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PREVENTION OF PERITONEAL ADHESIONS: FROM SURGERY TO FARMACOLOGY
Bukata V.,
MD, PhD, assistant professor of the Department of General Surgery, I. Horbachevsky Ternopil State Medical University, Ukraine Chornomydz A.
MD, PhD, Senior Lecturer of the Department of Pharmacology and Clinical Pharmacology, I. Horbachevsky Ternopil State Medical University, Ukraine.
Abstract
Based on literature analysis, in our article, we have highlighted the cardinal principles of preventing the adhesions formation in the abdominal cavity after surgical interference. In addition to surgical prevention methods, our primary focus was on the usage of local and system anti-spastic drugs, barrier methods of preventing adhesive peritoneal disease formation.
Keywords: adhesions formation, peritoneal damage, anti-adhesions drugs, anti-adhesions barriers.
The development of abdominal surgery has improved chances of many abdominal disease treatment. The adhesion problem is increasing with the expansion in the number of abdominal surgical interventions and represents one of the most urgent problems of modern abdominal surgery [1,2].
The formation of adhesions is a universal, defense, adaptive reaction in the body to peritoneal irritation (trauma). Nevertheless, under certain conditions of localization, generalization and severity, peritoneal adhesions are formed, which in turn can lead to such a terrible complication as adhesive intestinal obstruction [3,4,5,6]. The peritoneal adhesive process not always leads to the progression of adhesive intestinal obstruction, oftimes pain syndrome and the development of secondary infertility in women are the main manifestations [1].
In fact, adhesion is "a dark side of abdominal surgery," its "tendo Achillis," or as Rene Lerish has aptly called it "a terrible scourge of abdominal surgery" [7]. Significant development of adhesive intestinal obstruction cases concerned not only with the surgical interferences increasing, but also with the lack of reliable methods of perioperative prophylaxis of the adhesive process in the abdominal cavity [8,9,10].
Currently, six basic mechanisms exist for preventing the formation of adhesions:
1. Frequency reduction of peritoneal damage.
2. Reduction of the primary response to inflammation.
3. Prevention of the fibrin formation.
4. Activation of fibrinolysis.
5. Preventing the accumulation of fibrin and the development of fibroblastic processes.
6. Usage of drugs that serve as barriers for the adhesion formation [11,12,13,14,15].
Surgical prevention methods of adhesions formation, that is, the frequency reduction of peritoneal damage, are mandatory and can be complemented with other approaches, but in no case should be replaced by them [16].
General principles of surgical prevention methods of adhesions formation include operative measure techniques, regardless of the surgical access variant [17]:
• the usage of mini-invasive and non-traumatic surgical techniques is desirable;
• minimization of operation time, usage of light and mild heating of tissues;
• avoidance of peritoneum traumatizing with tools and electrocoagulation;
• minimal intrusion into the abdominal cavity of foreign contaminants such as patches, surgical mesh, suture material;
• application of wet wipes and tampons, peritoneum humectation with a physiological salt solution to minimize dehydration of the surface of the mesothe-lium;
• washing the abdominal cavity to remove residual blood clots, avoiding the use of solutions that irritate the peritoneum;
• reducing the risk of infection by creating aseptic operation conditions and the use of prophylactic antibiotics;
• desirable usage of latex and non-tactile gloves;
• usage of the minimum possible pressure of insufflation and humidified gas during laparoscopy [17,18,19,20].
Techniques such as avoiding unnecessary perineal dissection, preventing peritoneal contamination with intestinal contents or gallstones, are basic principles that are meant to be used to all patients [17]. It is extremely important to avoid the penetration of aggressive antiseptic solutions (alcohols, iodine, etc.) into the abdominal cavity [21], to remove all necrotic tissues, to make meticulous hemostasis, to minimize ischemia and to mobilize organs, to use modern non-immunogenic suture material, etc. [16,22,23].
Another strategy for adhesion prevention involves the use of pharmacological agents that can be directed against various causes and components of the inflammatory process (e.g., infections, endotoxins, exudation) and/or the adhesion formation (e.g., coagulation, fibrin deposition, and fibroblast activity and proliferation) [24]
Before the treatment with medication, it is necessary to overcome a number of technical obstacles:
1) ischemic zones are prone to the adhesions formation, but they are cut off from the blood flow and, consequently, from the influence of the means administered enterally and parenterally;
2) the mechanism of extremely rapid absorption, typical for the peritoneal membrane, limits the half-life and efficiency of many drugs introduced intraperitone-ally;
3) any anti-adhesion medication should effect specifically against the process of adhesions formation, but not against normal wound healing; the processes of adhesions formation and remesotelization use the same cascade (exudation, coagulation, fibrin accumulation, fibroblast activity, and proliferation) [24,25,26].
Currently, the influence on the process of adhesion of the following pharmacological agents has been sufficiently studied: non-steroidal anti-inflammatory drugs, glucocorticoid and antihistamine drugs, progesterone-estrogen agents, anticoagulants, fibrinolytic drugs, antibiotics, gonadotropin-releasing factor agonists, calcium channel blockers, histamine antagonists, antioxidants, vitamins, colchicine, and others. [15,25,27,28,29]. Results of clinical trials and animal studies indicate that all of these approaches have only limited success, aggravate insufficient safety, efficacy and a host of side effects, and do not eliminate the problem of post-surgical adhesion [25].
Non-steroidal anti-inflammatory drugs (NSAID) change the metabolism of arachidonic acid, altering the activity of cyclooxygenase, prevent the synthesis of prostaglandin and thromboxane, reduce vascular permeability, inhibit plasmin activity, reduce platelet aggregation and coagulation, and improve the function of macrophages. Unlike COX-1, which is present in most of the platelets and endothelial cells of normal blood vessels, COX-2 is detected in new angiogenic endothe-lial cells, as well as in fibroblasts. Thus, selective COX-
2 inhibitors, such as celecoxib, have the greatest potential in reducing the formation of adhesions in the abdominal cavity [26,30,31]. NSAID modulate several aspects of inflammation and reduce the formation of adhesions in the peritoneum in many but not all animal models [15,24,26,29,32].
Corticosteroid therapy weaken relieves the inflammatory response by reducing vascular permeability and release of cytokines and chemotactic factors. This therapy is associated with confounded results [15,24], and sometimes anti-adhesive effect has not been observed [29]. Corticosteroids, such as dexame-thasone, hydrocortisone, and prednisone, were studied independently or with antihistamines such as prometh-azine, by intra-abdominal injection [33,34]. Their usage is very limited due to potential side effects such as significant immunosuppressive action, inhibition of reparative processes, development of purulent complications, and long-term drug administration can lead to relative and even absolute adrenal insufficiency [21,24,29].
The usage of progesterone, taking into account clinical studies, proved to be ineffective in preventing the adhesions formation [24,35,36]. Gonadotropin-re-leasing hormone agonists in some studies have shown moderate efficacy in the adhesions formation, probably due to the reduction of estrogen activity, which contributes to the formation of adhesion. [29].
The anticoagulants usage for preventing the adhesion formation process in the abdominal cavity was enthusiastically reported in the literature [37]. Heparin is the most studied anticoagulant used for adhesions prevention [24]. However, its efficacy was rather low or absent in many clinical trials [29]. The use of heparin is complicated by bleeding and delayed wound repair [24].
Fibrinolytic agents such as streptokinase and recombinant tissue plasminogen activator, when applied locally, reduced adhesion in animal models [13]. Three different drugs, tPA (Actilyse), fondaparinux (Arixtra) and activated drotrecogin alfa (Xigris), which affect the coagulation process at various stages, have proved to be effective on animal models in rats [38]. However, further research has shown that all these drugs may have only limited success [29]. In addition, fibrinolytic drugs can cause hemorrhagic complications [34] and are quite expensive [13,29].
Antibiotics for intraabdominal use actually caused the adhesion formation and are not recommended as the only agent for adhesion preventing [29,39,24].
As noted by Bezhenar V. F. and others (2011), currently the only pharmacological agent with experimentally and clinically proven anti-adhesion activity is a drug from the group of agonists GnRH - leuprorelin, which is used in the treatment of endometriosis and uterine fibroids [25,27,40].
It was also established that single intraoperative intraperitoneal injection of verapamil to patients operated on non-inflammatory gynecological diseases contributes to the prevention of peritoneal adhesion [41].
Vitamin E is the most studied vitamin in the adhesion prevention. In vitro studies have shown that vita-
min E has antioxidant, anti-inflammatory, anticoagulant, and anti-fibrotic effects, and reduces collagen production [42,43,44]. Corrales and others [42] showed that vitamin E, injected intraperitoneally, showed significant anti-adhesive properties [29].
We also found a positive effect of succinic acid on the risk of re-adhesion after surgery for adhesive intestinal obstruction [45,46].
There are other agents that were used to prevent the formation of adhesions and which had limited success. Among them are the following: halofuginone, the inhibitor of the type-I collagen synthesis [13], local anesthetics [29], methylene blue [47,48], sandostatin and alprostadil [49], polyglucin, rheopolyglucin, "Refor-tan" [21], cytostatics [17]. The promising results were obtained with the use of alpha-lipoic acid [50], kliquinol [51], selenium [52], as well as bee pollen and honey [53,54,55], etc. [17].
Cytostatics, isoniazid, interleukin-10, phosphatidylcholine, ketorolac, poly(pentapeptide) of elastin, tolmetin, allopurinol, medroxyprogesterone acetate, il-oprost, tenoxicam, diltiazem, hepatocyte growth factor (HGF) [29], sodium cromoglicate showed the anti-adhesive properties in the experiment [26]. All authors noted a significant decrease in the number of adhesions compared with the control in the experiment, however none of these drugs has a sufficient clinical evidence base [17,21,56,57].
Several other methods for the prevention of adhesions formation were tested: gut lavage with antibacterial formula and sorbents [12,58] hyperbaric oxygenation [12], peritoneal lavage with ozonized solution [58,59,60], imposing oxygenopertoneum in the early postoperative period [21], abdominal irradiation with low energy laser in combination with intravenous laser radiation of blood [21].
Great significance in the formation of adhesions is given to the early regenerative process of the motor-evacuation function of the intestine. A number of authors recommend using prokinetics, sympatholytics, ganglion blockers, serotonin, and different types of electrostimulators [17,21]. The main positive side is the possibility of using these drugs in the early postoperative period in combination with other prophylactic agents, in particular, barriers [10].
In recent years, there has been a sharp increase in interest in mechanical barrier contraceptive precautions preventing consolidation and protecting wound surfaces [21]. Mechanical barriers are available in two forms: "liquid" and "solid" or membrane barriers. They avert the adhesions formation by preventing tissue contact during the period of peritoneal recovery and adhesions development. High viscosity, no side effects, bi-ocompatibility, and low peritoneal reabsorption rates are important characteristics of liquid barriers. [10,21,26].
Synthetic barriers include pastes (Gelfoam) and Gel (Surgicel, Intercoat, Silastic, Lintex Mesogel), expanded polytetrafluoroethylene (e-PTFE, Gore-Tex), solid forms - oxidized regenerated cellulose (Inter-ceed), biodegradable membrane (Seprafilm) - chemically modified sodium hyaluronate and carboxymethyl
cellulose (GC-CMC). etc. [27]. The drugs based on polytetrafluoroethylene, hyaluronic acid, cellulose, carboxymethyl cellulose and polyethylene oxide were the most widely used among the other barrier methods [16,28].
According to American FDA (Food and Drug Administration), the most extensively studied and permitted liquid anesthetics for adhesions preventing in lapa-roscopic surgery is Adept (4% icodextrin solution) [17,21]. As reported by many researchers [61,62,63], it was concluded that a 4% icodextrin solution can be used in a wide range of surgical operations and is quite effective in adhesion reducing. The main disadvantage of this agent is the inability to use drainage [27], although there are cases of increased number of suppura-tive complication, worsening of wound repair and anastomoses [26].
SprayGel is another barrier to prevent adhesions formation in the abdominal cavity based on hydrophilic polyethyleneglycol. The medication is used by simultaneous spraying of two liquid precursors at certain sites. The liquids are then polymerized to form a sticky gel that covers the tissues. 5 days after the hydrogel pool is reabsorbed. In a recent advanced clinical trial, this drug has shown decentish results in the prevention of adhesion formation [26].
There are reports of the effectiveness of the anti-adhesive effect of the drug "Mesogel" (sterile 4% car-boxymethylcellulose sodium salt aqueous solution (CMC-Na) [21].
Barrier, which is a derivative of carboxymethyl-cellulose and hyaluronic acid, as indicated by the results of studies, significantly reduces the adhesions. Using it is difficult because the medication is easily adhered to gloves, instruments or other tissue and also can be easily destroyed; its use in laparoscopy is accompanied by certain difficulties [27,62].
Actually, the use of hyaluronic acid based medications [64,65,66] as an anti-adhesive agent has become quite widespread.
In the human body, hyaluronic acid is in the form of sodium salt - sodium hyaluronate. This compound is found in almost all tissues, its highest concentrations is in the skin, synovial fluid, vitreous humour and cartilage tissues [28].
The usage of hyaluronic acid for adhesion prevention is justified by its physical (absorbability, high viscosity, lubricant properties) and biological properties (primarily anti-inflammatory and antioxidant activity) [16, 28].
Hyaluronic Acid properties:
• Mechanical effect: barrier between tissues;
• Moisturizing characteristics: high degree of water binding;
• Cicatrizing effect: normalization of cell migration and proliferation;
• Filling the defect space;
• Auxiliary function: interruption of the inflammatory cascade [11, 13].
Hyaluronic acid for the adhesions prevention is widely used throughout the world, especially in operative gynecology, and has been included in leading in-
ternational recommendations, in particular, the consensus of the experts of the American Society for Reproductive Medicine and the Society of Surgeons-Repro-ductologists (Society of Reproductive Surgeons) 2013. [16]. The gel, consisting of hyaluronic acid, can be easily applied using the applicator during laparoscopy [27]. The advantages of medications based on hyaluronic acid should also include their relatively low cost [16,28].
Such medications, which contain hyaluronic acid, are used in Ukraine: "Deviskar" (sodium hyaluronate) and multicomponent drug "Defensal" containing hya-luronic acid, sodium succinate and decamethoxinum [11]. In particular, on the experimental model of the adhesion process in rats, we have established the positive effect of the "Defensal" usage on the adhesions formation [67].
Currently, several surgical membranes are used for adhesions prevention. Unlike their liquid analogs, membrane forms act only in their domain of application. The most commonly used membranes are Inter-ceed, Seprafilm, Gore-Tex Surgical Membrane [26]. Medications "Seprafilm", "Intersid" and "Interceed" are not effective in the presence of blood [21,25,27,68]. Another disadvantage of these drugs is the difficulty in fixing them in the abdominal cavity and the difficulty of their use in laparoscopy [68].
High hopes also rely on new polymer materials that can serve not only as a mechanical barrier, but also as a carrier of medicinal substances with prolonged release of them into the abdominal cavity [17, 69].
The large number of barrier methods for preventing the adhesions formation were ineffective. For example, the method of "hydroflotation", which involves the intraabdominal administration of dextran solutions, physiological sodium chloride solution, Ringer-Locke solution for the creation of a "hydrobarrier" between organs and tissues of the abdominal cavity, proved not to be sufficiently effective. Older barrier methods of prophylaxis with instillation in the abdominal cavity of vaseline oil and glycerine also didn't yield good results [16,26,28].
Indications for anti-adhesion drugs usage are fuzzy; there are no clear algorithms and instructions for their application in clinical surgery. This is the reason why most surgeons do not use them [11,70,71]. The assessment of anti-adhesive agents effectiveness is also a problem. First, it is very difficult to evaluate the clinical efficacy of the drug due to the need of re-laparoscopy or laparotomy [27,72]. Secondly, the results of animal studies often do not correspond to clinical data [27].
Despite the considerable work in this area, little progress has been made and currently, there is no reliable method of preventing the formation of postoperative adhesions [13,73].
However, according to many researchers, for now, the combination of substances, which is locally active in the abdominal cavity, with drugs, which correct systemic abnormalities associated with adhesive disease, is the most optimal [3,74].
Conclusion. Summarizing the literature review, it can be noted that the adhesive process in the abdominal cavity is a very topical issue of modern clinical surgery
and medicine in particular. Proceeding from the fact that the adhesions formation is a rather complicated pluricausal process, it is difficult to determine which methods of adhesions preventing are preferable: avoidance of peritoneum traumatizing, reducing the inflammatory response in the surgical intervention area, reducing the probability of fibrin loss in the abdominal cavity, and distinguishing the damaged serous surfaces. The methods themselves are not always sufficiently effective since they are directed primarily to one of the mechanisms of adhesive disease. As a result, our understanding is that the most appropriate way of preventing the adhesions formation in the abdominal cavity and preventing the development of complications is the combined usage of such methods as: reducing the surgical peritoneum traumatizing (the use of minimally invasive intervention approach), using the barrier method of adhesion prevention and the effect on pathogenetic links of adhesions formation.
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INFLUENCE OF DAYTIME SLEEPINESS ON THE EFFECTIVENESS OF HYPERTENSION AND
TYPE 2 DIABETES MELLITUS TREATMENT
Isayeva A.,
MD, PhD, Head of the Department of Chronic Non-communicable Disease Prevention, The Government Institution "National Institute of Therapy named by L.T. Malaya of National Ukrainian Academy of Medical Science ", Kharkiv, Ukraine Buriakovska O.,
MD, Junior research Associate of Chronic Non-communicable Disease Prevention, The Government Institution "National Institute of Therapy named by L.T. Malaya of National Ukrainian Academy of Medical Science ", Kharkiv, Ukraine Smolkin M.
MD, Neurologist, The Government Institution "National Institute of Therapy named by L.T. Malaya of National Ukrainian Academy of Medical Science", Kharkiv, Ukraine
ВЛИЯНИЕ ДНЕВНОЙ СОНЛИВОСТИ НА ЭФФЕКТИВНОСТЬ ТЕРАПИИ ГИПЕРТОНИЧЕСКОЙ БОЛЕЗНИ И САХАРНОГО ДИАБЕТА 2 ТИПА
Исаева А.С.,
Д.мед.н., зав. отделом комплексного снижения риска хронических неинфекционных заболеваний ГУ «Национальный институт терапии им. Л.Т. Малой НАМН Украины», г. Харьков, Украина
Буряковская А.А.,
М.н.с отдела комплексного снижения риска хронических неинфекционных заболеваний ГУ «Национальный институт терапии им. Л.Т. Малой НАМН Украины», г. Харьков, Украина
Смолкин М.Г.
Врач-невропатолог ГУ «Национальный институт терапии имени Л.Т. Малой НАМН Украины»,
г. Харьков, Украина
Abstract
The article discusses the relationship between the presence of daytime symptoms of sleep disorders identified on the basis of the Epworth scale and the course, as well as the effectiveness of treatment of hypertension and type 2 diabetes mellitus. It also discusses the relationship between the presence of daytime symptoms of sleep disorders, identified on the basis of the Epworth scale and the composition of the human body.
Аннотация
В статье рассмотрены зависимость между наличием дневных симптомов нарушений сна, выявленных на основании шкалы Эпворта и течением, а также эффективностью терапии гипертонической болезни и сахарного диабета 2 типа. Также обсуждается взаимосвязь между наличием дневных симптомов нарушений сна, выявленных на основании шкалы Эпворта и составом тела человека.
Keywords: hypertension, diabetes mellitus, sleep disorders, daytime sleepness.
Ключевые слова: гипертоническая болезнь, сахарный диабет 2 тип, нарушения сна, дневная сонливость.
Сон составляет третью часть жизни человека, и обеспечивает периодическую блокаду сенсорных связей с окружающим миром, что необходимо для организации таких важных психических функций как эмоции, память, внимание и мыслительные процессы [1]. Тем не менее, функции сна гораздо шире и не ограничиваются только психической сферой. Безусловно, одной из базисных функций
сна является поддержание адекватного функционирования всех систем человека. Во время сна изменяется физиологические процессы во всех системах. Сон у здоровых лиц связан с умеренной альвеолярной гиповентиляцией, что приводит к увеличению на 2-8 мм рт. ст. РаС02 и снижению на 3-11 мм рт. ст. Ра02, что уменьшает среднее насыщение оксигемоглобином артерий на 2 %. При
