RU2392964C2 - Method for prevention of acute postoperative pancreatitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and concerns prevention of acute postoperative pancreatitis. That is ensured by intravenous drop-by-drop introduction of recombinant superoxide dismutase during operation and for the first 12 hours of the postoperative. The dose is specified individually considering dynamics of acid-base balance, blood gases and intraoperative injures.

EFFECT: method provides reduced intensity of lipid peroxidation, activity of free kinins and therefore prevents development of acute pancreatitis.

Description

The invention relates to medicine, namely to the field of surgery and anesthesiology. The method can be used to prevent acute postoperative pancreatitis.

Acute postoperative pancreatitis (AKP) most often occurs when performing surgical interventions on the pancreas, bile ducts, stomach, duodenum and spleen, but also occurs during operations outside the abdominal cavity: on the heart, spinal cord and brain and other organs, as well as after hemodialysis. According to statistical data, the incidence of AKI in patients who underwent surgery on the organs of the upper abdominal cavity varies widely from 0.36 to 58.5%. Lack of prophylaxis in risk groups and untimely started therapy can lead to the development of severe acute postoperative pancreatitis, which in turn leads to death in 40-50% of cases, and in other cases to an increase in the duration of hospitalization, disability of people, and a deterioration in the quality of life ( Acute postoperative pancreatitis // Yu.S. Polushin, A.V. Sukhovetsky, M.V. Surkov, O.V. Pashchenko, D.M. Shirokov. St. Petersburg, Folio 2003 157 p.).

Preventive measures aimed at preventing AKI are based on ideas about the pathogenesis of its development. A number of researchers believe that the main role in damage to the tissues of the gland itself, parapancreatic fiber, tissues of other organs and systems belongs primarily to circulatory disorders and the imbalance of kallikrein-kinin, prothrombin, fibrinolytic plasma systems, local homeostasis, coagulation, free radical oxidation processes, and not enzymatic self-digestion (Kornienko A.A. Disorders in the hemostatic system in acute pancreatitis and possible correction methods: Abstract of Candidate of Medical Sciences / A.A. Kornienko. - Cr snoyarsk, 2002. - 21 p.27; Acute pancreatitis as an immunological problem / A.D. Tolstoy, D.S. Sheyanov, E.V. Zakharova, etc. // Cytokines. Inflammation. Immunity: Abstracts of international scientific. practical conference - SPb., 2002. - P.67 .; Sarazov MP The importance of lipid peroxidation and antioxidant system in the development of pancreatitis: Abstract of thesis of Candidate of Medical Sciences / MPParazov. - SPb ., 1998. - p.22; Cherdantsev D.V. Correction of the systemic inflammatory response syndrome in acute pancreatitis: Abstract. Cand. honey. sciences / D.V. Cherdantsev. - Krasnoyarsk, 2002 .-- p.24; Anti-inflammatory cytokine response and clinical outcome in acute pancreatitis / M.O. Simovic, M.J. Bonham, F.M. Abu-Zidan, J.A. Windsor // Crit. Care Med. - 1999. - Vol. 27. - No. 12. - P.2662-2665., Menger, M.D. Microcirculatory dearmgements in acute pancreatitis / M. D. Menger, T. Plusczyk, B. Volmar // J. Hepatobiliary Pancreat Surg. - 2001. - Vol.8, No. 3. - P.187-194).

There is a high correlation between the activity of peroxidation processes and the severity of acute pancreatitis. Peroxidation products are factors of pancreatic aggression. The activation of peroxidation processes makes the main contribution to the formation of endogenous intoxication syndrome in acute pancreatitis. Lipid peroxidation plays an essential role in the formation of foci of lesions of the gland already in the first hours, and subsequently determines the size of necrosis, damage to other organs and systems and, accordingly, determines the prognosis (Abu-Zidan, F.M. / Severity of acute pancreatitis: a multivariate analysis of oxidative stress markers and modified Glasgow criteria / F.M. Abu-Zidan, M.J. Bonham, JAWindsor // Br.J.Surg. - 2000. - Vol. 87. - No. 8. - P. 1019-1023. Oxidative stress in acute pancreatitis / HUSchuiz, C. Niederau, H. Klonowski-Stumpe, W. Halangk, R. Luthen, H. Lippert // Hepatogastroenterology. - 1999. - Vol. 46. - No. 29. - P.2736-2750 .; Kriuchyna, Ie. A. Lipid peroxidation, the antioxidant system and the trace element level in acute pancreatitis / Ie. A. Kriuchyna // Lik Sprava. - 2000. - No. 2. - P.34-37. Oxidative stress as an early prognostic factor in acute pancreatitis (AP): its correlation with serum phospholipase A2 (PLA2) and plasma polymorphonuclear elastase (PMN-E) in different-severity forms of human AP / Wereszczynska-Siemiatkowska , A.Dabrowski, M.Jedynak, A.Gabryelewicz // Pancreas. - 1998. - Vol.17, No. 2. - P.163-168).

Various schemes of intraoperative drug prophylaxis of AKI are recommended, but work on this problem cannot be considered completed. Based on the analysis of literature data, it can be noted that most authors by the term “AKI prophylaxis” most often mean a preventive course of therapy, which essentially does not differ from that in the treatment of a developed disease.

Directly prophylactic methods can conditionally be divided into several groups.

The first group includes recommended surgical techniques aimed at minimizing trauma to the parenchyma of the gland and surrounding structures (Grigoryan A.V. Prevention and treatment of postoperative pancreatitis // Surgery. - 1976. - No. 1. - P.120-124).

Another group of AKI prophylaxis includes a number of additional intraoperative manipulations acting on various parts of the pathogenesis of AKI. It is recommended that gastric resection be supplemented with periarterial sympathectomy of the gastroduodenal artery and prolonged drug blockade of the celiac plexus (Lubyansky V.G., Nasonov S.V. Acute pancreatitis after resection of the stomach due to low duodenal ulcer. // Chir. - 2001. - No. 3). To create a large concentration of inhibitors in the lesion, i.e. in the pancreas, it is recommended selective catheterization of the celiac artery according to Seldinger (A.B. Lee, V.F. Tskhai. Diagnosis and treatment of postoperative pancreatitis. // Surgery. - 1991. - No. 12. - P.122). To reduce the flow of enzymes and bacterial toxins into the blood, detoxification and decompression of the interstitial space of the pancreas, liver, retroperitoneal space, prolonged external drainage of the thoracic lymphatic duct in AKI is recommended (Savelyev BC, Buyanov V.M., Ognev V.Yu. Acute pancreatitis. - M .: Medicine, 1983; 240 p.).

In addition, there is a group of methods of drug prevention. The main directions of drug prevention of AKI are generally consistent with those in the treatment of AKI. The use of alkylating cytotoxic drugs to inhibit the synthesis of pancreatic enzymes, the use of protease inhibitors, antispasmodic, detoxification therapy (Vinogradov V.V. Postoperative pancreatitis // Surgery. Surgery. - 1983. - No. 10. - P. 89-92 .; Gostischev V. K. Postoperative pancreatitis // Surgery. - 1983. - No. 9. - P.134-139 .; Acute postoperative pancreatitis // Yu.S. Polushin, A.V. Sukhovetsky, M.V. Surkov, O.V. Pashchenko, D.M. Shirokov; St. Petersburg, Tome 2003 157 pp. V.M.Buyanov et al. Technique of pancreatoduodenal resection and intraoperation diet prevention of acute pancreatitis // Surgery, -. 1996. - №2, p.5).

Synthetic analogues of the hormone somatostatin (sandostitin, octreotide) are widely used for the treatment of AKI. However, the available literature data on the effectiveness of these drugs in the prevention of AKI are contradictory. Moreover, one of the claimed probable complications of somatostatin analogues is the development of acute pancreatitis, which limits the possibility of its widespread use (A. Severtsev “Sandostatin in abdominal surgery” A. N. Severtsev, V. A. Stupin, M., Triada. - 2005. - p.143).

The use of IL 10 (Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. // Deviere J, Le Moine 0, Van Laethem JL, Eisendrath P, Ghilain A, Severs N, Cohard M. Gastroenterology is proposed for the prevention of AKI after RCH). 2001 Feb; 120 (2): 498-505).

These methods have several disadvantages. So, the need for a careful attitude to the tissues during the operation is obvious, but often the surgical intervention is performed under altered conditions and requires quite aggressive technique. Performing additional intraoperative manipulations delays surgery, increases the burden on the patient and is not always effective. The use of a full course of treatment of acute pancreatitis for preventive purposes significantly increases the cost of treatment, lengthens the recovery time. In addition, a number of drugs included in the complex treatment of acute pancreatitis have a number of serious side effects. The prophylactic use of highly toxic cytotoxic drugs for prophylactic purposes cannot be applied to all patients. The need for the selective use of such prevention methods is evidenced by a large number of systems for predicting the development of AKI (acute postoperative pancreatitis // Yu.S. Polushin, A.V. Sukhovetsky, M.V. Surkov, O.V. Pashchenko, D.M. Shirokov; St. Petersburg, Folio 2003, 157 pp.).

The closest in combination of essential features is the method for the prevention of ARI proposed by Wollschlager S et al. The authors recommend oral administration before the intervention of 40 mg of prednisolone and 200 mg of allopurinol to inhibit oxidative processes.

This method has the following disadvantages: the use of the glucocorticoid hormone prednisone is associated with a number of side effects characteristic of drugs in this group. Allopurinol, inhibiting xanthine oxidase, does not affect other, more significant mechanisms of the formation of reactive oxygen species. In their study, the authors themselves pointed out the low efficiency of the proposed method (A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis. // Budzynska A, Marek T, Nowak A, Kaczor R, Nowakowska- Dulawa E. Endoscopy 2001 Sep; 33 (9): 766-72).

In order to increase the effectiveness of the prevention of acute postoperative pancreatitis, we propose a method based on the use of a recombinant superoxide dismutase preparation.

The superoxide dismutase enzyme converts the superoxide anion radical into hydrogen peroxide, which is then destroyed by catalase and the glutathione enzyme system to water and oxygen. Thus, superoxide dismutase prevents the generation of a number of reactive oxygen species that are more toxic than the superoxid anion radical, damaging macromolecules and cells. The introduction of superoxide dismutase preparations also reduces the intensity of lipid peroxidation processes. In addition, superoxide dismutase preparations indirectly prevent thrombosis, dysfunction of the kinin system, restore the permeability of microvessels, and have other effects. The introduction of superoxide dismutase prevents the inactivation of nitric oxide caused by the action of superoxide anion radical. Thus, the introduction of human Cu-, Zn-superoxide dismutase provides the inactivation of most types of reactive oxygen species, reduces the activity of free kinins and prevents the progression of any inflammatory process. Of particular note is the catalytic nature of the action of the enzyme (Beckmann R. Ten years of experience in the therapeutic use of superoxide dismutase / R. Beckman, R. Floe, K. Wilmsmann // M .: Medicine: compact information for your practice. Appendix 1/1987. - 30 p. .).

To study the effectiveness of the proposed method, the results of AKI prophylaxis were studied in 24 patients who underwent an operation - gastrectomy with esophageojunoanastomosis according to Gilyarovich for stomach cancer. Patients are divided into the main (n = 10) and comparison groups (n = 14), comparable in age, gender, comorbidity, and anesthetic management.

In both groups according to Yu.S. Polushin et al. (2003) the prognostic index (PrI) was determined before surgery and in the first 4-5 days of the postoperative period, the diagnostic index (CI) of AKI development: PrI = 0.002 (blood amylase in u / l) +0.021 (blood creatinine in umol / l) + 0.005 (lactate dehydrogenase in u / l) +0.071 (blood urea in umol / l) +0.147 (when the contrast flows into the pancreas) +1.098 (in the presence of intraoperative pancreatic injury) -3.058 and CI = 0.041 (gamma-glutamyl transpeptidase in u ) +0.076 (lactate dehydrogenase in u / l) +0.059 (ESR in mm / h) +0.008 (duration of operation / min) +0.162 (heart rate in beats / min) -36.4. With a positive value of CRI, AKI prophylaxis was required. With a CI value of less than 5, the presence of AKI is very doubtful and did not require specific treatment.

Research result: In the main and comparison groups, the PRI was 1.88 ± 0.46 and 1.63 ± 0.53, respectively. In the comparison group for the prevention of AKI during surgery, the potential of specific (5-fluorouracil, contrical or ingitrile, sandostatin) and nonspecific (prednisone, diclofenac) drugs was intravenously injected into the clinic. In the main group for specific prophylaxis of AKI, only REXOD was used. The human recombinant Cu-Zn superoxide dismutase preparation Rexod is administered intravenously. Immediately at the beginning of the operation, after induction of anesthesia, a bolus was administered at a dose of 0.1 mg / kg in 20 ml of a 0.9% NaCl solution. Further SOD was carried out in infusion media (solutions of 5% glucose, 0.9% NaCl solution) at a rate of 0.1 mg / kg / h. During particularly traumatic stages of the operation, the rate of administration was increased to 40 mg / h. Administration was continued for 12 hours after surgery. The main criterion for the adequacy of the therapy was considered indicators of the acid-base state, blood gases.

In the next three days of treatment in the intensive care unit, the intensive care programs in both groups did not differ. In the main group of patients, the CI was less than 5 (1.19 ± 0.8), which indicated the absence of any signs of AKI. In patients of the comparison group, the CI was significantly higher (4.22 ± 1.6) than in the main one. Moreover, in 6 (42.8%) of them, DI was more than 5, and in two (14.3%) patients, AKI, despite the prophylaxis, was clinically pronounced (CI = 17.6 and 10.97).

The results of comparing the incidence of AKI in both groups are evidence of the effectiveness of the use of SOD for the prevention of AKI

Claims (1)

The method of drug prophylaxis of acute postoperative pancreatitis, which consists in the use of an antioxidant preparation, characterized in that, as such, during the operation and the first 12 hours of the postoperative period, a recombinant superoxide dismutase preparation is administered intravenously, dropwise, the dose is individually selected based on the dynamics of the indicators of the acid-base state, blood gases and the invasiveness of surgery.