (LPSI); Grup 3: Modifiye Sigh; Grup 4: Kontrol grubu. Kan kültürleri bakteri verilmeden önce, ilk bir saat her yeniden kazandırma manevrasından sonra ve son manevradan 75 dakika sonra olmak üzere toplam altı kez alındı. Daha sonra sıçanlar arter içine verilen sodium tiyopental ile sakrifiye edilerek toraks açılıp akciğerler çıkarıldı. Sol akciğer yaş kuru ağırlık (WW/DW) oranı için, sağ akciğer patolojik inceleme için kullanıldı. BULGULAR: Kan kültürlerine bakıldığında Grup 3 de daha erken dönemde kan kültürlerinde üreme tespit edildi. Grup 3’de patolojik skorlar daha yüksek bulundu. TARTIŞMA: Bakteriyel translokasyon ve histopatolojik değerlendirmelerle modifiye Sigh ile daha ciddi ventilatör ilişkili akciğer hasarı oluşmuştur. Anahtar sözcükler: Bakteriyel translokasyon; mekanik ventilasyon; sign; ventilator ilişkili akciğer hasarı; yeniden kazandırma manevrası. Ulus Travma Acil Cerrahi Derg 2016;22(2):127–133

doi: 10.5505/tjtes.2015.05406

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EXPERIMENTAL STUDY

Neuroprotective effects of adalimumab on rats with experimental peripheral nerve injury: An electron microscopic and biochemical study Ersin Polat, M.D.,1 Ergün Dağlıoğlu, M.D.,2 Güner Menekşe, M.D.,3 Mehmet Serdar Dike, M.D.,4 Çağatay Özdöl, M.D.,5 Cezmi Çağrı Türk, M.D.,5 Ali Erdem Yıldırım, M.D.,2 Fatih Alagöz, M.D.,2 Ali Dalgıç, M.D.,2 Deniz Belen, M.D.2 1

Department of Neurosurgery, Bafra State Hospital, Samsun-Turkey

Department of Neurosurgery, Ankara Numune Training and Research Hospital, Ankara-Turkey

Department of Neurosurgery, Ankara Training and Research Hospital, Ankara-Turkey

Department of Neurosurgery, Ceyhan State Hospital, Adana-Turkey

Department of Neurosurgery, Antalya Training and Research Hospital, Antalya-Turkey

ABSTRACT BACKGROUND: Adalimumab, a new-generation anti-inflammatory agent, exerts its effect through tumor necrosis factor α (TNF-α), secreted from immune response cells such as macrophages and lymphocytes. TNF-α has been shown to play an important role in the processes of apoptosis and demyelination, and blockage of its activity may improve neural healing. Investigated in the present study is the probable neuroprotective influence of adalimumab in rats using a peripheral nerve injury model with biochemical and electron microscopic methods. METHODS: Forty adult Wistar albino rats were randomly divided into control, sciatic nerve trauma, low-dose adalimumab, and highdose adalimumab groups. Six rats from each group were assigned biochemical microscopy, and 4 were assigned electron microscopy. Neural injury was induced with clip compression following dissection of sciatic nerves. Adalimumab was simultaneously injected. The rats were sacrificed after 2 weeks of adalimumab treatment. RESULTS: Nerve tissue lipid peroxidation values were found to be significantly decreased in both the low- and high-dose adalimumab treatment groups, compared to the group subjected only to sciatic nerve trauma. CONCLUSION: Results demonstrate that adalimumab is an effective neuroprotective agent for neural healing, particularly in the early phase. Keywords: Adalimumab; electron microscope study; lipid peroxidation; neuroprotection, peripheral nerve injury; rat; TNF-α.

INTRODUCTION Peripheral nerve injuries are common, significant causes of long-term morbidity.[1] Incidence is approximately 2.8% of all cases of trauma.[2] Upon exposure to nerve compression, a Address for correspondence: Ergün Dağlıoğlu, M.D. Ankara Numune Eğitim ve Araştırma Hastanesi, Nöroşirürji Kliniği, Ankara, Turkey Tel: +90 312 - 508 52 75 E-mail: ergundaglioglu@gmail.com Qucik Response Code

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spectrum of functional loss may occur, from slight weakness to total paralysis of muscles, or from total loss of sensation to mild paresthesias. Degree of severity is related to the involved nerve and location, level of pressure, and duration of compression. Nerve damage may continue, even after relief of compression.[3] Ischemic reperfusion injury is responsible for the majority of damage to nervous tissue,[4] and typically occurs due to free oxygen radicals and inflammatory reactions, which are caused by reduction reactions and neutrophilic infiltrations, respectively.[5] Contemporary management of peripheral nerve injuries includes the use of non-steroidal anti-inflammatory drugs, steroids, nerve-growth factors, thyroid hormones, growth hormone, adrenocorticotropic hormone, and insulin-like peptides.[6,7] Investigated in the present Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Polat et al. Neuroprotective effects of adalimumab on rats with experimental peripheral nerve injury

study were the effects of a monoclonal antibody agent, adalimumab, on injured nerve tissue in rats, using an experimental clip compression injury model.

signed region and stained with uranyl acetate-lead citrate for examination under microscope with EVO LS10 transmission attachment.

MATERIALS AND METHODS

Measurement of thiobarbituric acid (TBA)-reactive components was used to ascertain lipid peroxidation, as defined by Mihara and Uchiyama.[8] Tissue samples were homogenized in potassium phosphate buffer solution 1:10 (w:v) using Dounce homogenization. After 0.5 mL homogenate was mixed with 3 mL of 1% phosphoric acid, 1 mL of 0.67% TBA was added. Tubes were suspended in boiling water for 45 minutes. After cooling, TBA components were separated into butanol, and 532 nm absorbance was determined. TBA reactive components-malondialdehyde complex base molar absorption value was determined as 0.156x105 M-1 cm-1, and level of lipid peroxide was calculated as nanomoles per gram of tissue.

Forty male Wistar albino rats, with body weights ranging from 180–210 g and aged between 3–5 months, were used. The rats were housed in cages (each accommodating 4) in a room with controlled temperature of 18–21°C and with automatic lighting (alternating 12-hour periods of light and dark). Food and water were available ad libitum. The rats were randomly categorized into 4 groups: the control group, the trauma group, and the low- and high-dose adalimumab groups. Following overnight fast, the rats were weighed prior to surgical procedure, which was performed under general anesthesia. The rats were anesthetized intraperitoneally with mixture of 10 mg/kg xylocaine (Rompun® 2% solution; Bayer, Leverkusen, Germany) and 50 mg/ kg ketamine hydrochloride (Ketalar® 5% solution; ParkeDavis Pharmaceutical Industries under license of Eczacıbaşı, İstanbul, Turkey). Once anesthetized, the rats were placed in prone position with extremities aside. Superficial sterilization was achieved using polyvinylpyrrolidone iodine (Polyod® 10% solution; Drogsan Pharmaceuticals, İstanbul, Turkey) to cover the sacral area and both lower extremities. Longitudinal skin incision was made in the right lower extremity at trochanter level. Following dissection, the sciatic nerve was exposed by vertically incising the gluteus maximus. The sciatic nerve was meticulously dissected, preserving the perineurium, without tractional injury. The nerve was compressed for 2 minutes using a Yasargil FE 693 temporary aneurysm clip with a closing force of 50 g/cm2 (Aesculap, Inc., Corporate Parkway Center Valley, PA, USA). The injured region was proximally and distally marked with Prolene polypropylene thread (Ethicon, Inc., Somerville, NJ, USA). Procedure was repeated in each rat. Those in the low- and high-dose groups were intraperitoneally administered adalimumab 3 times (during surgery, and at 1 and 2 weeks of the injury) in 5 mg/kg and 50 mg/kg doses, respectively. Two weeks later, the rats were sacrificed with high-dose anesthesia, and sciatic nerve segments were removed. Tissue samples were cut into 1-mm3 pieces and kept in 0.1 M, phosphate-buffered, 2.5% glutaraldehyde solution (pH 7.4) for 2-hour fixation. After being washed 3 times with buffered solution, the samples were exposed to 1% osmium tetroxide for 1 hour as postfixation. They were later dehydrated in alcohol. Finally, samples processed with propylene oxide and blocs were prepared with embedding material, using the Araldite® CY212 kit (Huntsman Advanced Materials LLC, Salt Lake City, UT, USA). Blocks were polymerized in an oven of 560°C for 48 hours, after which semi-thin sections were obtained and stained with toluidine blue for examination under light microscopy. Thin sections were taken from the asUlus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

RESULTS Test results revealed differences in measured values among the groups. Analysis revealed a statistically significant change in peroxidation values in the trauma group, compared to the control group (p=0.02; Table 1). In addition, comparison revealed statistically significant differences between the control group and low-dose group (p=0.002), as well as between the low- and high-dose groups (p=0.009), but not between the control group and high-dose group (p=0.394). Results indicated that adalimumab effectively decreased lipid peroxidation with demonstrated positive effects on the healing of injured nervous tissue (high-dose vs low-dose comparison: p=0.009). The high-dose adalimumab group clearly benefitted the most, in terms of nerve healing (Table 1). As a result of electron microscopy, sciatic nerve trauma induced phagocytic transformations in Schwann cells, particularly those on unmyelinated fibers (Fig. 1). It was hypothesized that low-dose adalimumab therapy would accelerate the healing process, resulting in fewer Schwann cells with phagocytic activity (Fig. 2a). Increase in number of mitochondria was observed in this group (Fig. 2b). The high dosage of adalimumab corresponded to more positive effects of healing, achieving a cross-sectional histological appearance quite Table 1. Results of Mann-Whitney U test, used to compare differences among groups Groups p Trauma and control

0.02

Trauma and low-dose adalimumab

0.026

Trauma and high-dose adalimumab

0.002

Low-dose adalimumab and control

0.002

High-dose adalimumab and control

0.394*

High-dose adalimumab and low dose adalimumab

0.009

*: Statistically significant.

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similar to that of the control group. However, the high dosage was also shown to increase number of mitochondria and oxidative stress (Figs. 3a, b). While high-dose adalimumab may accelerate the regeneration process, it may also have negative effects on structure of myelinated nerve fibers.

DISCUSSION

Figure 1. Electron microscopic examination of the trauma group. My: Myelinated nerve fibers; M: Unmyelinated nerve fibers; En: Endoneurium; t: Schwann cell nucleus; ì: Axoneme; ù: Degenerated Schwann cells, including autophagic vacuoles.

(a)

Factors affecting the healing process following peripheral nerve injury also determine clinical improvement. In addition to primary injury of the peripheral nerve, nerve compression causing secondary ischemic injury is a well-known factor that affects the healing process.[9] Through this process, inflammatory reaction has beneficial and harmful effects on nerve tissue. Extensive degeneration in the axons and myelin sheath follows injury before being regenerated during the healing process. Cytokines, particularly TNF-α, play a major role in inflammatory reactions. TNF-α has important pro-

(b)

Figure 2. (a) Electron microscopic examination of low-dose adalimumab group. (b) Another section of low-dose group. My: Myelinated nerve fibers; M: Unmyelinated nerve fibers; En: Endoneurium; t: Schwann cell nucleus; ì: Axoneme; ù: Degenerated Schwann cells, including autophagic vacuoles; ¤: Mitochondria in axon and Schwann cells.

(a)

(b)

Figure 3. (a) Electron microscopic examination of high-dose adalimumab group. (b) Another section of high-dose group. My: Myelinated nerve fibers; En: Endoneurium; t: Schwann cell nucleus; ì: Axoneme; ¤: Mitochondria in axon and Schwann cells; Å: Tubulus of rough endoplasmic reticulum.

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inflammatory properties in the peripheral immune system, regulating antigen-presenting cellular activities and autoreactive T cells in apoptosis.[10–13] In overall pathogenesis of inflammatory demyelination, invasion by autoreactive T cells, in addition to interactions between adhesion molecules and metalloproteinases, is important.[8,14,15] Results of clinical trials concerned with autoimmune arthritis, ulcerative colitis, and Crohn’s disease (in which increased inflammatory reaction and increased TNF-α levels are accounted for in pathogenesis), have supported the assumption that decreased levels of TNF-α may have a positive effect on nerve healing.[16] In that respect, adalimumab-positive, anti-inflammatory effectiveness, as shown in cases of psoriasis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, would have similar beneficial impact on inflammatory nervous system demyelination.[17] This was also demonstrated in an experimental autoimmune encephalitis model; with inhibition of TNF-α, demyelinating lesions in CNS showed regression.[18] In the present study, Schwann cells, particularly on non-myelinated fibers in the sciatic nerve, underwent pronounced phagocytic transformation, an indicator of the natural healing process. Results indicated that even with lower doses of adalimumab, the number of Schwann cells with phagocytic functions decreased, and the healing process was simultaneously accelerated. Moreover, it was interesting to note that increase in mitochondria could be induced, even with relatively small doses. With higher doses of adalimumab, regeneration was precipitated, so that a structural appearance comparable to that of the control group could be achieved on histological examination, particularly in non-myelinated nerves. With regard to healing, there is an obvious difference between myelinated and non-myelinated fibers, which may be due to penetration level of the drug into target tissues. Following the relief of peripheral nerve compression, ease in circulation provides required nutrients and oxygen to the nervous tissue. Subsequently, reperfusion injury can ensue, with free oxygen radicals and consequent increase in lipid peroxidation.[19,20] Present results indicate that adalimumab has statistically significant, doserelated beneficial effects on decrease in lipid peroxidation, acting as a neuroprotective agent. The present is the first study to report neuroprotective activity parallel to anti-inflammatory effects in an alternative mechanism to previously reported cyclooxygenase and lipoxygenase pathways.[20,21]

Conclusion The present study demonstrated that adalimumab caused particular changes in phagocytic activity, with positive effects on the healing process of nervous tissue. Beneficial effects on lipid peroxidation and anti-inflammatory activity support the adoption of adalimumab, which has neuroprotective properties, as a future candidate for treatment of patients with peripheral nerve injury. Conflict of interest: None declared. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

REFERENCES 1. Li Y, Bickel KD, Im MJ, Hu L, Dellon AL, Vander Kolk CA, et al. Effects of deferoxamine on ischemia/reperfusion injury after peripheral nerve compression. Ann Plast Surg 1996;36:365–9. 2. Lundborg G, Dahlin LB. Anatomy, function, and pathophysiology of peripheral nerves and nerve compression. Hand Clin 1996;12:185–93. 3. Kollias G, Douni E, Kassiotis G, Kontoyiannis D. The function of tumour necrosis factor and receptors in models of multi-organ inflammation, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Ann Rheum Dis 1999;58 Suppl 1:I32–9. 4. Van der Zee CE, Brakkee JH, Gispen WH. Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat. Br J Pharmacol 1991;103:1041–6. 5. Wang X, Hu W, Cao Y, Yao J, Wu J, Gu X. Dog sciatic nerve regeneration across a 30-mm defect bridged by a chitosan/PGA artificial nerve graft. Brain 2005;128:1897–910. 6. Rabinovsky ED. The multifunctional role of IGF-1 in peripheral nerve regeneration. Neurol Res 2004;26:204–10. 7. Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44:1977–83. 8. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978;86:271–8. 9. Chen MB, Zhang F, Lineaweaver WC. Luminal fillers in nerve conduits for peripheral nerve repair. Ann Plast Surg 2006;57:462–71. 10. Hong J, Smith TJ, Ho CT, August DA, Yang CS. Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem Pharmacol 2001;62:1175–83. 11. Fern R, Harrison PJ. The contribution of ischaemia and deformation to the conduction block generated by compression of the cat sciatic nerve. Exp Physiol 1994;79:583–92. 12. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997;185:1573–84. 13. Kieseier BC, Krivacic K, Jung S, Pischel H, Toyka KV, Ransohoff RM, et al. Sequential expression of chemokines in experimental autoimmune neuritis. J Neuroimmunol 2000;110:121–9. 14. Kieseier BC, Clements JM, Pischel HB, Wells GM, Miller K, Gearing AJ, et al. Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome. Ann Neurol 1998;43:427–34. 15. Katiyar SK, Mukhtar H. Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols. Carcinogenesis 1997;18:1911–6. 16. Sharief MK, Hentges R. Association between tumor necrosis factoralpha and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325:467–72. 17. Selmaj K, Raine CS, Cross AH. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol 1991;30:694–700. 18. Shah SB, Hanauer SB. Risks and benefits of the use of concomitant immunosuppressives and biologics in inflammatory bowel disease. Rev Gastroenterol Disord 2008;8:159–68. 19. Sayan H, Ozacmak VH, Ozen OA, Coskun O, Arslan SO, Sezen SC, et al. Beneficial effects of melatonin on reperfusion injury in rat sciatic nerve. J Pineal Res 2004;37:143–8. 20. Kieseier BC, Kiefer R, Gold R, Hemmer B, Willison HJ, Hartung HP. Advances in understanding and treatment of immune-mediated disor-

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cytokines in the development and function of the autoreactive T-cell repertoire. Res Immunol 1997;148:307–12.

DENEYSEL ÇALIŞMA - ÖZET OLGU SUNUMU

Deneysel periferik sinir hasarı yapılan sıçanlarda adalimumabın nöroprotektif etkileri: Elektron mikroskobik ve biyokimyasal bir çalışma Dr. Ersin Polat,1 Dr. Ergün Dağlıoğlu,2 Dr. Güner Menekşe,3 Dr. Mehmet Serdar Dike,4 Dr. Çağatay Özdöl,5 Dr. Cezmi Çağrı Türk,5 Dr. Ali Erdem Yıldırım,2 Dr. Fatih Alagöz,2 Dr. Ali Dalgıç,2 Dr. Deniz Belen2 Bafra Devlet Hastanesi, Nöroşirürji Kliniği, Samsun Ankara Numune Eğitim ve Araştırma Hastanesi, Nöroşirürji Kliniği, Ankara 3 Ankara Eğitim ve Araştırma Hastanesi, Nöroşirürji Kliniği, Ankara 4 Ceyhan Devlet Hastanesi, Nöroşirürji Kliniği, Adana 5 Antalya Eğitim ve Araştırma Hastanesi, Nöroşirürji Kliniği, Ankara 1 2

AMAÇ: Yeni nesil bir antienflamatuvar ajan olan adalimumab, etkisini makrofaj ve lenfositler gibi hücresel immün yanıt elemanlarından salınan tümör nekrozu faktörü (TNF-α) üzerinden gösterir. Özellikle apoptoz ve demiyelinizasyon gibi süreçlerde önemli rol oynayan TNF-α aktivitesinin önlenmesi ile nöral iyileşmede artış gözlenebilir. Bu çalışmada, sıçan deneysel siyatik sinir hasarı modelinde adalimumabın nöroprotektif etkinliği elektron mikroskobik ve biyokimyasal olarak incelendi. GEREÇ VE YÖNTEM: Çalışmada toplam 40 adet Wistar albino cinsi sıçan sham, travma, düşük doz adalimumab ve yüksek doz adalimumab olmak üzere rastgele dört gruba ayrıldı. Her gruptan altı sıçan biyokimyasal ve dört sıçan elektron mikroskobik analizde kullanıldı. Siyatik sinirleri diseke edilen sıçanlara klip kompresyonu ile periferik sinir hasar modeli uygulandı. Siyatik sinirleri diseke edilen sıçanlara klip kompresyonu ile periferik sinir hasar modeli uygulandı ve eş zamanlı adalimumab tedavisi uygulandı. İki haftalık adalimumab tedavisi sonrası sıçanlar sakrifiye edildi. BULGULAR: Düşük doz ve yüksek doz grubunun her ikisinde de yapılan incelemelerde adalimumabın, sinir dokusu lipid peroksidasyon değerlerini istatistiksel olarak anlamlı biçimde azalttığı görüldü. TARTIŞMA: Bu çalışmanın sonuçları adalimumabın nöral doku iyileşmesinde özellikle erken döneminde etkili nöroprotektif bir ajan olduğunu göstermiştir. Anahtar sözcükler: Adalimumab; elektron mikroskobik çalışma; lipid peroksidasyonu; nöroprotektif etki; periferik sinir hasar; sıçan; TNF-α. Ulus Travma Acil Cerrahi Derg 2016;22(2):134–138

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ORIG I N A L A R T IC L E

Is every intussusception treatment an emergency intervention or surgery? Lütfi Hakan Güney, M.D., Ender Fakıoğlu, M.D., Tuğba Acer, M.D., İbrahim Ötgün, M.D., Esra Elif Arslan, M.D., Müge Sağnak Akıllı, M.D., Akgün Hiçsönmez, M.D. Department of Pediatric Surgery, Başkent University Faculty of Medicine, Ankara-Turkey

ABSTRACT BACKGROUND: Intussusception is the second most common cause of acute abdomen in children, following appendicitis. The aim of the present study was to evaluate the experience of the authors, in an effort to promote intussusception management, especially that of small bowel intussusception. METHODS: Records of intussusception diagnosed between July 2002 and September 2014 were evaluated in terms of patient age, sex, clinical findings, admission time, ultrasonographic findings, treatment methods, and outcomes. RESULTS: Eighty-one patients, 52 males and 29 females, were included (mean age: 10.6 months). Intussusceptions were ileocolic (IC) in 52 cases, ileoileal (IL) in 26, and jejunojejunal ( JJ) in 3. Nineteen (23.5%) patients underwent surgery. Hydrostatic reduction was performed in 45 (55.5%) IC cases. Seventeen (21%) patients with small bowel intussusceptions (SBIs), measuring 1.8-2.3 cm in length, spontaneously reduced. All patients who underwent surgery had intussusceptums ≥4 cm. Three of the 4 intestinal resection cases had history of abdominal surgery. CONCLUSION: If peritoneal irritation is present, patients with intussusception must undergo surgery. Otherwise, in patients with IC intussusception and no sign of peritoneal irritation, hydrostatic or pneumatic reduction is indicated. When this fails, surgery is the next step. SBIs free of peritoneal irritation and shorter than 2.3 cm tend to spontaneously reduce. For those longer than 4 cm, particularly in patients with history of abdominal surgery, spontaneous reduction is unlikely. Keywords: Benign intussusception; intussusception; small bowel intussusceptions; spontaneous reduction; transient intussusception.

INTRODUCTION Intussusception is the second most common cause of acute abdomen in children, following appendicitis.[1–3] It occurs most frequently in the first 3 years of life, and peaks between the third and ninth months. Sudden onset of vomiting, intermittent abdominal pain, and rectal bleeding in the form of currant jelly are typical symptoms.[3–5] While aspects of etiology still require clarification, upper respiratory tract infection, adenovirus-associated gastroenteritis, and particularly rotavirus vaccine and infection have been widely Address for correspondence: Lütfi Hakan Güney, M.D. 6. Cadde, No: 70/1, Bahçelievler, 06490 Ankara, Turkey Tel: +90 312 - 215 72 28 E-mail: dr.guney@gmail.com Qucik Response Code

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thought to contribute.[6–10] If treatment is delayed, cascade beginning with vascular congestion and edema of intussuscepted intestinal wall may demonstrate a highly morbid, even fatal course, with tissue ischemia, necrosis, and intestinal perforation.[11] Intussusception is diagnosed based on characteristic findings of target (doughnut) and/or pseudokidney signs on ultrasonography (USG), which is highly accurate.[12,13] Depending on the clinical situation, treatment for ileocolic (IC) and colocolic (CC) intussusception may be non-surgical (pneumatic or hydrostatic pressure enemas under fluoroscopy or USG) or surgical (operative, manual reduction and/or resection or enterostomy intervention as needed). If spontaneous reduction of small bowel intussusceptions (SBIs) does not occur, the only means of reduction is surgery. The terms “transient” or “benign” intussusception are used for those that have spontaneously reduced. However, criteria to determine the treatment of choice (surgery or observation) has been a subject of debate.[12] 139

Güney et al. Is every intussusception treatment an emergency intervention or surgery?

The aim of the present study was to evaluate experience with intussusception between July 2002 and September 2014, and to gather data in an effort to promote management of intussusception, particularly SBI, a debated issue.

ception type, and treatment methods. Statistical assessment of data was conducted by the biostatistics department. SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA) was used for data analysis.

MATERIALS AND METHODS

The present study was approved by the local institutional review board (Project no: KA15/50).

At the authors’ hospital, intussusception is almost always diagnosed in an emergency setting. Pediatric surgeons are consulted by pediatric emergency physicians on patients suspected of having diseases that require surgery upon presenting to emergency department. When history and physical examination suggest intussusception, definite diagnosis is reached upon confirmation with USG findings. Pediatric surgeons are consulted also on patients incidentally reported to have intussusception on USG performed for other reasons. Once diagnosed, reduction of IC or CC intussusception is attempted as soon as possible, either surgically or non-surgically, depending upon the patient’s clinical situation. For cases of ileoileal (IL) and jejunojejunal (JJ) intussusception free of clinical deterioration, intestinal obstruction, and acute abdominal findings, preferred treatment is close observation, with physical examination every 2 hours and USG at least once every 12 hours. After the first eventless 24-hour-period, the patient is fed orally, and is discharged following the second eventless period. Upon sign of clinical deterioration with persisting intussusception on USG, surgery is performed.

RESULTS A total of 81 patients, 52 males and 29 females, were included. Mean age was 10.6 months (1–102 months). When grouped according to age (younger than 1 year old, aged between 1 and 4 years, and older than 4 years), the groups included 27, 41, and 13 patients, respectively. Based on USG findings, 3 types of intussusception were detected: IC, IL, and JJ. Distribution of types among age groups is presented in Table 1. USG was performed by the USG team of the department of radiology, which comprises 5 academic staff members. Chief complaint was abdominal pain in all patients. Additional complaint was vomiting in 67 cases (82.7%), and blood in stool in 10 cases (12.4%). Abdominal mass was palpated in 5 cases (6.2%). Intussusceptions were IC in 52 patients, IL in 26 patients, and JJ in 3 patients. One of the 52 IC intussusception cases underwent immediate surgery due to acute abdomen. In 45 (55.6% of total) of the remaining 51 cases, hydrostatic reduction was ensured with barium enema concomitant with fluoroscopy. Surgery was performed as needed following unsuccessful hydrostatic reduction attempts in 6 IC intussusception cases.

Cases registered in the electronic database of a tertiary health care center (university hospital) with an ICD-10 code of “intussusception,” indicating definite diagnosis, between July 2002 and September 2014 were retrospectively reviewed. Records were evaluated in terms of patient age, sex, clinical signs upon presentation, admission time, USG data, intussus-

Table 1. Types of intussusception according to age groups

Ileo-colic

Ileo-ileal

Jejuno-jejunal

Total

<1 y.o.* 22

–

1-4 y.o.

>4 y.o.

Total 52 26

3 81

*Year(s) old.

Table 2. Types of intussusception according to management

140

Ileo-colic

Ileo-ileal

Jejuno-jejunal

Total

Hydrostatic reduction

–

Surgery

7 11

1 19

Follow-up

– 15

2 17

Total

52 26

3 81

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Table 3. Admission times according to management Admission time

Invaginated segment

Surgery

Hydrostatic reduction

<24 hours

Ileo-colic

–

Ileo-ileal –

Jejuno-jejunal –

24-72 hours

Ileo-colic

Ileo-ileal 4

Jejuno-jejunal –

>72 hours

Ileo-colic

Ileo-ileal 7

Jejuno-jejunal 1

Total

Nineteen patients (23%) received surgical treatment, 7 for IC, 11 for IL, and 1 for JJ intussusception (Table 2). Mean age of patients who underwent surgery was 3.4 years (min: 7

Figure 1. Typical pseudokidney sign (doughnut sign) indicating IL intussusception. Ultrasonographic view from the right paraumbilical region of a patient with transient SBI.

Follow-up

Total

–

17 81

months, max: 8.5 years). Intestinal resection was performed in 4 of the patients who underwent surgery, all of whom had IL intussusception, with intussuscepted segments ranging between 4 and 10 cm in length. Manual reduction was performed in the remaining 15 patients who underwent surgery, with intussuscepted segments ranging from 4 to 12 cm. Three of the 15 patients had undergone prior abdominal surgery; 1 had undergone liver transplantation (JJ) and 2 had undergone intra-abdominal tumor surgery (IL). Among the 19 patients who received surgical treatment, no leading point was detected in 7 (36.8%). Leading points detected in the others were lymph nodes in 10 (52.6%), Meckel’s diverticulum in 1, (5.3%) and mesenteric cyst in 1 (5.3%). Thirty patients presented to emergency department in the first 24 hours following onset of symptoms. None required surgery; hydrostatic reduction was performed in 18 (60%) and 12 patients (40%) were observed until spontaneous reduction occurred. Twenty-seven patients presented to emergency department services 24–72 hours after symptom onset, 6 of whom (22.2%) underwent surgery, while 18 (66.7%) underwent hydrostatic reduction, and 3 (11.1%) were observed. Twenty-four patients presented more than 72 hours after symptom onset, 13 of whom (54.2%) underwent surgery, while 9 (37.5%) underwent hydrostatic reduction, and 2 (8.3%) were observed until spontaneous reduction occurred (Table 3). Diagnostic USG of IL and JJ intussusceptions revealed lengths of 4–12 cm (mean: 6.1; median: 5.9) in patients who had undergone surgery, while lengths of intussusceptums that had spontaneously reduced were between 10 and 23 mm (mean: 18; median 20; Figs 1, 2). No mortality or morbidity was observed.

Figure 2. A 4-year-old male with transient SBI. Ultrasonographic view of intussusceptum with a vertical section, 1.84 cm in length.

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DISCUSSION If diagnosed early, IC intussusception may be easily treated 141

Güney et al. Is every intussusception treatment an emergency intervention or surgery?

by non-surgical methods including hydrostatic or pneumatic reduction. Surgery is indicated when non-surgical methods fail, or when intestinal perforation or peritoneal irritation is present. Manual reduction, if possible, is the primary goal of surgery. Intestinal necrosis, perforation and sepsis may complicate intussusception, requiring more extensive surgery such as intestinal resection, longer hospital stays; even resulting in mortality in late diagnosed patients.[14,15] Tran et al. reported in a study that included patients from 14 countries that reported rates of surgically treated intussusception range between 2.5% and 95%. The authors attributed this enormous range to differences in ease of hospital accessibility and divergent intervals between onset time of symptoms and treatment initiation time after arrival to hospital (due to local factors). The authors also noted the potential mistake of recording surgically treated intussusception cases in diagnosis databases with codes for gastrointestinal diseases rarely associated with intussusceptions or for potential complications of intussusception, such as “intestinal obstruction.”[16] While the majority (51 cases, 63%) were diagnosed at least 24 hours after onset of the symptoms, 23.5% of cases required surgery. Of the 19 patients who underwent surgery, only 4 (4.9% of the total patient population) required resection of necrotic intussuscepted intestinal segments. All 4 were admitted at least 72 hours after onset of symptoms. This emphasizes the importance of timely intervention and that complaints of abdominal pain and vomiting should not be underestimated.[3,4,17] Hydrostatic or pneumatic reduction is the first treatment option in childhood cases of IC or CC intussusception without perforation and/or peritonitis. Barium and physiological saline solution are used for enema in hydrostatic reduction under fluoroscopic or ultrasonographic vision. No widely accepted, prominent superiority of these methods has been reported in any large, controlled, prospective study.[15,18,19] Experience, personal preference, expertise of the physician involved, and local conditions are the main determinants of the choice of technique.[18] Hydrostatic reduction with barium enema under fluoroscopy was performed in the present study, with a reduction success of 88.2% (45 of 51 reduction attempts), which is acceptable, compliant with the overall success rate for all nonsurgical reduction techniques and higher than the reported success rate of hydrostatic reduction under fluoroscopy in the literature.[18] No complication was encountered. Incidences of IL and JJ intussusception are considerably lower, compared to IC intussusception.[20] According to the literature, underlying disease and a leading point are generally suspected to exist in cases of SBI, which mostly occur in older children, and surgery is reportedly indicated.[21–23] Classical symptoms may be lacking in cases of SBI, which may prolong the diagnosis period and lead to severe consequences. [12] In spite of such dire consequences, possibility of spontaneous reduction of SBIs should be considered.[16,24,25] Of the 81 patients in the present study, 17 had SBI (15 IL, 2 JJ) that reduced spontaneously. 142

Among the patients who underwent surgery, 12 had SBI, 11 had IL, and 1 had JJ intussusception, the latter of whom had a history of liver transplantation 2 years prior. Two of the patients who underwent surgery for IL intussusception had undergone major intra-abdominal surgeries (1 due to neuroblastoma 6 months prior, 1 due to ganglioneuroma 3 weeks prior). The lymph nodes were the leading points in all 3 cases. In cases of SBI, history of abdominal surgery must be considered an important factor, increasing the probability of the need for surgery. Among the cases of IL and JJ intussusception, a prominent difference in length of segments was observed on USG between those who required surgery and those for whom intussusceptions reduced without intervention. No spontaneously reduced intussusceptum was greater than 2.3 cm in length (min: 1; max: 2.3; mean: 1.8; median: 2 cm), while all intussusceptums that required surgery were at least 4 cm (min: 4; max: 12; mean: 6.1; median:5.9). These cases were diagnosed as transient or benign SBI. Similarly, Doi et al. suggested the term benign SBIs, which are diagnosed incidentally and resolve spontaneously.[25] A limitation to the present study was the retrospective nature of the data. All procedures were conducted at a single institution, and number of patients was limited, allowing for descriptive, rather than comparative, analyses. USG was not performed by a single radiologist, but rather by the USG team of the radiology department, which is composed of academic staff members of similar experience and educational background working in collaboration. In addition to the relatively specific and easily detectible nature of intussusception signs on USG, this collaboration may be considered a factor that minimizes potential radiologist-dependent variation of USG accuracy. Randomized, controlled, prospective studies with greater numbers of patients are needed to confirm the present results. Although the classic picture of vomiting, currant jelly stools, age less than 2 years, and palpable abdominal mass is reported in less than 25% of children, the present patient population had even lower incidences of palpable abdominal mass (6.2%) and rectal bleeding (12.4%).[14,26] Easy accessibility of the hospital and high socio-economic status of the neighboring population may be the contributing factors, as heightened sensitivity of parents to symptoms may have led to earlier records of symptom onset. Further studies, designed to assess the impact of these and other possible factors are necessary. IC/CC intussusceptions and SBI should be considered 2 distinct subgroups. Urgent surgery is indicated in every case of intussusception with intestinal perforation and/or peritoneal irritation. Cases that present without acute abdomen should be managed according to the anatomic location of the intussuscepted segment. For CC or IC intussusceptions with no sign of peritoneal Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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irritation or intestinal perforation, hydrostatic or pneumatic reduction is the treatment choice. When reduction attempt fails, surgery is the next step. As there is no known nonsurgical reduction method for SBI, surgery may seem to be the only treatment option. However, reports of spontaneous reductionof SBI, which use the terms “transient” or “benign” intussusception face pediatric surgeons with the necessity to distinguish the cases who are likely to reduce spontaneously from the unlikely ones.[12,20,25] Data of the present study indicates the unlikely need for intervention when SBI segments are shorter than 2.3 cm. Following these cases with careful clinical monitoring, frequent physical examinations, and USG controls would be sufficient. Surgery should be considered for SBI segments longer than 4 cm, as spontaneous reduction is unlikely. History of prior abdominal surgery should suggest high likelihood of need for urgent surgery in cases of SBI. Conflict of interest: None declared.

REFERENCES 1. Bines J, Ivanoff B. Acute Intussusception in infants and children: Incidence, clinical presentation and management: a global perspective. Geneva: World Health Organization; 2002. 2. Pepper VK, Stanfill AB, Pearl RH. Diagnosis and management of pediatric appendicitis, intussusception, and Meckel diverticulum. Surg Clin North Am 2012;92:505–26 3. Huppertz HI, Soriano-Gabarró M, Grimprel E, Franco E, Mezner Z, Desselberger U, et al. Intussusception among young children in Europe. Pediatr Infect Dis J 2006;25(1 Suppl):22–9. 4. Mandeville K, Chien M, Willyerd FA, Mandell G, Hostetler MA, Bulloch B. Intussusception: clinical presentations and imaging characteristics. Pediatr Emerg Care 2012;28:842–4. 5. Ein SH, Stephens CA. Intussusception: 354 cases in 10 years. J Pediatr Surg 1971;6:16–27. 6. Mansour AM, El Koutby M, El Barbary MM, Mohamed W, Shehata S, El Mohammady H, et al. Enteric viral infections as potential risk factors for intussusception. J Infect Dev Ctries 2013;7:28–35. 7. Nylund CM, Denson LA, Noel JM. Bacterial enteritis as a risk factor for childhood intussusception: a retrospective cohort study. J Pediatr 2010;156:761–5. 8. Lappalainen S, Ylitalo S, Arola A, Halkosalo A, Räsänen S, Vesikari T. Simultaneous presence of human herpesvirus 6 and adenovirus infections in intestinal intussusception of young children. Acta Paediatr 2012;101:663–70. 9. Hsu HY, Kao CL, Huang LM, Ni YH, Lai HS, Lin FY, et al. Viral etiology of intussusception in Taiwanese childhood. Pediatr Infect Dis J

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1998;17:893–8. 10. Bines JE, Liem NT, Justice FA, Son TN, Kirkwood CD, de Campo M, et al. Risk factors for intussusception in infants in Vietnam and Australia: adenovirus implicated, but not rotavirus. J Pediatr 2006;149:452–60. 11. Sigmound EH, Daneman A. Intussusception. In: Grosfeld JL, O’Neil JA, Fonkalsrud EW, editors. Pediatric surgery. 6th ed. Philadelphia: Mosby Year Book Inc; 2006. p. 1313–41. 12. Zhang Y, Bai YZ, Li SX, Liu SJ, Ren WD, Zheng LQ. Sonographic findings predictive of the need for surgical management in pediatric patients with small bowel intussusceptions. Langenbecks Arch Surg 2011;396:1035–40. 13. Munden MM, Bruzzi JF, Coley BD, Munden RF. Sonography of pediatric small-bowel intussusception: differentiating surgical from nonsurgical cases. AJR Am J Roentgenol 2007;188:275–9. 14. Fallon SC, Lopez ME, Zhang W, Brandt ML, Wesson DE, Lee TC, et al. Risk factors for surgery in pediatric intussusception in the era of pneumatic reduction. J Pediatr Surg 2013;48:1032–6. 15. Betz BW, Hagedorn JE, Guikema JS, Barnes CL. Therapeutic enema for pediatric ileocolic intussusception: using a balloon catheter improves efficacy. Emerg Radiol 2013;20:385–91. 16. Tran LA, Yoshida LM, Nakagomi T, Gauchan P, Ariyoshi K, Anh DD, et al. A High Incidence of Intussusception Revealed by a Retrospective Hospital-Based Study in Nha Trang, Vietnam between 2009 and 2011. Trop Med Health 2013;41:121–7. 17. Lochhead A, Jamjoom R, Ratnapalan S. Intussusception in children presenting to the emergency department. Clin Pediatr (Phila) 2013;52:1029–33. 18. Daneman A, Navarro O. Intussusception. Part 2: An update on the evolution of management. Pediatr Radiol 2004;34:97–108; quiz 187. 19. Katz M, Phelan E, Carlin JB, Beasley SW. Gas enema for the reduction of intussusception: relationship between clinical signs and symptoms and outcome. AJR Am J Roentgenol 1993;160:363–6. 20. Kornecki A, Daneman A, Navarro O, Connolly B, Manson D, Alton DJ. Spontaneous reduction of intussusception: clinical spectrum, management and outcome. Pediatr Radiol 2000;30:58–63. 21. Merine D, Fishman EK, Jones B, Siegelman SS. Enteroenteric intussusception: CT findings in nine patients. AJR Am J Roentgenol 1987;148:1129–32. 22. Cox TD, Winters WD, Weinberger E. CT of intussusception in the pediatric patient: diagnosis and pitfalls. Pediatr Radiol 1996;26:26–32. 23. Kim JH. US features of transient small bowel intussusception in pediatric patients. Korean J Radiol 2004;5:178–84. 24. Strouse PJ, DiPietro MA, Saez F. Transient small-bowel intussusception in children on CT. Pediatr Radiol 2003;33:316–20. 25. Doi O, Aoyama K, Hutson JM. Twenty-one cases of small bowel intussusception: the pathophysiology of idiopathic intussusception and the concept of benign small bowel intussusception. Pediatr Surg Int 2004;20:140–3. 26. Kaiser AD, Applegate KE, Ladd AP. Current success in the treatment of intussusception in children. Surgery 2007;142:469–77.

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ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Her intususepsiyon tedavisi acil girişim veya cerrahi midir? Dr. Lütfi Hakan Güney, Dr. Ender Fakıoğlu, Dr. Tuğba Acer, Dr. İbrahim Ötgün, Dr. Esra Elif Arslan, Dr. Müge Sağnak Akıllı, Dr. Akgün Hiçsönmez Başkent Üniversitesi Tıp Fakültesi, Çocuk Cerrahisi Anabilim Dalı, Ankara

AMAÇ: İntususepsiyon, çocuklarda akut apandisitten sonra en yaygın akut karın sebebidir. İntususepsiyon deneyimlerimizi, ileo-kolik ve ince bağırsak intususepsiyonlarına yaklaşım seçeneklerini gözden geçirmeyi hedefledik. GEREÇ VE YÖNTEM: Temmuz 2002–Eylül 2014 yılları arasında kliniğimizde intususepsiyon tanısı almış olguların kayıtları tarandı; yaş, cinsiyet, klinik bulgular, başvuru süresi, ultrasonografi bulguları ve uygulanan tedavi seçenekleri ve sonuçları değerlendirildi. BULGULAR: Toplamda 81 olgunun 52’si erkek, 29’u kız, ortalama yaşları 10.6 aydı. İntususepsiyon 52 hastada ileokolik, 26 hastada ileoileal, üç hastada jejunojejunaldi. On dokuz (%23.5) olguda cerrahi, tümü ileokolik 45 (%55.5) olguda hidrostatik redüksiyon uygulandı. Periton irritasyonu bulgusu olmayan 17 (%21) hasta fiziksel inceleme, ultrasonografi ve klinik izleme alındı. Tamamı ince bağırsakta olan invajine segmentlerinin uzunlukları ultrasonografik olarak 1.8–2.3 cm arasında ölçülen bu hastalarda komplikasyonsuz spontan redüksiyon izlendi. Cerrahi uygulanan hastaların tümünde invajine segment en az 4 cm uzunluğundaydı. Rezeksiyon yapılan dört hastanın üçünde cerrahi öyküsü vardı. TARTIŞMA: Periton irritasyonu bulguları olan tüm intususepsiyon olgularında tedavi cerrahidir. Diğer durumlarda, tedavi yaklaşımı açısından ince bağırsak intususepsiyonları ileokolik intususepsiyonlardan ayrı değerlendirilmelidir. İnce bağırsak intususepsiyonu 2.3 cm’den kısaysa ultrasonografi desteğiyle klinik izlem güvenlidir; 4 cm’den uzun ve geçirilmiş karın cerrahisi varsa cerrahi müdahale ön planda düşünülmelidir. Anahtar sözcükler: benign intususepsiyon; geçici intususepsiyon; ince bağırsak intususepsiyonu; intususepsiyon; spontan redüksiyon. Ulus Travma Acil Cerrahi Derg 2016;22(2):139–144

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doi: 10.5505/tjtes.2015.06013

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ORIG I N A L A R T IC L E

Work-related injuries sustained by emergency medical technicians and paramedics in Turkey Bedia Gülen, M.D.,1 Mustafa Serinken, M.D.,2 Celile Hatipoğlu, M.D.,3 Derya Özaşır, M.D.,4 Ertan Sönmez, M.D.,1 Gökhan Kaya, M.D.,5 Güleser Akpınar, M.D.6 1

Department of Emergency Medicine, Bezmialem Vakıf University Faculty of Medicine, İstanbul-Turkey

Department of Emergency Medicine, Pamukkale University Faculty of Medicine, Denizli-Turkey

Department of Public Health, Rize Provincial Directorate of Public Health, Rize-Turkey

Health Directorate of İstanbul, Emergency and Disaster Medical Services, İstanbul-Turkey

Department of Emergency Medicine, Antalya Training and Research Hospital, Antalya-Turkey

Department of Emergency Medicine, Şişli Training and Research Hospital, İstanbul-Turkey

ABSTRACT BACKGROUND: Evaluated in the present study were locations, descriptions, and results of work-related injuries (WRIs) sustained by emergency medical technicians (EMTs) and paramedics in Turkey’s most crowded city, İstanbul. METHODS: After the present study had been accepted by the urban health authority, a questionnaire was emailed to the healthcare personnel of İstanbul’s 195 ambulance stations. RESULTS: Included in the present study were the responses of 901 members of staff (660 EMTs and 241 paramedics), with a mean age of 29.5±6.1 (min: 18; max: 61). The majority of participants (94.9%) had encountered verbal abuse from the public, and 39.8% had encountered physical violence from patients’ relatives. Levels of satisfaction with work in emergency medical services (EMS) was also evaluated, and 510 participants (57.6%) were unhappy. Regarding gender, female employees were more likely to be verbally attacked (p=0.01), while males were more likely to be physically attacked (p=0.001). It was reported that motor vehicle accidents (MVAs) were the most common cause of WRIs (81.4%), followed by needle-stick injuries (52.2%), ocular exposure to blood and other fluids (30.9%), and sharp injuries (22.5%). Only 10.5% (n=95) of WRIs were reported to authorities; 488 (54.2%) of participants just attended to the practice to prevent possible WRIs. CONCLUSION: For paramedics and EMTs, risk of WRI is obviously high. Strategies to decrease and prevent verbal and physical violence should be developed. Keywords: Accident; ambulance; paramedic; work-related.

INTRODUCTION Emergency medical technicians (EMTs) and paramedics take immediate care of patients who are injured or unhealthy, and ensure their transportation to or from the hospital. Time spent at work is relatively longer for these healthcare emAddress for correspondence: Bedia Gülen, M.D. Bezmialem Vakıf Üniversitesi Tıp Fakültesi, Acil Tıp Anabilim Dalı, İstanbul, Turkey Tel: +90 212 - 453 17 00 E-mail: drbediagulen@yahoo.com Qucik Response Code

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ployees, compared to those in other fields.[1,2] Risk of injury to EMTs and paramedics is reportedly significantly higher, and the rate of work-related injuries (WRIs) has increased.[3] Motor vehicle accidents (MVAs) play a primary role in all kinds of frequently encountered WRIs. Mortality rates have risen by 40% in Turkey, due to the increased use of ambulances (increased by 83.2%).[4] Nevertheless, due to insufficient reporting of WRIs world-wide, it is now crucial that reliable information regarding WRIs sustained by EMTs and paramedics be obtained in Turkey and in other countries. It is important to note that the most common WRIs sustained by EMTs and paramedics involve contact with bloodborne pathogens from needle sticks, injuries sustained during transportation (lifting and moving patients, etc.), wounds sustained due to patient violence, and injuries sustained as a re145

Gülen et al. Work-related injuries sustained by emergency medical technicians and paramedics in Turkey

sult of traffic accidents while on duty in ambulances.[5,6] There are many other potential causes of WRIs, such as conflict with patients’ relatives, stressful conditions, and long working hours, all of which can negatively affect personnel health. In the present study, locations, descriptions, and results of WRIs sustained by EMTs and paramedics in Turkey’s most populous city were analyzed.

MATERIALS AND METHODS The present study was performed between March and July of 2014 in Turkey’s multicultural hub, İstanbul (approximate population: 14 million). The study was approved by the Health Directorate of İstanbul. There are a total of 195 ambulance stations in the city (123 on the European side and 72 on the Asian side). These stations contain 248 emergency rescue ambulances and 1401 healthcare personnel (1099 EMTs and 302 paramedics). Following the study’s subsequent ac-

ceptance by the urban health authority, a questionnaire was emailed to all emergency healthcare personnel, who were instructed to fully complete it. Participants were strongly advised not to enter any personal information, and were informed that collected data would be used only for scientific analysis. EMTs and paramedics with less than 1 year of experience who declined to participate were exempted. The questionnaire included 23 multiple choice questions regarding frequently encountered scenarios during which WRIs may be sustained in the field of emergency medical services (EMS).

Statistical Analysis

483

53.6

All data were analyzed using SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA). Numerical variables are presented as median and interquartile ratio, while categorical variables are presented as frequencies (n) and percentages. Group comparisons were performed for numeric variables using the Kruskal–Wallis test, and the chi-square test was used for categorical variables. Post-hoc analysis was performed using the Mann–Whitney U test with Bonferroni correction. All hypotheses were two-tailed, and an alpha critical value of 0.05 was considered significant.

18–25

194

21.5

RESULTS

26–30

408

45.3

A total of 1401 EMS personnel were identified, of whom 984

31–35

203

22.5

35>

10.7

Table 1. Characteristics of participants (n=901) Gender Female Age range

Run years in 112

2–3 years

360

40.0

4–5 years

205

22.7

6 years and more

336

Table 2. Frequency of WRI as reported by EMTs and paramedics during the past two years Mechanism

Number of injuries

None

168

18.6

37.3

Motor vehicle accidents

655 72.7

By patient’s relatives

649

72.0

58 6.5

By society

855

94.9

20 2.2

Exposed to verbal attack

Exposed physical attack

Needlestick

By patient’s relatives

359

39.8

None

431 47.8

389 43.2

18.4

Reported by staff?

54 6.0

27.6

27 3.0

Institute inquired after attack?

Eye contact with blood

None

623

69.1

Yes

201

22.3

By society Yes

166 249

15.2

and other bodily fluids

Pleased to work in 112?

59 6.6

Very well

5.7

18 2.0

Well

331

36.7

Sharp injuries

137

Not well

362

40.2

Not very well

157

17.4

*Rate of attack during past 2 years.

146

None

698

77.5

168 18.6

25 2.8

10 1.1

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participated (70.2%). A total of 83 personnel (8.4%) who had been working in EMS for less than 1 year were excluded. A total of 901 personnel (660 EMTs and 241 paramedics) with a mean age of 29.5±6.1 (min=18, max=61) were included. Years spent with EMS (also known as the 112, after the EMS dialing code in Turkey) ranged from 2–3 for 40% of participants (n=360). Demographic characteristics are shown in Table 1. Participants were questioned regarding incidence of verbal violence (insults, swearing, etc.), as well as physical violence. Participants were asked whether they had been to exposed to violence in either form by patients or their relatives in the past 2 years. Participants were also asked whether they had reported violent incidents to the administration. According to responses, 94.9% of participants had encountered verbal violence, and 39.8% had encountered physical violence from patients’ relatives. Participants were also asked to describe their level of satisTable 3. Data regarding mechanisms and results of injuries*

Mechanisms of MVAs

Ambulance collision with another vehicle

483

53.6

Ambulance crashed by another vehicle

424

47.1

Sudden break (injured inside ambulance)

276

30.6

Collision with other object

140

15.5

Derailing from road

10.6

Other

27 3.0

The result of accident

No injury

442

49.1

Only injured by myself

6.4

Injured only the one of 112 staff

168

18.6

Injured more than one of 112 staff

4.7

Injured someone on the other vehicle

114

12.7

Injured on pedestrian

4.0

Injured patient inside of the ambulance

3.1

Other

11 1.2

Mechanisms of needlestick injuries

faction with work in the 112, and 519 participants (57.6%) reported that they were not satisfied (Table 1). No significant difference in level of satisfaction was found between male and female employees (p=0.359). In addition, no significant correlation was found between level of satisfaction and exposure to violence (p=0.762 and p=0.284, respectively). However, level of satisfaction among those exposed to physical violence was significantly lower (p=0.001 and 0.03, respectively). While verbal violence was more prevalent among female employees (p=0.01), physical violence was more prevalent among male employees (p=0.001). The most commonly reported causes of WRI were MVAs (81.4%), needle-stick injuries (52.2%), ocular contact with blood and other bodily fluids (30.9%), and sharp injuries (i.e., injuries by sharps other than needle sticks; 22.5%), respectively (Table 2). A total of 81.4% of participants (n=733) had been in at least 1 traffic accident while on duty in an ambulance; most often, the ambulance had collided with another vehicle (53.6%). Three healthcare personnel and 7 others died as a result of these accidents. Personnel who had not been in an on-duty traffic accident were found to have higher levels of satisfaction with 112 employment (p=0.005). Needle-stick injuries frequently occurred as a result of intravenous line procedures (55.3%) and processes conducted in the ambulance (34.7%; Table 3). As the age of employees increased, the number of needle-stick injuries decreased (r=-0.63, p=0.02). In addition, the number of needle-stick injuries decreased with augmentation of years spent in the 112 (r=-0.43, p=0.01). Responses regarding the most common causes of WRIs are described in Table 4. Most frequently reported were injuries sustained while riding in ambulances (30.9%). A total of 82.2% of respondents (n=741) reported that were properly gloved, and 37.4% (n=337) reported that they were properly masked while routinely performing their jobs. Table 4. Most common causes of WRI, according to respondents*

During IV procedures

321

55.3

Recapping

161

27.7

Puncture by other needles

Feasible reason of the WRI regarding the respondents

(following improper disposal of needles)

11.0

Cruising ambulance

278

30.9

Hurrying up

231

25.6

Location of the personnel when the

Carelessness

141 15.6

needlestick injury occurred

Patient’s movement

119

13.2

Other

35 6.0

Inside the cruising ambulance

313

34.7

Failure in disposal of devices, needles etc.

104

11.5

Inside the stationary ambulance

125

13.9

Due to the relatives of the patient

1.6

On the field

151

16.7

Other

21 2.3

*Some subjects selected more than one choice.

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Only 10.5% (n=95) of WRIs were properly reported to authorities. In association, 488 (54.2%) participants had reportedly attended an orientation designed to provide information regarding prevention of WRIs.

DISCUSSION The present is among the largest studies of WRIs in EMS. Data indicates that 58% of participants were generally dissatisfied with EMS employment. The rate of verbal and physical violence against healthcare personnel is significantly high, and physical violence negatively affects levels of satisfaction. Findings indicate that exposure to both chronic and critical incident stressors increases the risk of EMS personnel developing post-traumatic stress reactions.[7] It has been demonstrated that EMS personnel encounter violence in the workplace world-wide, regardless of the country’s development status.[8,9] In a study conducted in Australia, the rate of attacks on paramedics was doubled, compared to the rate of attacks on police officers.[10] Several factors contribute to patient violence toward EMS personnel; proper measures taken to prevent and reduce patient violence may decrease WRIs.[11] News portraying EMS personnel in an unfavorable light is prevalent in the Turkish media,[12] and there can be no doubt that this increases the rate of violence, causing health service personnel additional, unnecessary stress. The present study demonstrated that the risk of WRIs to EMS personnel is higher than may have been expected. It was reported that 81% of participants had experienced at least 1 MVA, and that 52% had experienced at least 1 needle-stick injury in the past 2 years. Furthermore, the study demonstrated that needle-stick injuries most commonly occurred during intravenous administration while the ambulance was in motion. İstanbul has a very severe traffic problem, and arrival times of ambulances often surpass acceptable margins. This delay leads to ambulances rushing more, increasing the risk that EMS members will experience accidents and sustain WRIs. It is not surprising that only 10.5% of serious WRIs, including needle sticks, penetrating injuries, and ocular contact with fluids were reported to proper authorities. In a similar study performed in another large city in Turkey, only 12% of WRIs sustained by EMS personnel were properly reported.[13] Unfortunately, the deficiency in WRI reporting is general. In the present study, a total of 46% of participants had reportedly not undergone training related to WRIs, either before or after their EMS employment had begun. This is a significantly low rate. A close correlation between a safe working environment and safe work performed by EMS employees has been indicated.[14] In Turkey, programs specifically designed to train EMS personnel in WRI prevention and reduction should be performed and regularly repeated. 148

Limitations The present was a demonstrative study that included EMS personnel based in İstanbul. Due to conditions specific to İstanbul and the limited scope of the survey, results may not be indicative of general conditions in Turkey. While deaths resulting from WRIs were investigated, non-fatal injuries were not. Furthermore, the survey concerned WRIs sustained in the past 2 years. Accuracy of responses was not verified by an outside source.

Conclusion Risk of WRIs to paramedics and EMTs is obviously high. In order to decrease rates of physical and verbal violence against EMS personnel, additional planning and sanctions should be studied. In addition, organizations must ensure that a high level of morale is maintained. Most importantly, a mandatory certification course for all EMS and healthcare personnel should be conducted on an annual basis. Conflict of interest: None declared.

REFERENCES 1. Kidak L, Sofuoğlu T, Keskinoğlu P, Olmezoğlu Z. A motivating experience for emergency medical services: the first Turkish Ambulance Rally. [Article in Turkish] Ulus Travma Acil Cerrahi Derg 2009;15:584–90. 2. Wood K, Crouch R, Rowland E, Pope C. Clinical handovers between prehospital and hospital staff: literature review. Emerg Med J 2015;32:577– 81. 3. Reichard AA, Marsh SM, Moore PH. Fatal and nonfatal injuries among emergency medical technicians and paramedics. Prehosp Emerg Care 2011;15:511–7. 4. Maguire BJ, Smith S. Injuries and fatalities among emergency medical technicians and paramedics in the United States. Prehosp Disaster Med 2013;28:376–82. 5. Maguire BJ, Smith S. Injuries and fatalities among emergency medical technicians and paramedics in the United States. Prehosp Disaster Med 2013;28:376–82. 6. Raman S, Ramnarayan P. Impact of stops for road traffic accidents on the inter-hospital transport of critically ill children. Emerg Med J 2013. [Epub ahead of print] 7. Donnelly E. Work-related stress and posttraumatic stress in emergency medical services. Prehosp Emerg Care 2012;16:76–85. 8. Bigham BL, Jensen JL, Tavares W, Drennan IR, Saleem H, Dainty KN, et al. Paramedic self-reported exposure to violence in the emergency medical services (EMS) workplace: a mixed-methods cross-sectional survey. Prehosp Emerg Care 2014;18:489–94. 9. Rahmani A, Hassankhani H, Mills J, Dadashzadeh A. Exposure of Iranian emergency medical technicians to workplace violence: a cross-sectional analysis. Emerg Med Australas 2012;24:105–10. 10. Maguire BJ, O’Meara PF, Brightwell RF, O’Neill BJ, Fitzgerald GJ. Occupational injury risk among Australian paramedics: an analysis of national data. Med J Aust 2014;200:477–80. 11. Cheney PR, Gossett L, Fullerton-Gleason L, Weiss SJ, Ernst AA, Sklar D. Relationship of restraint use, patient injury, and assaults on EMS personnel. Prehosp Emerg Care 2006;10:207–12.

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Gülen et al. Work-related injuries sustained by emergency medical technicians and paramedics in Turkey 12. Acar YA, Çevik E, Uyguner C, Cınar O. ‘Emergency Service’ from Press Media Perspective: Content Analysis of the News About Emergency Service in the National Newspapers of Turkey. J Emerg Med 2013;13:166–70. 13. Yılmaz A, Dal O, Yaylacı S, Uyanık E. Rate of Exposure to Violence in

112 Staff in Denizli City. Eurasian J Emerg Med 2015;14:103–6. 14. Eliseo LJ, Murray KA, White LF, Dyer S, Mitchell PA, Fernandez WG. EMS providers’ perceptions of safety climate and adherence to safe work practices. Prehosp Emerg Care 2012;16:53–8.

ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Türkiye’de acil tıp teknisyenleri ve paramediklerin karşılaştıkları iş kazaları Dr. Bedia Gülen,1 Dr. Mustafa Serinken,2 Dr. Celile Hatipoğlu,3 Dr. Derya Özaşır,4 Dr. Ertan Sönmez,1 Dr. Gökhan Kaya,5 Dr. Güleser Akpınar6 Bezmialem Vakıf Üniversitesi Tıp Fakültesi, Acil Tıp Anabilim Dalı, İstanbul Pamukkale Üniversitesi Tıp Fakültesi, Acil Tıp Anabilim Dalı, Denizli Rize İl Sağlık Müdürlüğü, Halk Sağlığı Departmanı, Rize 4 İstanbul İl Sağlık Müdürlüğ, Acil ve Afet Yönetimi, İstanbul 5 Antalya Eğitim ve Araştırma Hastanesi, Acil Tıp Anabilim Dalı, Antalya 6 Şişli Etfal Eğitim ve Araştırma Hastanesi, Acil Tıp Anabilim Dalı, İstanbul 1 2 3

AMAÇ: Bu çalışmada, Türkiye’nin en kalabalık şehri olan İstanbul’da acil tıp teknisyenleri ve paramediklerin işle ilişkili yaralanmaları tanımlandı. GEREÇ VE YÖNTEM: İstanbul’da toplam 195 ambulans istasyonu mevcuttur. Çalışma İstanbul İl Sağlık Müdürlüğü tarafından onaylandı. Çalışma anketi 112 sağlık çalışanlarının e-posta adreslerine gönderildi ve doldurulması istendi. BULGULAR: Çalışmaya ortalama yaşları 29.5±6.1 (min: 18-maks: 61) olan 901 personel (660 acil tıp teknisyeni [ATT] ve 241 paramedik) katıldı. Çalışanların halk tarafından sözel şiddete uğrama oranı %94.9, hasta yakınları tarafından fiziksel şiddet oranı %39.8 olarak belirlendi. Bunun yanında çalışanların 112’de çalışmaktan memnun olup olmadığı araştırıldı. Beş yüz on (%57.6) katılımcı memnun değildi. Cinsiyete göre kadın katılımcılar sözel şiddete (p=0.01), fakat erkek katılımcılar da fiziksel şiddete kadınlardan daha fazla maruz kalmıştı (p=0.01). İş ilişkili yaralanmaların en çoğu motorlu araç kazaları (%81.4), iğne batma yaralanmaları (%52.2), kan veya vücut sıvıları ile göz teması (%30.9) ve keskin alet yaranmaları (%22.5) idi. İş ilişkili yaralanmaların %10.5’i (n=95) örneğin iğne batma yaralanmaları ve vücut sıvılarının göze teması gibi yaralanmalar yönetime rapor edilmişti ve bildirilmişti. Katılımcıların 488’i (%54.2) olası iş ilişkili yaralanmaları önlemek için hizmet içi eğitimlere katılmıştı. TARTIŞMA: Ülkemizde iş ilişkili yaralanmalarda ATT ve paramediklerin riski oldukça açık bir şekilde yüksektir. Bu nedenle acil çağrı sistemi personeline fiziksel-sözel şiddeti önlemek için daha ileri stratejiler geliştirilmeli ve iş kazalarına yönelik hizmet içi eğitimler artırılmalıdır. Anahtar sözcükler: Ambulans; iş-ilişkili; kaza; paramedik. Ulus Travma Acil Cerrahi Derg 2016;22(2):145–149

doi: 10.5505/tjtes.2015.94224

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ORIG I N A L A R T IC L E

Can outcome of pancreatic pseudocysts be predicted? Proposal for a new scoring system Kazım Şenol, M.D.,1 Özgür Akgül, M.D.,1 Salih Burak Gündoğdu, M.D.,1 İhsan Aydoğan, M.D.,1 Mesut Tez, M.D.,1 Faruk Çoşkun, M.D.,1 Deniz Necdet Tihan, M.D.2 1

Department of General Surgery, Ankara Numune Training and Research Hospital, Ankara-Turkey

Department of General Surgery, Şevket Yılmaz Training and Research Hospital, Bursa-Turkey

ABSTRACT BACKGROUND: The spontaneous resolution rate of pancreatic pseudocysts (PPs) is 86%, and the serious complication rate is 3-9%. The aim of the present study was to develop a scoring system that would predict spontaneous resolution of PPs. METHODS: Medical records of 70 patients were retrospectively reviewed. Two patients were excluded. Demographic data and laboratory measurements were obtained from patient records. RESULTS: Mean age of the 68 patients included was 56.6 years. Female:male ratio was 1.34:1. Causes of pancreatitis were stones (48.5%), alcohol consumption (26.5%), and unknown etiology (25%). Mean size of PP was 71 mm. Pseudocysts disappeared in 32 patients (47.1%). With univariate analysis, serum direct bilirubin level (>0.95 mg/dL), cyst carcinoembryonic antigen (CEA) level (>1.5), and cyst diameter (>55 mm) were found to be significantly different between patients with and without spontaneous resolution. In multivariate analysis, these variables were statistically significant. Scores were calculated with points assigned to each variable. Final scores predicted spontaneous resolution in approximately 80% of patients. CONCLUSION: The scoring system developed to predict resolution of PPs is simple and useful, but requires validation. Keywords: Pancreas; prognosis; pseudocyst; scoring system; spontaneous resolution.

INTRODUCTION In the revised Atlanta classification, local complications of acute pancreatitis are defined as acute peripancreatic fluid collections, pancreatic pseudocysts, acute pancreatic or peripancreatic necrotic collections, and walled-off necrosis. [1] Pancreatic pseudocysts and peripancreatic fluid collections are the most commonly reported clinical manifestations.[2] Pancreatic pseudocysts (PPs) are defined as fluid collections with no or minimal solid components, surrounded by a nonepithelial wall of fibrous or granulated tissue, arising as a consequence of acute pancreatitis.[1] Incidence ranges from 5% to 16% and is reported to be higher in patients with underlying Address for correspondence: Deniz Necdet Tihan, M.D. Şevket Yılmaz Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, Bursa, Turkey Tel: +90 224 - 295 50 00 E-mail: dtihan@yahoo.com Qucik Response Code

150

chronic pancreatitis.[3] Management of PPs has traditionally included a period of observation from 4 to 6 weeks, allowing the cystic wall to mature. Therapeutic modalities include endoscopic and radiologic intervention, as well as surgical approach. Selection of modality depends upon the etiology, location, size, and clinical course of the pseudocyst.[4] Recent studies have suggested that spontaneous resolution can be safely and effectively achieved in up to 86% of patients if longer periods of observation are employed. Serious complications may develop in only 3-9% of cases during an averaged 1-year expectant follow-up.[4,5] In the present study, a scoring system designed to predict spontaneous resolution of PPs was developed.

MATERIALS AND METHODS The present was an observational cohort study. Medical records of 40 patients with PPs were retrospectively reviewed at the Emergency Surgery Department of the Ankara Numune Training and Research Hospital between January 2005 and June 2012. Patients were identified from hospital records, aided by a computerized search (International Classification of Diseases-10 code K86.3). Definition of pseudocyst was Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Şenol et al. Can outcome of pancreatic pseudocysts be predicted? Proposal for a new scoring system

taken from the Atlanta classification. Patients who received primary treatment at another hospital and those misclassified were excluded. Sixty-eight of the initial 70 patients fulfilled the criteria for true PPs, with the exception of postnecrotic collections that constituted walled-off necrosis formation. Etiology was considered to be of biliary origin when gallstones were found on radiologic examination. Alcohol was registered as the etiological factor when there was history of alcohol abuse. In the absence of gallstones or alcohol abuse, the etiology was considered to be other, or unknown. Treatments offered were conservative management, percutaneous puncture and/or drainage, and surgery (e.g. internal drainage with cystogastrostomy or cystojejunostomy and resection). Percutaneous puncture and drainage procedures were performed with guidance of ultrasound or computed tomography.

Independent Variables Demographic data and the following laboratory measurements were obtained from each patient record: serum amylase, white blood cell count, platelets, hematocrit, calcium, blood glucose, creatinine, blood urea nitrogen, total/direct bilirubin, alkaline phosphatase (AP), lactate dehydrogenase, γ-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, cyst diameter, and cyst fluid carcinoembryonic antigen (CEA) level.

Dependent Variable Primary endpoint was spontaneous resolution of PPs, including partial and complete resolution, with uneventful followup.

Statistical Analysis Continuous data were presented as mean±SD, and differences between groups were analyzed with Mann-Whitney U test. Shapiro-Wilk test was used to assess normality. Categorical variables were analyzed with χ2 tests. Logistic regression was used to identify variables associated with spontaneous resolution. To calculate scores, a logistic regression model was developed, in which presence of spontaneous resolution was the dependent variable, and clinical and pathologic variables were considered to be numerical or categorical covariates. The final model generated a set of independent prognostic variables with β regression coefficients, standard error (SE) of coefficients, and p values. The fit of the model was verified by the Hosmer-Lemeshow goodness-of-fit test. Clinical scores were based on the final logistic regression model. Model discrimination was determined by measuring by the area under the receiver operating characteristic (ROC) curve (AUC). Discrimination of a prognostic model is considered to be perfect if AUC=1, good if AUC >0.8, moderate if AUC is 0.6–0.8, and poor if AUC <0.6.

RESULTS Mean (SD) age of patient population was 56.6 (16.7) years, and female:male ratio was 1.34:1. Causes of pancreatitis were stones (48.5%), alcohol (26.5%), and unknown (25%). The most common symptom associated with the complicated clinical course of the disease was abdominal pain (in 42 patients, 61.7%). Mean size of pseudocyst was 71±54 mm (range: 8–240 mm). PPs were located around the head of the pancreas in 42 patients (61.8%), and in the body or tail of the pancreas in 26 patients (28.2%). Demographic characteristics are shown in Table 1.

Table 1. Demographic and clinical characteristics of patients with and without spontaneous resolution Variable

Spontaneous resolution (n=32)

Required intervention (n=36)

Mean age

53 ±14

55 ±15

Sex, male/female

13/19

16/20

Pancreatitis history (present/absent)

24/8

26/10

White blood cell count (per mm )

9.357±5.2

10.533±4.9 NS

Cyst fluid CEA level (0–2.5 ng/mL)

1.59±1.53

2.36±1.46

0.002

Serum glucose level (mg/dL)

174±114

147±73

Serum amylase level (U/L)

397±81.5

454±97.7

Serum alkaline phosphatase level (U/L)

113.9 (31)

110.1 (32)

Serum lactate dehydrogenase level (U/L)

259 ±130

250 ±118

Serum direct bilirubin level (mg/dl)

1.07±0.97

2.32±1

0.004

35 ±9

71±8

0.004

Cyst diameter (mm) CEA: Carcinoembryonic antigen.

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Table 2. Multivariable logistic regression model for prediction of spontaneous resolution

Regression coefficient

Standard error of coefficient

Score points

Elevated direct bilirubin level (>0.9 mg/dL)

1.8

1.3

0.03

Elevated CEA (>1.5)

2.9

1.2

0.008

Cyst diameter (>55 mm)

1.2

0.9

0.04

CEA: Carcinoembryonic antigen.

Table 3. Scoring system for spontaneous resolution and resolution rates Pancreatic pseudocysts score

Number of patients n

Score

Points

17.9

91.7

34.3

56.5

III

20.9

35.7

27.9

16.7

Pseudocyst disappeared in 32 (47.1%) patients, 24 (66.6%) patients underwent external drainage, 7 (19.4%) underwent cystogastrostomy, 3 (8.3%) underwent cystojejunostomy, and 2 (5.5%) underwent pancreas resection. With univariate analysis, serum direct bilirubin levels (>0.95 mg/dL), cyst CEA levels (>1.5), and cyst diameters (>55 mm) were found to be significantly different between patients with and without spontaneous resolution. With multivariate analysis, the same variables were found to be statistically significant (Table 2). Scores were calculated by assigning points to these variables. In spite of differences in regression coefficients, which ranged from 1.2 to 2.9, for the sake of simplicity, 1 point was assigned for cyst diameter (>55 mm), 2 points were assigned for cyst CEA level (>1.5), and 1 point was assigned for serum direct bilirubin level (>0.95 mg/dL). The resulting score ranged from 0 to 4. Four groups of patients were identified, based on score. The first group (score 1) had a spontaneous resolution rate of 91.7%, comprised approximately 17.9% of the cohort, and included patients with 0 points. The second group (score 2) had a spontaneous resolution rate of 56.5%, comprised approximately 34.3% of the cohort, and included patients with 1 point. The third group (score 3) had a spontaneous resolution rate of 35.7%, comprised approximately 20.9% of the cohort, and included patients with 2 points. Spontaneous resolution rates were 16.7% and 0% for patients with 3 and 4 points, respectively (score 4). Rates are displayed in Table 3. The Hosmer-Lemeshow goodness-of-fit test of the final model was p=0.961, indicating a quite adequate fit of the model to the data. AUC of the new score was 0.789 (0.682 to 0.896). 152

Spontaneous resolution n

DISCUSSION Primary treatment modality of PPs involves conservative approaches until the PPs become asymptomatic.[6] Recent studies have concluded that 8–86% of PPs resolve spontaneously, while 5–15% of collections form symptomatic mature pseudocysts.[7] During an averaged 1-year expectant follow-up, 3–9% of mature PPs presented with serious complications, including infection, bleeding, and jaundice.[4] PPs larger than 6 cm are closely correlated with increased risk of complication. [5] It has been demonstrated in a majority of related studies that PPs larger than 5 or 6 cm have lower rates of spontaneous resolution.[8–11] Authors have emphasized that, depending on size, early operation or drainage of pseudocyts improves rates of morbidity and mortality.[12] Therefore, it is strongly suggested that surgical or percutaneous drainage be considered in cases of PPs larger than 6 cm.[6] While data regarding PP size and clinical course varies between studies, cysts smaller than 4 cm are considered to be independent factors for spontaneous resolution and favorable outcome.[4,13] In the present study, 47% of PPs showed uneventful partial or complete resolution during early stages of follow-up (mean: 15±11.55 months). Significant differences in cyst diameter were found between the resolution and intervention groups (35±9 mm vs 71±8 mm, p=0.004). More complicated clinical courses were observed in the intervention group, related to increased PP size. Both univariate and multivariate analysis demonstrated that cyst diameter <53 mm was a predictive factor for spontaneous resolution. Differences in cyst diameter among groups indicated that percutaneous intervention and/or surgical treatment must be considered as treatment options for larger PPs, in accordance with the literature. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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However, Cheruvu et al. have demonstrated that size of pseudocyst is a less-important indicator. Clinical outcomes of patients with median PP size of 8 cm and median PP size of 7 cm required intervention, and patients in both groups received conservative treatment.[14] In addition, Nguyen et al. demonstrated similar results regarding rates of spontaneous resolution, intervention, recurrence, and mortality in PPs larger or smaller than 6 cm. The authors concluded that etiology of AP is a more efficient means of predicting clinical outcome than cyst size.[15] Thus, pseudocyst size is not a significant indicator of spontaneous resolution, requiring more efficient parameters for the prediction of eventual outcome. PPs comprise 75% of pancreatic cysts. History of unnoticed acute pancreatitis renders distinction between cystic neoplasms, retention cysts, congenital cysts, and pseudocysts difficult until intervention is performed.[16] In a clinical setting, data obtained from cyst fluid informs the differential diagnosis of a pseudocyst. No remarkable literature regarding biological predictive factors for spontaneous resolution of PPs could be found. Complicated clinical course of PPs and practical manifestation of serum markers should lead clinicians to consider the option of medical therapy. Several studies have shown that cyst fluid analysis with elevated amylase in the thousands and low CEA level (<192 ng/mL) supports the diagnosis of a pseudocyst and helps determine the optimal therapeutic strategy by excluding pancreatic cystic malignancies.[17–19] Cyst fluid may contain acute and chronic inflammatory cells, histiocytes, and macrophages.[20] Only complicated cases with gastrointestinal epithelial and mucin contamination, particularly from the stomach, should include cystic lining epithelial cells. [19,21,22] Van der Waaij et al. analyzed 12 studies and demonstrated that CEA levels below 5 ng/mL present a specificity of 95% for pseudocyst formation.[18] Biliary complications of PPs manifest as obstructive jaundice, requiring intervention until the pseudocyst resolves. Jaundice may result from distortion and narrowing of the intra-pancreatic segment of the common bile duct by progressive fibrosis of the pancreatic tissue, as exhibited in cases of chronic pancreatitis (or rarely by compression of the duct by a pseudocyst).[23,24] In the present study, cyst fluid CEA mean levels were significantly lower in the resolution group than in the intervention group (1.59±1.53 ng/mL vs 2.36±1.46 ng/mL, p=0.002). This indicated a correlation between higher levels of CEA and complicated clinical course of disease. When CEA levels did not indicate malignancy, pseudocyst fluid levels with CEA>1.5 ng/ mL demonstrated inverse predictive power of spontaneous resolution. In addition, 21 patients (32.3%) had symptoms of jaundice, while only 4 (5.8%) responded well to conservative treatment. Serum direct bilirubin levels of the resolution group were significantly lower than those of the intervention group (1.07±0.97 mg/dL vs 2.32±1 mg/dL, p=0.004). In both univariate and multivariate analyses, elevation of direct bilirubin levels higher than 0.95 mg/dL were closely correlated with surgical or percutaneous intervention and lower rates of resolution. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

In routine practice, asymptomatic PPs are safely observed, depending on size and location of cyst and secondary complications. Treatment algorithms and indications for therapeutic intervention were primarily developed according to challenges faced in the management of the disease. Therefore, accurate and effective prognostic scoring systems are essential to prevent characteristic complications of PPs and attendant therapeutic challenges.

Conclusion A scoring system based on cyst diameter, serum direct bilirubin, and cyst CEA level was developed in the present study. This system is simple and employs routinely collected radiologic and laboratory parameters. PPs with cyst diameter <53 mm, cyst fluid CEA level <1.5 ng/mL, and serum direct bilirubin level <0.9 mg/dL have high tendency to spontaneously resolve. PPs with scores of 3 and 4 are complicated, with unfavorable clinical outcomes. Adverse outcome and prolonged follow-up should be reduced by applying this scoring system during management of the disease in a clinical setting. The present retrospective cohort study requires validation with prospective randomized clinical studies. Conflict of interest: None declared.

REFERENCES 1. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102–11. 2. Cui ML, Kim KH, Kim HG, Han J, Kim H, Cho KB, et al. Incidence, risk factors and clinical course of pancreatic fluid collections in acute pancreatitis. Dig Dis Sci 2014;59:1055–62. 3. Kim KO, Kim TN. Acute pancreatic pseudocyst: incidence, risk factors, and clinical outcomes. Pancreas 2012;41:577–81. 4. Samuelson AL, Shah RJ. Endoscopic management of pancreatic pseudocysts. Gastroenterol Clin North Am 2012;41:47–62. 5. Bergman S, Melvin WS. Operative and nonoperative management of pancreatic pseudocysts. Surg Clin North Am 2007;87:1447–60. 6. Behrns KE, Ben-David K. Surgical therapy of pancreatic pseudocysts. J Gastrointest Surg 2008;12:2231–9. 7. Cannon JW, Callery MP, Vollmer CM Jr. Diagnosis and management of pancreatic pseudocysts: what is the evidence? J Am Coll Surg 2009;209:385–93. 8. Sankaran S, Walt AJ. The natural and unnatural history of pancreatic pseudocysts. Br J Surg 1975;62:37–44. 9. Warshaw AL, Rattner DW. Timing of surgical drainage for pancreatic pseudocyst. Clinical and chemical criteria. Ann Surg 1985;202:720–4. 10. Yeo CJ, Bastidas JA, Lynch-Nyhan A, Fishman EK, Zinner MJ, Cameron JL. The natural history of pancreatic pseudocysts documented by computed tomography. Surg Gynecol Obstet 1990;170:411–7. 11. Walt AJ, Bouwman DL, Weaver DW, Sachs RJ. The impact of technology on the management of pancreatic pseudocyst. Fifth annual Samuel Jason Mixter Lecture. Arch Surg 1990;125:759–63. 12. Behrman SW, Melvin WS, Ellison EC. Pancreatic pseudocysts following acute pancreatitis. Am J Surg 1996;172:228–31.

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19. Gonzalez Obeso E, Murphy E, Brugge W, Deshpande V. Pseudocyst of the pancreas: the role of cytology and special stains for mucin. Cancer 2009;117:101–7.

14. Cheruvu CV, Clarke MG, Prentice M, Eyre-Brook IA. Conservative treatment as an option in the management of pancreatic pseudocyst. Ann R Coll Surg Engl 2003;85:313–6.

20. Pitman MB, Lewandrowski K, Shen J, Sahani D, Brugge W, Fernandezdel Castillo C. Pancreatic cysts: preoperative diagnosis and clinical management. Cancer Cytopathol 2010;118:1–13.

15. Nguyen BL, Thompson JS, Edney JA, Bragg LE, Rikkers LF. Influence of the etiology of pancreatitis on the natural history of pancreatic pseudocysts. Am J Surg 1991;162:527–31.

21. Nagle JA, Wilbur DC, Pitman MB. Cytomorphology of gastric and duodenal epithelium and reactivity to B72.3: a baseline for comparison to pancreatic lesions aspirated by EUS-FNAB. Diagn Cytopathol 2005;33:381–6.

16. Pitchumoni CS, Agarwal N. Pancreatic pseudocysts. When and how should drainage be performed? Gastroenterol Clin North Am 1999;28:615–39. 17. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, Centeno BA, Szydlo T, Regan S, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–6. 18. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005;62:383–9.

22. Nawgiri RS, Nagle JA, Wilbur DC, Pitman MB. Cytomorphology and B72.3 labeling of benign and malignant ductal epithelium in pancreatic lesions compared to gastrointestinal epithelium. Diagn Cytopathol 2007;35:300–5. 23. Gonzalez LL, Jaffe MS, Wiot JF, Altemeier WA. Pancreatic pseudocyst: A cause of obstructive jaundice. Ann Surg 1965;161:569–76. 24. Warshaw AL, Rattner DW. Facts and fallacies of common bile duct obstruction by pancreatic pseudocysts. Ann Surg 1980;192:33–7.

ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Pankreatik psödokistin sonuçları tahmin edilebilir mi? Yeni bir skorlama sistemi önerisi Dr. Kazım Şenol,1 Dr. Özgür Akgül,1 Dr. Salih Burak Gündoğdu,1 Dr. İhsan Aydoğan,1 Dr. Mesut Tez,1 Dr. Faruk Çoşkun,1 Dr. Deniz Necdet Tihan2 1 2

Ankara Numune Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, Ankara Şevket Yılmaz Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, Bursa

AMAÇ: Pankreatik psödokistlerinde spontan rezolüsyon oranı %86, ciddi komplikasyon oranı ise %3–9 olarak bildirilmektedir. Bu çalışmanın amacı psödokistlerin spontan rezolüsyonunu öngörebilen yeni bir skorlama sistemi geliştirmektir. GEREÇ VE YÖNTEM: Yetmiş hastanın tıbbi kayıtları geçmişe yönelik incelendi. İki hasta çalışma dışı bırakıldı. Her hastanın kayıtlarından demografik verileri ve laboratuvar değerleri elde edildi. BULGULAR: Altmış sekiz hastanın ortalama yaşı 56.6 ve kadın/erkek oranı 1.34/1 olarak bulundu. Hastaların %48.5’inde pankreatitin nedeni safra taşları, %26.5’inde kronik alkol kullanımı, %25’inde ise idiopatikti. Ortalama kist çapı 71 mm idi. Takip esnasında 32 hastada (%47.1) psödokist kayboldu. Tek değişkenli analizler incelendiğinde kist çapı (>55 mm) ile serum dierkt bilirübin (>0.95 mg/dL) ve kist CEA (>1.5) değerlerinin spontan rezolüsyon saptanan ve saptanmayan hastalar arasında anlamlı derecede farklı olduğu görüldü. Çok değişkenli analizler sonrasında da aynı değişkenlerde istatistiksel anlamlı farklılık saptandı. Skorlar bu değişkenlere atanan puanlar toplanarak elde edildi. Nihai puanlar ile %80 hastada spontan rezolüsyon tahmin edilebildi. TARTIŞMA: Basit ve kolay uygulanabilir olan skorlama sistemimiz ile psödokist rezolüsyonunu tahmin etmek mümkün olabileceği kannatindeyiz; yine de geçerlilik ve güvenilirliğinin daha detaylı değerlendirilmesi gerekmektedir. Anahtar sözcükler: Pankreas; prognoz; psödokist; skorlama sistemi; spontan rezolüsyon. Ulus Travma Acil Cerrahi Derg 2016;22(2):150–154

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doi: 10.5505/tjtes.2016.07377

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ORIG I N A L A R T IC L E

Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis: an analysis of 3392 cases Mert Mahsuni Sevinç, M.D., Erdem Kınacı, M.D., Ekrem Çakar, M.D., Savaş Bayrak, M.D., Abdulkerim Özakay, M.D., Acar Aren, M.D., Serkan Sarı, M.D. Department of General Surgery, İstanbul Training and Research Hospital, İstanbul-Turkey

ABSTRACT BACKGROUND: The aim of the present study was to examine the efficacy of simple laboratory parameters including neutrophilto-lymphocyte ratio (NLR), platelet count (PLT), mean platelet volume (MPV), and serum bilirubin level in the diagnosis of acute appendicitis and recognition of perforated appendicitis. METHODS: Records of 3392 patients who underwent appendectomy in a 10-year period were reviewed retrospectively. Patients were divided into 2 groups according to histopathological examination results: Group 1 had normal appendix, Group 2 had acute appendicitis. Patients with acute appendicitis were divided into subgroups: Group 2A had simple acute appendicitis, while Group 2B had perforated appendicitis. Efficacy of the aforementioned laboratory parameters was evaluated in the diagnosis of acute appendicitis and recognition of perforated appendicitis. Independent variables were determined by univariate analysis and multivariate analysis was performed. Receiver operating characteristic (ROC) curve analysis was used to identify significant parameters in multivariate analysis. Cut-off values, sensitivity, specificity, and accuracy calculations performed for parameters with area under curve (AUC) >0.600 were accepted as “significant parameters.” RESULTS: White cell count (WCC), bilirubin, and NLR were significant parameters for the diagnosis of acute appendicitis. Cut-off values were 11900/mm3 for WCC (sensitivity: 71.2%; specificity: 67.2%; OR: 5.13), 1.0 mg/dl for bilirubin (sensitivity: 19.1%; specificity: 92.4%; OR: 2.96), and 3.0 for NLR (sensitivity: 81.2%; specificity: 53.1%; OR: 4.27). Serum bilirubin and NLR were independent variables for the diagnosis of perforated appendicitis. Cut-off values were 1.0 mg/dl for bilirubin (sensitivity: 78.4%; specificity: 41.7%; OR: 2.6) and 4.8 for NLR (sensitivity: 81.2%; specificity: 53.1%; OR: 2.6). CONCLUSION: Presence of at least 1 of the following findings in a patient suspected of having acute appendicitis was significantly associated with a definite diagnosis: WCC >11.900 mm3, serum bilirubin >1.0 mg/dl, NLR >3.0. In patients with acute appendicitis, serum bilirubin >1.0 mg/dl or NLR >4.8 were significantly associated with the presence of perforation. While WCC is a significant parameter for diagnosis of acute appendicitis, no significant association with perforated appendicitis was found. PLT and MPV were not useful parameters when diagnosing acute appendicitis. Keywords: Appendicitis; bilirubin; mean platelet volume; neutrophil-to-lymphocyte ratio; platelet count.

INTRODUCTION In addition to so-called “leukocytosis,” many laboratory parameters have been used to diagnose or determine severity of infectious or inflammatory diseases such as acute appenAddress for correspondence: Mert Mahsuni Sevinç, M.D. İstanbul Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, 34098 Fatih, İstanbul, Turkey Tel: +90 212 - 459 60 00 E-mail: mertsevinc34@gmail.com Qucik Response Code

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dicitis. As diversity of such parameters increases, attendant problems arise, including availability, accuracy, intelligibility, time-effectiveness, and cost-effectiveness. When the relatively high incidence of acute appendicitis is considered, these problems take on great importance. Radiological modalities, particularly ultrasonography and computed tomography, have been widely and successfully used in the diagnosis of acute appendicitis and its complications.[1,2] However, because these modalities require special equipment and experienced radiologists, surgeons seek simpler means of definitive diagnosis. In the last decade, simple parameters included in a standard complete blood count and routine preoperative tests, including neutrophil count, neutrophil ratio,[3] neutrophil-to-lymphocyte ratio (NLR),[4–7] platelet count (PLT),[8,9] mean platelet volume (MPV),[8–13] and serum bilirubin level,[14–20] have been studied for potential value in diagnosis of acute appendicitis 155

Sevinç et al. Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis

bilirubinemia, including hereditary enzyme deficiency syndromes such as Gilbert’s syndrome, could not be determined due to the retrospective nature of the study.

and prediction of possible complications. However, reported results widely vary, and the number of patients studied has been relatively small. The aim of the present study was to evaluate the predictive value of simple laboratory parameters including white cell count (WCC), NLR, PLT, MPV, and serum bilirubin level in the diagnosis of acute appendicitis and its complications in a very large case series.

Statistical Analysis SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. In univariate analysis, normally distributed continuous variables were expressed as mean±SD and compared using t-test. Variables not normally distributed were expressed as median (range) and compared using Mann-Whitney U test. Nominal data were expressed as case numbers and percentages, and were compared using Fisher’s exact test. Logistic regression analysis was performed as multivariate analysis on parameters with significant differences observed in univariate analysis. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curve analysis. Appropriate cut-off values were identified, and sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio were calculated for parameters with an area under the curve (AUC) of above 0.600. All tests were two-sided. A value of p<0.05 was considered statistically significant.

MATERIALS AND METHODS Records of patients who underwent open or laparoscopic appendectomy between March 2005 and December 2014 were reviewed retrospectively. Demography, recorded anamneses, histopathological diagnoses, and preoperative laboratory findings including WCC, neutrophil count, lymphocyte count, PLT, MPV, and serum bilirubin level were reviewed, and NLR was calculated. Patients were divided into 2 groups according to histopathological evaluation. Group 1 included patients with normal appendix, and Group 2 included patients with acute appendicitis. Group 2 patients were divided into subgroups: Group 2A included patients with simple acute appendicitis according to histopathological examination, Group 2B included patients with perforated appendicitis. Basic demographic data (age, gender) and preoperative laboratory findings were compared between Groups 1 and 2, and between Groups 2A and 2B, providing reliable results regarding the diagnosis of acute appendicitis and the prediction of perforation, respectively.

RESULTS A total of 3392 patients who underwent appendectomy between March 2005 and December 2014 were included. Median age was 32 (range: 16–95) years, and the majority of patients were male (59.2% male, 40.8% female).

Exclusion criteria were age younger than 15 years, presence of malignant diseases, current course of chemotherapy or radiotherapy, pregnancy, intraoperative diagnosis of intraabdominal pathology other than appendicitis, and presence of known liver diseases. Clinically insignificant causes of hyper-

Negative laparotomy was more common in females. WCC, MPV, serum bilirubin, and NLR values were significantly different between Groups 1 and 2 in univariate analyses. These parameters were independent variables for the diagnosis of

Table 1. Comparison of the two groups

Univariate analysis

Parameters

Group 1

Number of cases Age (years)† Gender (n)

Group 2

Multivariate analysis p

95% CI (min-max)

AUC

95%CI (min-max)

531

2861

33 (16–95)

32 (16-91)

0.000

ROC curve analysis

Male (%)

205 (39%)

1803 (63%)

0.000

Female (%)

326 (61%)

1058 (37%)

WCC (x10³/mm³)‡

10.8±3.8

14.3±4.2 0.000 1.23

PLT (x10³/mm³)

251±70

254±72

0.296

MPV (fL)‡

8.5±1.2

8.3±1.1

0.001 0.89

‡

1.20–1.27

0.82–0.97

0.000 0.748

0.725–0.771

0.000

0.011 0.543

0.517–0.570

0.002

Bilirubin (mg/dl)

0.6 (0.1–2.1)

0.6 (0.1–9.0)

0.000

4.27

2.78–6.57

0.000 0.621

0.596–0.646

0.000

NLR†

3.0 (0.1–72.0)

5.7 (0.2–150) 0.000

1.03

1.00–1.06

0.007 0.692

0.667–0.717

0.000

†

† Median (range); ‡Mean (±standard deviation). OR: Odds ratio; AUC: Area under the curve; WCC: White cell count; PLT: Platelet count; MPV: Mean platelet volume; NLR: Neutrophil-to-lymphocyte ratio.

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(b)

ROC Curve Analysis of WCC

1.0

0.8

0.6

0.4

0.2 AUC: 0.748 (95% CI: 0.725–0.771) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

1.0

(d)

ROC Curve Analysis of Serum Bilirubin

1.0

0.0 0.0

0.8

0.6

0.4

0.2

AUC: 0.543 (95% CI: 0.517–0.570) p=0.002

0.2

0.4 0.6 1 - Specificity

0.8

1.0

ROC Curve Analysis of NLR

1.0

0.8

Sensitivity

0.4

0.2

0.0 0.0

(c)

ROC Curve Analysis of MPV

1.0

0.8

Sensitivity

(a)

0.4

0.2

0.0 0.0

AUC: 0.621 (95% CI: 0.596–0.646) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

0.0 0.0

1.0

AUC: 0.692 (95% CI: 0.667–0.717) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 1. Receiver operating characteristic (ROC) curve analyses of significant parameters for the diagnosis of acute appendicitis: (a) white cell count (WCC), (b) mean platelet volume (MPV), (c) serum bilirubin, (d) neutrophil-tolymphocyte ratio (NLR).

acute appendicitis in multivariate logistic regression analysis. Comparison between Groups 1 and 2 is detailed in Table 1. In ROC curve analyses of these independent variables, AUC was above 0.600 for WCC, bilirubin, and NLR (Figure 1). Proposed cut-off values and performance characteristics for these variables are shown in Table 2.

Each parameter considered (WCC, PLT, MPV, bilirubin, and NLR) were significantly different between patients with simple (Group 2A) and perforated (Group 2B) appendicitis. Each parameter was an independent variable for recognition of perforated appendicitis in multivariate logistic regression analysis. Comparison of Groups 2A and 2B is detailed in Ta-

Table 2. Proposed cut-off values for significant parameters in diagnosis of acute appendicitis

Cut-off value

Sensitivity (%)

Specificity (%)

11,900

71.2

67.2

0.92 0.30 5.13 2.15 0.43 0.748

Bilirubin (mg/dl)

1.0

19.1

92.4

0.93 0.17 2.96 2.5 0.87 0.621

NLR

3.0

81.2

53.1

0.89 0.36 4.87 1.72 0.35 0.692

WCC (/mm³)

PPV

NPV

pLLR

nLLR

AUC

WCC: White cell count; NLR: Neutrophil-to-lymphocyte ratio; PPV: Positive predictive value; NPV: Negative predictive value; OR: Odds ratio; pLLR: Positive likelihood ratio; nLLR: Negative likelihood ratio; AUC: Area under the curve.

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Sevinç et al. Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis

Table 3. Comparison of the subgroups of Group 2

Univariate analysis

Parameters

Group 2A

Number of cases Age (years)‡ Gender (n)

Multivariate analysis

Group 2B

ROC curve analysis

95%CI (min-max)

AUC

95%CI (min-max)

2675

186

33.9±12.2

38.7±15.8

0.000

0.388

Male (%)

1680 (63%)

123 (66%)

Female (%)

995 (37%)

63 (34%)

WCC (x10³/mm³)‡ 14.2±4.1 15.8±4.9 0.000 1.06 1.02–1.10 0.001 0.596 0.554–0.638 0.000 PLT (x10³/mm³)‡ 253±70

278±98 0.001 1.00 1.00–1.01 0.000 0.570 0.525–0.615 0.001

MPV (fL)‡

8.0±1.1 0.001 0.83 0.72–0.95 0.008 0.588 0.546–0.630 0.000

8.3±1.1

Bilirubin (mg/dl)

0.6 (0.1–9.0)

0.7 (0.2–3.4)

0.000

1.43

1.16–1.76

0.001

0.602

0.563–0.639

0.000

NLR†

5.5 (0.2–150)

7.8 (0.4–58.6)

0.000

1.02

1.00–1.04

0.018

0.624

0.584–0.665

0.000

†

Table 4. Proposed cut-off values for significant parameters in prediction of perforation

Cut-off value

Sensitivity (%)

Specificity (%)

PPV

NPV

pLLR

nLLR

AUC

Bilirubin (mg/dl)

1.0

34.4

81.4

0.11

0.94

2.6

1.84

0.80

0.594

NLR

4.8

78.4

41.7

0.08

0.96

2.6

1.34

0.51

0.624

ble 3. In ROC curve analyses of these independent variables, AUC above 0.600 was found only in bilirubin and NLR (Figure 2). Proposed cut-off values and performance characteristics for these 2 variables are shown in Table 4.

DISCUSSION Acute appendicitis is one of the most common causes of emergency surgery. Diagnosis is based on physical examination and presence of specific anamnesis. With technological advances in radiological modalities, successful diagnosis is more easily achieved.[1,2] However, availability, intelligibility, time-effectiveness, and cost-effectiveness of these modalities remain disadvantageous, particularly to relatively small hospitals. Thus the potential of simple laboratory parameters to aid in diagnosis of acute appendicitis and prediction of perforations has attracted interest of surgeons. In the present study, simple, well-studied parameters were given particular consideration, and comprehensive and reliable data from a very large case series was provided. Moderate leukocytosis is an expected laboratory finding in cases of acute appendicitis.[15] According to the present results, WCC is a significant parameter for the diagnosis of acute appendicitis. However, it is not a perfect indicator, due 158

to relatively low sensitivity and specificity. With a cut-off value of 11900/mm3, 71% sensitivity and 68% specificity were found. In a recent study, Rafiq et al.[21] reported very high sensitivity and specificity (87% and 92%, respectively) with the same cut-off value. Nevertheless, in previous studies, sensitivity and specificity of WCC have been reported between 67%–87% and 43%–81%, respectively.[3,22] While accuracy of the test remains controversial, the significant positive correlation between WCC and diagnosis of acute appendicitis can be agreed upon. As the present study included a very large number of participants, the authors believe the results are comprehensive. Regarding recognition of complicated cases, results were similar to the diagnosis of acute appendicitis. While a significant difference between patients with and without perforation was found in univariate analysis, WCC did not greatly aid in determining it (OR: 1.06; AUC: 0.596). However, Atema et al.[1] suggested WCC >13000/mm3 as a component of a scoring system for differential diagnosis of non-complicated and complicated appendicitis. Due to the lower AUC level, the present authors did not create a cut-off value for WCC in predicting perforation. While WCC alone may not efficiently predict incidence of perforation, it may prove valuable when used in conjunction with other parameters. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Sevinç et al. Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis

Sensitivity

1.0

(b)

ROC Curve Analysis of WCC

1.0

0.8

0.6

Sensitivity

(a)

0.4

0.2

0.0 0.0

1.0

AUC: 0.596 (95% CI: 0.554–0.638) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

(d)

ROC Curve Analysis of MPV

1.0

0.8

0.6

0.4

0.0 0.0

1.0

AUC: 0.570 (95% CI: 0.525–0.615) p=0.001

0.2

0.4 0.6 1 - Specificity

0.8

1.0

ROC Curve Analysis of Serum Bilirubin

0.4

0.2 AUC: 0.588 (95% CI: 0.546–0.630) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

1.0

ROC Curve Analysis of NLR

0.0 0.0

AUC: 0.602 (95% CI: 0.563–0.639) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 2. Receiver operating characteristic (ROC) curve analyses of significant parameters for diagnosis of appendicitis: (a) white cell count (WCC), (b) platelet count (PLT), (c) mean platelet volume (MPV), (d) serum bilirubin, (e) neutrophil-to-lymphocyte ratio (NLR).

0.8

Sensitivity

0.0 0.0

1.0

0.2

(e)

0.4

0.2

Sensitivity

(c)

ROC Curve Analysis of PLT

0.6

0.4

0.2

0.0 0.0

AUC: 0.624 (95% CI: 0.584–0.665) p=0.000

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Neutrophilia and lymphocytopenia are components of the cellular response in systemic inflammation.[23] Increase in the difference between neutrophil and lymphocyte counts reflects severity of inflammatory response. Hence, neutroUlus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

phil-to-lymphocyte ratio has long been used as a marker for many pathologies, including malignancies, chronic inflammatory diseases, and postoperative complications.[23,24] Use of NLR for diagnosis of acute appendicitis is not a new idea. 159

Sevinç et al. Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis

The argument that NLR is a more sensitive parameter than the number of leukocytes was put forth 20 years earlier by Goodman et al.[25] Four studies have been published in the last 5 years regarding this issue.[4–7] Shimizu et al.[7] suggest a NLR cut-off value of 5.0 for the diagnosis of acute appendicitis, with 44% sensitivity and 22% specificity. Ishizuka et al.[5] determined a cut-off value of 8.0 for NLR to differentiate gangrenous appendicitis from catarrhal appendicitis, with 73% sensitivity and 39% specificity. Kahramanca et al.[6] reported 2 NLR cut-off values of 4.68 (65% sensitivity, 55% specificity) and 5.74 (71% sensitivity, 49% specificity) to distinguish acute appendicitis from normal appendix, and complicated appendicitis from non-complicated appendicitis, respectively. According to the present results, NLR cut-off values were 3.0 (81% sensitivity, 53% specificity) and 5.5 (78.4% sensitivity, 41.7% specificity) for the diagnosis of acute appendicitis and perforated appendicitis, respectively (Tables 2 and 4). In spite of conflicting suggestions regarding cut-off values, the authors believe that NLR is a significant parameter for diagnosing acute appendicitis and differentiating complicated cases. According to the present results, PLT was not a useful indicator. However, it was significantly higher in patients with perforated appendicitis, compared to simple appendicitis. Platelet count is a well-known indicator of the severity of systemic infections.[26] However, data regarding the diagnostic value of PLT for acute appendicitis remains limited. Two recent studies that each included fewer than 260 patients similarly found that PLT had no diagnostic value for acute appendicitis.[8,9] According to the present results, neither was PLT a reliable indicator of perforation (OR: 1.0; AUC: 0.570). Platelet size is at least as important as platelet number. According to present results, MPV was significantly lower in cases of appendicitis, compared to normal appendix. In addition, MPV was significantly lower in patients with complicated appendicitis. Conflicting results have been reported regarding the relationship between MPV and active inflammatory processes. Kim et al.[27] defined an increase in MPV from baseline as an independent risk factor for mortality in patients with sepsis, while decreases in MPV have been associated with activation of rheumatologic diseases, including rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. [28] Five of 6 studies to address the relationship between MPV and acute appendicitis reported results consistent with those of the present study.[8–12] However, in the sixth study, conflicting results were reported.[13] Reported MPV cut-off values in the 5 studies with similar results were between 7.3 and 7.95 fL.[8–12] However, in the present study, the AUC was 0.543. Thus, in spite of significant differences between groups, a reliable cut-off value for MPV was not suggested in the present study. In addition, differences in MPV values between groups were very small in each of these studies, including the present. Therefore, the authors believe that MPV is not a useful parameter for daily clinical practice. Likewise, Leader et al.[29] concluded in a review that MPV has limited value for clinical 160

use, in spite of statistically significant differences. It was confirmed in the present study that serum bilirubin level above 1 mg/dl has a highly specific significant relationship with diagnoses of acute appendicitis (92.4% specificity) and perforated appendicitis (81.4% specificity). However, the sensitivity of this test was quite low (19% for acute appendicitis, 34% for perforated appendicitis). In 3 previous studies, reported sensitivities and specificities of serum bilirubin level of 1.0 mg/dl for diagnosis of appendicitis were 27%–96%,[14] 30%–88%,[20] and 69%–56%,[15] respectively. For prediction of perforation, reported sensitivities were between 38% and 77%, and specificities were between 66% and 87%.[14–20] In the present results, ORs were 2.5 and 3.0 for simple and perforated appendicitis, respectively, while very high values (including some above 10) have been reported.[14] Correlation of hyperbilirubinemia and severe appendicitis has long been known.[30] However, the measure is not widely used in daily clinical practice, possibly due to the very low sensitivity of this test. Nevertheless, the present authors suggest that surgeons consider total serum bilirubin level when attempting to rule out diagnosis of acute appendicitis or predict perforation. The primary limitation of the present study was its retrospective nature. Only patients who underwent appendectomy were included; data did not reflect patients suspected of having acute appendicitis who did not undergo surgery. However, the patient population was very large, and the authors believe that comprehensive data is provided regarding diagnostic accuracy of simple laboratory parameters in cases of suspected acute appendicitis. An additional limitation was lack of data regarding patients with suspicious abdominal findings who did not undergo surgery. However, the authors believe that in spite of these limitations, the present study provides comprehensive results and contributes valuable reference data. In conclusion, it was demonstrated that no simple yet perfect test currently exists for diagnosing acute appendicitis and recognizing perforation. However, increases in WCC, serum bilirubin level, and NLR can be considered moderately reliable indicators for the diagnosis of acute appendicitis. Serum bilirubin level and NLR are useful indicators for the recognition of perforated appendicitis. Although MPV was an independent variable for diagnosis, differences between groups were minimal, rendering this test impossible to use in daily clinical practice. Neither is PLT a reliable indicator of acute appendicitis or perforation.

Acknowledgement The authors acknowledge no competing interests and are alone responsible for the content and composition of the present article. Ethics committee approval was not needed due to the retrospective nature of the study. Conflict of interest: None declared. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Sevinç et al. Diagnostic value of basic laboratory parameters for simple and perforated acute appendicitis

REFERENCES 1. Atema JJ, van Rossem CC, Leeuwenburgh MM, Stoker J, Boermeester MA. Scoring system to distinguish uncomplicated from complicated acute appendicitis. Br J Surg 2015;102:979–90. 2. Xiong B, Zhong B, Li Z, Zhou F, Hu R, Feng Z, Xu S, et al. Diagnostic Accuracy of Noncontrast CT in Detecting Acute Appendicitis: A Metaanalysis of Prospective Studies. Am Surg 2015;81:626–9. 3. Şahbaz NA, Bat O, Kaya B, Ulukent SC, İlkgül Ö, Özgün MY, et al. The clinical value of leucocyte count and neutrophil percentage in diagnosing uncomplicated (simple) appendicitis and predicting complicated appendicitis. Ulus Travma Acil Cerrahi Derg 2014;20:423–6. 4. Markar SR, Karthikesalingam A, Falzon A, Kan Y. The diagnostic value of neutrophil: lymphocyte ratio in adults with suspected acute appendicitis. Acta Chir Belg 2010;110:543–7. 5. Ishizuka M, Shimizu T, Kubota K. Neutrophil-to-lymphocyte ratio has a close association with gangrenous appendicitis in patients undergoing appendectomy. Int Surg 2012;97:299–304. 6. Kahramanca S, Ozgehan G, Seker D, Gökce EI, Seker G, Tunç G, et al. Neutrophil-to-lymphocyte ratio as a predictor of acute appendicitis. Ulus Travma Acil Cerrahi Derg 2014;20:19–22. 7. Shimizu T, Ishizuka M, Kubota K. A lower neutrophil to lymphocyte ratio is closely associated with catarrhal appendicitis versus severe appendicitis. Surg Today 2016;46:84–9. 8. Erdem H, Aktimur R, Cetinkunar S, Reyhan E, Gokler C, Irkorucu O, et al. Evaluation of mean platelet volume as a diagnostic biomarker in acute appendicitis. Int J Clin Exp Med 2015;8:1291–5. 9. Tanrikulu CS, Tanrikulu Y, Sabuncuoglu MZ, Karamercan MA, Akkapulu N, Coskun F. Mean platelet volume and red cell distribution width as a diagnostic marker in acute appendicitis. Iran Red Crescent Med J 2014;16:e10211. 10. Dinc B, Oskay A, Dinc SE, Bas B, Tekin S. New parameter in diagnosis of acute appendicitis: platelet distribution width. World J Gastroenterol 2015;21:1821–6. 11. Albayrak Y, Albayrak A, Albayrak F, Yildirim R, Aylu B, Uyanik A, et al. Mean platelet volume: a new predictor in confirming acute appendicitis diagnosis. Clin Appl Thromb Hemost 2011;17:362–6. 12. Bilici S, Sekmenli T, Göksu M, Melek M, Avci V. Mean platelet volume in diagnosis of acute appendicitis in children. Afr Health Sci 2011;11:427– 32. 13. Narci H, Turk E, Karagulle E, Togan T, Karabulut K. The role of mean platelet volume in the diagnosis of acute appendicitis: a retrospective case-controlled study. Iran Red Crescent Med J 2013;15:e11934. 14. D’Souza N, Karim D, Sunthareswaran R. Bilirubin; a diagnostic marker for appendicitis. Int J Surg 2013;11:1114–7.

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15. Farooqui W, Pommergaard HC, Burcharth J, Eriksen JR. The diagnostic value of a panel of serological markers in acute appendicitis. Scand J Surg 2015;104:72–8. 16. Hong YR, Chung CW, Kim JW, Kwon CI, Ahn DH, Kwon SW, et al. Hyperbilirubinemia is a significant indicator for the severity of acute appendicitis. J Korean Soc Coloproctol 2012;28:247–52. 17. Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis. Am J Surg 2009;198:193–8. 18. Atahan K, Üreyen O, Aslan E, Deniz M, Çökmez A, Gür S, et al. Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. J Int Med Res 2011;39:609–18. 19. Käser SA, Fankhauser G, Willi N, Maurer CA. C-reactive protein is superior to bilirubin for anticipation of perforation in acute appendicitis. Scand J Gastroenterol 2010;45:885–92. 20. Emmanuel A, Murchan P, Wilson I, Balfe P. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann R Coll Surg Engl 2011;93:213–7. 21. Rafiq MS, Khan MM, Khan A, Ahmad B. Total leukocyte and neutrophil count as preventive tools in reducing negative appendectomies. Ulus Travma Acil Cerrahi Derg 2015;21:102–6. 22. Kamran H, Naveed D, Asad S, Hameed M, Khan U. Evaluation of modified Alvarado score for frequency of negative appendicectomies. J Ayub Med Coll Abbottabad 2010;22:46–9. 23. Zahorec R. Ratio of neutrophil to lymphocyte counts-rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 2001;102:5–14. 24. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99. 25. Goodman DA, Goodman CB, Monk JS. Use of the neutrophil:lymphocyte ratio in the diagnosis of appendicitis. Am Surg 1995;61:257–9. 26. Mihajlovic D, Lendak D, Mitic G, Cebovic T, Draskovic B, Novakov A, et al. Prognostic value of hemostasis-related parameters for prediction of organ dysfunction and mortality in sepsis. Turk J Med Sci 2015;45:93–8. 27. Kim CH, Kim SJ, Lee MJ, Kwon YE, Kim YL, Park KS, et al. An increase in mean platelet volume from baseline is associated with mortality in patients with severe sepsis or septic shock. PLoS One 2015;10:e0119437. 28. Kisacik B, Tufan A, Kalyoncu U, Karadag O, Akdogan A, Ozturk MA, et al. Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Joint Bone Spine 2008;75:291– 4. 29. Leader A, Pereg D, Lishner M. Are platelet volume indices of clinical use? A multidisciplinary review. Ann Med 2012;44:805–16. 30. Miller DF, Irvine RW. Jaundice in acute appendicitis. Lancet 1969;94:201–6.

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ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Basit ve perfore apandisitlerde temel laboratuvar testlerinin tanısal değeri: 3392 olgu analizi Dr. Mert Mahsuni Sevinç, Dr. Erdem Kınacı, Dr. Ekrem Çakar, Dr. Savaş Bayrak, Dr. Abdulkerim Özakay, Dr. Acar Aren, Dr. Serkan Sarı İstanbul Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, İstanbul

AMAÇ: Bu çalışmada ameliyat öncesi lökosit (WCC), nötrofil/lenfosit oranı (NLR), trombosit (PLT), ortalama-trombosit-hacmi (MPV) ve serum bilirubin düzeyleri gibi basit laboratuvar incelemelerinin akut apandisit tanısı koymakta veya perfore olguların basit apandisitlerden ayırmını yapmaktaki etkinliğini ortaya koymayı amaçladık. GEREÇ VE YÖNTEM: Apendektomi ameliyatı uygulanmış 3392 hasta geriye dönük olarak değerlendirildi. Hastalar histopatolojik tanılarına göre öncelikle iki gruba ayrıldı. Normal appendiks bulguları olan olgular (Grup 1) ve akut apandisit olan olgular (Grup 2). Daha sonra ikinci gruptaki olgular basit akut apandisit olguları (Grup 2A) ve perfore apandisit olguları (Grup 2B) olarak alt gruplara ayrıldı. Gruplar arasında ameliyat öncesi WCC, NLR, PLT, MPV ve serum bilirubin düzeyleri karşılaştırıldı. Önce univariate analiz ile bağımsız değişkenler saptandı, daha sonra bunlardan çok değişkenli analizde p değeri 0.05’den küçük olanlara ROC eğrisi analizi uygulandı. Eğrinin altında kalan alan 0.600’den büyük olan parametreler anlamlı paremtetre olarak kabul edilerek eşik değer hesaplandı. BULGULAR: WCC, bilirubin ve NLR, akut apandisit tanısında klinik kullanımda anlamlı parametreler olarak saptandı. Lökositoz için eşik değer 11.900/mm3 (sensitivite %71.2, spesifisite %67.2, OR: 5.13), bilirubin için 1.0 mg/dl (sensitivite %19.1, spesifisite %92.4, OR: 2.96) ve NLR için 3.0 (sensitivite %81.2, spesifisite %53.1, OR: 4.27) idi. Bilirubin ve NLR, perfore apandisit olgularının ayırımında anlamlı parametrelerdi. Bilirubin için eşik değer 1.0 mg/dl (sensitivite %78.4, spesifisite %41.7, OR: 2.6) ve NLR için 4.8 (sensitivite %81.2, spesifisite %53.1, OR: 2.6) idi. TARTIŞMA: Akut apandisit şüphesi oluşturan bulgularla gelen bir olguda serum lökosit değerinin 11.900/mm3’den, bilirubin değerinin 1.0 mg/ dl’den, veya nötrofil/lenfosit oranının 3.0’den fazla olması akut apandisit tanısı destekler. Akut apandisit düşünülen bir olguda ise bilirubin değerinin 1.0 mg/dl’den veya nötrofil/lenfosit oranının 4.8’den büyük olması olguda perforasyon geliştiğini destekler verilerdir. WCC, akut apandisit tanısında anlamlı olmasına rağmen, perfore olguların tanınmasında güçlü bir parametre değildir. PLT ve MPV akut apandisit şüpheli olgularda tanısal anlam taşımamaktadırlar. Anahtar sözcükler: Apandisit; bilirubin; nötrofil/lenfosit oranı; ortalama trombosit hacmi; trombosit sayısı. Ulus Travma Acil Cerrahi Derg 2016;22(2):155–162

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ORIG I N A L A R T IC L E

Neutrophil-lymphocyte ratio and mean platelet volume can be a predictor for severity of acute appendicitis Samet Yardımcı, M.D., Mustafa Ümit Uğurlu, M.D., Mümin Coşkun, M.D., Wafi Attaallah, M.D., Şevket Cumhur Yeğen, M.D., Department of General Surgery, Marmara University Faculty of Medicine, İstanbul-Turkey

ABSTRACT BACKGROUND: Early diagnosis of perforation in acute appendicitis (AA) allows surgeons to select the most appropriate treatment. The aim of the present study was to determine whether preoperative neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) could predict perforation in AA. METHODS: Data collected from 413 consecutive patients with AA and 100 healthy controls were analyzed retrospectively. Patients were categorized as having had phlegmonous appendicitis, appendicitis with localized peritonitis, or appendicitis with perforation and/ or gangrene. MPV and NLR values were compared among the control group and the 3 groups of patients with AA. RESULTS: Means values of MPV were 9.3±8 fL for the patient group and 8.5±0.9 fL for the healthy control group (p=0.0005). Mean values of MPV by patient subgroup were 8.8±5.8 for phlegmonous appendicitis, 8.9±5.8 for localized peritonitis, and 12.8±9.7 for appendicitis with perforation and/or gangrene (p=0.005). Cut-off value of MPV was set at 8.92 to differentiate AA with perforation and/ or gangrene from other types of AA. Mean NLRs of patients with phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/or gangrene were 8.3±5.6, 9.1±6.2, and 10.6±6.4, respectively; p=0.023. The cut-off value for NLR was set at 7.95 to differentiate AA with perforation and/or gangrene from other types of AA. CONCLUSION: Both NLR and MPV can be useful in predicting severity of AA. Keywords: Appendicitis; lymphocyte; mean platelet volume; neutrophil; predictive factors.

INTRODUCTION Acute appendicitis (AA) is one of the most common acute surgical conditions of the abdomen, and has a lifetime risk of approximately 7%.[1] Although urgent appendectomy is still considered the gold standard treatment, recent evidence has shown that AA can be treated conservatively without surgery.[2] However, conservative treatment is likely inconvenient in cases of perforated AA. Therefore, any factor that allows for prediction of perforation in AA contributes significantly to patient-specific treatment. Furthermore, early diagnosis of perforation is likely to improve outcomes, allowing Address for correspondence: Mustafa Ümit Uğurlu, M.D. Mimar Sinan Cad., Marmara Üniversitesi Pendik EAH Genel Cerrahi Departmanı, Kat: -1, Üst Kaynarca, Pendik, İstanbul, Turkey Tel: +90 216 - 657 06 06 E-mail: umitugurlu@gmail.com Qucik Response Code

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the surgeon to prepare for a relatively troublesome operation, including the selection of laparoscopy or laparotomy, etc. Aside from symptoms and specific physical examination findings, ultrasonography and computed tomography have become the most useful tools in the diagnosis of perforation in AA, prior to surgery. However, these examinations can be very costly. While it has been reported that raised bilirubin and C-reactive protein (CRP) levels are markers of perforation, they are not sufficiently accurate.[3] Mean platelet volume (MPV) is a marker derived from megakaryocytes during platelet production, associated with platelet function and activation. [4] Its roles in thrombosis and inflammation have been investigated.[5] Neutrophil-lymphocyte ratio (NLR), an inflammatory marker, has been found to be predictive in the prognosis of colorectal cancer and cardiovascular diseases.[6,7] The predictive powers of NLR and MPV in the diagnosis of AA have been evaluated.[8,9] However, information regarding severity of AA was not included in these studies. The aim of the present study was to determine whether preoperative NLR and/or MPV levels could predict severity of AA. 163

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MATERIALS AND METHODS Patients A prospective database of 434 patients who underwent appendectomies between January 2012 and October 2013 was reviewed. Patients with non-inflamed appendix tissues on final pathology reports were included. Patients who underwent appendectomy as part of another abdominal operation were excluded (n=22). Hence, 413 patients were found to be eligible.

Healthy Volunteers Healthy volunteers (n=100) admitted to the general surgery outpatient clinic were enrolled for comparison with the patient group. The volunteers were all tumor- and inflammation-free, with no history of malignancy or recent local/systemic inflammation. They were age-matched to the patient population.

Data In addition to demographic data, complete blood count tests were preoperatively obtained from the patient and control groups to assess leukocyte, neutrophil, lymphocyte, and MPV counts. Laboratory analysis was conducted with an automated hematology analyzer (Coulter® LH 780; Beckman Coulter Inc., Brea, CA, USA). NLRs were then calculated in accordance to complete blood counts. Postoperatively, all appendix specimens were pathologically evaluated. In accordance with per-operative findings, pathology specimens were categorized as phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/ or gangrene.

Statistical Analysis Descriptive analysis was performed, and data were presented as mean±SD. Differences among the groups were analyzed using chi-square and analysis of variance (ANOVA) tests. Rec-

ommended cut-off values for NLR and MPV were obtained with receiver operating curve (ROC) analysis. Logistic regression test was used for univariate analysis and to calculate odds ratios (OR) with 95% confidence interval (CI). SPSS analysis was performed using SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA), and significance level was set at p<0.005.

RESULTS Demographics Mean age of the patient group was 32.4 (range 16–82), and mean age of the healthy controls was 42.7 (range 18–83). No statistical significance was found between the patient and healthy control groups (p=0.45). The patient group consisted of 295 males (71.4%), and 118 females (28.6%); the healthy controls consisted of 90 males (89.1%) and 11 females (10.9%). No statistical significance (p=0.82) was found between the patient and healthy control groups (Table 1). Appendix pathology was grouped as phlegmonous appendicitis (n=233; 56.4%), appendicitis with localized peritonitis (n=133; 32.2%), and appendicitis with perforation and/or gangrene (n=47; 11.4%).

Complete Blood Cell Counts Means of leukocyte counts were 14.4±3.7 x 103/µl for the patient group and 7.5±1.7x 103/µl for the healthy control group. Statistical significance was found between the patient and healthy control groups (95% CI: 7.2–7.9; 95% CI: 13.9–14.7; p=0.0005, respectively). The white blood cell (WBC) counts of patients with phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/or gangrene were 14.2±3.6 x 103/µl, 14.2±3.8 x 103/µl, and 15.6±3.8 x 103/ µl; p=0.06, respectively. Neutrophil counts of patients with phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/or gangrene were 11.5±3.6 x 103/µl, 11.6±3.7 x 103/µl, and 12.7±3.5 x 103/µl;

Table 1. The demographic data of the patients with appendicitis and the healthy controls Number of patients Mean age (range)

Acute appendicitis n

Healthy controls

% Mean±SD

413 32.4 (16–82)

% Mean±SD

101 42.7 (18–83)

0.45

Gender 0.82 Male

295

71.4

89.1

Female

118

28.6

10.9

WBC (x103/µl) 14.4±3.7 7.5±1.7 0.0005 NL ratio 8.7±5.9 2.7±2.2 0.009 MPV (Fl) 9.3±8 8.5±0.9 0.0005 SD: Standard deviation; WBC: White blood cell; NL: Neutrophil-lymphocyte; MPV: Mean platelet volume.

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Yardımcı et al. Neutrophil-lymphocyte ratio and mean platelet volume can be a predictor for severity of acute appendicitis

Table 2. Relationship between laboratory parameters of patients with different forms of appendicitis Flegmonous appendicitis

Appendicitis with localized peritonitis

Appendicitis with perforation or gangrene

n % Mean±SD n % Mean±SD n % Mean±SD

No. of patients

233

56.4

Mean age

133

32.2

32.7±11.8

11.4

31.8±10.8

34.1±13.9

0.42

Gender Male

168 91 36 0.34

Female

WBC (x10 /µl) 14.2±3.6 14.2±3.8 15.6±3.8 0.06 3

Neutrophil (x103/µl) 11.5±3.6 11.6±3.7 12.7±3.5 0.13 Lymphocyte (x103/µl) 1.7±0.7 1.6±0.7 1.7±0.9 0.34 NLR

8.3±5.6

9.1±6.2 10.6±6.4 0.023

MPV (Fl)

8.8±5.8

8.9±5.8

12.8±9.7

0.005

SD: Standard deviation; WBC: White blood cell; NLR: Neutrophil-lymphocyte ratio; MPV: Mean platelet volume.

p=0.13, respectively. Lymphocyte counts of patients with phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/or gangrene were 1.7±0.7 x 103/µl, 1.6±6.9 x 103/µl, and 1.7±9.4 x 103/µl; p=0. 34, respectively (Table 2).

Mean Platelet Volume Means of MPVs were 9.3±8 fL for the patient group and 8.5±0.9 fL for the healthy control group. Statistical significance was found between the patient and healthy control

Neutrophil-Leucocyte Ratios

ROC Curve

Means of NLRs of patients with phlegmonous appendicitis, appendicitis with localized peritonitis, and appendicitis with perforation and/or gangrene were 8.3±5.6, 9.1±6.2, and 10.6±6.4, respectively, p=0.023. ROC analysis was performed to determine cut-off value to identify patients with perforation and/or gangrene. The cut-off value was set as 7.95 (AUC: 0.763; 95% CI: 0.66-0.84; sensitivity: 78%; specificity: 67%; p=0.001; Fig. 1).

1.0

Sensitivity

0.8

0.6

0.4

0.2

0.0

0.2

0.4 0.6 1-Specificity

groups (95% CI: 8.3–8.5; 95% CI: 8.3–10.1; p=0.0005, respectively). Means of MPVs according to pathologies in the patient group were 8.8±5.8 (range: 6–96) for phlegmonous appendicitis, 8.9±5.8 (range: 6.1–74) for localized peritonitis, and 12.8±9.7 (range 6.7–87) for appendicitis with perforation and/or gangrene. Statistical significance was found among the patient groups (95% CI: 8.5–10.1; p=0.005). According to ROC analysis, the cut-off value in differential diagnosis of AA was set at 8.92, with sensitivity of 73% and specificity of 57% (AUC: 0.57; 95% CI: 0.49–0.62; p=0.0005).

0.8

1.0

Diagonal segments are produced by ties

Figure 1. ROC analysis of neutrophil-lymphocyte ratios to set cut-off value for appendicitis with perforation and/or gangrene (AUC: 0.763; 95% CI: 0.66-0.84; sensitivity: 78%; specificity: 67%; p=0.001).

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Univariate analysis was performed to determine association between laboratory parameters and appendicitis with perforation and/or gangrene. The analysis demonstrated OR as WBC levels (OR: 1.001; 95% CI: 1.000–1.002; p=0.017), neutrophil counts (OR: 0.999; 95% CI: 0.998–1.000; p=0.018), NLR being over 7.95 (OR: 3.037; 95% CI: 2.458–5.218; p=0.001), and MPV (OR: 1.036; 95% CI: 1.010–1.075; p=0.007; Table 3).

DISCUSSION Early diagnosis of AA, prior to progression to gangrene and/ or perforation, is important in order to minimize morbidity from this common entity. In spite of radiological advances, 165

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Table 3. Univariate analysis of clinical features in relation to appendicitis with perforation or gangrene Variables

Odds Ratio

95% CI

White blood cell

0.017

1.001

1.000–1.002

Neutrophil count

0.018

0.999

0.998–1.000

Lymphocyte count

0.164

0.999

0.998–1.000

Sex (male/female)

0.843

0.929

0.446–1.932

Neutrophil-lymphocyte ratio (≤7.95/>7.95)

0.001

3.037

2.458–5.218

Mean platelet volume

0.007

1.036

1.010–1.075

95% CI, 95% confidence interval.

differentiating subgroups of patients with severe disease may be challenging for the surgeon. As the percentage of perforated appendicitis is 18.3–34%, a test that aids in diagnosis of AA complications may be useful.[3] Leucocyte count was reportedly the earliest test to indicate appendiceal inflammation, with a sensitivity of 82–96%.[10,11] Rises in leucocyte and neutrophil counts were found to be related to severity of AA.[12] The sensitivity of neutrophil count in AA was shown to be 60–87% in prior trials.[13] Hyperbilirubinemia, high erythrocyte sedimentation rates, and high CRP levels were have also been reported as markers of complications in AA.[3,14,15] Raised CRP values have 40–99% sensitivity and 27–90% specificity in the diagnosis of AA.[16] In the present study, comparison of high leukocyte and neutrophil counts to healthy controls was as expected (p=0.005 and p=0.009, respectively). No statistical significance was observed among the appendicitis groups concerning leucocyte and neutrophil counts (p=0.06 and p=0.13, respectively). These tests are invaluable, not only in the diagnostic work-up, but also in differentiating severe forms of AA. MPV, a platelet index calculated by automatic cell analyzer, is used for differential diagnosis of both thrombocytosis and thrombocytopenia.[17] MPV is actually a marker of functional status of platelets. It increases with production of young platelets; hence, MPV count indicates platelet activation.[18] MPV is also thought to reflect inflammatory burden in ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, chronic obstructive pulmonary disease, diabetes mellitus, and myocardial infarction.[19–22] Controversy persists regarding MPV response in AA. Studies have shown MPV decrements in AA, compared to healthy controls.[23,24] However, a recent study found higher values of MPV in AA patients, with a cutoff above 7.87 fL, and low sensitivity and specificity (66% and 51%, respectively).[8] In the present study, higher values of MPV were found in patients with AA, compared to healthy controls (9.3±8 vs 9.3±8, p=0.0005). The aim of the present study was to determine the role of MPV in predicting more severe forms of AA, such as appendicitis with perforation and/or gangrene. The 166

cut-off value to differentiate AA patients with perforation and/or gangrene from other AA patients was 8.92 fL, with a sensitivity of 73% and a specificity of 57%. Regarding NLR, it was presently demonstrated that a cut-off value of 7.95 could significantly differentiate AA patients with perforation and/or gangrene from those with less-severe AA, with a sensitivity of 78% and a specificity of 67%. A recent trial showed that NLR values >8 demonstrated significant association with gangrenous appendicitis. Lymphocyte counts may fall in severe cases of AA.[25] However, no statistically significant decrease in lymphocyte count was found in cases of appendicitis with perforation and/or gangrene in the present study (p=0.34). According to the present results, NLR values were statistically significant among the AA groups (p=0.023). Thus, both NLR and MPV can aid in the assignment of patients with complications to appropriate subgroups. The non-operative approach in the treatment of AA, with clinical observation, has the risk of peritonitis and the need for emergency appendectomy in about 8–10% of cases. Therefore, it is an acceptable option in cases of uncomplicated appendicitis.[26,27] Once surgical treatment has been selected, options include open or laparoscopic appendectomy. Abe et al. recently reported that complicated appendicitis and diffuse peritonitis were risk factors of conversion to open during laparoscopic appendectomy.[28] Furthermore, in a comparison of open to laparoscopic appendectomies, the Cochrane review reported a nearly threefold increase in intra-abdominal abscesses following laparoscopic appendectomy, which may lead surgeons to choose open appendectomy in cases of perforated appendicitis.[29]

Conclusion There is still no single diagnostic tool to determine severity of AA. The choice between clinical observation and emergency surgery depends upon the expertise of the surgeon. Laboratory parameters such as MPV and NLR may aid in the prediction of perforation, and in the choice between follow-up and suitable operative technique. Conflict of interest: None declared. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Yardımcı et al. Neutrophil-lymphocyte ratio and mean platelet volume can be a predictor for severity of acute appendicitis

REFERENCES 1. Ergul E. Importance of family history and genetics for the prediction of acute appendicitis. Internet J Surg 2007;10:2. 2. Simillis C, Symeonides P, Shorthouse AJ, Tekkis PP. A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon). Surgery.2010;147:818–29. 3. McGowan DR, Sims HM, Zia K, Uheba M, Shaikh IA. The value of biochemical markers in predicting a perforation in acute appendicitis. ANZ J Surg 2013;83:79–83. 4. Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983;32:443–60. 5. Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des 2011;17:47–58.

2012;176:79–83. 16. Hallan S, Asberg A. The accuracy of C-reactive protein in diagnosing acute appendicitis-a meta-analysis. Scand J Clin Lab Invest 1997;57:373– 80. 17. Ntaios G, Papadopoulos A, Chatzinikolaou A, Saouli Z, Karalazou P, Kaiafa G, et al. Increased values of mean platelet volume and platelet size deviation width may provide a safe positive diagnosis of idiopathic thrombocytopenic purpura. Acta Haematol 2008;119:173–7. 18. Park Y, Schoene N, Harris W. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets 2002;13:301–6. 19. Yüksel O, Helvaci K, Başar O, Köklü S, Caner S, Helvaci N, et al. An overlooked indicator of disease activity in ulcerative colitis: mean platelet volume. Platelets 2009;20:277–81. 20. Kisacik B, Tufan A, Kalyoncu U, Karadag O, Akdogan A, Ozturk MA, et al. Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Joint Bone Spine 2008;75:291– 4.

6. Absenger G, Szkandera J, Pichler M, Stotz M, Arminger F, Weissmueller M, et al. A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer 2013;109:395– 400.

21. Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinolysis 1996;7:157–61.

7. Bhat T, Teli S, Rijal J, Bhat H, Raza M, Khoueiry G, et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther 2013;11:55–9.

23. Bilici S, Sekmenli T, Göksu M, Melek M, Avci V. Mean platelet volume in diagnosis of acute appendicitis in children. Afr Health Sci 2011;11:427– 32.

8. Albayrak Y, Albayrak A, Albayrak F, Yildirim R, Aylu B, Uyanik A, et al. Mean platelet volume: a new predictor in confirming acute appendicitis diagnosis. Clin Appl Thromb Hemost 2011;17:362–6.

24. Narci H, Turk E, Karagulle E, Togan T, Karabulut K. The role of mean platelet volume in the diagnosis of acute appendicitis: a retrospective case-controlled study. Iran Red Crescent Med J 2013;15:e11934.

9. Goodman DA, Goodman CB, Monk JS. Use of the neutrophil:lymphocyte ratio in the diagnosis of appendicitis. Am Surg 1995;61:257–9.

25. Hoffmann J, Rasmussen OO. Aids in the diagnosis of acute appendicitis. Br J Surg 1989;76:774–9.

10. Hallan S, Asberg A, Edna TH. Additional value of biochemical tests in suspected acute appendicitis. Eur J Surg 1997;163:533–8.

26. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet 2011;377:1573–9.

11. Thompson MM, Underwood MJ, Dookeran KA, Lloyd DM, Bell PR. Role of sequential leucocyte counts and C-reactive protein measurements in acute appendicitis. Br J Surg 1992;79:822–4. 12. Chen SC, Wang SM. C-reactive protein in the diagnosis of acute appendicitis. Am J Emerg Med 1996;14:101–3. 13. Yang HR, Wang YC, Chung PK, Chen WK, Jeng LB, Chen RJ. Laboratory tests in patients with acute appendicitis. ANZ J Surg 2006;76:71–4. 14. Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis. Am J Surg. 2009;198:193–8. 15. Bröker ME, van Lieshout EM, van der Elst M, Stassen LP, Schepers T. Discriminating between simple and perforated appendicitis. J Surg Res

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22. Vij AG. Effect of prolonged stay at high altitude on platelet aggregation and fibrinogen levels. Platelets 2009;20:421–7.

27. Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg 2009;96:473–81. 28. Abe T, Nagaie T, Miyazaki M, Ochi M, Fukuya T, Kajiyama K. Risk factors of converting to laparotomy in laparoscopic appendectomy for acute appendicitis. Clin Exp Gastroenterol 2013;6:109–14. 29. Sauerland S, Lefering R, Neugebauer EA. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev 2004;4:CD001546.

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ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Nötrofil-lenfosit oranı ve ortalama trombosit hacminin akut apandisitin şiddetini belirlemedeki rolü Dr. Samet Yardımcı, Dr. Mustafa Ümit Uğurlu, Dr. Mümin Coşkun, Dr. Wafi Attaallah, Dr. Şevket Cumhur Yeğen Marmara Üniversitesi Tıp Fakültesi, Genel Cerrahi Anabilim Dalı, İstanbul

AMAÇ: Perfore akut apandisitin (AA) erken tanınması zor olabilmektedir. Bu çalışmada, ameliyat öncesi nötrofil-lenfosit oranı (NLR) ve ortalama trombosit hacmi (MPV) ölçümlerinin akut apandisit olgularında perforasyonu belirlemedeki rolü araştırıldı. GEREÇ VE YÖNTEM: Dört yüz on üç AA’lı olguya ait geriye dönük veriler ile 100 sağlıklı kontrol çalışmaya dahil edildi. Akut apandisitli olgulara ait patolojiler flegmonöz apandisit, lokalize peritonitin eşlik ettiği apandisit ve perforasyonlu ve/veya gangrenöz apandisit olguları olarak üç grupta incelendi. Hastalara ait MPV ve NLR değerleri gruplar içerisinde ve sağlıklı kontrollere ait sonuçlarla karşılaştırıldı. BULGULAR: Ortalama MPV değeri AA grubunda 9.3±8 FL ve sağlıklı kontrollerde 8.5±0.9 Fl idi (p=0.0005). Ortalama MPV değerleri flegmonöz apandisit grubunda 8.8±5.8, lokalize apandisit grubunda 8.9±5.8 FL ve perforasyonlu ve/veya gangrenöz apandisit grubunda 12.8±9.7 FL olarak saptandı (p=0.005). Perforasyonlu/gangrenöz apandisitli olguları diğer apandisit olgularından ayırmak için ölçülen eşik MPV değeri 8.92 Fl idi. Ortalama NPV değerleri basit apandisit, lokalize apandisit, perforansyonlu/gangrenöz apandisit gruplarında sırasıyla 8.3±5.6, 9.1±6.2 ve 10.6±6.4 olarak saptandı (p=0.023). Perforasyonlu/gangrenöz apandisitli olguları diğer apandisit olgularından ayırmak için ölçülen eşik NPV değeri 7.95 idi. TARTIŞMA: Nötrofil-lenfosit oranı ve MPV ölçümleri akut apandisitin şiddetini belirlemede klinik tanıya yardımcı olabilir. Anahtar sözcükler: Apandisit; lenfosir; nötrofil; ortalama platelet hacmi; prediktif faktörler. Ulus Travma Acil Cerrahi Derg 2016;22(2):163–168

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doi: 10.5505/tjtes.2015.89346

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ORIG I N A L A R T IC L E

High velocity missile-related colorectal injuries: In-theatre application of injury scores and their effects on ostomy rates Şahin Kaymak, M.D., Aytekin Ünlü, M.D., Ali Harlak, M.D., Nail Ersöz, M.D., Rahman Şenocak, M.D., Ali Kağan Coşkun, M.D., Nazif Zeybek, M.D., Emin Lapsekili, M.D., Orhan Kozak, M.D. Department of General Surgery, Gülhane Military Medical Academy, Ankara-Turkey

ABSTRACT BACKGROUND: Treatment of colorectal injuries (CRIs) remains a significant cause of morbidity and mortality. The aim of the present study was to analyze treatment trends of Turkish surgeons and effects of the American Association for the Surgery of Trauma (AAST), Injury Severity (ISS), and Penetrating Abdominal Trauma Index (PATI) scoring systems on decision-making processes and clinical outcomes. METHODS: Data regarding high velocity missile (HVM)-related CRIs were retrospectively gathered. Four patient groups were included: Group 1 (stoma), Group 2 (no stoma in primary surgery), Group 2a (conversion to stoma in secondary surgery), and Group 2b (remaining Group 2 patients). RESULTS: Groups 1, 2, 2a, and 2b included 39 (66%), 20 (34%), 6 (30%), and 14 (70%) casualties, respectively. Ostomies were performed in casualties with significantly higher AAST scores (p<0.001). However, PATI and ISS scores were not decisive factors in the performance of ostomy (p=0.61; p=0.28, respectively). Ostomy rates of civilian and military surgeons were 62% and 68%, respectively (p=0.47). Receiver operating characteristic (ROC) analysis showed that AAST score was a more accurate guide for performing ostomy, with sensitivity and specificity rates of 80% and 92.9%, respectively. CONCLUSION: Clinical significance of diversion in HVM-related CRIs remains. Stomas were associated with lower complication rates and significantly higher AAST colon/rectum injury scores. Keywords: Colorectal injuries; high velocity missile; military; ostomy.

INTRODUCTION The colon is the second most commonly involved organ in penetrating abdominal injuries.[1,2] Rectal injuries are frequently associated with pelvis fractures caused by non-penetrating injuries.[3,4] Management of colorectal injuries (CRIs) has been dramatically influenced by experience gained during military conflicts, civilian experience, and technical advances over the last cenAddress for correspondence: Şahin Kaymak, M.D. Gülhane Askeri Tıp Akademisi, Genel Cerrahi Anabilim Dalı, Etlik, Ankara, Turkey Tel: +90 312 - 304 51 21 E-mail: skaymak@gata.edu.tr Qucik Response Code

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tury.[5–7] Due to high mortality rates in World War II, the past, dogmatic “exteriorization or proximal stoma” approach to colorectal injury has finally shifted toward the assured stance that “primary repair or resection-anastomosis can be safely performed in selected cases.”[8–10] However, the majority of studies that favor primary repair or resection-anastomosis are based on penetrating low velocity missile (LVM) injuries. [9,10] High velocity missiles (HVMs) cause injuries that are significantly more severe. Moreover, assessment and treatment of HVM-related injuries are frequently complicated by association with other injuries, transfusion requirements, and extended time to surgical treatment.[6–8] Choice of CRI management primarily depends upon severity of injury. The American Association for the Surgery of Trauma (AAST) injury scoring scale is frequently used to classify severity of colorectal injuries.[11–13] The Penetrating Abdominal Trauma Index (PATI) can also be used to assess penetrating injuries to the abdomen.[2] The Injury Severity Score (ISS) is the anatomical scoring system most frequently used to assess severity of whole-body trauma.[14] 169

Kaymak et al. High velocity missile-related colorectal injuries: in-theatre application of injury scores and their effects on ostomy rates

The aim of the present study was to analyze surgical treatment tendencies of Turkish surgeons regarding ostomy performance in HVM-related CRIs. Additional aims were to analyze relevance of AAST, ISS, and PATI scores in decisionmaking processes, and to present clinical outcomes gathered from available data.

MATERIALS AND METHODS Following approval from the Gülhane Military Medical Academy Ethics Committee, retrospective data regarding all casualties treated over the past 4 years were obtained. Patients who had sustained injuries to the colon, rectum, or anus caused by HVMs were identified. Data regarding casualty demographics, injury characteristics, associated injuries, management, and subsequent outcomes were collected. Preferred surgical intervention was at the discretion of the attending military or civilian surgeon. Detailed data obtained during admission, including presence of hypotension or metabolic acidosis, was significantly lacking. All casualties had been evacuated to the nearest Role 2 or civilian hospital via military helicopter and were admitted to hospital within 1 hour of injury. ISS, AAST colon/rectum injury scores, and PATI scores were calculated for each casualty.

sive devices (IEDs) and gunshots accounted for 44% and 56% of casualties, respectively. Secondary fragments from IEDs cause multiple, patchy abdominal wall injuries, placing significant burden on surgical triage and complicating expedited diagnostic workup of casualties. Routinely, fragment-related intra-abdominal injuries are diagnosed by ultrasound examination of suspicious abdominal wall wounds, as well as by exploration under local anesthesia to identify full-thickness fascial defects. All casualties that underwent surgical exploration had intra-abdominal injuries that required surgical treatment. All casualties were evacuated to Role 4 hospital following initial surgery, and all had variable hospital stays in military and civilian hospitals. All treatment of complications and reoperations were performed in Role 4. Mean age was 23.4 (SD±5.2). There were 39 (66.1%) casualties in Group 1 and 20 (33.9%) in Group 2. In Group 2, 6 (30%) casualties underwent reoperation with colostomy (Group 2a), and the remaining 14 (70%; Group 2b) had uneventful recoveries (Table 1).

Casualties were grouped according to presence of stoma. The stoma group (Group 1) included patients with any type of proximal stoma performed during initial surgery. Group 2 included primary repair casualties without stoma. Primary repair was defined as debridement and primary closure or resection with primary anastomosis. Following initial surgery, casualties that required reoperation were also identified. Reoperations secondary to colorectal injury were analyzed separately, and were performed due to presence of either radiographic or surgical confirmation of leak, or other complications including postoperative hemorrhage, entry wound necrotizing fasciitis, postoperative abdominal pain and distention, and stoma retraction. Group 2 patients that underwent reoperation and either required or did not require stoma were classified as Group 2a and Group 2b, respectively.

CRI-related complications required surgical and nonsurgical interventions in 27 (45%) and 3 (5.1%) casualties, respectively (Table 2). In Group 1, 18 (46.2%) of the 39 patients underwent reoperation, and 5 (27.8%) had CRI-related complications. Nine (45%) of the 20 patients in Group 2 underwent reoperation, due to CRI-related complication in 7 (77.8%). In Group 2, the CRI-related reoperation rate was significantly higher (odds ratio, 3.5; 95% CI, 1.04-11.88; p=0.03; Table 3). In Group 1, types of stoma performed were ileostomy, colostomy, and ileostomy-colostomy in 10 patients (25.6%), 28 patients (71.8%), and 1 (5%) patient, respectively. Ostomy types were transverse end, sigmoid loop, and cecostomy in 13 (46.4%), 14 (50%), and 1 (3.6%) casualty, respectively. In Group 2, 13 of the 20 (65%) casualties were treated with primary repair and 7 (35%) underwent resection-anastomosis. Rates of ostomies performed by civilian and military surgeons were 62% and 38%, respectively. No statistically significant difference in ostomy rates between civilian and military surgeons was found (p=0.47).

Data were analyzed using SPSS software (version 15.0; SPSS Inc., Chicago, IL, USA) Independent samples t-test or MannWhitney U test was used to compare continuous variables, as appropriate. Chi-square test was used to compare categorical variables. Linear association was analyzed with Spearman’s Rho correlation test. Receiver operating characteristic (ROC) analysis was used to determine optimal cutoff value for best sensitivity and specificity rates. Odds ratios with 95% confidence interval were calculated from contingency tables. Statistical significance was set at p<0.05.

AAST scores of Groups 1 and 2 were compared, and it was determined that surgeons chose to perform stomas (Group 1) in casualties with significantly higher AAST scores (p<0.001). When data of Groups 1 and 2 were analyzed individually, no association for either ISS or PATI score was found, (p=0.36, p=0.23, respectively). Thus, it was hypothesized that if AAST score was correct in indicating casualties that required stomas, no statistically significant difference between Groups 1 and 2a should be present. Analysis confirmed this (p=0.40; Tables 4, 5).

RESULTS

ROC curve analysis was performed to determine accuracy of AAST scores regarding selection of colostomy as treatment method, and a cutoff score of 3 to compare Groups 1 and 2 was determined. In Group 1, 18% and 82% of casualties had

Included were 59 male casualties that had sustained HVMrelated colorectal injuries. Wounds from improvised explo170

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AAST scores of ≤2 and ≥3, respectively. In Group 2, however, 75% and 25% of casualties had AAST scores of ≤2 and ≥3, respectively. Given the cutoff points, the sensitivity and specificity of AAST scores in the choice of colostomy as treatment meth-

od were 82.1% and 75%, respectively. (AUC=0.83, p<0.001). Interestingly, AAST score was also decisive between the ostomy and non-ostomy groups (p<0.001). Casualties were

Table 1. Distribution of colorectal injuries (CRI) Groups (n) Right colon Transvers colon Left colon Sigmoid colon Anus and rectum

n % n % n % n % n %

Group 1 (39)

20.5

15.3

28.2

Group 2 (20) 1 5 7 35 5 25 6 30 1 5 Group 2a (6) 1 16.6 2 33.6 1 16.6 1 16.6 1 16.6 Group 2b (14) 0 0 5 35.7 4 28.6 5 35.7 0 0

Table 2. Causes and distribution of reoperations and non-operative management

Complications

n % Total

Re-operation

Anastomosis leakage

15.2

Intraabdominal abscess

5.1

Necrotizing fasciitis

5.1

Signs of peritoneal irritation

13.5

Hemorrhage

3 5.1

Ostomy retraction

1.6

Non-operative management

Surgical site abscess

5.1

Table 3. Distribution of re-operations in Group 1 and Group 2 n % Reoperated casualties in Group 1

18/39

Reoperated casualties in Group 2

9/20

Total

27/59

Re-operations due to CRI-related complications

Other indications for re-operations

n % 5/18

7/9

n %

12/27 45

13/18

2/9

15/27 55

Table 4. Distribution of AAST colon/rectum injury scores (1–5) among study groups

Scor 1

Scor 2

Scor 3

Scor 4

Scor 5

n % n % n % n % n % Group 1

39 0 0 7 17.9 22 56.4 7 17.9 3 7.7

Group 2

20 12 60 3 15 3 15 2 10 0 0

Group 2a

6 1 16.6 1 16.6 2 33.3 2 33.3 0 0

Group 2b

14 11 78.6 2 14.3 1 7.1 0 0 0 0

Colorectal injury 59 12 20.3 10 16.9 25 42.3 9 15.2 3 5.08 AAST: American Association for the Surgery of Trauma.

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Table 5. Mean severity scores of colorectal injury groups

PATI (0–200)

ISS (0–75)

Colorectal injury

21.78

16.72

Group 1

22.93

17.30

Group 2

19.84

15.60

Group 2a

18.50

Group 2b

19.42

14.75

PATI: Penetrating Abdominal Trauma Index; ISS: Injury Severity Score.

Table 6. Statistical analyses between groups for severity scores Groups Compared Group 1 & Group 2

AAST-AIS 90 (p)

PATI (p)

0.001*

ISS (p)

0.23 0.36

Group 1 & Group 2a

0.40

0.49

Group 2a & Group 2b

0.01

0.61 0.28

Group 1 & Group 2b

0.001*

0.21 0.07

0.71

*Statistically significant (p<0.05). AAST: American Association for the Surgery of Trauma; AIS: Abbreviated Injury Scale; PATI: Penetrating Abdominal Trauma Index; ISS: Injury Severity Score.

further analyzed as ostomy (Group 1 + Group 2a) and nonostomy (Group 2b) groups using ROC curve analysis. A cutoff AAST score of 3 was determined for analysis. In the ostomy group, 20% and 80% of casualties had scores of ≤2 and ≥3, respectively. In the non-ostomy group, however, 93% and 7% of casualties had AAST scores of ≤2 and ≥3, respectively. Given the cutoff points, the sensitivity and specificity of AAST scores in the selection of colostomy were 80% and 92.9%, respectively (AUC=0.94; p<0.001). Accordingly, 4 of 6 casualties had AAST scores of ≥3 in Group 2a. The authors speculate that the second surgical intervention could have been prevented if colostomy had been performed during initial surgery. PATI and ISS scores were not statistically significant in Group 1, compared to Group 2b (p=0.21, p=0.07), or in Group 2a, compared to Group 2b (p=0.61, p=0.28; Table 6). Ten (17%) patients underwent damage control procedures, nine (90%) of whom underwent a colostomy. These patients underwent a mean of 2.4 (range, 1–4) operations following the initial damage control. No mortalities occurred during CRI treatment in the general surgery clinic.

DISCUSSION Throughout history, various surgical approaches to colorectal injuries have been practiced. During World War II, the Surgeon General of the United States mandated proximal stoma or bowel exteriorization, which led to significant decrease in rates of mortality and morbidity.[15,16] In the 1970s, the para172

digm shifted toward use of primary repair in the treatment of uncomplicated colorectal injuries, in accordance with advances in evacuation, resuscitation, and antibiotherapy of casualties. In 1979, Stone et al.[9] published the first widely accepted research to oppose mandatory performance of stomas. The authors demonstrated that rates of infectious complications were 48% in primary repair and 57% in colostomized patients. However, mortality rates were 1.5% and 1.4%, and the difference was obviously not statistically significant. Moreover, the study showed that primary repair was associated with shorter hospital stays, and was cost-effective. In 1989, Nelken and Lewis compared 3 different scoring systems (ISS, PATI, and the Flint colon injury score) in CRI patients who had undergone either colostomy or primary repair. The authors concluded that PATI was the system most sensitive in predicting success and complications in primary repair patients.[17] In order to decrease the magnitude of confounding factor effects on outcomes, vascular injuries were excluded from the present study. Instead of PATI, surgeons regarded AAST score as a more convenient system when choosing between primary repair and ostomy. Moreover, no statistically significant differences in PATI scores were found between the ostomy and repair groups, and CRI-related or unrelated complications. In the 1990s, primary repair rates reached 60–93% in civilian settings. As a general rule when primary repair of colon injuries is performed, patients are required to have stable vital Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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signs, short prehospital periods, no additional organ injuries, and no extensive peritoneal contamination.[15,18,19] Otherwise, a stoma is generally required.[20] According to the Eastern Association for the Surgery of Trauma’s 1998 guidelines, if PATI score is >25, hemodynamic instability and significant comorbidities occur. Surgeons are advised to perform colostomy for destructive colon injuries. [21] In 2003, it was demonstrated in a retrospective study that primary repair or resection-anastomosis were the most viable treatment options in normotensive patients with PATI scores <15 and minimal peritoneal contamination.[22] PATI calculations are based on operative findings and used to predict postoperative outcome.[23] Findings of the present study suggest that despite its versatility in evaluating intra-abdominal organ injuries, PATI analysis during surgical intervention is impractical. In the present study, mean PATI was 23 and 20 in ostomized and non-ostomized patients, respectively. ISS is the anatomical scoring system most commonly used to evaluate casualties with multiple injuries.[24] However, it has been shown to be excellent only at retrospective comparison of overall injury data.[25] In the present study, mean ISS was 17.3 and 15.6 in ostomized and non-ostomized patients, respectively. In the present study, both ISS and PATI scores were found to be inferior at determining required surgical treatment of CRI, compared to the AAST score. Glasgow et al. investigated 977 CRI cases and found that diversion rate in rectal injuries was approximately twice that in colon injuries. Similarly, rates in the present study were 90% and 36% in rectum and colon injuries, respectively. [26]

Non-operative management of penetrating abdominal injuries has been proposed in selected cases.[27,28] Unlike civilian mechanisms of injury, however, terrorist attacks tend to cause multiple HVM-related injuries.[29] Thus, laparotomy was advocated, provided that full-thickness abdominal wall penetration had been diagnosed.[30] In the present study, 47% of casualties underwent reoperation due to CRIs and other associated injuries. Damage control surgery has recently been extended to involve CRI.[31] Fecal diversion is traditionally performed during damage control surgery in CRI patients. The rate of damage control surgery was 17% in the present study, and a stoma was performed in 90% of these cases. HVM-related injuries are frequently extensive, grossly contaminated, and complicated by long evacuation times. Civilian LVM injuries are not grossly contaminated and involve short prehospital periods.[32] Thus, LVM-related CRIs are amenable to primary repair.[33,34] HVM-related intestinal perforations are larger, with irregular margins. Moreover, temporary cavity-related Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

microvascular injury may cause ischemia and perforations. Primary repair of these injuries has higher complication rates.[35] Limitations of the present study stem from its retrospective nature. Critical data was missing, including vital signs and blood gas analysis results obtained during hospital admittance of patients with vascular injury associated with CRIs, extent of abdominal contamination during laparotomy, and rectal and abdominal drain placement, etc. This data could have provided more insight. In addition, limited long-term follow-up data was available. Following CRI treatment, patients are invariably transferred to other clinics for specific treatment of associated (i.e. orthopedic) injuries. This is one reason the study failed to include duration of hospital stays. However, the present study included one of the largest cohorts of HVM-related CRIs in Turkey, and also focused on trends in management and outcomes.

Conclusion Numerous studies have demonstrated the safety of primary repair or resection-anastomosis in CRI. However, clinical significance of diversion in HVM-related CRIs remains ill defined. It was determined in the present study that stomas were associated with lower complication rates and were more frequently correlated with significantly higher AAST scores. No significant difference in stoma rates between civilian and military surgeons was found. AAST scores seem to be a more accurate guide for selecting a treatment method of ostomy or primary repair, with a sensitivity and specificity rate of 80% and 92.9%, respectively. Accordingly, an AAST score ≤2 may indicate repair and one of ≥3 may indicate the need for ostomy. Conflict of interest: None declared.

REFERENCES 1. Huber PJ Jr, Thal ER. Management of colon injuries. Surg Clin North Am 1990;70:561–73. 2. Moore EE, Dunn EL, Moore JB, Thompson JS. Penetrating abdominal trauma index. J Trauma 1981;21:439–45. 3. Tile M. Pelvic ring fractures: should they be fixed? J Bone Joint Surg Br 1988;70:1–12. 4. Star AJ, Malekzadeh AS. Fractures of the pelvic ring. In: Bucholz RW, Heckman JD, Court-Brown CM, editors. Rockwood & Green’s fractures in adults. 6th ed., Vol. 2, Philadelphia: Lippincott Williams & Wilkins; Chapter 4: 2006. p. 1585–663. 5. Army, Office of the Surgeon General. Circular Letter 1943;178. 6. Burch JM, Brock JC, Gevirtzman L, Feliciano DV, Mattox KL, Jordan GL Jr, et al. The injured colon. Ann Surg 1986;203:701–11. 7. Chappuis CW, Frey DJ, Dietzen CD, Panetta TP, Buechter KJ, Cohn I Jr. Management of penetrating colon injuries. A prospective randomized trial. Ann Surg 1991;213:492–8. 8. George SM Jr, Fabian TC, Voeller GR, Kudsk KA, Mangiante EC, Britt LG. Primary repair of colon wounds. A prospective trial in nonselected patients. Ann Surg 1989;209:728–4.

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Kaymak et al. High velocity missile-related colorectal injuries: in-theatre application of injury scores and their effects on ostomy rates 9. Stone HH, Fabian TC. Management of perforating colon trauma: randomization between primary closure and exteriorization. Ann Surg 1979;190:430–6. 10. Woodhall Jp, Ochsner A. The management of perforating injuries of the colon and rectum in civilian practice. Surgery 1951;29:305–20. 11. Galandiuk S, Polk HC. Traumatic colorectal injuries, foreign bodies, and anal wounds. In: Zuidema GD, Yeo CJ, editors. Surgery of the alimentary tract. 5 th ed. Philedelphia: W.B. Saunders Company; 2002. p. 55–61. 12. Fry RD. Anorectal trauma and foreign bodies. Surg Clin North Am 1994;74:1491–505. 13. Moore EE, Cogbill TH, Malangoni MA, Jurkovich GJ, Champion HR, Gennarelli TA, et al. Organ injury scaling, II: Pancreas, duodenum, small bowel, colon, and rectum. J Trauma 1990;30:1427–9. 14. Baker SP, O’Neill B, Haddon W Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974;14:187–96. 15. Demetriades D, Murray JA, Chan L, Ordoñez C, Bowley D, Nagy KK, et al. Penetrating colon injuries requiring resection: diversion or primary anastomosis? An AAST prospective multicenter study. J Trauma 2001;50:765–75. 16. Culliford A, Ibrahim I, Worth MH. Traumatic perforation of the sigmoid colon through schistosomal ulcerations. Am J Surg 1975;129:705–8. 17. Nelken N, Lewis F. The influence of injury severity on complication rates after primary closure or colostomy for penetrating colon trauma. Ann Surg 1989;209:439–47. 18. Gonzalez RP, Merlotti GJ, Holevar MR. Colostomy in penetrating colon injury: is it necessary? J Trauma 1996;41:271–5. 19. Sasaki LS, Allaben RD, Golwala R, Mittal VK. Primary repair of colon injuries: a prospective randomized study. J Trauma 1995;39:895–901. 20. Schrock TR, Christensen N. Management of perforating injuries of the colon. Surg Gynecol Obstet 1972;135:65–8. 21. Pasquale M, Fabian TC. Practice management guidelines for trauma from the Eastern Association for the Surgery of Trauma. J Trauma 1998;44:941–57. 22. Mickevicius A, Klizaite J, Tamelis A, Saladzinskas Z, Pavalkis D. Pen-

etrating colorectal trauma: index of severity and results of treatment. [Article in Lithuanian] Medicina (Kaunas) 2003;39:562–9. [Abstract] 23. Gomez-Leon JF. Penetrating abdominal trauma index: Sensitivity and specificity for morbidity and mortality by roc analysis. Indian J Surg 2004;66;347–51. 24. Baker SP, O’Neill B, Haddon W Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974;14:187–96. 25. Linn S. The injury severity score--importance and uses. Ann Epidemiol 1995;5:440–6. 26. Glasgow SC, Steele SR, Duncan JE, Rasmussen TE. Epidemiology of modern battlefield colorectal trauma: a review of 977 coalition casualties. J Trauma Acute Care Surg 2012;73(6 Suppl 5):503–8. 27. Morrison JJ, Clasper JC, Gibb I, Midwinter M. Management of penetrating abdominal trauma in the conflict environment: the role of computed tomography scanning. World J Surg 2011;35:27–33. 28. Pryor JP, Reilly PM, Dabrowski GP, Grossman MD, Schwab CW. Nonoperative management of abdominal gunshot wounds. Ann Emerg Med 2004;43:344–53. 29. Taş H, Mesci A, Eryılmaz M, Zeybek N, Peker Y. The affecting factors on the complication ratio in abdominal gunshot wounds. [Article in Turkish] Ulus Travma Acil Cerrahi Derg 2011;17:450–4. 30. Unlü A, Petrone P, Karşıdağ T, Asensio JA. Unexpected multiple intraabdominal injuries after projectile fragmentation: report of three cases. Ulus Travma Acil Cerrahi Derg 2012;18:531–4. 31. McPartland KJ, Hyman NH. Damage control: what is its role in colorectal surgery? Dis Colon Rectum 2003;46:981–6. 32. DeMuth WE Jr. Ballistic characteristics of “magnum” sidearm bullets. J Trauma 1974;14:227–9. 33. Velmahos GC, Souter I, Degiannis E, Hatzitheophilou C. Primary repair for colonic gunshot wounds. Aust N Z J Surg 1996;66:344–7. 34. Fackler ML, Surinchak JS, Malinowski JA, Bowen RE. Bullet fragmentation: a major cause of tissue disruption. J Trauma 1984;24:35–9. 35. Kozak O, Uzar Aİ, Güleç B. Ateşli silahlarla oluşan karın yaralanmaları. T Klin J Surgery 1997;2:139–47.

ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Yüksek kinetik enerjili parça tesirine bağlı kolorektal yaralanmalar: Cerrahi esnasında skorlama sistemlerinin uygulanması ve ostomi oranları üzerine etkisi Dr. Şahin Kaymak, Dr. Aytekin Ünlü, Dr. Ali Harlak, Dr. Nail Ersöz, Dr. Rahman Şenocak, Dr. Ali Kağan Coşkun, Dr. Nazif Zeybek, Dr. Emin Lapsekili, Dr. Orhan Kozak Gülhane Askeri Tıp Akademisi, Genel Cerrahi Anabilim Dalı, Ankara

AMAÇ: Kolorektal yaralanmalar halen önemli bir mortalite ve morbidite nedenidir. Çalışmanın amacı Türk cerrahların tedavi kararı konusunda American Association for the Surgery of Trauma (AAST) kolon/rektum yaralanma skoru, Injury Severity Score (ISS) ve Penetrating Abdominal Trauma Index (PATI) skorlarını kullanmaya eğilimlerini ve mevcut klinik sonuçlarını analiz etmektir. GEREÇ VE YÖNTEM: Dört yıllık bir periyot içerisinde yüksek kinetik enerjili silahların neden olduğu kolorektal yaralanmalı hastaların verileri geriye dönük olarak toplandı. İlk ameliyatta ostomi açılanlar grup 1, açılmayanalar grup 2, sonradan ostomi açılanlar grup 2a ve hiç ostomi açılmayanlar grup 2b olarak belirlendi. BULGULAR: Otuz dokuz (%66) hastaya ilk ameliyatta ostomi açılmış, 20 (%34) hastaya açılmamıştı. İlk ameliyatta ostomi açılmayan altı (%30) hastaya daha sonra ostomi açılırken, 14 (%70) hastaya hiç ostomi açılmamıştı. Belirgin şekilde AAST skorları yüksek olan hastalara ostomi açıldığı görüldü (p<0.001). Fakat PATI ve ISS skorları ostomi açma konusunda belirleyici olmamıştı (p=0.61, p=0.28). Sivil ve askeri cerrahların ostomi oranları sırasıyla %62 ve %68 olarak bulundu (p=0.47). Receiver operating characteristic (ROC) analizine göre AAST skorunun ostomi açma konusunda daha belirleyici olduğu görüldü. TARTIŞMA: Yüksek kinetik enerjili silahlarla meydana gelen ateşli silah yaralanmalarında diversiyon halen önemini korumaktadır. Diversiyon uygulaması ve sonrasında gözlenen daha düşük komplikasyon oranları AAST skoru yüksekliği ile ilişkili bulundu. Anahtar sözcükler: Askeri; kolorektal yaralanmalar; ostomi; yüksek hızlı mermiler. Ulus Travma Acil Cerrahi Derg 2016;22(2):169–174

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doi: 10.5505/tjtes.2015.85727

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ORIG I N A L A R T IC L E

Views of emergency physicians working in university and state hospitals in Turkey regarding the use of analgesics in patients with acute abdominal pain Özgür Özen, M.D., Selahattin Kıyan, M.D. Department of Emergency Medicine, Ege University Faculty of Medicine Hospital, İzmir-Turkey

ABSTRACT BACKGROUND: Use of narcotic analgesics in patients with acute abdominal pain does not cause delayed misdiagnosis, increases patient comfort and does not suppresses physical examination. The purpose of this study was to determine attitudes anddaily practices of emergency medicine (EM) specialists, residents and faculty members in Turkey on the use of analgesics in patients with acute abdominal pain and factors affecting their decisions on the use of analgesics. METHODS: A cross-sectional study was performed between November 15, 2013 and January 25, 2014 by conducting a questionnaire to EM physicians working in University Hospitals, Education and Research Hospitals of the Ministry of Health, State Hospitals, and Private Hospitals in Turkey. RESULTS: A total of 803 questionnaires (participation rate: 47%) were completed. 59.3% (n=470) of the participants were research assistants. 49.5% of the participants reported that analgesic drugs “suppressed’’ physical examination findings. They stated that 90% of the patients “always’’ and “often’’ requested analgesics and that 34.6% of surgery consultant physicians “rarely” recommended the use of analgesics, while 28.7% “never” recommended, and that there was no common policy established together with surgical departments (79.1%). According to the comparison between the EM specialists and residents, residents in the group stating that they would “never’’ use analgesics were higher than specialists in number (p=0.002); residents reported that they administered analgesics “upon surgical intervention decision”, while specialists reported that they administered analgesics “after patient’s examination and treatment plan” (p=0.021); residents reported that analgesics “suppressed’’ physical examination findings, while specialists reported that analgesics “clarified’’ physical examination findings (p<0.0001); residents reported that they did not administer analgesics “before examination by surgeon’’, while specialists reported otherwise (p=0.0001). Senior residents (>24 months) reported that they administered analgesics “often’’ compared to junior residents (p=0.034) and that junior residents believed that the use of analgesics would “suppress physical examination findings’’ at a higher percentage (p=0.002). CONCLUSION: The rates of use of analgesics in patients with acute abdominal pain by EM physicians are very low. The rates of use of analgesics by EM residents are much lower compared to EM specialists, and they highly believe that analgesic drugs suppress physical examination findings. Residents tend to administer analgesic drugs at a later stage. As seniority of residents increases, the rate of analgesics use and the opinion that analgesic drugs have no effect on physical examination findings increases. Keywords: Abdominal pain; analgesics; emergency physicians; survey.

Address for correspondence: Selahattin Kıyan, M.D. Ege Üniversitesi Tıp Fakültesi Hastanesi, Acil Tıp Anabilim Dalı, 35100 İzmir, Turkey Tel: +90 232 - 390 23 26 E-mail: selahattin.kiyan@ege.edu.tr Qucik Response Code

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INTRODUCTION The concern in the general surgery practice that the use of analgesics for patients with acute abdominal pain without establishing a final diagnosis will change physical examination findings is rather high.[1] It was underlined that analgesics would alter physical examination findings, suppress progression of symptoms, affect accuracy of diagnosis, and increase time to establish diagnosis.[1] However, surgical[2–4] and EM studies[5–11] conducted in the last two decades have completely changed this opinion. Finally, this was clearly set forth in the 175

Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

ACEP (American College of Emergency Medicine) clinical policy[12] in 2010 and in the Cochrane review in 2011 (there are sufficient data in this review to suggest that the use of opioid analgesics in patients with AAP does not increase the risk of inadequate treatment decisions; and indeed, it significantly improves the patient’s comfort level while the diagnostic process is brought to a conclusion).[13] The use of narcotic analgesics has also become recommendable in classic surgery textbooks.[14] Apart from a similar survey study carried out again by us in our country in 2006,[15] there is no study conducted on the frequency of use of analgesics in patients with acute abdominal pain by EM and general surgery departments and factors affecting the use of analgesics by physicians. Moreover, there is no consensus or algorithm established between these departments in the subject matter. With this study, we intended to cover a wider study population (322 versus 803 participants) and all work places of EM physicians (university hospitals versus state hospitals, private hospitals, education and research hospitals and universities) and determine attitudes of EM physicians towards the use of analgesics, their daily practices, factors affecting the decision to use analgesics and understand changes in behaviours and causes for these changes unlike the similar study we conducted in 2006.

Materials and Methods This cross-sectional study was conducted between November 15, 2013 and January 25, 2014 after obtaining the approval of the ethics committee of Ege University Faculty of Medicine. The study was performed conducting a questionnaire on EM physicians (EM residents, specialists and faculty members) working in University Hospitals, Education and Research Hospitals of the Ministry of Health, state hospitals and private hospitals in Turkey.

Data Collection The questionnaires were conducted via the web-address (https:// docs.google.com/forms/d/1a6nTje_WxjWW260oB2Q AG8Pz1zFxhmmo T_X-OEtc0Sk/viewform) and e-mail. Those who did not respond were e-mailed two more times and reached out through their mobile phones. Participants were asked about their socio-demographic characteristics, organizations of employment and types of positions in the first chapter of the questionnaire form. In the second chapter, a total of 25 survey questions were asked. Seven out of these questions were about practices and attitudes of physicians on the administration of analgesics (frequency, time of administration of analgesic, demand by patients for analgesics, frequency of administration of analgesics without examination by surgeons or without definitive diagnosis, drug preferences and maintaining pain control). Four out of these questions were about opinions and joint follow-up patient 176

strategies of surgeons whom emergency physicians worked together. Fourteen questions in the questionnaire consisted of questions regarding the opinions of emergency physicians on the use of analgesics (reasons for supporting or not supporting the administration of analgesics, whether or not age, gender, educational status, nature, region, severity of pain, physical examination, laboratory findings and final diagnosis of patients were effective). Data was analysed by a statistical package program. For descriptive analysis; mean, standard deviation and frequency tables were used. For further analysis, Chi-Square and Student’s t Test and ANOVA were used. p<0.05 was accepted as significant (CI: 95%).

Results According to the data of the personnel department of the Ministry of Health and EM profession societies as of 2014, fifty-seven academic emergency departments of university hospitals and 39 Education and Research Hospitals of the Ministry of Health provide emergency medical training in emergency clinics. As of the date we conducted our study, the total number of EM specialists was 708 (57 in university hospitals, 37 in private hospitals and 614 state-education-research hospitals), including 11 EM professors, 79 EM associates (18 in education-research hospitals, 61 in university hospitals), and the total number of EM residents was 1002 (482 in education-research hospitals, 520 in university hospitals). A total of 803 questionnaires (participation rate: 47%) were completed through internet connection (n=410) and e-mail (n=393).

Socio-Demographic Data Organizations of employment of participants were 48.3% education and research hospitals (n=355), 40.5% university hospitals (n=298), and 11.2% state hospitals (n=82), respectively. 59.3% (n=470) of the participants were research assistants, 35.1% (n=278) were emergency medicine specialists, and 5.7% (n=45) of the emergency medicine specialists were faculty members in university and education and research hospitals.

Practices, Attitudes and Opinions of EM Physicians on the Use of Analgesics When the participants were asked how the use of analgesics affected physical examination findings, the answers given by the participants were; “suppressed” in 49.5% (n=395), “did not affect’’in 45.9% (n=366), and “clarified” in 4.6% (n=37), respectively. When the participants were asked about the frequency of use of analgesics, 34.5% (n=276) of the participants stated that they used analgesics “often’’, 32.3% (n=259), ‘sometimes’, 6% (n=50) “always”, and 4.9% “never”. When the participants were asked about the time of use of analgesics, it was observed that 50.7% (n=393) of the participants reported that they administered analgesics “After Patient’s ExamiUlus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

nation and Treatment Plan’’, 16.6% (n=129) “upon exclusion of surgical intervention”, 16.4% (n=127) “After Diagnosis”, 14.5% (n=112) “after examination by surgeon”, and 1.8% (n=14) “upon surgical intervention decision”. When the participants were asked about the administration of analgesics before examination by a general surgeon, 60.6% (n=487) of the participants gave the answer “I do administer’’ and it was observed that 56.9% (n=457) of the participants reported that they used analgesics. When the participants were asked about the frequency of requests for analgesics by patients, 47.9% (n=383) of the participants reported that patients “always” requested analgesics, while 41.6% (n=333) reported “often’’. Reasons of the participants for supporting and not supporting the use of analgesics are given in Table 1. When the participants were asked about the analgesics they used, 60.8% (n=488) of the participants reported that they used fentanyl, 32.8% (n=263) spasmolytic, 26% (n=209) morphine, 19.9% (n=160) paracetamol, 18.7% (n=150) NSAIDs (non-steroidal anti-inflammatory drugs), 17.8% (n=143) meperidine, and 16.4% (n=132) tradamol, respectively. When the participants were asked about the frequency of recommendation of analgesics by surgery consultant physicians, it was determined that 34.6% (n=272) of the participants answered “rarely’’, 28.7% (n=225) “never’’, and 24.4% (n=196) “sometimes’’. When it was asked to the participants whether they had a common policy established with surgical departments, 79.1% (n=628) of the participants answered they did not, while 11.3% (n=90) answered they had.

When the participants were asked about the factors affecting their decisions on administering analgesics pre-general surgery consultation and the levels of importance of these factors, 45.9% (n=358) of the participants reported that “degree of severity of patient’s pain” was very important, while 26.8% (n=208) of the participants reported “time elapsed for surgical consultation” was very important; and these answers were followed by “concern for the alteration of physical examination” by 22.4% (n=174), “concern for diagnostic accuracy” by 17.5% (n=136), and “concern for disagreement with consultant physician’’ by 9.5% (n=73). When the participants’ opinions on patient-related factors were examined (Table 2), it was found out that the use of analgesics by the participants was largely supported if the patient had a colic, severe pain only in terms of the pain characteristics, had normal physical examination findings only in terms of the physical examination findings, had an abdominal tomography within normal limits only in terms of the radiological examinations and if the patient’s diagnosis was established (independently of diagnosis, in the diagnosis of renal colic the most frequently);however, patient’s age, gender, socio-cultural level, and laboratory findings did not affect their decision to use analgesics.

Academic Hierarchy and Decisions on the Use of Analgesics by Institutions a. Comparison of EM specialists (State vs. University Hospitals) No statistically significant difference was found when EM specialists and faculty were compared in terms of the frequency

Table 1. Distribution of the reasons of emergency physicians for supporting and not supporting the use of analgesics in patients with acute abdominal pain

Your reasons to support the use of analgesics

It does not affect physical examination findings

209

35.6

It is unethical to monitor patients when they are suffering from pain

180

30.7

It increases not only patients’ comfort, but also physicians’ comfort

10.9

The literature supports that analgesics are safe

10.2

It is the patient’s right to ask for relief of his/her pain

8.7

It accelerates the process of establishing diagnosis

2.4

Your reasons no to support the use of analgesics

It suppresses physical examination findings

116

41.6

It causes delay in accurate diagnosis of the patient

21.1

It may lead to disagreements with surgery consultant physicians

12.9

Evidence in the literature is not sufficient to support that analgesics are safe

9.0

It causes misdiagnosis

9.0

The pain suffered should be endured until diagnosis is established

2.9

I do hold off from administering analgesics because they may lead to complications

2.2

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Table 2. Distribution of patient-related factors in deciding the use of analgesics Factors

Disagree (%)

Uncertain (%)

Agree (%)

Age

I use analgesics if the patient is young

52.7

15.4

31.9

I use analgesics if the patient is elderly

58.6

17.6

23.8

Gender

I use analgesics if the patient is male

60.1

14.5

25.3

I use analgesics if the patient is female

61.2

15.0

23.7

Socio-cultural structure

I use analgesics if the patient has a high socio-cultural level

57.1

13.9

29.0

I use analgesics if the patient has a low socio-cultural level

61.2

15.0

23.9

23.1

13.8

63.1

Features of pain

I use analgesics if the pain is colic

I use analgesics if the patient has a previous history of admission

to emergency department for similar pain reasons

31.5

19.5

49.0

I use analgesics if the pain is severe

28.7

16.3

55.0

I use analgesics if the pain is blunt

42.8

21.3

35.8

I use analgesics if the pain is bearable

57.9

20.3

21.8

Physical examination findings

I use analgesics if abdominal examination findings are typical

19.1

66.9

I use analgesics only if there is a sensitivity in upper left quadrant

43.6

17.8

38.6

I use analgesics only if there is a sensitivity in upper right quadrant

45.1

15.7

39.2

I use analgesics only if there is a sensitivity in lower left quadrant

47.6

17.2

35.3

I use analgesics if there a defence or rebound is found during the examination

47.1

18.4

34.5

I use analgesics only if there is a sensitivity in lower right quadrant

63.4

15.0

21.6

I use analgesics only if there is a sensitivity in periumbilical region

55.9

17.1

27.1

I use analgesics if the patient does not have fever

57.1

14.6

28.3

I use analgesics if the patient has fever

56.3

15.5

28.2

Laboratory findings

I use analgesics if there is no leucocytosis followed by the pain

46.8

19.2

34.0

I use analgesics if there is leucocytosis followed by the pain

60.9

15.7

23.4

Radiologic findings

I use analgesics if the patient’s abdominal tomography results are normal

20.2

19.7

60.2

I use analgesics if the patient’s abdominal ultrasound results are normal

35.0

25.9

39.0

I use analgesics if the patient’s upright abdominal X-ray results are normal

53.4

18.0

28.6

Diagnostıc approach

I use analgesics if the diagnosis is established

11.7

8.9

79.4

I use analgesics if the patient is diagnosed with acute cholecystitis

10.2

9.4

80.4 79.9

I use analgesics if the patient is diagnosed with acute pancreatitis

10.4

9.7

I use analgesics if the patient is diagnosed with acute appendicitis

17.7

11.8

70.5

I use analgesics if the patient is diagnosed with acute gastroenteritis

15.7

15.1

69.2

I use analgesics if the patient is diagnosed with acute mesenteric ischaemia

16.6

17.5

65.8

I use analgesics if the patient is diagnosed with ileus

26.8

15.7

57.5

I use analgesics if the patient is diagnosed with renal colic

6.7

5.7

87.6

I use analgesics if the diagnosis is not clear

47.6

22.3

30.1

of use of analgesics, medication times, effects on physical examination findings, administration before examination of patient by surgical consultant specialist reasons for suppor178

ting and not supporting the use of analgesics before definitive diagnosis, and the effect of patient-related factors on the use of analgesics. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

b. Comparison of EM specialists (state-university) and residents When the frequency of use of analgesics was examined, while there was no difference between those stating that they would use analgesics “often’’ and “always’’, the number of residents who sated that they would “never’’ use was statistically greater and significant compared to the specialist physicians (Chi-square: 17.484, p=0.002) (Table 3). According to the time of analgesics administration, residents reported that they administered analgesics “’upon surgical intervention decision”, while specialist physicians reported that they administered analgesics “after patient’s examination and treatment plan’’ (Chi-square: 11.595, p=0.021) (Table 4). When the participants were asked about the effect of the use of analgesics on physical examination findings, residents reported that analgesics “suppressed’’ physical examination findings, while specialists physicians reported that analgesics “clarified’’ the findings (Chi-square: 31.760, p<0.0001) (Table 5). About the administration of analgesics before examination by surgeon, residents (71.1%, n=219) reported that they would not administer analgesics “before examination by surgeon”, while spe-

cialist physicians (48.2%, n=234) reported otherwise (Fisher’s Exact p=0.0001). The most common reasons stated by the residents, among the reasons for not supporting the use of analgesics are given Table 6. When the analgesics used were examined, it was figured out that both residents and specialist physicians used narcotic analgesics the most, and it was observed that the rates of use of NSAIDs were also higher in the two groups (n=80 residents, n=66 specialist physicians). c. Comparison of EM residents employed in State Hospitals to University Hospitals When the frequency of use of analgesics was examined, the number of those who reported that they would “never’’ and “rarely’’ use analgesics (21.2%, n=91) was statistically greater and significant than those employed in university hospitals (9.3%, n=40), while there was no difference between those who reported that they would use analgesics “often and “always’’ (Chi-square: 18.719 p=0.001). No difference was found between the two groups in terms of answers given about the effect of use of analgesics on physical examination findings. The two groups gave the answer that

Table 3. Comparison of emergency medicine specialists (state-university) and emergency medicine residents by the frequency of use of analgesics Frequency of use of analgesics

Emergency medicine resident

Never

24 61.5

Emergency medicine specialist n

Total n

15 38.5

Rarely

126 71.6

50 28.4

176

Sometimes

147 57.9

107 42.1

254

Often

149 54.6

124 45.4

273

Always

23 46

27 54

Total

469 59.2

323 40.8

792

Chi-square: 17.484; p=0.002.

Table 4. Comparison of emergency medicine specialists (state-university) and emergency medicine residents by time of administering analgesic drugs Time of administering analgesic drugs

Emergency medicine resident n

Emergency medicine specialist n

Total n

After examination, plan

210

53.6

182

46.4

392

After examination by surgeon consultant

61.8

38.2

110

When surgical intervention is excluded

61.6

38.4

125

After diagnosis

67.7

32.3

124

When decision for surgery is made

78.6

21.4

Total

431 58.8

285 41.2

14 716

Chi-square: 11.595; p=0.021.

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Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

Table 5. Comparison of opinions of emergency medicine specialists (state-university) and emergency medicine residents regarding the effects of use of analgesics on physical examination findings Effects on physical examination findings

Emergency medicine resident

Emergency medicine specialist

Total

Suppressing

271 69.5

119 30.5

390

Clarifying

17 45.9

20 54.1

No effect

182

180

362

Total

470 59.6

50.3

49.7

319 40.4

789

Chi-square: 31.760; p<0.0001.

Table 6. Comparison of emergency medicine specialists (state-university) and emergency medicine residents by reasons for not supporting the use of analgesics Reasons for not supporting

Emergency medicine resident

Emergency medicine specialist

Total

n % n % n

It represses physical examination findings

71.9

28.1

114

It causes delays in accurate diagnosis of the patient

83.6

16.4

The patient should bear the pain until his/her diagnosis is established

62.5

37.5

There is no supporting data in the literature

72.0

28.0

He/she fears some complications that are likely to emerge

66.7

33.3

It causes misdiagnosis

He/she has concerns about disagreements with surgery consultant physician

57.1

42.9

Total

195

28 268

Chi-square: 16.461; p=0.021.

analgesics would suppress physical examination findings at the rate of 57%. d. Comparison of EM residents by their seniority (under and over 24 months) When the frequency of use of analgesics was examined, a statistical difference was found between the two groups, and it was observed that this difference resulted from the fact that senior residents (>24 months) administered analgesics “often” compared to junior residents (40% versus 27%) (Chisquare: 10.434, p=0.034). A statistical difference was also found in answers for the effect of use of analgesics on physical examination findings, and it was observed that this difference resulted from the answer given by junior residents that use of analgesics would “suppress physical examination findings” (68% versus 40%) (Chi-square: 12.683, p=0.002).

Discussion It was found out in our study that the frequency of use of analgesics by EM physicians in Turkey was relatively low and half 180

of physicians still believed that analgesics “suppressed physical examination findings”. It was observed that general surgeons did not recommend the use of analgesics in many hospitals, and there was no consensus or algorithms established to date between the two departments. EM residents used less analgesics than EM specialists, but administered them “upon surgical intervention decision”, did not administer them “before examination by general surgeon’’, and believed that the use of analgesics “suppressed physical examination findings”. Thoughts in relation to that analgesics suppressed physical examination findings decreased as seniority of the residents increased, and analgesics were used more often. Our study was the continuation of the study we conducted in 2006.[15] Fifty four percent of the emergency physicians in our study in 2006 had reported that the use of analgesics “suppressed physical examination findings”. Thirty five percent of them had reported that they administered analgesics “after patient’s examination and treatment plan’’ while 32% of them had reported that they administered “before examination by general surgeon”, and the most important factor in deciding to Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

administer analgesics was “patient’s degree of pain’’ and “time elapsed for examination of patient by surgical consultant’’. It was observed in the current study that opinions of physicians regarding that the use of analgesics suppressed physical examination findings, and the most important factors in deciding to administer analgesics had not changed, but physicians using analgesics administered analgesics “independent of surgeon” at a higher rate (60%) and “after patient’s treatment plan” (50%) and “before definitive diagnosis” (60%). Although evidence in the literature supports and it is included in surgery and EM textbooks, what might the reasons be for EM physicians to hesitate using analgesics? First of all, this subject is not sufficiently explained to residents during annual training programs, adequate theoretical training about the subject matter is not delivered and it is not emphasized during point-of-care training in daily practice. The fact that residents reported that they used analgesics less compared to specialists and believed that the use of analgesics would suppress physical examination findings and also the rates of residents to use analgesics increased as their seniority increased in our study supports our hypothesis. Concern for disagreement with surgeon and that surgeons strictly do not recommend administration of analgesics to patients may be another reason. Practices of EM residents in administering analgesics to patients “upon surgical intervention decision” and “after examination by surgeon” also support our hypothesis. EM residents may not receive sufficient support from their specialists and trainers in patient follow-up and may stay alone with surgeons. This situation may cause EM residents to remain undecided to administer analgesics to patients because they cannot receive support from EM specialists. Fear of misdiagnosis, delayed diagnosis, hesitation from malpractice especially in our country has increased significantly in the recent years due to lawsuits filed against physicians. When fear of harming patients is added to these drawbacks, it may seem more preferable to EM physicians to decide on “not to make a decision independent of surgeon” and”not to administer analgesics until surgery”. Administering analgesics to patients may also be delayed in teaching hospitals because of the hierarchical system of most surgical programs. Often a surgical intern and then a junior staff member are sent to evaluate emergency patients before speaking with the surgical senior or the attending physician. These examinations may be quite time consuming.[15] When patients do not receive analgesia in the ED, the first dose of pain medication is delayed at an average of 5.7 hours. This delay is often attributed to junior staff hesitation in administering medication due to the concern of possibly masking important symptoms.[16] The fact that EM physicians did not use analgesics although they reported that approximately 90% of the patients requested for analgesics “always” and “frequently” is anotUlus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

her striking finding. Article 11 of the regulation on patients’ rights[17] states that “Patients have the right to be diagnosed, to be treated and claim to be cared in accordance with the requirements of the current medical knowledge and technology’’, and Article 14 states that “it is necessary to endeavour to reduce or relieve patient’s pain”. It should be remembered that patient’s pain and suffering can be subject to a separate complaint and lawsuit on the ground that EM physicians and surgeons fail to administer a literature-proved treatment which must be used due to “fear of misdiagnosis, delayed diagnosis, harming patients and fear of malpractice”. In the literature, studies have assessed the factors effective in the decision-making process regarding how to deal with the pain of the patients regarding their ages, sexes, languages, cultural and ethnic differences, moral values, life styles, and habits.[16,18–23] The previous study discovered that physical examination, laboratory findings, nature and severity of pain and final diagnosis affected decisions of EM physicians in addition to these factors. This current study showed that these factors did not affect the decision of use of analgesics for EM physicians. Based on our findings, it seems logical to think that physicians supporting the use of analgesics have administered analgesics independently of these factors and those not supporting the use of analgesics have not administered analgesics independently of these factors. It was found out in this study that EM physicians used narcotic analgesics the most at similar rates compared to the previous study. It is striking that physicians reported the use of NSAIDs at the rates (20 & 23%) similar to the previous study. Narcotic analgesics are used for abdominal analgesia. It is particularly emphasized that NSAID drugs should not be used.[13] Although the reason for such significantly high use cannot be fully understood, it may be a reason that EM physicians administer NSAIDs to patients who will undergo surgery, who are established a final diagnosis or who do not require surgery and will be followed up (cholecystitis, pancreatitis, renal colic, non-specific abdominal pain, etc.). This preliminary study has some limitations. First, this study is a questionnaire study based on comments, and therefore, it may not reflect everyday clinical practice. Since most of the questions were attitudinal questions, memory and judgement are not likely to have played a role in how these questions were answered. It was not possible to reach out all EM physicians in Turkey, and we believe that the result would be different if it was possible to reach all physicians out. Other limitations may include the social desirability bias and the central tendency bias of the participants.

Conclusion The rates of administration of analgesic drugs by EM physicians to patients with acute abdominal pain are quite low. Whi181

Özen et al. Analgesic use in patients with acute abdominal pain in the emergency department

le no difference was found between attitudes, daily practices of EM specialists, and being employed in state and university hospitals towards the use of analgesics and factors affecting their decision on the use of analgesics, there was a difference between EM residents and EM specialists. EM residents use analgesics much less than EM specialists. EM residents do not implement their decisions on the use of analgesics before the surgeon makes a decision about patient and consents to administer analgesics. There is a need for further studies in which surgeons will be included on this subject.

Acknowledgements We would like to thank to Gül Kitapcıoğlu for help assistance in statistical analysis. Conflict of interest: None declared.

REFERENCES 1. Silen W. Cope’s Early Diagnosis of the Acute Abdomen. 17th ed. New York, NY: Oxford University Press 1987. p. 5. 2. Boey J The acute abdomen. In: Way L, editor. Current-surgical diagnosis and treatment. 10th ed. Norwalk CT, Appleton and Lange; 1994. p. 441–52. 3. Nissman SA, Kaplan LJ, Mann BD. Critically reappraising the literature-driven practice of analgesia administration for acute abdominal pain in the emergency room prior to surgical evaluation. Am J Surg 2003;185:291–6. 4. Thomas SH, Silen W. Effect on diagnostic efficiency of analgesia for undifferentiated abdominal pain. Br J Surg 2003;90:5–9. 5. Lee JS, Stiell IG, Wells GA, Elder BR, Vandemheen K, Shapiro S. Adverse outcomes and opioid analgesic administration in acute abdominal pain. Acad Emerg Med 2000;7:980–7. 6. LoVecchio F, Oster N, Sturmann K, Nelson LS, Flashner S, Finger R. The use of analgesics in patients with acute abdominal pain. J Emerg Med 1997;15:775–9. 7. Pace S, Burke TF. Intravenous morphine for early pain relief in patients with acute abdominal pain. Acad Emerg Med 1996;3:1086–92. 8. Attard AR, Corlett MJ, Kidner NJ, Leslie AP, Fraser IA. Safety of early pain relief for acute abdominal pain. BMJ 1992;305:554–6.

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9. Mackway-Jones K, Harrison M. Towards evidence based emergency medicine: best BETS from the Manchester Royal Infirmary. Analgesia and assessment of abdominal pain. J Accid Emerg Med 2000;17:126–9. 10. Brewster GS, Herbert ME, Hoffman JR. Medical myth: Analgesia should not be given to patients with an acute abdomen because it obscures the diagnosis. West J Med 2000;172:209–10. 11. Zoltie N, Cust MP. Analgesia in the acute abdomen. Ann R Coll Surg Engl 1986;68:209–10. 12. Howell JM, Eddy OL, Lukens TW, Thiessen ME, Weingart SD, Decker WW; American College of Emergency Physicians. Clinical policy: Critical issues in the evaluation and management of emergency department patients with suspected appendicitis. Ann Emerg Med 2010;55:71–116. 13. Manterola C, VialM, Moraga J, Astudillo P. Analgesia in patients with acute abdominal pain. Cochrane Database Syst Rev. 2011;1:CD005660. 14. Silen W. Cope’s early diagnosis of the acute abdomen. 20th ed. New York: Oxford University Press 2000. 15. Kiyan S, Kitapcioglu G, Aksay E, Ersel M, Ozsarac M, Yuruktumen A. Views of Emergency Physicians Working at University Hospitals in Turkey Regarding Use of Analgesics in Patients with Acute Abdominal Pain and Factors Affecting the Use Of Analgesics. Balkan Medical Journal 2011;28:173–8. 16. Wolfe JM, Lein DY, Lenkoski K, Smithline HA. Analgesic administration to patients with an acute abdomen: a survey of emergency medicine physicians. Am J Emerg Med 2000;18:250–3. 17. http://www.saglik.gov.tr/TR/belge/1-555/hasta-haklari-yonetmeligi. html. 18. Graber MA, Ely JW, Clarke S, Kurtz S, Weir R. Informed consent and general surgeons’ attitudes toward the use of pain medication in the acute abdomen. Am J Emerg Med 1999;17:113–6. 19. Kim MK, Galustyan S, Sato TT, Bergholte J, Hennes HM. Analgesia for children with acute abdominal pain: a survey of pediatric emergency physicians and pediatric surgeons. Pediatrics 2003;112:1122–6. 20. Hashikawa C, Burke TF, Pallin DJ, Briggs-Malonson M. Analgesia administration for acute abdominal pain: a survey of emergency physicians. Ann Emerg Med 2007;50:91–2. 21. Goldman RD, Narula N, Klein-Kremer A, Finkelstein Y, Rogovik AL. Predictors for opioid analgesia administration in children with abdominal pain presenting to the emergency department. Clin J Pain 2008;24:11–5. 22. Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med 2004;43:494–503. 23. Todd KH, Deaton C, D’Adamo AP, Goe L. Ethnicity and analgesic practice. Ann Emerg Med 2000;35:11–6.

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ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Türkiye’de üniversite ve eğitim araştırma hastanelerinde çalışan acil tıp hekimlerinin akut karın ağrısında analjezik kullanım sıklığı ve bunu etkileyen faktörler Dr. Özgür Özen, Dr. Selahattin Kıyan Ege Üniversitesi Tıp Fakültesi Hastanesi, Acil Tıp Anabilim Dalı, İzmir

AMAÇ: Türkiye’de çalışan acil tıp uzman, asistan ve öğretim üyelerinin akut karın ağrılı hastalarda analjezik kullanımı konusundaki tutumları, günlük pratik uygulamaları ve analjezik kullanım kararını etkileyen faktörleri belirlemektir. GEREÇ VE YÖNTEM: Kesitsel analitik çalışma 15 Kasım 2013–25 Ocak 2014 tarihleri arasında Türkiye’deki üniversite hastaneleri, Sağlık Bakanlığı eğitim ve araştırma hastaneleri, devlet hastaneleri ve özel hastanelerde çalışan acil tıp hekimlerine anket formu uygulanarak yapıldı. BULGULAR: İnternet bağlantısıyla (n=410) ve posta (n=393) yoluyla toplam 803 anket dolduruldu (Katılım oranı: %47). Katılımcıların %59.3’ü (n=470) araştırma görevlisi, %35.1’i (n=278) acil tıp uzmanı ve %5.7’si (n=45) öğretim üyesiydi. Katılımcıların analjezik ilaçların; fizik muayene bulgularını %49.5’i “baskıladığını”, %34.5’inin “sıklıkla” kullandığı, %50.7’sinin “muayene ve hastanın planlaması yapıldıktan sonra” uyguladığını, %60.6’sının “cerrah hastayı görmeden”, %56.9’unun da “kesin tanı konmadan önce uyguladığını” bildirdi. Hastaların %47.9’unun “her zaman”, %41.6’sının “sıklıkla” analjezik talep ettiklerini bildirdiler. Cerrahi konsültan hekiminin %34.6’sı “nadiren”, %28.7’si “hiçbir zaman” analjezik kullanımını önermediği ve cerrahi bölümlerle oluşturulmuş ortak politika olmadığı (%79.1) yanıtını verdiler. Acil tıp uzmanlarının (devlet ve üniversite) analjezik kullanımı ve hastaya ait faktörler konusunda istatistiksel olarak fark yoktu. Acil tıp uzmanları ve asistanları arasında ise, asistanların “hiçbir zaman” analjezik kullanmam diyen grubu, uzmanlara göre fazlaydı (p=0.002), asistanlar “operasyon kararı verildiğinde”, uzmanlar ise “muayene ve hasta yönetim planı yapıldıktan sonra” analjezik uyguladıklarını (p=0.021), asistanlar analjeziklerin fizik muayene bulgularını “baskıladığını”, uzmanlar ise “netleştirdiğini” (p<0.0001), asistanlar “cerrah muayene etmeden analjezik uygulamadıkları”, uzmanlarsa uyguladıklarını bildirdi (p=0.0001). Hem asistanların hem de uzmanların en sık narkotik analjezik kullandıkları, NSAID kullanım oranlarının her iki grup içinde yüksek olduğu görüldü. Asistanlar ağrı şiddeti, fizik muayene bulguları, inceleme sonuçları ve farklı tanılarda analjezik kullanımı konusunda da uzmanlara göre istatistiksel olarak anlamlı oranda kararsız kalmaktaydı. Devlette çalışan asistanların analjezikleri “hiçbir zaman” ve “nadiren” kullanırım diyen grubu, üniversitede çalışanlara göre fazlaydı (p=0.001). Her iki grupta analjezik kullanımının fizik muayene bulgularına %57 oranında baskılar yanıtını verdiler. Kıdemli asistanlar (>24 ay) analjeziği kıdemsizlere göre “sıklıkla” uyguladıklarını (p=0.034) ve kıdemsiz asistanların daha çok oranda analjezik kullanımının “fizik muayene bulgularını baskıladığını” inandıklarını bildirdiler (p=0.002). TARTIŞMA: Acil tıp hekimlerinin akut karın ağrılı hastalarda analjezik kullanım oranları çok düşüktür ve yıllar içerisinde değişiklik olmamıştır. Acil tıp asistanlarının uzmanlarına oranla analjezik kullanım oranları çok daha düşüktür ve analjeziklerin fizik muayeneyi baskıladığına, cerrah hastayı muayene etmeden uygulamaması gerekliliğine inançları yüksektir. Asistanların, analjezik uygulama zamanı daha geçtir. Asistanın kıdemi arttıkça kullanım oranı ve fizik muayene etkilemediği görüşü artmaktadır. Anahtar sözcükler: Abdominal ağrı; analjezikler; acil hekimleri; anket. Ulus Travma Acil Cerrahi Derg 2016;22(2):175–183

doi: 10.5505/tjtes.2015.06706

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ORIG I N A L A R T IC L E

Intramedullary nailing of adult isolated diaphyseal radius fractures Ahmet Köse, M.D.,1 Ali Aydın, M.D.,2 Naci Ezirmik, M.D.,2 Murat Topal, M.D.,2 Cahit Emre Can, M.D.,3 Sinan Yılar, M.D.2 1

Department of Orthopaedics and Traumatology, Horasan State Hospital, Erzurum-Turkey

Department of Orthopaedics and Traumatology, Atatürk University Faculty of Medicine, Erzurum-Turkey

Department of Orthopaedics and Traumatology, Çankırı State Hospital, Çankırı-Turkey

ABSTRACT BACKGROUND: The aim of the present study was to evaluate functional and cosmetic outcomes of adult patients who underwent intramedullary nailing with newly designed intramedullary radius nails for isolated radius diaphyseal fractures. METHODS: Seventeen adult patients who had undergone intramedullary nailing for radius diaphyseal fractures were retrospectively evaluated. Patients with isolated radius diaphyseal closed fractures were included. Closed reduction was achieved in all patients. Wrist and elbow ranges of movement were calculated at final follow-up. Grip strength was calculated using a hydraulic hand dynamometer. Maximum radial bowing (MRB) and maximum radial bowing localization (MRBL) were calculated for treated and uninjured arms. Functional evaluation was performed using Grace-Eversman evaluation criteria and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score. RESULTS: Of the 17 patients with isolated radius diaphyseal fractures evaluated, 11 (64.7%) were male and 6 (35.3%) were female, with a mean age of 35.76 years (range: 23–61 years). Fractures were right-sided in 11 (64.7%) and left-sided in 6 (35.3%) patients. Mean time to bone union was 10.2 weeks (range: 8–20 weeks). Mean supination was 75.35º (range: 67º–80º), pronation was 85.18º (range: 74º–90º). According to Grace-Eversman evaluation criteria, results were excellent in 16 (94%) and good in 1 (6%) patient. Mean DASH score was 12.58 (3.3–32.5). CONCLUSION: The gold-standard treatment of adult isolated radius diaphyseal fractures is plate and screw osteosynthesis. However, intramedullary nailing of isolated radius fractures is a good alternative treatment method, with excellent functional results and union rates similar to those of plate and screw osteosynthesis. Keywords: Diaphyseal fracture; intramedullary nail; radius.

INTRODUCTION Fractures of the radius that occur without fracture of the ulna are not common, due to the protective position of the ulna in direct trauma, and the abundance of protective muscle and soft tissue mass around the radius.[1–2] The forearm bone should be considered intra-articular due to functional charAddress for correspondence: Ahmet Köse, M.D. Yukarı Köşk Mahallesi, Malazgirt Sokak, Doğuş Apt., A Blok, Kat: 5, Daire: 10, Erzurum, Turkey Tel: +90 442 - 711 30 08 E-mail: kose.ahmet.46@hotmail.com Qucik Response Code

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acteristics and spatial orientation. Therefore, the main aim in treatment of radius diaphyseal fractures is maintaining axial and rotational stability and preserving bone length.[3–5] Consensus exists regarding surgical treatment of displaced isolated radius diaphyseal fractures,[1–5] with open reduction, and plate and screw osteosynthesis accepted as the gold standard. However, there are disadvantages to plate and screw osteosynthesis, including cosmetic problems, soft tissue injury, neural injury, evacuation of fracture hematoma, and impairment of periosteal blood flow due to periosteal stripping.[1–3] Early reports of intramedullary nailing treatment of forearm fractures described high non-union rates and unsatisfactory rotational stability, as a result of which, nailing was not a preferred method. However, the new design of intramedullary radius nails provides satisfactory functional and clinical outcomes, and the treatment method has come to be used more widely.[4–18] Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

The aim of the present study was to evaluate functional outcomes and efficiency of newly designed intramedullary radius nails in the treatment of adult isolated diaphyseal radius fractures.

MATERIALS AND METHODS Patients who had undergone intramedullary nailing for isolated radial diaphyseal fracture were included. Informed consent was preoperatively obtained, and approval was granted by the institutional review board. Anteroposterior (AP) and lateral direct forearm radiographs were obtained on first admission following trauma. Fractures were classified according to Association for the Study of Internal Fixation (AO/ASIF) guidelines. Patients with isolated diaphyseal radial closed fractures were included. Patients with open fractures, open physeal lines, pathological fractures, Galeazzi fracture dislocations, distal radioulnar joint instabilities, neurovascular problems on initial admission, bilateral fractures, and/or multitrauma were excluded. Bone union was evaluated according to lateral and AP radiographs obtained at final follow-up examination. Cortical trabeculation, formation of callus, radiologically observed disappearance of the fracture line, and clinical loss of tenderness with palpation over the fracture line were accepted as bone union. Absence of signs of union at the 6th month was accepted as non-union. Angulation >10º, shortening, and rotational deformities were accepted as melanin. Maximum radial bowing (MRB) and maximum radial bowing localization (MRBL) were determined on radiography obtained on first admission and after bone union for both arms (Fig. 1). Radiological and clinical evaluation of patients with implant removal was performed prior to removal. Hand grip strength of patients with union was evaluated with a hydraulic hand dynamometer (SH5001; Saehan Inc., Masan, South Korea). Separate measurements were taken for treated and healthy forearms with the patient in a seated position, with neutral shoulders and abduction, neutral forearm and wrist, and with the elbow in 90º flexion. In order to prevent muscle fatigue, measurements were taken at 3-minute intervals, and the average of 3 values was accepted as grip strength. Wrist, forearm, and elbow joint ranges of motion were measured with a goniometer. Functional evaluation incorporated Grace-Eversman evaluation criteria and Disabilities of the

Figure 1. Schemitsch and Richards method for determining maximum radial bowing and maximum radial bowing localization.

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Arm, Shoulder, and Hand (DASH) questionnaire score.[19]

Surgical Technique Surgeries were performed with the patient in supine position. Radiolucent arm support was situated under the injured extremity. General anesthesia was applied to 12 (70.59%) patients and regional anesthesia to 5. Cefazolin (2 gr) was intravenously administered 30 min prior to surgery. C-arm fluoroscopy was positioned on the fracture side to aid in reduction evaluation. Preoperative AP and lateral x-rays were used to ensure appropriate nail selection. Radial nail length was calculated by subtracting 3 cm from the distance between the radial styloid and the radial head proximal end. Appropriate nail diameter is selected with consideration of the narrowest inter-cortical distance on AP and lateral radiographs. A 10% margin of error (due to incorrect imaging) must be kept in mind while evaluating radiographs, and a range of nail sizes should be available during surgery. Closed reduction with fluoroscopic guidance was achieved in all patients. When stability was ensured with closed reduction, closed surgery was performed. At a minimum 1 cm proximal of the distal joint of the radius, a 1–1.5-cm longitudinal incision was made from the dorsolateral part of the distal metaphysis (lateral to Lister’s tubercle). The extensor carpi radialis longus and brevis tendons were located. The extensor carpi radialis brevis tendon sheath was longitudinally exposed with blunt dissection. First entry was performed with use of awl vertical to the radial metaphysis in the second extensor compartment. Depending upon experience and preference of the surgeon, the first, second, or fourth extensor compartments can be used as first entry point. First entry point was widened with bent awl targeting the medullary cavity. Radius nail was advanced with radius holder using rotational movements. Closed reduction was applied when nail tip reached the fracture line. Following closed reduction, the intramedullary position of the nail was verified with fluoroscopy. The distal end of the nail was advanced until full contact was made with the metaphyseal cortex, and static distal locking was performed. Passive rotational range of motion of the forearm must be evaluated following fixation.

Design of the Radius Nail Radius nails are made of titanium alloys (TST Rakor Tıbbi Aletler San. ve Tic. Ltd., İstanbul, Turkey). A radius nail is solid and round, with a parabolic shape that angulates 10º toward the anterior in the 3-cm proximal section. It has a distal static locking screw and provides stability on the principle of 3-point fixation (Fig. 2). The distal static locking screw provides locking with 17º of proximal and volar angle. This angle prevents the screw from directing toward the distal joint surface of the radius. The distal locking screw is 2.7 mm in diameter and has length options of 16, 18, 20, 22, and 24 mm. The same nail can be used for both the right and left sides. Nail diameter may be 3, 3.5, or 4 mm, and length may be 18, 19, 20, 21, 22, 23, or 25 cm. They are used unreamed. 185

Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

(a)

(b)

Figure 2. (a) Free radius nail and radius nail over application guide. (b) Radial nail placement on cadaveric bone model, parabolic shape of the radius nail; 10 degrees of anterior angulation of the proximal 3 cm and 15 anterior angulation of the distal end.

Statistical Methods

RESULTS

SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA) was used to analyze data. Data were expressed as number, percentage, mean, and SD. Kolmogorov-Smirnov test was used to assess normal distribution of variables. Spearman’s correlation analysis was used to detect correlation between parameters. Relationship between grip strength, pronation, and supination of the treated and uninjured forearms was evaluated using Mann-Whitney U test. Spearman’s correlation coefficient was used to analyze correlation between grip strength, pronation, and supination of the treated and uninjured forearms. A value of p<0.05 was considered statistically significant.

Of the 17 adult patients with isolated radius diaphyseal fractures evaluated, 11 (64.7%) were male, and 6 (35.3%) were female, with a mean age of 35.76 years (range: 23–61 years). According to AO/ASIF classification, 13 (76.4%) patients had Type A fractures, and 4 (23.6%) had Type B fractures. Cause of fracture was a fall in 12 (70.59%), traffic accident in 3 (17.65%), and industrial accident in 2 (11.76%) cases. The injury was on the right side in 11 (64.7%) cases and on the left in 6 (35.3%). Surgeries were performed at a mean of 16.4 (8–24) hours after initial admission. Mean duration of hospitalization was 3.1 days. Demographic information, and radiological and clinical outcomes are displayed in Table 1.

Table 1. Demographic data of patients, radiological and clinical outcomes Patients Age Sex Side Etiology Immobilization AO Outcomes DASH Fluoroscopy Operation period (days) fracture according to Score time duration type Grace-Eversman (minutes) (minutes) criteria 1

32 M R

Fall

22A2

Perfect

26.7

29 F R

Fall

22B2

Perfect

3.3

22A2

Perfect

1.2

22B2

Perfect

12 3.3

42 M R

25 M R

Traffic accident Fall Fall Industrial accident

22A2

Perfect

22A2

Perfect

1 2 1.6

32 25 30 25

44 M R

Fall

22A2

Perfect

1.3

27 M L

Fall

22B2

Good

32.5

2.7

33 F R

Fall

22A2

Perfect

1.1

49 M L

Fall

22A2

Perfect

9.2

22A2

Perfect

17.5

33 M R

Fall

22B2

Perfect

8.3

51 M R

Fall

22A2

Perfect

18.5

0.3

26 F R

Fall

22A2

Perfect

0.5

Industrial accident

Fall

2.3 1

24 20

30 M R

22A2

Perfect

0.5

Traffic accident

22A2

Perfect

17.5

0.5

Traffic accident

22A2

Perfect

17.5

0.2

AO: Arbeitsgemeinschaft für Osteosynthesefragen; DASH: Disabilities of the Arm, Shoulder, and Hand; M: Male: F: Female; R: Right; L: Left.

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Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

Table 1. Demographic data of patients, radiological and clinical outcomes (continued) Patients Grip strength Supination Pronation Elbow Flexion Maximum radial bow Maximum radial Blood Time to (Uninjured/ (Uninjured/treated (Uninjured/treated (Uninjured/treated (Uninjured/treated bow localization loss union treated forearm degrees) forearm degrees) forearm degrees) forearm mm) (Uninjured/treated (ml) (weeks) forearm kg) forearm %) 1

65.5/60

80/75

90/85

143/140

12.78/13

40/35

80/78

90/87

145/145

12.5/13

57.2/58.2 7 9

68/68

80/80

90/88

143/143

13.27/14.19

62.2/64.4 10 8 53.2/60.8 15 8

58.2/60

10 10

70/65

80/76

90/88

145/143

13.7/14.2

65/60

80/70

90/85

145/145

14/14.2

59.2/60 20 9

40/35

80/80

90/90

145/145

13.56/13.57

60.2/60.3 10 8

55/50

80/70

90/80

145/138

13.13/14

58.5/60.1 15 10

129/110

80/65

90/74

145/142

12.1/14.2

45/45

80/78

90/84

144/144

13.4/13.6

50/60.2

120 12

57.2/63.3 15 10

40/35

80/77

90/83

145/143

13.3/13.5

59.1/60.3 10 10

50/45

80/75

90/86

145/140

14.8/15

57.08/60.7 20 12

68/64

80/76

90/86

145/143

13.7/14

58/50

15 11

45/40

80/75

90/86

145/145

14.6/14.9

49/59.4

20 12

35/33

80/76

90/88

145/145

13.4/13.7

36/34

80/77

90/87

145/145

13.26/13.49

48/44

80/77

90/86

145/143

13.7/13.9

58.1/58.23 10 11

40/36

80/76

90/85

145/143

13.3/13.65

57.3/58.17 20 11

Mean follow-up period was 38 months (range: 36–52 months). Mean duration of surgery was 27.5 minutes (range: 17–70 mins). Mean amount of blood lost during surgery was 10.3 ml (range: 10–30 ml), with mean fluoroscopy time of 1.5 mins (range: 0.2–5 mins). Variations in duration of surgery and fluoroscopy times are shown in Fig. 3. Mean time to union was 10.2 (8–20) weeks. Bridging callus formation was observed at the 6th postoperative week in all patients (Figs. 4, 5). Non-union or malunion Operation time (min) Fluoroscopy time (min)

Minute 70

60/60.4

15 11

was not observed. Evaluation of patients according to GraceEversman functional criteria and union rates indicated excellent results in 16 patients and good results in 1 (Table 1). Brace immobilization was applied for a mean of 2.5 (1–5) days. Immobilization was terminated when patients were able to tolerate the level of pain, and active movement was initiated. Closed reduction was performed in all patients. No iatrogenic damage to vessels, nerves, tendons, or bone occurred. No additional postoperative fixation, due to insufficient fixation during follow-up, was needed. There were no cases of implant insufficiency, implant break, or mechanical irritation. Following union, 3 patients underwent implant removal by request at a mean of 18 months (range: 16–20 months). Calculation of wrist and elbow range of motion was performed by goniometer. Mean supination of forearm was 75.35º (range: 67º–80º). Mean forearm pronation was 85.18º (range: 74º–90º). Mean elbow flexion was 143.05º (range: 138º–145º). Mean elbow extension was 0.64º (range: 0º–5º), mean wrist flexion was 75.2º (range: 75º–79º), and mean wrist extension was 79.17º (range: 75º–80º). No significant difference was found between the uninjured and treated arms with respect to range of motion (p>0.05).

60 50 40 30 20 10 0

59.2/60.3 10 11

8 9 10 11 12 13 14 15 16 17 Patients

Figure 3. Variations of fluoroscopy and operation times.

Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

In addition, functional results were evaluated; mean DASH score was 12.58 (range: 3.3–32.5). Mean hand grip strength, calculated by hydraulic hand dynamometer, was 50.5 kg (range: 33–110 kg). Mean MRB was 13.45 mm (range: 12.1– 14.8 mm), and mean MRBL was 57.55% (range: 49%–64.4%) 187

Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

(a)

(b)

Figure 4. (a) Preoperative X-ray view of 21-year-old female with AO/ASIF Type 22A2 radial diaphyseal fracture. (b) Postoperative 12th-month X-ray view.

on radiography. Spearman’s correlation analysis was used to detect correlations between functional and radiographic results of the treated forearms. No significant relationship between MRB, MRBL, pronation angle, and hand grip strength was found (p>0.05). The relationship between MRB, MRBL, grip strength, pronation, and supination of treated and uninjured forearms was evaluated using Mann-Whitney U test. A statistically significant difference was determined regarding MRB and MRBL (p<0.05), but no significant difference was found regarding grip strength, pronation, and supination (p>0.05; Table 2). A statistically significant difference in hand

(a)

(b)

grip strength was found between males and females (p<0.05), though not between treated and uninjured arms (p>0.05).

DISCUSSION Adult isolated radial fractures are rare.[4] The main aim in the treatment of radius diaphyseal fractures is to maintain axial and rotational stability, and to preserve bone length. Forearm supination is provided by the rotational movement of radius over ulna. Functional anatomic reduction is mandatory for optimal rotational forearm motion.[1–4] Displaced radius diaphyseal fracture usually requires surgical treatment.[1–18]

(c)

(d)

Figure 5. (a) Preoperative X-ray view of 32-year-old-male with AO/ASIF Type 22B2 radial diaphyseal fracture. (b) Postoperative 1st-month x-ray view. (c) Postoperative 6th-month X-ray view. (d) Postoperative 12th-month X-ray view.

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Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

Table 2. Radiologic and functional results of treated and uninjured forearms Variables Grip strength

Treated forearm

Uninjured forearm

Min.–Max. Mean±SD p Min.–Max. Mean±SD p 33–110

50.5±14.67

0.972

35.00–129.00

55.26±22.61

0.254

Supination

67–80

75.35±3.80 0.777

80–80

80±.0

0.115

Pronation

74–90

85.18±3.66 0.269

90–90

90±.0

0.70

MRB MRBL

12.10–14.80 13.45±.65 0

12.78–15

49–64.40 57.55±3.77 0.261 58.17–63.3

13.87±.57 0.261 60±1.39

MRB: Maximum radial bowing; MRBL: Maximum radial bowing localization.

The most commonly used and accepted method is osteosynthesis with plate and screws.[1,2] The number of studies that have evaluated outcome of isolated radius or isolated ulna fractures is limited. Most studies have been concerned with fractures of both bones of the forearm.[1–18] Therefore, as the present study focuses on outcome of treatment of isolated radius fractures, it can be considered a valuable contribution to the literature. K-wire, ender nails, and rush nails were the fixation materials found in early reports of the intramedullary treatment of forearm fractures. In 1959, the triangular nail was the first to have been specifically designed for the forearm.[20] However, as initial reports revealed that the nails could not provide satisfactory rotational stability and rates of non-union were high, the intramedullary nail was not widely used for the treatment of forearm diaphyseal fractures. Additional fixation material was required to provide rotational stability, such as long-arm casts, braces, or splint immobilization. More recently, a newly designed radius nail, which provides rotational stability and does not require additional fixation material, has begun to be used in the treatment of radius diaphyseal fractures.[4–18] In the present study, a splint was used until patients could tolerate the pain, though splint immobilization was unrelated to the stability of fixation. In patients who could tolerate the pain following splinting, active movements were immediately initiated. Restoration of radial bowing and preservation of interosseous distance is required for normal forearm function and architecture. Insufficient restoration of radial bowing causes impairment of supination and hand grip strength.[4] Achieving anatomic reduction is more difficult in intramedullary nailing than in open reduction.[21] The femur, tibia, humerus, and ulna have anatomic landmarks that facilitate the evaluation of rotational anatomic reduction. However, no anatomic landmarks are available in the radius to aid in the evaluation of anatomic and rotational stability reduction.[13] The parabolic shape and titanium elastic properties of the radius nail provide rotational stabilization on a 3-point principle.[7–9] Maintaining anatomic alignment and ensuring that cortical thickness is the Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

same at the distal and proximal ends of the fracture are the most useful aids.[13] Full range of motion during perioperative evaluation of passive supination and pronation after distal static locking demonstrates that exact anatomic reduction has been achieved.[7–9] Crenshaw reported that static locking is not necessary during intramedullary nailing,[21] as evaluation of the stability of fixation should guide the decision for static locking during surgery.[4] Some radius nails have both proximal and distal locking options, though proximal locking carries certain risks. [5,6,18] The radius has two curvatures in the sagittal and coronal planes.[22] There is no guide that allows for both distal and proximal locking. Proximal locking is performed with freehanded technique, is made more difficult by thick muscle tissue and rotational instability, and causes increased exposure to radiation.[5,6] Plate and screw osteosynthesis provides exact anatomic reduction with restoration of the radial bowing and radial bowing localization.[1,2,23] However, certain evidence suggests that despite exact anatomic restoration of radial bowing and interosseous distance, limited rotational motion can be an effect of plate screw osteosynthesis. Fibrosis of the soft tissues, scarring of the skin, adhesion, shortened interosseous distance, and late mobilization can lead to limited forearm rotation.[5–24] Differences in the restoration of radial bowing and radial bowing localization were reported in studies that compared plate and screw osteosynthesis with intramedullary nailing, though no significant differences in functional and clinical outcomes were reported.[10] This result is most likely due to short immobilization period and early rehabilitation. Union rates of 87%–98% have been reported for plate and screw osteosynthesis.[1–3] Regarding intramedullary nailing, a bone union rate of 97% was reported by Lee et al.,[6] 100% by Gao et al.,[5] and 94% by Moerman et al.[15] In the present study, the bone union rate was 100% with intramedullary nailing.[5–17] Mean time to bone union with plate and screw osteosynthesis was reported as 7.4 weeks by Anderson et al.,[25] and as 17 weeks by Leung and Chow.[24] Mean time 189

Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures

to union with intramedullary nailing was determined as 10 (9–12) weeks in a study by Ozkaya et al.,[16] 3.5 months by Weckbach et al.,[13] 14 (9–32) weeks by Lee et al.,[6] and 10 (7–12) weeks by Gao et al.[5] Mean time to union in the present study was 10.2 (8–20) weeks. Time to bone union was similar for both methods. Using the Grace-Eversman[26] functional evaluation criteria, Gao et al.[5] reported 72% excellent and good, 17% acceptable, and 11% unacceptable results. Ozkaya et al.[16] reported 80% excellent, 10% good, and 10% acceptable results. Visna et al.[12] reported 88% excellent and good results, and Lee et al.[6] 81% excellent, 11% good, and 8% acceptable results. In the present study, 16 (94%) cases were categorized as excellent and 1 (6%) was categorized as good. With intramedullary nailing of forearm fractures, Lee et al.[6] reported a mean DASH score[19] of 15 (5–61), Gao et al.[5] reported a mean DASH score of 19 (4–72), Lil et al.[17] reported 15 (4–36), and Bansal et al[14] reported 14 (8–36). Mean DASH score of the present study was 12.58 (3.3–32.5). Intramedullary nailing bears certain risks, as does all treatment methods.[4–18] The use of nails with too large a diameter can cause iatrogenic fracture, while nails with too small a diameter can cause rotational instability.[4] Use of nails with proximal locking screws risks damaging the posterior interosseous nerve. There is risk to the extensor pollicis longus tendon and the superficial branch of the radial nerve at the point of entry of the nail.[18] Preoperative planning and a cautious approach during surgery minimizes the rate of complications caused by inappropriate nail selection and incorrect surgical technique.[5] No iatrogenic trauma to the bones, vessels, or nerves occurred in the present study. Use of nails without proximal locking screws removes risk of pin damage.[9] Intramedullary nailing, of proximal 1/3 radius diaphyseal fractures in particular, can be considered more advantageous than plate and screw osteosynthesis. Diverging opinions exist regarding the removal of implants used for fixation of radius diaphyseal fractures.[2,27,28] Open and comminuted fractures, fractures caused by high energy trauma, insufficient compression and reduction in comminuted fractures, and concomitant fracture in the same extremity increase the rate of refracture.[27,28] Removal of the implant within 8 postoperative months decreases the rate of refractures,[29] which generally occur 2–24 months after implant removal.[29] In plate and screw osteosynthesis, cortical atrophy may occur around the screw holes, causing high rate of refracture following implant removal.[2,27,29] Intramedullary nailing provides firm peripheral callus, resulting in low refracture rates.[4] Implant removal is performed via the same incision in intramedullary nailing, and even after implant removal, intramedullary nailing has better cosmetic outcomes.[5–17] Three patients in the present population requested implant removal after bone union, though no signs of irritation were present. Implants were removed, and no refracture was observed. 190

Certain limitations affected the present study, including the limited number of cases that would lead to satisfactory statistical results, the short follow-up period, and the limited number of studies in the literature for comparison. Further studies that include more patients with isolated radius fractures and longer follow-up periods are warranted, as are studies that compare clinical outcomes of plate and screw osteosynthesis with those of intramedullary nailing. In order to determine the necessity of restoration of radial bowing and interosseous distance, cadaveric studies and biomechanical studies using the latest technology are necessary.

Conclusion The newly designed intramedullary radius nails can be applied with closed reduction or with mini-open reduction, resulting in limited soft tissue injury. These nails can be applied with a shorter operating time and have better cosmetic results. They provide reliable stability, do not require additional fixation material, and allow for early active movement. Intramedullary nailing has excellent clinical and functional outcomes, and intramedullary nailing of radius diaphyseal fractures can be a reliable alternative to osteosynthesis with plate and screws. Conflict of interest: None declared.

REFERENCES 1. Schulte LM, Meals CG, Neviaser RJ. Management of adult diaphyseal both-bone forearm fractures. J Am Acad Orthop Surg. 2014;22:437–46. 2. Henle P, Ortlieb K, Kuminack K, Mueller CA, Suedkamp NP. Problems of bridging plate fixation for the treatment of forearm shaft fractures with the locking compression plate. Arch Orthop Trauma Surg 2011;131:85– 91. 3. Reilly TJ. Isolated and combined fractures of the diaphysis of the radius and ulna. Hand Clin 2002;18:179–94. 4. Crenshaw AH, Zinar DM, Pickering RM. Intramedullary nailing of forearm fractures. Instr Course Lect 2002;51:279–89. 5. Gao H, Luo CF, Zhang CQ, Shi HP, Fan CY, Zen BF.Internal fixation of diaphyseal fractures of the forearm by interlocking intramedullary nail: short-term results in eighteen patients. J Orthop Trauma 2005;19:384– 91. 6. Lee YH, Lee SK, Chung MS, Baek GH, Gong HS, Kim KH. Interlocking contoured ıntramedullary nail fixation for selected diaphyseal fractures of the forearm in adults. J Bone Joint Surg Am 2008;90:1891–8. 7. Saka G, Saglam N, Kurtulmus T, Bakir U, Avci CC, Akpinar F, et al. Treatment of isolated diaphyseal fractures of the radius with an intramedullary nail in adults. Eur J Orthop Surg Traumatol 2014;24:1085–93. 8. Saka G, Saglam N, Kurtulmuş T, Avcı CC, Akpinar F, Kovaci H, et al. New interlocking intramedullary radius and ulna nails for treating forearm diaphyseal fractures in adults: a retrospective study. Injury. 2014;45 Suppl 1:16–23. 9. Köse A, Aydın A, Ezirmik N, Can CE, Topal M, Tipi T. Alternative treatment of forearm double fractures: new design intramedullary nail.Arch Orthop Trauma Surg 2014;134:1387–96. 10. Lee SK, Kim KJ, Lee JW, Choy WS. Plate osteosynthesis versus intramedullary nailing for both forearm bones fractures. Eur J Orthop Surg

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Köse et al. Intramedullary nailing of adult isolated diaphyseal radius fractures Traumatol 2014;24:769–76. 11. Rehman S, Sokunbi G. Intramedullary fixation of forearm fractures. Hand Clin 2010;26:391–401. 12. Visna P, Beitl E, Pilny J, Cizmár I, Vlcek M, Kalvach J, et al. Interlocking nailing of forearm fractures. Acta Chir Belg 2008;108:333–8. 13. Weckbach A, Blattert TR, Weisser Ch. Interlocking nailing of forearm fractures. Arch Orthop Trauma Surg 2006;126:309–15. 14. Bansal H. Intramedullary fixation of forearm fractures with new locked nail. Indian J Orthop 2011;45:410–6. 15. Moerman J, Lenaert A, De Coninck D, Haeck L, Verbeke S, Uyttendaele D, et al. Intramedullary fixation of forearm fractures in adults. Acta Orthop Belg 1996;62:34–40. 16. Ozkaya U, Kiliç A, Ozdoğan U, Beng K, Kabukçuoğlu Y. Comparison between locked intramedullary nailing and plate osteosynthesis in the management of adult forearm fractures. [Article in Turkish] Acta Orthop Traumatol Turc 2009;43:14–20. 17. Lil NA, Makkar DS, Aleem AA. Results of Closed Intramedullary Nailing using Talwarkar Square Nail in Adult Forearm Fractures. Malaysian Orthop J 2012;6:7–12.

20. Sage FP, Smith HC. Medullary fixation of forearm fractures. J Bone Jt Surg 1957;39:91–8. 21. Crenshaw AH Jr. Fractures of shoulder girdle, arm, and forearm. In: Canale ST, Beaty JH, editors. Campbell’s operative orthopaedics. 11th ed. St. Louis: Mosby; 2008. p. 3431–41. 22. Rupasinghe SL, Poon PC. Radius morphology and its effects on rotation with contoured and noncontoured plating of the proximal radius. J Shoulder Elbow Surg 2012;21:568–73. 23. Schemitsch EH, Richards RR. The effect of malunion on functional outcome following plate fixation of fractures of both ones of the forearm in the adult. J Bone Joint Surg Am 1992;74:1068–78. 24. Leung F, Chow SP. A prospective, randomized trial comparing the limited contact dynamic compression plate with the point contact fixator for forearm fractures. J Bone Joint Surg Am 2003;85:2343–8. 25. Anderson LD, Sisk D, Tooms RE, Park WI 3rd. Compression- plate fixation in acute diaphyseal fractures of the radius and ulna. J Bone Joint Surg Am 1975;57:287–97. 26. Grace TG, Eversmann WW Jr. Forearm fracture: treatment by rigid fixation with early motion. J Bone Joint Surg Am 1980;62:433–8.

18. Fanuele J, Blazar P. Extensor pollicis longus tendon rupture in an adult after intramedullary nailing of a radius fracture: case report. J Hand Surg Am 2009;34:627–9.

27. Deluca PA, Lindsey RW, Ruwe PA. Refracture of bones of the forearm after the removal of compression plates. J Bone Joint Surg Am 1988;70:1372–6.

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28. Labosky DA, Cermak MB, Waggy CA. Forearm fracture plates: to remove or not to remove. J Hand Surg Am 1990;15:294–301. 29. Langkamer VG, Ackroyd CE. Internal fixation of forearm fractures in the 1980s: lessons to be learnt. Injury 1991;22:97–102.

ORİJİNAL ÇALIŞMA - ÖZET OLGU SUNUMU

Yetişkin izole radius kırıklarında intramedüller çivi tedavisi Dr. Ahmet Köse,1 Dr. Ali Aydın,2 Dr. Naci Ezirmik,2 Dr. Murat Topal,2 Dr. Cahit Emre Can,3 Dr. Sinan Yılar2 1 2 3

Horasan Devlet Hastanesi, Ortopedi ve Travmatoloji Kliniği, Erzurum Atatürk Üniversitesi Tıp Fakültesi, Ortopedi ve Travmatoloji Anabilim Dalı, Erzurum Çankırı Devlet Hastanesi, Ortopedi ve Travmatoloji Kliniği, Çankırı

AMAÇ: Bu çalışmada izole radius diafiz kırığı nedeniyle yeni dizayn intramedüller radius çivi tedavisi uyguladığımız erişkin hastalarda intramedüller çivi tedavisinin etkinliğini, fonksiyonel ve kozmetik sonuçlarını değerlendirmeyi amaçladık. GEREÇ VE YÖNTEM: İzole deplase radius diafiz kırığı nedeniyle intramedüller çivi tedavisi uygulanan17 hasta geriye dönük olarak değerlendirildi. Çalışmaya kapalı izole radius diafiz kırığı olan hastalar dahil edildi. Tüm hastalara kapalı yöntemle tespit uygulandı. Hastaların son kontrollerinde gonyometre ile önkol ve dirsek hareket açıları ölçüldü. Hidrolik el dinamometresi ile sağlam ve tedavi edilen önkollar için kavrama gücü ölçüldü. Önkol direkt grafide maksimum radial eğim ve lokalizasyonları sağlam ve tedavi edilen ekstremiteler için ayrı ayrı ölçüldü. Kaynama ve fonksiyonel sonuçların değerlendirilmesi Grace-Eversman kriterleri ve Disabilities of the Arm, Shoulder and Hand (DASH) scoreanketine göre yapıldı. BULGULAR: İzole radius diafiz kırığı olan 17 erişkin hasta değerlendirmeye alındı. Hastaların 11’i (%64.7) erkek, altısı (%35.3) kadındı. Yaş ortalaması 35.76 (23–61) idi. On bir (%64.7) hastada sağ, altı (%35.3) hastada sol tarafta kırık vardı. Ortalama kaynama süresi 10.2 (8–20) hafta olarak değerlendirildi. Ortalama supinasyon 75.35 (67–80) derece, pronasyon 85.18 (74–90) derece idi. Grace-Eversman değerlendirme kriterlerine göre 16 (%94) olguda mükemmel bir (%6) olguda iyi sonuç elde edildi. Hastaların DASH ortalaması 12.58 (3.3–32.5) olarak değerlendirildi. TARTIŞMA: Erişkin deplase radius diafiz kırıklarının cerrahi tedavisinde altın standart tedavi yöntemi plak vida osteosentezidir. Ancak fonksiyonel sonuçlarının çok iyi olması ve plak vida osteosentezine benzer kaynama oranları nedeniyle intramedüller çivi tedavisinin izole radius diafiz kırıklarında alternatif bir tedavi yöntemi olarak kullanılabileceğini düşünüyoruz. Anahtar sözcükler: Diafizyal kırık; intramedüller çivi; radius. Ulus Travma Acil Cerrahi Derg 2016;22(2):184–191

doi: 10.5505/tjtes.2015.87036

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CA S E REP OR T

Triple gastric peptic ulcer perforation Milan Radojkovic, M.D.,1 Suncica Mihajlovic, M.D.,2 Miroslav Stojanovic, M.D.,1 Goran Stanojevic, M.D.,1 Zoran Damnjanovic, M.D.3 1

Department of Surgery, Nis University Faculty of Medicene, Nis-Serbia

Department of Surgery, Clinical Center Nis, Nis-Serbia

Department of Vascular Surgery, Clinical Center Nis, Nis-Serbia

ABSTRACT Patients with advanced or metastatic cancer have compromised nutritional, metabolic, and immune conditions. Nevertheless, little is known about gastroduodenal perforation in cancer patients. Described in the present report is the case of a 41-year old woman with stage IV recurrent laryngeal cancer, who used homeopathic anticancer therapy and who had triple peptic ulcer perforation (PUP) that required surgical repair. Triple gastric PUP is a rare complication. Self-administration of homeopathic anticancer medication should be strongly discouraged when evidence-based data regarding efficacy and toxicity is lacking. Keywords: Peptic ulcer; perforation.

INTRODUCTION Perforation is very often the first clinical presentation of peptic ulcer disease (PUD), occurring in 2–10% of PUD patients and associated with more than 70% of PUD patient deaths.[1] The most common perforation site is the anterior wall of the duodenum (60%), as well as the gastric antrum (20%) and the lesser curvature (20%).[2] While perforation is still considered a disorder that primarily affects younger male patients, the average age of patients with peptic ulcer perforation (PUP) has recently been increasing— affecting predominantly females, with current incidence peak of 40–60 years of age.[3,4] Despite the introduction of powerful anti-peptic-ulcer medications, growing experience with Taylor’s method, and persistent post-surgery mortality rate, incidence of PUP requiring surgical treatment has remained stable or even increased.[2] Increasing incidences of both PUD and PUP may be due to widespread use of certain drugs such as aspirin, ibuprofen, and other nonsteroidal antiAddress for correspondence: Milan Radojkovic, M.D. Bul.dr Zorana Djindjica 48 18000 Nis - Serbia Tel: +381 18 506950 E-mail: mida71@open.telekom.rs Qucik Response Code

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inflammatory drugs. Immunocompromised patients, including those who are stressed, elderly, traumatized, and/or who have chronic disease are at higher risk of both PUD and PUP. Described in the present report is the case of a cancer patient with an unusual form of PUP who had been taking anticancer homeopathic therapy.

CASE REPORT A 41-year old woman presented to the emergency department with sudden, severe epigastric pain that had begun 7 hours prior to admittance. The pain was constant, had progressive intensity, and was spreading to the entire abdomen without accompaniment of vomiting or stool changes. On physical examination, the patient had generalized tenderness with guarding and rigidity. She was very pale, fatigued, and afebrile, with a pulse of 102 bpm, blood pressure of 90/60 mmHg, and respiratory rate of 22 breaths per minute. The patient was not able to speak due to present tracheostomy. Her body weight was very low, and she had an overall appearance characteristic of malignant cachexia. Heteroanamnesis revealed that the patient had been diagnosed with stage IV laryngeal (planocellular focally keratinized) cancer 19 months prior, and had undergone total laryngectomy and tracheotomy, as well as radiation therapy (68 Gy in 34 fractions). She had been subsequently diagnosed with recurrent cancer locally infiltrating the hypopharynx, for which she was receiving only symptomatic therapy. In the 3 months prior to Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Radojkovic et al. Triple gastric peptic ulcer perforation

ment.[6] Serious GI complications tend to develop in patients with underlying GI diseases and/or who receive therapeutic agents with high GI toxicity profiles. While double perforations can occur,[7] triple PUP is very rare. Radiotherapy is a well-known risk factor for GI perforation due to radiation injuries that involve ischemic tissue changes.[8,9] While the present patient had recurrent disease, it was not localized in the GI tract; radiotherapy was not directed to the patient’s abdomen. With the exception of former heavy smoking with its well-known ulcerogenic effects and psychological stress, the patient had no history of PUD or other chronic GI disease predisposing her to perforations. The absence of callosity due to chronic inflammatory changes, the hallmark of perforated ulcers, around perforation sites led to the conclusion that perforation was not the result of chronic PUD. Whether these perforations could be induced solely by cigarette toxicity and/or psychological stress may be debatable, especially considering the unusual occurrence of triple PUP and the fact that the patient had quit smoking nearly 2 years earlier. Still, compromised immunity and malnutrition due to malignancy contributed to the intensity of PUD complication. Cancer-induced immunodeficiency and additional, anticancer-therapy-induced immunosuppression affected the gastrointestinal tract, causing loss of gastric acidity, impaired immune response, reduced mucosal integrity, and compromised mucosal regeneration.[10] Figure 1. Triple gastric peptic ulcer perforation on the anterior wall of the pyloric region.

admittance, the patient had been self-administering homeopathic anticancer treatment consisting of sublingual intake of 5 drops, every 12 hours, of Vidatox® Homeopático 30CH (Labiofam, Holguin, Cuba). The drug is produced from 5 protein peptides extracted from the venom of the blue scorpion, Rhopalurus junceus, in a 33% hydroalcoholic solution.[5] Plain abdominal radiography showed massive pneumoperitoneum. Laboratory studies revealed leukocytosis (16.3x109/L) and anemia (hemoglobin of 161 mg/L). After brief stabilization, prophylactic antibiotics were administered, and the patient underwent upper midline laparotomy. Intraoperatively, diffuse peritonitis due to triple gastric PUPs, each measuring to 4–6 mm in diameter, was found on the anterior wall of the pyloric region (Fig. 1). Following excision, Heineke-Mikulicz pyloroplasty was performed, as was Kader-Stamm gastrostomy. The abdominal cavity was rinsed, drained, and closed. Postoperative course was uneventful. Histopathological examination of the specimen excluded gastric malignancy and confirmed the peptic nature of the lesions.

DISCUSSION Spontaneous gastroduodenal perforation has been reported in patients with non-gastrointestinal (non-GI) forms of cancer who were administered cytotoxic drugs, corticosteroids, or radiation therapy as primary or adjuvant treatUlus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Chemotherapy has been identified as an important factor, influencing non-favorable, short-term postoperative results in cancer patients with PUP.[11] In addition, the unusual addition of homeopathic medication was present, the active principle of which is venom in water and ethanol. It is stated on the official commercial website of the manufacturer that the homeopathic medication improves quality of life and survival rates of cancer patients, provides pain relief, prevents symptoms produced by cytostatic drugs and ionizing radiation, has antitumoral and antimetastatic effects on solid tumors, and is a non-toxic product with no side effects that can have a synergic or potentiating effect with other conventional anticancer treatment if used simultaneously.[5] The present authors were not able to find evidence-based clinical or experimental reports that investigated features, therapeutic effects, or toxicity of this medication on available internet databases. Compromised immune response could also have allowed for severe Helicobacter pylori infection in the patient, which appears to also have been associated with PUP in up to twothirds of PUD patients.[12] Surgeons should have high suspicion of PUP in cancer patients presenting with severe acute abdominal pain; triple gastric PUP is a rare complication of PUD. Self-administration of homeopathic anticancer medication in the absence of evidence-based data regarding efficacy and toxicity should be strongly discouraged. Conflict of interest: None declared. 193

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REFERENCES 1. Druart ML, Van Hee R, Etienne J, Cadière GB, Gigot JF, Legrand M, et al. Laparoscopic repair of perforated duodenal ulcer. A prospective multicenter clinical trial. Surg Endosc 1997;11:1017–20. 2. Zittel TT, Jehle EC, Becker HD. Surgical management of peptic ulcer disease today--indication, technique and outcome. Langenbecks Arch Surg 2000;385:84–96. 3. Lunevicius R, Morkevicius M. Management strategies, early results, benefits, and risk factors of laparoscopic repair of perforated peptic ulcer. World J Surg 2005;29:1299–310. 4. Imhof M, Epstein S, Ohmann C, Röher HD. Duration of survival after peptic ulcer perforation. World J Surg 2008;32:408–12. 5. http://www.labiofam.cu/en/productos/vidatox-30ch.html. 6. Liaw CC, Huang JS, Wang HM, Wang CH. Spontaneous gastroduodenal perforation in patients with cancer receiving chemotherapy and steroids. Report of four cases combining 5-fluorouracil infusion and cisplatin with antiemetics dexamethasone. Cancer 1993;72:1382–5.

7. Bertleff MJ, Lange JF. Perforated peptic ulcer disease: a review of history and treatment. Dig Surg 2010;27:161–9. 8. Casey EM, Harb W, Bradford D, Bufill J, Nattam S, Patel J, et al. Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemonaïve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116. J Thorac Oncol 2010;5:1815–20. 9. Shen X, Denittis A, Werner-Wasik M, Axelrod R, Gilman P, Meyer T, et al. Phase i study of ‘dose-dense’ pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma. Radiat Oncol 2011;6:17. 10. Aggarwal V, Williams MD, Beath SV. Gastrointestinal problems in the immunosuppressed patient. Arch Dis Child 1998;78:5–8. 11. Chao TC, Wang CS, Chen MF. Gastroduodenal perforation in cancer patients. Hepatogastroenterology 1999;46:2878–81. 12. Hussain AA, Abro AH, Siddiqui FG, Memon AA. Prevalence of helicobacter pylori infection in patients with perforated peptic ulcer. JLUMHS 2012;11:172–5.

OLGU SUNUMU - ÖZET

Üçlü gastrik peptik ülser perforasyonu Dr. Milan Radojkovic,1 Dr. Suncica Mihajlovic,2 Dr. Miroslav Stojanovic,1 Dr. Goran Stanojevic,1 Dr. Zoran Damnjanovic3 Nis Üniversitesi Tıp Fakültesi, Cerrahi Anabilim Dalı, Nis, Sırbistan Nis Klinik Merkezi, Cerrahi Kliniği, Nis, Sırbistan 3 Nis Klinik Merkezi, Vasküler Cerrahi Kliniği, Nis, Sırbistan 1 2

İleri veya metastatik kanser hastalarının beslenme, metabolizma ve bağışıklık durumları risk altındadır. Buna rağmen kanser hastalarında gastroduodenal perforasyon hakkında az miktarda bilgi mevcuttur. Bu yazıda, 41 yaşındaki evre IV yinelenen larenks kanseri olup homeopatik antikanser tedavisi gören ve cerrahi onarım gerektiren üç adet peptik perforasyonu olan bir kadın hastayı sunmaktayız. Üçlü gastrik peptik ülser perforasyonu nadir görülen olağandışı bir komplikasyondur. Hastaların kendi kendilerine etkinlik ve toksisitesine ilişkin kanıtlara dayalı veriler olmayan homeopatik kanser ilaçlarını kullanmaktan kuvvetle vazgeçirmek gerekir. Anahtar sözcükler: Peptik ülser; perforasyon. Ulus Travma Acil Cerrahi Derg 2016;22(2):192–194

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CAS E R EP O RT

Should warm fresh whole blood be the first choice in acute massive hemorrhage in emergency conditions? Pınar Kendigelen, M.D.,1 Zeynep Kamalak, M.D.,2 Deniz Abat, M.D.3 1

Department of Anesthesiology and Reanimation, Afşin State Hospital, Kahramanmaraş-Turkey

Department of Gynecology and Obstetrics, Afşin State Hospital, Kahramanmaraş-Turkey

Department of Urology, Afşin State Hospital, Kahramanmaraş-Turkey

ABSTRACT Early management of rapid massive hemorrhage requires early administration of blood products and rapid surgical control of bleeding. Professionals in peripheral hospitals with limited resources often work under conditions similar to those in the military. Described in the present report are 3 cases in which warm fresh whole blood (WFWB) was used in patients with massive bleeding who presented to a peripheral hospital that had no blood products suitable for emergency conditions. Described first is the case of a 16-year-old female patient who underwent emergency cesarean section.The patient had massive bleeding from the uterus due to atony. Her hemoglobin (Hb) dropped to 3.5 g/dL. Six units of WFWB were transfused during surgery. Hemodynamic parameters and complete blood count (CBC) stabilized. She was transferred from the intensive care unit (ICU) to obstetrics on day 2 and was discharged on day 7. Described second is the case of a 35-year-old female patient who also underwent emergency cesarean section, and for whom massive bleeding was due to uterine atony. Hb dropped to 2 g/dL and hematocrit (HCT) to 5.4%. Nine units of WFWB were transfused, after which hemodynamic and laboratory parameters stabilized. The patient was extubated the following day, transferred from the ICU to obstetrics on day 3, and was discharged on day 8. Described third is the case of a 36-year-old male patient with stab injuries and hemorrhagic shock who underwent emergency surgery. The patient had injuries to the right renal artery and kidney. Nine units of WFWB were transfused due to continued hemorrhage during surgery. Following surgical control of bleeding and transfusion, hemodynamic parameters improved. The patient was transferred from the ICU on day 5 and discharged on day 10. WFWB transfusion nearly disappeared from civilian medicine after blood was separated into components, and whole blood is not usually available at blood banks. In massive transfusions, WFWB effectively replaces red blood cells (RBCs), platelets, plasma volume, and coagulation factors, while preventing hypothermia and dilutional coagulopathy. Blood components go through biochemical, biomechanical, and immunological changes during long storage, the duration of which affects both transfusion efficacy and associated risks. In the future, with the use of fast donor tests, fast ABO compatibility tests, platelet-sparing leukocyte filters, and developments in pathogen-decreasing technology, fresh whole blood (FWB) may be the first choice for massive transfusion. Future studies will reveal new procedures. Keywords: Massive hemorrhage; massive transfusion; warm fresh whole blood.

INTRODUCTION Whole-blood transfusion was widely used in the first half of the 20th century, particularly in cases of massive hemorrhage Address for correspondence: Pınar Kendigelen, M.D. Afşin Devlet Hastanesi, Anesteziyoloji ve Reanimasyon Kliniği, Kahramanmaraş, Turkey Tel: +90 344 - 511 53 05 E-mail: pinarken@gmail.com Qucik Response Code

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due to trauma. Following World War II, the use of whole blood declined, and component therapy predominated. Present knowledge of whole-blood transfusion comes mainly from military studies, according to which, whole-blood transfusion may provide survival advantage, though safety concerns limit its widespread use.[1] However, in low-resource settings in which blood products are not always readily available, transfusion of fresh whole blood (FWB) can be life-saving. As presently described, warm fresh whole blood (WFWB) was transfused in 3 patients with massive bleeding who presented to a peripheral hospital that did not have blood products suitable for emergency conditions. Full clinical recovery was observed in all cases. 195

Kendigelen et al. Should warm fresh whole blood be the first choice in acute massive hemorrhage in emergency conditions?

CASE REPORTS Case 1– A 16-year-old female patient underwent emergency cesarean section due to fetal stress at 38 weeks of gestation. She had premature rupture of membranes and protracted descent of fetus in the first stage of labor, with late decelerations. Initial hemoglobin (Hb) was 11.4 g/dL, hematocrit (HCT) was 34.3%, and platelet count was 154000/μL. She delivered a male with a birth weight of 3550 g and an Apgar score of 7. No placental or uterine abnormality was observed. However, proper uterine contraction could not be achieved, despite uterine massage and administration of oxytocin and ergot alkaloids, causing massive uterine bleeding. A central venous catheter was inserted in the right internal jugular vein. Boluses of crystalloid and colloid fluids was administered. Systolic arterial pressure (SAP) was 80–90 mmHg, diastolic arterial pressure (DAP) was 50–60 mmHg, and heart rate (HR) was 100–130 bpm. Despite maintenance of normovolemia, hemoglobin count was 3.5 g/dL due to hemodilution, and bleeding persisted. Treatment of transfusion with FWB was decided upon, as fractionated blood products were not readily available. Six units of FWB were transfused, after which SAP rose to 100–110 mmHg, DAP to 60–70 mmHg, HR decreased to 100–110 bpm, and diuresis was 1 mL/kg/h. Emergency hysterectomy was performed due to persistent bleeding of atonic uterus. On postoperative complete blood count (CBC), Hb was 9.7 g/dL, HCT was 28%, and platelet count was 168000/μL. The patient was transferred to the intensive care unit (ICU) of a tertiary center, where she was extubated the same day. Hemodynamic parameters and CBC stabilized, and the patient was transferred from the ICU to obstetrics on day 2. She was discharged on day 7. Case 2– A 35-year-old woman with placental abruption underwent emergency cesarean section. On preoperative CBC, Hb was 9.9 g/dL, HCT was 25.5%, and platelet count was 224000/μL. She delivered a 2500 g male with an Apgar score of 8. The patient bled en route to surgery, and bleeding continued following delivery. SAP was 70 mmHg, DAP was 50 mmHg, and HR was 130–140 bpm. A central venous catheter was inserted, and crystalloid and colloid bolus infusions were initiated. In spite of all efforts to maintain normovolemia, CBC showed Hb of 2 g/dL, HCT of 5.4%, and platelet count of 65000/μL. Nine units of FWB were transfused, after which SAP was 60–110 mmHg, DAP was 40–70 mmHg, HR was 80–130 bpm, and diuresis was 0.5–1 mL/kg/h. Emergency hysterectomy was performed due to persistent bleeding of atonic uterus. Postoperative CBC showed Hb of 9.7 g/dL, HCT of 29%, and platelet count of 110000/μL. The patient was transferred to the ICU of a tertiary center and was extubated the following day, transferred to obstetrics on day 3, and discharged on day 8. Case 3– A 36-year-old male patient with stab injuries and hemorrhagic shock underwent emergency surgery. At first monitoring, SAP was 60 mmHg, DAP was 30 mmHg, and HR 196

was 120–130 bpm. Following intubation, central and peripheral venous catheters were inserted. Crystalloid and colloid bolus infusion was initiated, and 2 units of red blood cells (RBCs) that had been prepared for a planned surgery were transfused. Following the transfusion, control CBC showed Hb of 6 g/dL, HCT of 20%, and platelet count of 135000/ μL. Having sustained injuries to the right renal artery and right kidney, the patient bled throughout the surgery, and 9 units of WFWB were transfused. Hemodynamic parameters improved following surgical control of bleeding, nephrectomy, and binding of the artery. Postoperative CBC showed Hb of 10 g/dL, HCT of 29%, and platelet count of 146000/μL. Still intubated, the patient was transferred to the ICU of a tertiary center. He was transferred out of the ICU on day 5 and was discharged on day 10.

DISCUSSION Acute hemorrhage leading to acute hypovolemic shock is a medical emergency, and initial resuscitation requires rapid intravenous boluses of crystalloid and colloid solution in order to achieve volume replacement. Early management of rapid massive hemorrhage requires early administration of blood products and rapid surgical control of bleeding. Massive blood transfusion is commonly defined as transfusion of 10 or more units of blood within 24 hours.[2] FWB transfusion almost disappeared from civilian medicine after blood was fractionated into RBCs, fresh frozen plasma (FFP), platelet concentrations (PLT), and cryoprecipitate. Following World War II, blood banks fractionated, stored, and transported blood. Blood products are used as targeted replacement to treat conditions such as anemia, thrombocytopenia, and coagulation factor deficiency. While donated blood is used more economically, unnecessary reactions to transfusion have also decreased. Component therapy is a valuable modality, particularly in the preservation of resources. Due to this advancement, however, whole blood is not typically available at blood banks, and the use of whole blood has become increasingly less frequent in civilian medicine.[3] Meanwhile, transfusion of RBCs, which have extended shelf life, has renewed the study of changes that occur during storage. Multiple studies have identified these biochemical, biomechanical, and immunologic changes, termed “RBC storage lesion.” Intracellular pH, 2,3-diphosphoglycerate, and adenosine triphosphate levels fall within a few weeks of refrigerated storage. In addition, extracellular pH drops, and potassium, free Hb, histamine, interleukin-1, and tumor-necrosis-factor levels rise.[3] Duration of storage affects both transfusion efficacy and associated risks. Selection of treatment method for massive hemorrhage poses an important question, even when blood components are available. Whether FWB is less harmful than blood components that have been stored for prolonged periods is similarly unclear.[3] Red Cell Storage Duration Study (RECESS) Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

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trials have long been ongoing. Their results will demonstrate whether long RBC storage time is harmful.[4] FWB is more concentrated than blood products prepared with a 1:1:1 ratio of RBCs, frozen plasma, and platelets, and is the only functional alternative that includes all fractions. Nessen et al.[5] evaluated the therapeutic role of additional FWB treatment in patients who required platelet replacement after having received RBCs and FFP. It was concluded that administration of FWB increased survival. Spinella et al.[6] compared WFWB and stored blood products in trauma patients with shock and observed that use of long-storage-duration RBCs was associated with increased risk of multiple organ insufficiency and mortality. Patients transfused with WFWB had better chance of 30-day survival, compared to those transfused with stored blood products.[6] Massive transfusion may increase risk of hemorrhage due to presence of anticoagulants and high levels of preservative solutions, which may lead to dilutional coagulopathy within the first 24 hours.[7] WFWB has the several advantages. Risk of hypothermia is reduced, oxygen delivery capacity is maintained in RBCs, and platelets and coagulation factors can be preserved for up to 72 hours. The use of anemic, thrombocytopenic, coagulopathic, and cold blood products with prolonged storage times may increase mortality due to hypothermia, acidosis, anemia, coagulopathy, citrate toxicity, hypocalcemia, and hyperkalemia following massive transfusion.[6] Repine et al.[7] suggested that FWB supported resuscitation and corrected acidosis, hypothermia, and coagulopathy. Perkins et al.[8] compared trauma patients who had received massive transfusions of FWB or PLT and found survival in both groups to be equivalent. According to the authors, although it is too early to suggest that whole blood be used in routine management of civilian trauma, it is an appropriate option when blood components are not accessible. While circumstances in military and civilian life vary, conditions at peripheral hospitals with limited resources can resemble those of the military. WFWB was used out of necessity in the cases described in the present report. FWB is not currently indicated for routine practice. However, it can be a life-saving treatment option when all blood components are needed simultaneously, particularly in low-resource settings.

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The main risks associated with FWB transfusion are transfusion-transmitted infectious diseases, leukocyte-associated acute pulmonary injury, microchimerism, and graft-versushost disease.[9] The risk of transmitted infectious diseases can be decreased with quick tests for HIV, and hepatitis B and C. In conclusion, full clinical recovery was achieved in all 3 patients who received massive transfusions of WFWB. FWB transfusion as an emergency treatment is supported by the literature. In the future, FWB may even be the first choice for massive transfusions, aided by the implementation of fast donor tests, ABO compatibility tests, thrombocyte-sparing leukocyte filters, and developments in pathogen-decreasing technology. New procedures will be revealed in upcoming studies. Conflict of interest: None declared.

REFERENCES 1. Murdock AD, Berséus O, Hervig T, Strandenes G, Lunde TH. Whole blood: the future of traumatic hemorrhagic shock resuscitation. Shock 2014;41 Suppl 1:62–9. 2. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma 2006;60(6 Suppl):91–6. 3. Kaufman R. A fresh take on whole blood. Transfusion 2011;51:230–3. 4. Steiner ME, Assmann SF, Levy JH, Marshall J, Pulkrabek S, Sloan SR, et al. Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7). Transfus Apher Sci 2010;43:107–16. 5. Nessen SC, Eastridge BJ, Cronk D, Craig RM, Berséus O, Ellison R, et al. Fresh whole blood use by forward surgical teams in Afghanistan is associated with improved survival compared to component therapy without platelets. Transfusion 2013;53 Suppl 1:107–113. 6. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma 2009;66(4 Suppl):69–76. 7. Repine TB, Perkins JG, Kauvar DS, Blackborne L. The use of fresh whole blood in massive transfusion. J Trauma 2006;60(6 Suppl):59–69. 8. Perkins JG, Cap AP, Spinella PC, Shorr AF, Beekley AC, Grathwohl KW, et al. Comparison of platelet transfusion as fresh whole blood versus apheresis platelets for massively transfused combat trauma patients (CME). Transfusion 2011;51:242–52. 9. Ho KM, Leonard AD. Lack of effect of unrefrigerated young whole blood transfusion on patient outcomes after massive transfusion in a civilian setting. Transfusion 2011;51:1669–75.

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OLGU SUNUMU - ÖZET

Sıcak taze tam kan masif kanamalı acil durumlarda ilk seçenek olmalı mıdır? Dr. Pınar Kendigelen,1 Dr. Zeynep Kamalak,2 Dr. Deniz Abat3 1 2 3

Afşin Devlet Hastanesi, Anesteziyoloji ve Reanimasyon Kliniği, Kahramanmaraş Afşin Devlet Hastanesi, Kadın Hastalıkları ve Doğum Kliniği, Kahramanmaraş Afşin Devlet Hastanesi, Üroloji Kliniği, Kahramanmaraş

Hızlı masif kanamanın erken yönetimi, kan ürünlerinin erken verilmesi ve hızlı cerrahi kontrolün sağlanmasını gerektirir. Periferik hastaneler kaynak kısıtlılığı nedeniyle askeri koşullara benzer. Kan ürünleri bulunmayan periferik bir hastanede masif kanamayla nedeniyle sıcak taze tam kan (TTK) verdiğimiz üç olgu sunuldu. Olgu1: On altı yaşında kadın hasta acil sezaryana alındı. Uterus atonisi nedeniyle masif kanaması olan hastanın Hb değeri 3.5g/dl’ye kadar düştü. Cerrahi süresince altı ünite sıcak TTK transfüzyonu yapıldıktan sonra, hemodinamik parametreleri ve tam kan sayımı normal düzeye geldi. İki gün yoğun bakımda takibi yapılan hasta, yedinci gün taburcu edildi. Olgu 2: Otuz beş yaşında kadın hasta acil sezaryana alındı. Uterus atonisi nedeniyle masif kanayan hastanın Hb’i 2g/dl, Htc’i %5.4’e kadar düştü. Dokuz ünite sıcak taze tam kan verilen hastanın hemodinamik ve laboratuvar değerleri normal düzeye geldi. Ertesi gün ekstübe edilip üçüncü gün yoğun bakımdan servise çıkarılan hasta sekizinci günde taburcu edildi. Olgu 3: Otuz altı yaşında erkek hasta bıçak yaralanması sonrası hemorajik şokta acil cerrahiye alındı. Hastada sağ renal arter ve böbrek yaralanması vardı. Cerrahi süresince kanamaya devam eden hastaya dokuz ünite sıcak TTK verildi. Cerrahi kontrol sağlanan ve kan transfüzyonu yapılan hastanın hemodinamik parametreleri düzeldi. Beşinci gününde yoğun bakımdan çıkarılan hasta 10. günde taburcu edildi. Kan bileşenlerine ayrılabildiğinden beri sivil tıpta TTK kullanımı neredeyse yoktur. Ayrıca, kan bankalarında tam kan rutin mevcut değildir. Bu nedenle tam kan kullanımı sivil tıpta azalmıştır. Sıcak TTK masif transfüzyonda, kırmızı kan hücrelerini, trombositleri, plazma volümünü, koagülasyon faktörlerini etkili bir şekilde yerine koyarken aynı zamanda hipotermiyi ve dilüsyonel koagülopatiyi önler. Kan ürünleri, uzun depolanma süresince biyokimyasal, biyomekanik ve immünolojik değişikliklere uğrar. Depolama süresi transfüzyon etkinliğini ve transfüzyonla ilişkili riskleri etkiler. Gelecekte hızlı ABO uyumluluğu testleri, trombosit koruyucu lökosit filtreleri ve patojenleri azaltan yeni teknolojilerin kullanımı ile TTK massif transfüzyonda ilk seçim olabilir. Yeni çalışmalar gelecekte yeni prosedürler ortaya çıkaracaktır. Anahtar sözcükler: Masif kanama; masif transfüzyon; sıcak taze tam kan. Ulus Travma Acil Cerrahi Derg 2016;22(2):195–198

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CAS E R EP O RT

A case of delayed carotid cavernous fistula after facial gunshot injury presented as loss of vision with symptom resolution after endovascular closure procedure Fatih Alagöz, M.D.,1 Fevzi Yılmaz, M.D.,2 Bedriye Müge Sönmez, M.D.,2 Ali Erdem Yıldırım, M.D.,1 Muhammed Evvah Karakılıç, M.D.2 1

Department of Neurosurgery, Ankara Numune Training and Research Hospital, Ankara-Turkey

Department of Emergency Medicine, Ankara Numune Training and Research Hospital, Ankara-Turkey

ABSTRACT Carotid cavernous fistulas (CCFs) are abnormal connections between the carotid artery and the cavernous sinus (CS), and can occur as a result of blunt and penetrating head injuries. While occurrence is rare, diagnosis can be made in the emergency department. Described in the present report is the case of a 26-year-old man who presented with complaints of pain, redness, blurred and loss of vision in the right eye, and swelling of the upper face due to a gunshot injury he had sustained 35 days prior. Keywords: Carotid cavernous fistula; endovascular intervention; endovascular treatment; gunshot injury.

INTRODUCTION Post-traumatic carotid cavernous fistulas (CCFs) are direct communications between the internal carotid artery (ICA) and the cavernous sinus (CS), frequently encountered as a complication of closed head trauma, though occurrence has been reported in relation to penetrating object or gunshot injury.[1] CCFs tend to be diagnosed a few weeks after trauma, and the majority of signs and symptoms result from increased venous pressure in an ophthalmic vein that lacks a valve.[2] While CCFs are not life-threatening, timing of diagnosis is extremely important, as permanent loss of vision may develop within hours or days of initial injury. The most common signs and symptoms are pulsatile exophthalmus, orbital murmur, conjunctival hyposphagma, ophthalmoplegia, orbital pain, and impaired visual acuity.[1,3]

Address for correspondence: Fevzi Yılmaz, M.D. Ankara Numune Eğitim ve Araştırma Hastanesi, Acil Tıp Kliniği, Altındağ, 06100 Ankara, Turkey Tel: +90 312 - 508 40 00 E-mail: fevzi_yilmaz2002@yahoo.com Qucik Response Code

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Computed tomography angiography with pathognomonic radiological signs can aid diagnosis and may be used for screening. Precise location of the fistula and nature of the lesion can be studied further with digital subtraction angiography.[4] Endovascular embolization has been the preferred treatment approach throughout the past 2 decades, and surgical treatment remains an option when endovascular treatment fails or is not possible.[5,6] Discussed in the present report is the presentation, pathogenesis, and management of carotid CS fistulas.

CASE REPORT A 26-year-old man presented to emergency services with pain, redness, and blurred and loss of vision in the right eye. Initial complaints were mild and first noted 15 days prior to clinical presentation. History was unremarkable with the exception of a gunshot injury to the face sustained 35 days prior, which had been managed through conservative measures. On physical examination, general status was normal, and scar tissue was noted over the right nasal sulcus, indicating bullet entry. Neurological examination revealed no abnormality. Typical murmur was audible at the right orbit, suggesting diagnosis of CCF. Initial radiographic scans revealed a bullet in the right side of the face (Fig. 1). The patient was referred to ophthalmology, and upon examination, corrected visual acuity 199

Alagöz et al. Carotid cavernous fistula after facial gunshot injury

was 0.3 on the right side and 1.0 on the left. Biomicroscopic evaluation was compatible with eyelid edema, chemosis, proptosis, dilated fixed pupils, and negative light reflex in the right eye. Fundoscopic examination revealed marked venous congestion and increased tortuosity, arteriolar thinning, and preretinal hemorrhages in the right eye. Intraocular pressure measured with tonometry was 34 mmHg in the right eye and 16 mmHg in the left. Color Doppler ultrasonography, orbital tomography with and without contrast on the axial plane, magnetic resonance imaging, magnetic resonance angiography, and digital subtraction angiography confirmed diagnosis of CCF. Examinations revealed fistula between the right ICA and right CS (Fig. 2a). Endovascular treatment was performed via femoral artery access under general anesthesia without complication. Postoperative course was uneventful, and typical murmurs disappeared on auscultation of the orbit. Complaints of pain, redness, and blurred and loss of vision in the right eye markedly improved within 3 weeks of intervention. Postoperative angiographic scans demonstrated complete obliteration of the fistula (Fig. 2b).

Figure 1. AP and lateral X-ray of the head reveal a bullet in the right side, in front of the C1 vertebra.

(a)

(b)

Figure 2. (a) AP digital subtraction angiography shows high-output arteriovenous fistula at the cavernous segment of the right ICA. (b) Fistula appears occluded, and filling pattern of distal segments of the right middle cerebral artery and anterior cerebral artery appear markedly improved on AP angiographic examination following stent-graft procedure.

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DISCUSSION CCFs are identified as direct and abnormal communication between the CS and the ICA, one of its branches, or the external carotid artery.[7] CCFs are rare complications of head trauma, with reported incidence around 0.2–0.3%.[3] Several classifications based on angiographic features (high-flow vs low-flow fistulas), mechanism of onset (spontaneous vs traumatic), morphological features, and angioarchitecture (direct vs indirect fistulas) have been suggested.[8] Drainage pattern and instant development of fistula are typically associated with the signs and symptoms. As a rule of thumb, direct fistulas usually exhibit more dramatic clinical presentation, not infrequently displaying the so-called “classical” triad of exophthalmus, chemosis, and loss of vision. A study of direct CCFs in a large patient series demonstrated that the most common symptoms at initial presentation were orbital bruit (80%), proptosis (72%), chemosis (55%), cranial nerve VI palsy (49%), complete ophthalmoplegia (24%), and loss of vision (18%).[6,9] In agreement with the literature, many of these clinical findings were observed in the present case. CCFs may go undiagnosed after major craniofacial trauma, and eyelid auscultation for potential murmur is an appropriate clinical approach. CCFs are commonly accompanied by diplopia due to etiology of ischemic or compressive mechanical cranial neuropathy, as well as restricted orbital motion inside the eye socket secondary to venous hypertension.[10] Both direct and indirect fistulas with retrograde cortical venous drainage could lead to intracranial bleeding. The latter is a particularly ominous occurrence, with a high rate of rebleeding over a short time in cases of direct CCF. Therefore, appropriate therapy should be initiated at once if such a devastating complication occurs.[11] Computed tomography and magnetic resonance imaging may reveal indirect signs of these fistulas, including engorgement of the CS region or abnormally dilated venous segments. Nevertheless, conventional transluminal angiography remains the gold standard for both detection and typing of CCFs. Complete and technically correct cerebellar angiography should provide information regarding internal and external carotid supply, and delineate contralateral side and posterior circulation.[12,13] In instances of traumatic fistula, intervention is required in urgent conditions such as progressive loss of vision, intolerable murmur, and headache, as well as in cases of traumatic aneurysm showing signs of dilatation behind the CS, hemiplegia secondary to intracranial hematoma, impairment of cortical venous drainage, severe epistaxis, or intraocular pressure exceeding 40 mmHg. Dural sinus fistulas may spontaneously regress in 20–50% of cases. In cases not requiring urgent intervention, carotid jugular compression may be another palliative treatment option.[14] Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Alagöz et al. Carotid cavernous fistula after facial gunshot injury

Modalities described for the treatment of CCFs vary from conservative management, surgical management, stereotactic radiosurgery, and endovascular repair through arterial or venous access. Treatment modality is selected according to type and exact anatomy of the fistula, size of the arterial defect, and operator/institutional preferences.[15,16] In cases of traumatic CCFs, embolization of the fistula by transarterial placement of detachable balloons, platinum coils, polyvinyl alcohol particulates, and liquid embolic agents has become preferred procedure, while combined approaches including stenting, either alone or with coil placement, can also be used.[17,18] While transvenous embolization is the preferred approach in cases of indirect CCF, it also serves as an alternative approach when arterial route has failed in cases of direct CCF.[19] Possible complications of arterial approach include cerebral ischemia or infarction due to displacement of embolic material, and arterial dissection or formation of pseudoaneurysm due to arterial wall injury.[6] Surgical treatment of CCFs must be limited to cases in which endovascular treatment fails or is not possible. Techniques may include the placement of packing inside the CS to occlude the fistula, suturing or clipping the fistula, sealing the fistula with fascia and glue, and/or ligation of the ICA.[18] Described in the present report was a case of traumatic carotid CS fistula successfully treated with advanced radiological techniques and interventions in a short period of time. The potential for occurrence of CCF should be kept in mind following facial gunshot injuries, in an effort to avoid ocular and cerebral complications. Conflict of interest: None declared.

REFERENCES 1. Wallick K 4th, Davidson P, Shockley L. Traumatic carotid cavernous sinus fistula following a gunshot wound to the face. J Emerg Med 1997;15:23–9. 2. Mostafa G, Sing RF, Matthews BD, Heniford BT. Traumatic carotid cavernous fistula. J Am Coll Surg 2002;194:841. 3. Vasconcelos BC, Porto GG, Carneiro SC. Post-trauma exophthal-

mos caused by a carotid-cavernous fistula. Braz J Otorhinolaryngol 2009;75:767. 4. Aissa A, Arous A, Alouini R, Taktak J, Allani M. Ballistic trauma resulting in carotid-cavernous fistula. [Article in French] J Fr Ophtalmol 2012;35:722.e1-4. [Abstract] 5. Kurata A, Takano M, Tokiwa K, Miyasaka Y, Yada K, Kan S. Spontaneous carotid cavernous fistula presenting only with cranial nerve palsies. AJNR Am J Neuroradiol 1993;14:1097–101. 6. Lewis AI, Tomsick TA, Tew JM Jr. Management of 100 consecutive direct carotid-cavernous fistulas: results of treatment with detachable balloons. Neurosurgery 1995;36:239–45. 7. Ringer AJ, Salud L, Tomsick TA. Carotid cavernous fistulas: anatomy, classification, and treatment. Neurosurg Clin N Am 2005;16:279–95. 8. Barrow DL, Spector RH, Braun IF, Landman JA, Tindall SC, Tindall GT. Classification and treatment of spontaneous carotid-cavernous sinus fistulas. J Neurosurg 1985;62:248–56. 9. Jacobson BE, Nesbit GM, Ahuja A, Barnwell SL. Traumatic indirect carotid-cavernous fistula: report of two cases. Neurosurgery 1996;39:1235–8. 10. Debrun GM, Viñuela F, Fox AJ, Davis KR, Ahn HS. Indications for treatment and classification of 132 carotid-cavernous fistulas. Neurosurgery 1988;22:285–9. 11. Argo A, Bono G, Zerbo S, Triolo V, Liotta R, Procaccianti P. Post-traumatic lethal carotid-cavernous fistula. J Forensic Leg Med 2008;15:266–8. 12. Chen YW, Jeng JS, Liu HM, Hwang BS, Lin WH, Yip PK. Carotid and transcranial color-coded duplex sonography in different types of carotidcavernous fistula. Stroke 2000;31:701–6. 13. Ouanounou S, Tomsick TA, Heitsman C, Holland CK. Cavernous sinus and inferior petrosal sinus flow signal on three-dimensional time-offlight MR angiography. AJNR Am J Neuroradiol 1999;20:1476–81. 14. Eggenberger E, Lee AG, Forget TR Jr, Rosenwasser R. A bruital headache and double vision. Surv Ophthalmol 2000;45:147–53. 15. Lu X, Hussain M, Ni L, Huang Q, Zhou F, Gu Z, et al. A comparison of different transarterial embolization techniques for direct carotid cavernous fistulas: a single center experience in 32 patients. J Vasc Interv Neurol 2014;7:35–47. 16. Kupersmith MJ, Berenstein A, Choi IS, Warren F, Flamm E. Management of nontraumatic vascular shunts involving the cavernous sinus. Ophthalmology 1988;95:121–30. 17. Wang W, Li YD, Li MH, Tan HQ, Gu BX, Wang J, et al. Endovascular treatment of post-traumatic direct carotid-cavernous fistulas: A singlecenter experience. J Clin Neurosci 2011;18:24–8. 18. Zhang Z, Wang C, Yang K, Tang J, Zhang C, Xie X, et al. Endovascular embolization of refractory traumatic carotid cavernous fistula with micro-coils: a preliminary experience. Turk Neurosurg 2014;24:190–5. 19. Gemmete JJ, Chaudhary N, Pandey A, Ansari S. Treatment of carotid cavernous fistulas. Curr Treat Options Neurol 2010;12:43–53.

OLGU SUNUMU - ÖZET

Yüz bölgesine ateşli silah yaralanması sonrası görme kaybı ile başvuran ve endovasküler tedavi sonrası semptomları düzelen gecikmiş karotikokavernöz fistül olgusu Dr. Fatih Alagöz,1 Dr. Fevzi Yılmaz,2 Dr. Bedriye Müge Sönmez,2 Dr. Ali Erdem Yıldırım,1 Dr. Muhammed Evvah Karakılıç2 1 2

Ankara Numune Eğitim ve Araştırma Hastanesi, Beyin Cerrahisi Kliniği, Ankara Ankara Numune Eğitim ve Araştırma Hastanesi, Acil Tıp Kliniği, Ankara

Karotit kavernöz fistüller karotis arter ve kavernöz sinüs arasındaki anormal bağlantılardır. Künt ve penetran kafa yaralanmaları karotikokavernöz fistül ile sonuçlanabilir. Her ne kadar nadir olarak ortaya çıksa da tanısı acil serviste konabilir. Bu yazıda, 35 gün önce yüzüne ateşli silah yaralanmasından sonra sağ gözünde kızarıklık, ağrı, görmede bulanıklık, görme kaybı ve yüzün üst yarısında şişme şikayeti ile acil servise başvuran 26 yaşındaki hasta sunuldu. Anahtar sözcükler: Ateşli silah yaralanması; endovasküler girişim; endovasküler tedavi; karotid kavernöz fistül. Ulus Travma Acil Cerrahi Derg 2016;22(2):199–201

doi: 10.5505/tjtes.2015.18234

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CA S E REP OR T

A different approach to simultaneously injured ulnar and radial arteries: Translocation of an arterial segment Hamit Serdar Başbuğ, M.D., Macit Bitargil, M.D., Kanat Özışık, M.D. Department of Cardiovascular Surgery, Kafkas University Faculty of Medicine, Kars-Turkey

ABSTRACT Upper-extremity arterial injury is a common and serious condition that may lead to amputation if improperly treated. Ligation of the ulnar or radial artery is frequently performed by vascular surgeons as a method of treatment, which should be avoided, particularly if the radial and ulnar arteries were both injured. A different approach to reconstruction is described in the present report. Keywords: Radial artery; ulnar artery; vascular injury.

INTRODUCTION

CASE REPORT

Upper-extremity vascular traumas comprise 30% of all peripheral vascular traumas, while vascular traumas comprise 1–3% of all injuries.[1] Among vascular traumas, blunt traumas comprise 2–9%; penetrating traumas comprise the majority. [2] Regarding the etiology of peripheral vascular injuries, traffic accidents, gunshot wounds, penetrating injuries, self-mutilation, and industrial injuries comprise most cases.[3] Prompt diagnosis and treatment are essential to the reduction of further morbidity and mortality.[4] In cases of upper-extremity vascular injury, hypovolemic shock, acute ischemia, and neurological deficit may frequently be encountered as acute manifestations, potentially leading to permanent damage and amputation. Arteriovenous fistula and pseudoaneurism may develop as chronic complications.[5] Distal pulses are palpable in 25% of brachial artery injuries and 50% of isolated radial or ulnar artery injuries, due to flow via collateral circulation.[6] Thus, detailed inspection of the injury site and evaluation of arterial currents with Duplex ultrasound (DUS) are essential for precise diagnosis.[5] Described in the present report is a different approach to surgical treatment in the rare circumstance that both the radial and ulnar arteries were injured.

A 62-year-old male was admitted to emergency services with a penetrating injury to his left forearm, sustained in an industrial accident in which a scroll saw cut to the left wrist caused massive trauma, with irregular laceration of the skin, muscles, and palmaris longus tendon. No neurologic motor deficit excluded median or radial nerve damage. Distal pulses, including those of the radial and ulnar arteries, were nonpalpable, with no active hemorrhage due to vasospasm. DUS images revealed interrupted currents in both the radial and ulnar arteries, which are otherwise superiorly triphasic, at the site of trauma.

Address for correspondence: Hamit Serdar Başbuğ, M.D. Kafkas Üniversitesi Tıp Fakültesi, Kalp ve Damar Cerrahisi Anabilim Dalı, Paşaçayırı, 36100 Kars, Turkey Tel: +90 474 - 225 11 49 E-mail: s_basbug@hotmail.com Qucik Response Code

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The patient was transferred to surgery with normal vital signs and normal complete blood count. Surgical exploration under regional anesthesia revealed a smooth cut of the ulnar artery, while the radial artery was torn, with a 2.5-cm segmental defect. An excessive portion of the ulnar artery was suitable for end-to-end anastomosis (Fig. 1a). However, the radial artery required the interposition of a conduit, as approximation was impossible due to long-segment loss. While preparing to harvest a piece of the saphenous vein to replace the defective portion of the radial artery, an excessive 2-cm portion of the ulnar artery was noted. This portion was resected and examined for intimal injury before being prepared as an autologous conduit for the deficient segment of the radial artery. The portion of the ulnar artery was then transferred to replace the deficient segment of the radial artery as an autologous conduit, and was successfully interposed and sutured end-to-end (Fig. 1b). The ends of the ulnar artery were then repaired, also with end-to-end anastomosis. Distal pulses became palpable in both arteries. In addition, DUS revealed triphasic patterns in both arterial segments distal to the reconstruction. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Başbuğ et al. A different approach to simultaneously injured ulnar and radial arteries: Translocation of an arterial segment

(a)

(b)

Figure 1. (a) Excess length of the clear-cut ulnar artery. (a) Repaired radial artery with ulnar segment interposition.

In anastomosis of both arterial repairs, 8–0 polypropylene sutures and 8-mm needles were used. Tendons and muscles were repaired with Vicryl sutures (Ethicon, Somerville, NJ, USA), and the skin was approximated as far as possible due to massive skin tissue loss. Surgery was concluded following complete revascularization and reconstitution of original circulation of the hand. First-generation cephalosporin (cefazolin sodium) and low-molecular-weight heparin (enoxaparin) were administered during the early postoperative period. The patient was discharged on the fifth postoperative day with patent radial and ulnar circulation verified by DUS imaging. No postoperative complication occurred. The patient was prescribed acetylsalicylic acid (100 mg/day) and scheduled for follow-up on the tenth day following discharge.

DISCUSSION Early diagnosis and prompt surgical intervention in arterial injuries of the elbow play an important role in preventing serious complication. Detailed physical examination and DUS imaging are required for diagnosis. Palpation of the peripheral pulse may be specious, as the spasmed arteries often maintain pulsatility when interrupted. Moreover, when blood pressure is below 60 mmHg, no pulsation can be transmitted to the distal vasculature.[7] Accordingly, massive arterial hemorrhage may not be apparent, as the cut end of the artery is typically spasmed. This may not exclude the possibility of vascular injury, and DUS imaging should be performed. DUS imaging has a specificity of 95% and a sensitivity of 99% in vascular injuries.[8] If a further investigation is necessary, contrast-injected computerized tomography may be terminally performed.[9] Revascularization of the interrupted artery should be performed rapidly during the critical ischemic period (4 hours following the event for proximal injuries, 12 hours following the event for distal injuries).[10] If this period is exceeded, amputation due to necrosis of the extremity should be taken into consideration. Ulus Travma Acil Cerrahi Derg, March 2016, Vol. 22, No. 2

Simultaneous interruption of both the radial and ulnar arteries occurs in only 4% of upper-extremity injuries; it is a very rare condition. Radial or ulnar artery damage occurs in 53% of upper-extremity injuries, damage to the brachial artery occurs in (36%), damage to the axillary artery in (5%) and damage to the subclavian artery in (4%).[11] Surgical techniques for primary repair include ligation, approximation (end-to-end anastomosis), and primary suturing, while techniques for secondary repair include graft interposition (either autologous or prosthetic) and patch plasty.[6] Secondary repair to the radial artery and primary repair to the ulnar artery were performed in the present case. Under more typical circumstances, the radial artery could have been ligated or reconstructed using an autologous graft from the saphenous or cephalic veins, rather than that of an ulnar artery segment. However, harvesting the saphenous vein would have caused additional interventional trauma, and the cephalic vein was unsuitable, as it had also been injured. The clear-cut ulnar artery was elongated, possibly due to traumatic stripping from the surrounding tissue, and offered the necessary length. Fortunately, this excess segment revealed no intimal injury and could be used as an intact graft. In conclusion, trauma to arteries in the elbow should be fully repaired, either by primary or secondary means, if possible. Ligation may be tolerated due to collateral circulation of the palmar arch, but should be reserved as a final option. Simultaneous radial and ulnar injuries are uncommon and require efficient, effective treatment. Conflict of interest: None declared.

REFERENCES 1. Weaves FA, Hood DB, Yelkin AE. Vascular injuries of the extremities. In: Rutherford RB, editor. Vascular surgery. Philadelphia: Saunders Company; 2000. p. 862–72. 2. Taşdemir K, Oğuzkaya F, Kahraman C, Ceyran H, Emiroğulları Ön,

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3. 4.

Yasım A. Upper extremity artery injuries. Turk Gogus Kalp Dama 1997;5:218–22. Tor F, Çakır H, Yıldız G, Özsöyler İ. Our Experience on Peripheral Vascular Trauma. Çukurova Üniversitesi Tıp Fakültesi Dergisi 2012;37:193–7. de Silva W, Ubayasiri R, Weerasinghe C, Wijeyaratne S. Challenges in the management of extremity vascular injuries: A wartime experience from a tertiary centre in Sri Lanka. World J Emerg Surg 2011;6:24. Tatar H, Öz BS, Şirin G, Akay HT, İyem H, Şarkışlalı K ve ark. Üst ekstremite damar yaralanmaları: cerrahi deneyimlerimiz. Turkish J Vasc Surg 2006;15:11–5. Lowrie AG, Berry MG, Kirkpatrick JJ, Lees VC, McGrouther DA. Arterial injuries at the elbow carry a high risk of muscle necrosis and warrant urgent revascularisation. Ann R Coll Surg Engl 2012;94:124–8. Popescu GI, Lupescu O, Nagea M, Patru C. Diagnosis and treatment of

limb fractures associated with acute peripheral ischemia. Chirurgia (Bucur) 2013;108:700–5. 8. Gürbüz A, Ergüneş K, Yılık L, Özbek C, Karahan N, Bayatlı K ve ark. Travmatik üst ekstremite arteryel yaralanmaları. Turkish J Vasc Surg 2006;15:39–44. 9. Van Waes OJ, Navsaria PH, Verschuren RC, Vroon LC, Van Lieshout EM, Halm JA, et al. Management of penetrating injuries of the upper extremities. Ulus Travma Acil Cerrahi Derg 2013;19:405–10. 10. Topal AE, Eren MN. Gradually increasing predominance of self-mutilation in upper extremity arterial injuries: less morbidity but with high threat to society. Ulus Travma Acil Cerrahi Derg 2010;16:527–31. 11. Ünlü Y, Vural U, Özyazıcıoğlu A, Ceviz M, Karapolat S, Koçak H. Upper Extremity Vascular Injuries (The Evaluation of 98 Cases). Turk Gogus Kalp Damar Cer Derg 1998;6:318–22.

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Birlikte yaralanmış ulnar ve radial arter onarımına farklı bir yaklaşım: Arteriyel segment translokasyonu Dr. Hamit Serdar Başbuğ, Dr. Macit Bitargil, Dr. Kanat Özışık Kafkas Üniversitesi Tıp Fakültesi, Kalp ve Damar Cerrahisi Anabilim Dalı, Kars

Üst ekstremite arter yaralanmaları, yaygın görülen ve ciddi bir durumdur ve eğer doğru tedavi edilmezse ekstremiteyi amputasyona kadar götürebilir. Radial ya da ulnar arterin bağlanması, vasküler cerahlar tarafından sıkça uygulanan bir tedavi metotudur. Eğer radial ve ulnar arterler her ikisi birden yaralanmışsa, bundan özellikle kaçınmak gerekir. Bu olguda, birlikte yaralanmış radial ve ulnar arterin tamirine yönelik farklı bir yaklaşım sunuldu. Anahtar sözcükler: Radial arter; ulnar arter; vasküler yaralanma. Ulus Travma Acil Cerrahi Derg 2016;22(2):202–204

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