Archives of the Balkan Medical Union vol. 50, no. 3, pp. 379-385 Copyright © 2015 CELSIUS September 2015

REVIEW

ETHIOPATHOGENIC CORRELATIONS AND TREATMENT MEANS IN UPPER NON-VARICOSE GASTROINTESTINAL BLEEDINGS

C. BÃLÃLÃU1, R.V. SCÃUNAÆU2, I. MOTOFEI1, N. BACALBAÆA1, V. D. CONSTANTIN1, O.D. BÃLÃLÃU3, A. STÃNESCU3 1Department of General Surgery, University of Medicine “Carol Davila”, Emergency Universitary Hospital “St. Pantelimon”, Bucharest 2Department of General Surgery, University of Medicine “Carol Davila”, Colåea Clinical Hospital, Bucharest 3St. John Emergency Hospital, Bucur Maternity, Bucharest

SUMMARY RÉSUMÉ

Applying the scores according to the ethiopthogenesis of the upper Corrélations étiopathogéniques et modalités de traitement gastrointestinal bleeding. Influencing the medication and surgical dans les saignements gastro-intestinaux supérieurs de nature treatment according to prognosis. Development of a prognosis non-variqueuse score modified for assessing the need or not for admission of some patients belonging to different risk groups, performing endoscopy L’application des scores en fonction de l’éthiopthogenèse du saigne- or blood transfusions in patients with upper gastrointestinal ment gastro-intestinal supérieur. Influencer le médicament et le bleeding of non-varicose origin. Prospective study on patients with traitement chirurgical selon les prévisions. Le développement d'un upper non- varicose gastrointestinal bleeding, the group approxi- pronostic du score modifié afin d’évaluer la nécessité ou non de mation being made based on the retrospective data gathered from l'admission de certains patients appartenant à différents groupes de the Emergency Department statistics and compared to the Surgery risque, à l’endoscopie ou aux transfusions sanguines des patients and Departments discharge documents. présentant un saignement gastro-intestinal supérieur d'origine non Key words: Upper gastrointestinal bleeding, ethiopathogenesis, variqueuse. L’étude prospective sur des patients atteints de treatment, Rockhall score saignement gastro-intestinal supérieur d’origine non variqueuse, l’évaluation du groupe étant faite à base de données rétrospectives recueillies des statistiques du Département d'urgence et rapportées aux documents des Départements de Chirurgie et de Gastro-entérologie. Mots-clés: saignement gastro-intestinal supérieur, éthiopatho- genèse, traitement, score Rockhal

INTRODUCTION nal bleeding in certain risk group and validating the results using endoscopy, will decrease the morbidity and mortality orrelation ofthe ethiopathogenesis and medical rates, the days of hospitalization and implicitly the costs, and and surgical treatment means. Outline the will even replace an useless hospitalization with the CC prognosis based on the upper gastrointestinal performance of some ambulatory additional investigation bleeding causes and influence it according to treatment. (endoscopy) for patients belonging to 0 risk group. Assess- Evaluating and fitting the patients with upper gastrointesti- ment of the influence exerted by the socio-economical or

Correspondence address: Scãunaæu Rãzvan Valentin, MD. Department of General Surgery, University of Medicine “Carol Davila”, Colåea Clinical Hospital, Bucharest, Romania e-mail: [email protected] ETHIOPATHOGENIC CORRELATIONS AND TREATMENT MEANS IN GASTROINTESTINAL BLEEDINGS - BÃLÃLÃU et al vol. 50, no. 3, 380 ethnical factors on the treatment and obtained results The age and the presence of comorbidities are the (morbidity, mortality). main factors that significantly influence the morbidity in Collection and multi-disciplinary statistical analysis upper gastrointestinal bleeding.[4,5] With age, the (medical, social, economical) of data, in order to identify frequency of hemorrhagic episodes increases significantly. some correlations, models or tendencies, which may be It has been noted that the risk of upper gastrointestinal utilized to the benefit of public health politics reform or bleeding among people older than 70 years, exceeds 20-30 prioritization. times that of people younger than 30 years.[4,5] Another cause may be the change of upper gastro- Ethiopathogenic correlations and treatment means in intestinal bleeding etiology. CORI’s (Clinical Outcome upper non-varicose upper gastrointestinal bleedings Research Initiative) data show the ratio change 2/3 duo- denal ulcer and 1/3 gastric ulcer in 56% gastric ulcers and Epidemiology 44% duodenal ulcers, gastric ulcers evaluating more Causes of upper gastrointestinal bleeding severely comparing with duodenal ulcer. Regarding the study realized under the guidance of the Treatment Romania Society of Digestive Endoscopy, in Romania Prognostic scores there is a reduced mortality caused by non-varicose supe- rior gastrointestinal bleeding (2.6%). The proportion of Upper gastrointestinal bleeding is defined as an extrava- non-varicose upper gastrointestinal bleedings from the sation of blood, originating from the upper digestive tract, total number hemorrhages, was 74.7%, the most frequent located above Treitz angle. cause being the duodenal ulcer, followed by: gastric ulcer, erosive gastroduodenitis, reflux esophagitis, Mallory Weiss Epidemiology syndrome, neoplasias.[6] The upper gastrointestinal bleeding represents a medico- Causes of upper gastrointestinal bleeding surgical emergency and also a very frequently encountered worldwide pathology, being accompanied by a high It has been noted that the most frequent cause is rep- incidence of complications and by a high rate of mortality. resented by the duodenal ulcer in proportion of 40%, fol- It is recorded an incidence of 48-160 cases per 100000 lowed by the gastric ulcer in approximately 10-20% of people per year and a mortality rate which varies between 3- cases, diffuse gastritis 15-20%, 10%, 12% with great differences between countries: USA 3.3%, Mallory-Weiss syndrome 10%,gastric carcinoma less than UK 7.4%, Hong Kong 7.1%, Japan 1.1%, Italy 6.9%, 5%.[1][2][3]. Denmark 11%.[4] It’s been proved that patients do not die Gastric and duodenal ulcer because of the hemorrhage, but because of the associated comorbidities. These difference may be owed to risk factors Despite of the numerous possibilities of medicamentous that depend on the patient, on the disease’s severity and on and endoscopic management, the duodenal ulcer continues the health systems. Many studies have reported a decrease of to be a frequent cause of upper gastrointestinal bleeding. incidence and mortality. [10,11] Hemorrhages caused by ulcer need surgical intervention in

Table I - Digestive diseases

Esophageal - esophageal varices, benign and malignant tumors, esophageal ulcer, erosive esophagitis, diverticula - trauma caused by foreign bodies or iatrogenic (endoscopic explorations, biopsies, instrumental dilatation) Mallory-Weiss syndrome Gastroduodenal - ulcer, acute and hemorrhagic chronic gastritis, duodenitis, Menetrier’s disease - hiatal hernia, benign and malignant tumors, diverticula - gastric or duodenal mucosa prolapse - trauma caused by foreign bodies or by endoscopy - infections (fungal, CMV, TBC, syphilis), ampula of Vater’s tumor, Crohn’s disease - gastric volvulus, irradiation gastritis

Table 2 - Other digestive diseases

- hepatic , splenopathies, portal , splenic thrombosis - suprahepatic obstruction or thrombosis (Budd Chiari syndrome) - hemobilia- bleeding’s cause may be hepatobiliary (trauma, hepatic artery broken , biliary duct trauma) or pancreatic (acute or chronic pancreatitis, tumors) - heterotopic gastric or pancreatic tissue, hemorrhagic celiac disease Archives of the Balkan Medical Union September 2015, 381

Table 3 - Extradigestive diseases

Hemopathies - idiopathic thrombocytopenic purpura, hemophilia, Henoch purpura - allergic purpura, policitemia vera, hemophilia, leukemia, Hodgkin disease - hypoprothrombinemia, hypofibrinogenemia, fibrinolisis - Glanzmann thrombastenia, pernicious anemia, Von Willebrand disease Vasculopathies - arterial , aorto-enteric fistula, mesenteric or hepatic artery aneurysm, Rendu-Osler disease (hereditary hemorrhagic telangiectesia) - hemangiomas, intestinal varices, Systemic diseases - polyarteritis nodosa, sarcoidosis, multiple myeloma, amyloidosis - systemic lupus erythematosus, Ehler-Danlos syndrome, pseudoxantoma elasticum -scurvy Renal diseases - those accompanied by uremia

4.3% of cases and hospital readmissions in 4.7% of cases [7]. gastrointestinal hemorrhage have mucosal (polyps) or The mortality is high but it varies between different muscular layer (leiomyomas) origin. They have in common countries: Canada 8.5%, Korea 2.2%, USA 2.5%, Turkey the fact that are diagnosed at middle age and are more 2.8%, Spain 3.1%, Sweden 6.2%, Denmark 11% and frequently located in gastric body or antrum. They may Holland 14%. prolapse in lumen, or on the contrary, they may develop out- The heterogeneity may be explained by the different wards. Small ulcerations orientated towards stomach lumen, prevalence of comorbidities, by the availability of endoscopy may develop on their surface. From shallow ulcerations and by the usage of pharmacotherapy [10]. Some studies occult hemorrhages may produce which can frequently lead showed that the incidence had decreased and had stabilized. to iron deficiency anemia, while massive ulcerations may For example, in Sweden, the incidence decreased from cause massive hemorrhage but also gastric ulcer like pain [3]. 64/100.000 in 1996 to 35/100.000 in 2014 and in Spain, Erosive gastritis from 55/100.000 to 25/100.000[8]. This decrease may be partially explained by the prevalence’s decrease of It’s defined by multiple gastroduodenal mucosal defects. Helicobacter Pylori [9]. Commonly, stress lesions are localized in the fundic and Duodenal ulcers have a more severe prognostic compared corporeal region of stomach, while the hemorrhagic gastritis to gastric ulcers, being associated to a higher rate of conditioned by the usage of NSAIDs, and affects the entire mortality, hospital readmission and surgical reintervention gastric mucosa, inclusively antral region. Erosive gastritis [11,12], probably because they are less endoscopically acces- may result in severe acute hemorrhage [3]. sible, especially in rural areas [13,14]. It has been noticed that the upper gastrointestinal hemorrhage caused by ulcer, Mallory-Weiss syndrome is accompanied by a more important blood loss, the In this case, the bleeding produces because of a linear conservative therapy and endoscopy have a lower efficacy laceration of the esophagogastric mucosa junction [15]. It and a higher necessity of surgical treatment, compared to most frequently appears in men with ages of 50-70 years, other ways of treatment [3]. alcohol, acetylsalicylic acid or both consumers [17]. Among the rarer causes that can lead to the onset of the syndrome, Gastroesophageal reflux the most popular are: anorexia, prolonged cough, epileptic When a massive hemorrhage appears in patient suffering convulsions, abdominal trauma, pregnancy and birth. Most from gastroesophageal reflux disease, this is most likely caused of the patients initially have vomiting with gastric content, by a penetrating esophageal ulcer, often distally localized. It subsequently having vomiting with blood [15,16]. has been observed that ordinarily, the esophageal ulcer Most of the gastric cardial region hemorrhages stop by develops from metaplasic epithelium and is localized at the themselves while in the other patients, therapeutic border between normal epithelium and cylindrical Barrett endoscopy represents the elective method, surgery being epithelium. A particular form of upper gastrointestinal bleed- reserved only for recurrences and transmural ruptures. The ing is that produced by an ulcer associated with a diaphrag- most efficient method is the guided through catheter matic hernia of the esophageal hiatus, also called Cameron angiographic embolization with gelfoam. Lethality in ulcer. It’s supposed that the triggering mechanism of these Mallory-Weiss syndrome constitutes 3-4%[15,3]. Some lesions is represented by local trauma and gastric wall studies have shown that the endoscopic evidence of active ischemia at diaphragm level. Frequently, the ulcer may remain bleeding and the shock as first manifestation, are risk undiagnosed [3]. factors for syndrome recurrence [18,19]. Tumors Watermelon stomach (antral vascular ectasia) It has been observed that in majority of cases, the most It represents about 4% of the cases of occult digestive frequent gastroduodenal benign tumors which cause upper hemorrhage, the main symptoms of patients being melena ETHIOPATHOGENIC CORRELATIONS AND TREATMENT MEANS IN GASTROINTESTINAL BLEEDINGS - BÃLÃLÃU et al vol. 50, no. 3, 382 and chronic anemia [20]. The affection appears more tion through puncture of clot forming promoters or absorbent frequently in old women and is characterized by multiple gelatins Gelafoam[34].The aim of the treatment is to stop dilated capillaries and corrugated vessels in the antral the bleeding and to reestablish the flow through the bile portion, which longitudinally cross the stomach towards ducts.The most efficient method is the angiography with pylorus [3]. embolization. Other methods include endoscopic sphinc- Medication may be applied using tranexamic acid, corti- terectomy and electrocoagulation. Surgery is required for the cotherapy, thalidomide, interferon, calcitonin, estroproges- cases of hepatic trauma, when debridement, drainage and teronic combinations or serotonin antagonists[21-25]. Endo- vessel ligation are necessary. It also has to be considered in scopic methods include sclerotherapy, thermocoagulation, cases of cholelithiasis, cholecystitis and resectable neoplasms. endoscopic resection, banding [26]. Argon plasma coagula- Although the surgical treatment is efficient in stopping tion, is the preferred method [3,26]. The surgical treatment hemobilia when the transcatheter embolization failed, this is reserved to severe cases. doesn’t rich the embolizations’s efficacy if used as first way of treatment[31]. Among the complications of transcatheter Dieulafoy lesion embolization, are the hepatobilary necrosis (6%), the forma- Frequently occurs in the proximal portion of the tion of abscesses (9%) and the bleeding (6%)[31,32,33]. stomach, close to the esogastric junction or on the small Pancreatic pseudocyst and curvature of the stomach and represents about 1-2% of the upper gastrointestinal bleeding causes [26,27]. Its source is They represent a rare cause, digestive hemorrhages pro- represented by the rupture of an artery belonging to the ducing in 10-15% of the patients with chronic pancreatitis gastroduodenal wall submucosa, with an unusual large and in 6-30% of those who develop pseudocyst. In case of an diameter (1-3 mm) and localized superficially in relation acute pancreatitis or in case of an due to a to the mucosa. Many patients are also NSAIDs con- chronic pancreatitis, the visceral may be injured, sumers, oral anticoagulants or aspirin, alcohol, which may causing a pseudoaneurysm.Bleeding’s control may be contribute to the onset of bleeding. Before the usage of obtained by radiological methods (bleeding’s source endoscopy, the mortality had been of 80% but it decreased embolization – the celiac trunk or the superior mesenteric to 0-22%. The treatment combines endoscopic methods, artery) or by surgical ones, in hemodynamically unstable injection of norepinephrine, of sclerosing agents, thermal patients. The studies have shown that a higher mortality in coagulation, laser photocoagulation, banding, hemoclips the pathology of acute pancreatitis 60% versus 22% in the etc. the recurrence is treated either in the same way as the case of chronic pathology, 43% in the case of cephalic first event, or surgically, by local excision or suture [3,27]. localized lesions[39,40]. Aorto-intestinal fistula Prognostic scores It represents communications between aorta and In emergency, it is necessary to sort the patients with . There are known two types. The acute upper gastrointestinal bleeding, to quickly recognize primary form is the most frequent and is produced by the those patients who immediately need endoscopic explo- rupture of an aneurysm of the abdominal aorta in the ration, to predict the possibility of appearance of a new intestinal lumen[3]. The secondary form has an incidence bleeding and to choose the best treatment option. In order of 1-4% and appears between the suture line of a vascular to achieve these goals, before performing any laboratory graft and bowel, after a long interval from the surgical investigations, there may be used different variables, upon intervention of vascular reconstruction [3,28]. In unstable which, have been realized scores and classifications. hemodynamic patients, the emergency laparotomy is Blatchford score is based on this clinical and laboratory necessary. Even in those who undergo a reintervention, information, being used for predicting medical intervention the mortality is of 60%[3,29]. of some kind. It consists of a scale of 0-23 points and the lowest score signifies the highest risk. Hemobilia Rockall score is the most frequently used score in order to It’s among the less frequent sources of upper gastro- stratify the risk of upper gastrointestinal hemorrhage. It is intestinal bleeding and it appears when there is a fistula calculated on the basis of the patient’s clinical parameters between vascular structures and the intrahepatic and extra- during his presentation to the hospital. Complete Rockhall hepatic biliary ducts. The most frequent causes are the iatro- score associates both clinical observations and endoscopic genic and traumatic ones, in 50% of cases. Other causes are criteria in order to determine the risk of a rebleeding or even the hepatic and biliary neoplasms, , vascular of death caused by bleeding. The score may be between 0 and causes, intrahepatic abscesses, choledocolithiasis and 11, 11 representing the highest risk. cholelithiasis. The patient presents for biliary (70%) of cases, Treatment jaundice (60%), digestive bleeding (100%), those composing Quincke triad which is present in 32-40% of cases [30,31]. Upper digestive hemorrhage needs emergency evaluation The bleeding may spontaneously stop in patients who and immediate treatment. Acid secretion suppression, endo- have undergone percutaneous angiography or hepatic scopic hemostasis techniques and H. Pylori identification as biopsy. Some authors recommend prophylactic administra- etiology have improved the treatment in superior digestive Archives of the Balkan Medical Union September 2015, 383 hemorrhage. Nevertheless, the upper gastrointestinal the necessity of transfusion, the need of surgery and the bleedings have a high degree of mortality and morbidity. duration of hospitalization. Yet, it hasn’t been proved an Neoadjuvant therapy with proton pump inhibitors have impact upon mortality [45,50,51]. The guides recommend become the empirical standard treatment for superior the use of proton pump inhibitors intravenously 3 days digestive hemorrhages because their main cause is the gastric after haemostatic endoscopy. In many studies, the ulcer. It have been proved that their administration doesn’t increased dose of proton pump inhibitors is defined as an affect the bleeding risk or the mortality, the last remaining initial bolus of omeprazol 80 mg, followed by continuous between 7-14% in the USA. perfusion of omeprazol 8 mg/h up to 72 hours [42]. For hemodynamically unstable patients the main goal Endoscopic evaluation represents an essential part in the of the initial management is the hydroelectrolitic and management of superior digestive hemorrhage. Emergency volume rebalancing. Risk stratification of patients is made endoscopy has been proposed as standard method in patients according to clinical and endoscopic criteria. Unfavorable with high-risk lesions, but the execution moment is variably prognostic predictors include: age >65 years, shock, defined. The American Society of Gastrointestinal malaise, associated comorbidities, decreased hemo- Endoscopy suggests that precocious endoscopy (in 24 hours) globin/hematocrit levels at presentation, active bleeding, is the most efficient, but has no recommendations regarding sepsis, increased creatinine and transaminases levels the exact moment which should be chosen in this interval of [42,43,44]. 24 h [52]. The optimum moment for endoscopy is frequently More studies have tried to find an answer to these debated. After volume resuscitation and hemodynamic questions. In a study of Sarin, endoscopy was effectuated stabilization, the endoscopy should be made in 24 hours in in 500 patients, in more time intervals: <6h, 6-24h and all patients with signs of upper gastrointestinal bleeding, >24h. There was no significant difference in mortality or with both diagnostic and therapeutic purposes. Based on the the need for surgery between the groups of <6h and 6- endoscopy, it can be taken the decision of sending home 24h, but there was a difference between the groups of those low-risk patients or hospitalizing those with severe <24h and>24h [53]. lesions, for diagnostic and further treatment. The concurrent The endoscopic techniques include 1) pharmacologic treatment with NSAIDs and antiplatelet agents like therapy, which presumes the injection of epinephrine, clopidogrel impact the etiology and the severity [42,43]. sclerosing substances, saline solution 2) clotting techniques There are some scores used for this purpose: APACHE II, which include mono or bipolar cauterization or plasma argon Forrest Classification, Blatchford, Rockall, Baylor, Cedars- coagulation 3) mechanical techniques which comprise Sinai Medical Center [46,47]. hemoclips and banding. Each of these is efficient in different Theoretically, the presence of fresh red blood in the naso- clinical situations. gastric suction probe, suggests active bleeding and necessi- Usually the choice is made basing on the clinical tates emergency esophagogastroduodenoscopy, while the judgment and experience. There are data which suggest that absence of blood in the nasogastric suction probe doesn’t epinephrine injection and a second endoscopic intervention exclude the superior digestive hemorrhage. According to a is superior than administering only epinephrine. Even if study realized by Aljebreen, 15% of the patients without endoscopy cannot realize ultimate hemostasis, it may have an blood in the nasogastric suction probe had upper gastro- important part in localizing the bleeding source and in intestinal bleeding [45]. Acid gastric secretion suppression choosing a non-endoscopic technique. Endoscopy repeat may has to be done using proton pump inhibitors, these offering assist the radiologic or surgical intervention. Second-look a better gastric secretion suppression than antihistamine, endoscopy decreases the rate of rebleeding but not also the which determines tachyphylaxis. risk of mortality or the necessity of surgery. Proton pump inhibitors administration as neoadjuvant Blood in the superior digestive tract limits the ability of treatment before endoscopic therapy is frequently recom- endoscopy to identify the bleeding source. Prokinetic agents mended, especially when the immediate access to endoscopy stimulate the gastrointestinal tract’s motility. American is limited [42]. It’s uncertain if the proton pump inhibitors Society of Gastroenterology recommends the use of administration before endoscopy influences the clinical erythromycin intravenously before endoscopy [52]. A recent evolution. One study had compared the administration of meta-analysis shows that it can also be used metroclopramide, proton pump inhibitors versus placebo before endoscopy and but none of them doesn’t influence the number of transfused revealed that a smaller number of the patients receiving blood units, the hospitalization period or the need of surgical proton pump inhibitors, had had active bleeding during intervention [55,56]. endoscopy. There were no significant differences regarding Long-term treatment with proton pump inhibitors is the rate of rebleeding, the necessity of surgical intervention, recommended for 6-8 weeks after endoscopy in order to allow or the mortality at 30 days. A meta-analysis has proved that mucosal healing. Some studies revealed proton pump neoadjuvant administration (before endoscopy) of proton inhibitors benefits in patients who use NSAIDs or to whom pump inhibitors, has no benefit upon decreasing the risk of the presence of H. Pylori had been confirmed. Other bleeding, necessity of surgery or mortality [49]. studies have tried to prove that proton pump inhibitors Adjuvant therapy administered after diagnostic and may have a role in secondary prevention in patients therapeutic endoscopy has proved efficient in decreasing belonging to these two categories [57]. Although is has ETHIOPATHOGENIC CORRELATIONS AND TREATMENT MEANS IN GASTROINTESTINAL BLEEDINGS - BÃLÃLÃU et al vol. 50, no. 3, 384 numerous benefits, it’s not completely risk-free. Chronic REFERENCES administration is associated with Clostridium Difficile infection, community-acquired pneumonia, calcium 1. Beuran Mircea, Manual de Chirurgie , volumul II, pg [899- malabsorbtion and risk of fracture [41,58]. 909] 2. Prof. Dr. Nicolae Angelescu Patologie chirurgicala pentru Emergency surgery or transcatheter embolization admitere in rezidentiat volumul 1, Editura Celsius, Bucuresti represent treatment options for recurrent or refractory 1997 pg [116-131] hemorrhage. 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