Украинский журнал хирургии 4 (19) 2012
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Features of Antisecretory Therapy in Patients with Bleeding Peptic Ulcers of The Upper Digestive Tract
Авторы: Radenko E.E., Donetsk National Medical University, named after M. Gorky
Рубрики: Хирургия
Разделы: Клинические исследования
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The analysis of treatment outcomes in 1369 patients with bleeding peptic ulcers of the upper digestive tract for the period from 2008 to 2011 was carried out. All patients underwent individually rational tactics. The features of acid suppressive therapy were studied. From 2008 to 2010 the number of recurrent bleeding increased from 8.9 to 10.6 %. Сorrelation between the increase in the number of recurrent bleeding and the composition of acid-suppressive drugs was noted. Proton pump inhibitors (PPIs) compose the control group for acid suppressive therapy. It is proved that efficiency of acid suppressive therapy has considerably increased in combination of two groups of drugs — PPIs and histamine H2-receptor blockers, thus reducing the number of recurrent bleeding from 10.6 to 9.1 %.
Проведен анализ результатов лечения 1369 пациентов с кровотечением, осложнившим пептические язвы верхних отделов пищеварительного канала, за период с 2008 по 2011 г. У всех пациентов применялась индивидуально-рациональная тактика. Изучены особенности проведения кислотосупрессивной терапии. С 2008 по 2010 г. количество рецидивов кровотечения увеличилось с 8,9 до 10,6 %. Отмечена корреляция между увеличением числа рецидивов кровотечения и составом антисекреторных препаратов. Основной группой препаратов при проведении кислотосупрессивной терапии были ингибиторы протонной помпы (ИПП). Доказано, что при сочетании двух групп препаратов — ИПП и Н2-блокаторов гистаминовых рецепторов — эффективность кислотосупрессивной терапии значительно возросла, что позволило снизить число рецидивов кровотечения с 10,6 до 9,1 %.
Проведений аналіз результатів лікування 1369 пацієнтів із кровотечею, що ускладнила пептичні виразки верхніх відділів травного каналу, за період із 2008 по 2011 р. У всіх пацієнтів застосовувалась індивідуально-раціональна тактика. Вивчені особливості проведення кислотосупресивної терапії. Із 2008 по 2010 р. кількість рецидивів кровотечі збільшилася з 8,9 до 10,6 %. Відмічена кореляція між збільшенням числа рецидивів кровотечі та складом антисекреторних препаратів. Основною групою препаратів при проведенні кислотосупресивної терапії були інгібітори протонної помпи (ІПП). Доведено, що при поєднанні двох груп препаратів — ІПП та Н2-блокаторів гістамінових рецепторів — ефективність кислотосупресивної терапії значно збільшилася, що дозволило знизити число рецидивів кровотечі з 10,6 до 9,1 %.
peptic ulcers bleeding, acid suppression therapy.
кровотечение, пептические язвы, кислотосупрессивная терапия.
кровотеча, пептичні виразки, кислотосупресивна терапія.
Actuality of the Problem
Prevention of recurrence bleeding (RB) is of primary importance in the treatment of patients with bleeding in digestive tract lumen.
An essentially important condition for thrombus formation in erosive vessel is not only the continuous increase of intragastric pH > 6, but the possibility of achieving this effect in the very first hours of treatment [6]. According to Collins and Langman (1985) the use of an adequate acid suppressive therapy the number of RB reduces to 10 %. It should be noted that the number of emergency surgical interventions was reduced to 20 %, mortality rate — to 30 %.
Priority in the treatment of acid depended haemorrhagic complications belongs to proton pump inhibitors (PPIs), as they do not aggravate local hypoxia and oxidative stress in periulcerous zone [2, 8]. However, in clinical study we repeatedly confront with torpid reaction of the organism to PPI drugs [3]. Besides, the period of drugs’ action considerably shortens, but the latent period practically doubles. However, we often tend to blame unscrupulous manufacturers, particularly in the case of generic drugs. Reducing the pH to acidic values, even for a short period of time, inevitably leads to thrombolysis by activating pepsinogen and reducing platelet aggregation [1, 5, 11, 12].
The well-known term «omeprazole resistance» is widely used in literature, but the causes of it, are still unknown. Diffe-rent systemic bioavailability, suppression of only actively secreting proton pumps, the difference in intensity of microsomal oxidation in the liver, hypersecretory status, duodenogastroesophageal reflux are assumed to be of a decisive importance. Abnormal structure in some individuals of the proton pump, that prevents binding omeprazole molecule is not excluded either (Hattebak, 99). According to V.T. Ivashkin et al., the resistance to PPIs in adults in the very first day of the drugs intake ranges from 25.7 to 42.4 %, and on the fourth day — from 5.6 to 27.8 % [4].
Purpose of the Research: to evaluate the efficacy of antisecretory therapy and its impact on the development of recurrent bleeding in order to improve the quality of care for patients with bleeding peptic ulcers of the upper digestive tract.
Materials and Methods
In the period from 2008 to 2011 1369 patients with bleeding peptic ulcers of the upper digestive tract were followed up. 1061 patients (77.5 %) were with chronic peptic ulcers, and 308 patients (22.5 %) — with acute erosive and ulcerative lesions.
The treatment of patients was carried out in the intensive care unit (ICU). The complex treatment included endoscopic therapeutic monitoring, acid suppressive and correcting therapy of blood loss and organ dysfunction. The main criteria for the effectiveness of the conducted treatment are the presence of RB and the duration of unreliable hemostasis. In the course of the analyzed period 133 episodes of RB were noted (Table 1).
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The terms of patients’ treatment of the intensive care unit (ICU) were determined on the basis of endoscopic monitoring. Transfer of patients into the general surgical department was carried out only in the presence of fibrinogens deposit in the bottom of the source of bleeding. The average duration of the treatment of patients with chronic ulcers was 33 ± 6 hours, and of the patients with acute ulcers — 27 ± 5 hours.
The given study included patients with RB and with continuous unreliable hemostasis (CUH). The latter group included patients with persistent symptoms of unreliable hemostasis ≥ 48 hours.
Individually rational tactics was used for the treatment of patients with bleeding (IRT) in which, alongside with the extensive use of diagnostic and therapeutic arsenal of endoscopic methods, acid suppressive therapy was an indispensable component. Special sample of patients, depending on the endoscopic picture and endoscopic techniques that were used were not conducted.
Results and their Discussion
In the process of clinical data the analysis of positive trend growth in the number of patients with the RB and the CUH from 8.9 % (2008) to 10.6 % was noted. Besides, we did not notice the increase of clinically meaningful RB, when, alongside with endoscopic manifestations, the clinical symptoms of the RB were identified either (reduction of blood pressure, loss of consciousness, significant reduction of red blood). As the endoscopic picture in patients with bleeding peptic ulcers of the upper gastric tract and conducted endoscopic medical monitoring for the investigated period did not differ significantly, the quality of acid suppressive therapy was studied.
Antisecretory therapy was performed, mainly, with proton pump inhibitors. Omeprazole (omez) was the reference drug. Esomeprazole (nexium), pantoprazole (сontroloс, pantasan), rabeprazole (razol, geerdin) were the drugs of choice. Moreover, histamine H2-receptor blockers — ranitidine and famotidine (quamatel) — were also used.
At different years the composition of medicines in group PPIs was different. A steady increase in patients treated with ± PPIs (from 82.1 % in 2008 to 96.7 % in 2010) as well as the reduction in the number of patients who used blockers H2-histamine receptors (from 17.9 % in 2008 to 3.3 % in 2010) should be noted.
Moreover, the number of patients treated with generic drugs (pantasan, geerdin, razol) increased, that can be explained by the changes in economic background. Taking into account the data in Table 1 that testify the increase in the number of patients with the RB and the CUH, it is logically to assume that this index was influenced by the composition of the preparations that were used for the carrying out acid suppressive therapy.
It should be noted, that all PPIs are prodrugs. They are transformed into active dosage forms only after proper metabolism in the liver. Genetically determined polymorphism of cytochrome P450 components (particularly CYP 2C19, performing biotransformation of PPIs), is able to influence the effectiveness of this class of drugs [9]. Prevalence of different genotypes of cytochrome P450 in the Ukrainian population is unknown. Pharmacogenetic dependence of acid suppressive effect of PPIs in, the so called «extensive metabolizers», was actively studied by foreign researchers [15]. M. Sugimoto et al. (2006), when compared the effects of omeprazole and amotidine in homo- and heterozygous extensive stabilizers showed that intravenous infusion of a combination of these drugs lead to a more pronounced and continuous increase of intragastric pH than monotherapy with each drug separately [10, 14]. Of great interest is the evidence of the fact that the effectiveness of acid suppression may also depend on the degree of contamination of Helicobacter pylori (Hp), or, the so called Hp-status of patients. T. Koike et al. (2007) research confirmed that famotidine increases intragastric pH in Hp-positive patients [13] more ffectively, and K. Futura et al. (2005) revealed that tolerance to famotidine occurs only in Hp-negative patients [15]. Thus, it was confirmed once more that eradication therapy, in the period of treatment of acid depended hemorrhagic complications was not the task of crucial importance.
Recently, we greatly reduced the use of generic drugs. Besides, in patients with high risk of RB (large ulcers, large thrombosed vessels and clots in the bottom of the ulcer, after endoscopic hemostasis), along with the use of PPIs, histamine H2-receptor blockers of the second (ranitidine) and third (famotidine) generation were also used. The conducted analysis of the results of the of treatment showed a decrease in the number of RB from 10.6 % (2010) to 9.1 % (2011). Besides, we noticed a decrease in the period of treatment in the intensive care unit with 32 ± 6 hours to 28 ± 3 hours in patients with chronic ulcers and from 27 ± 5 to 23 ± 3 hours in patients with acute erosive and ulcerative lesions.
Conclusions
1. All above-mentioned confirms the necessity of effective antisecretory drugs use in order to create the necessary conditions both for reliable clotting of a bleeding vessel in the bottom of the ulcer and for the prevention of early RB.
2. Existence of patients in whom the administration of acid suppressive drugs does not lead to the desirable effect confirms the postulate about deficiency in medical practice the drug that has absolute effectiveness.
3. Proton pump inhibitors compose the control group for acid suppressive therapy. At the same time, we consider that the combination of two groups of drugs — PPIs and histamine H2-receptor blockers — is necessary for the patients with high risk of RB from peptic ulcers of upper parts of digestive canal.
4. These features of the pharmacodynamics necessitate the individual approach to the administration of antisecretory preparations that allow us to take into account a favorable response to the given treatment or its correction. In some cases our «old» drug appears to be more effective than the «modern» one.
1. Брискин Б.С. Возможности использования ингибитора протонной помпы омепразола (Лосек) для лечения кровоточащих дуоденальных язв / Брискин Б.С., Гарсия Х.С. // Фарматека. — 2005. — № 4–5.
2. Гостищев В.К. Значение антисекреторной терапии в лечении острых гастродуоденальных язвенных кровотечений / Гостищев В.К., Евсеев М.А. // РМЖ. — 2004. — Т. 12, № 24.
3. Дорофеев А.Э., Березов В.М., Руденко Н.Н. Синдромная диагностика в гастроэнтерологии. Учебное пособие / Дорофеев А.Э., Березов В.М., Руденко Н.Н. — Донецк: Вебер, 2008. — 263 с.
4. Ивашкин В.Т. Современный подход к терапии гастроэзофагеальной рефлюксной болезни во врачебной практике / Ивашкин В.Т., Трухманов А.С. // Русский медицинский журнал. Болезни органов пищеварения. — 2003. — Т. 5, № 2.
5. Кондратенко П.Г. Острое кровотечение впросвет органов пищеварительного канала: Практическое руководство / Кондратенко П.Г., Смирнов Н.Л., Раден-ко Е.Е. — Донецк, 2006. — 420 с.
6. AbeY., Inamori M., Togawa J. et al. The comparative effects of single intravenous doses of omeprasole and famotidine on intragasric pH // J. Gastroenterol. — 2004. — 39(1). — 21-5.
7. Brunner G., Luna P., Hartmann M. et al. Optimizing the intragastric pH as a supportive therapy in upper GI bleeding // Yale J. Biol. Med. — 1996. — 69. — 225-231.
8. Collins R., Langman M. Treatment with histamine H2 antagonists in acute upper gastrointestinal haemorrhage: implications of randomised trials // N. Engl. J. Med. — 1985. — 313. — 660-665.
9. De Morais S.M., Wilkinson G.R., Blaisdell J. et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans // J. Biol. Chem. — 1994. — 269(22). — 15419-22.
10. Fandriks L., Lonroth H., Peterson A., Vakil N. Can famotidine and omeprazole be combined on a once-daily basis? // Scand. J. Gastroenterol. — 2007 Jun. — 42(6). — 689-94.
11. Fennerty M.B. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: Rationale for therapeutic benefits of acid suppression // Crit. Care Med. — 2002. — 30. — S351-S355.
12. Hussain H., Lapin S., Cappell M.S. Clinical scoring systems for determining the prognosis of gastrointestinal bleeding // Gastroenterol. Clin. N. Am. — 2000. — 29. — 445-464.
13. Koike T., Ohara S., Sehine H. et al. Effect of Helicobacter pylori status on intragastric pH during administration of lafutidine or famotidine // Hepatogastroenterology. — 2007 Jun. — 54(76). — 1280-4.
14. Sugimoto M., Futtura T., Shirai N. et al. Initial 48-hour acid inhibition by intravenous infusion of omeprasole, famotidine, or both in relation to cytochrome P 450 2C19 genotype status // Clin. Pharmacol Ther. — 2006. — 80(5). — 539-48.
15. Sugimoto M., Futtura T., Shirai N., et al. Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes // Clin. Pharmacol Ther. — 2005. — 77(4). — 302-11.