Skrypko, Deltsova, Klymenko, Gonchar, and Sheviak: The Use of Antihypoxant and Antioxidant Therapy in Comprehensive Treatment of Acute Small Intestinal Obstruction



Problem statement and analysis of the recent research

Despite the introduction of modern technologies of diagnostics and surgical interventions, acute small intestinal obstruction (ASIO) is one of actual problems in urgent abdominal surgery which is accompanied by high mortality of 12-25% [1, 2]. Change in secretory, absorption and barrier function of small intestine causes enteral insufficiency syndrome (ESI) which can leads to the development multiple organ failure and death at an early postoperative period [3, 4]. Timely resolution of acute intestinal obstruction is important in patients’ management. However, many trials have showed acute reperfusion damage of intestine wall develops after liquidation of strangulation and can cause increase in endogenous intoxication [5, 6].

Activation by free radical processes occurs as a result of metabolism disorders in case of ASIO. Lipid peroxidation products accumulate causing oxidative phosphorylation separation and inhibit electron transfer in mitochondrial respiratory chain. As a result, energy-depended functions are inhibited and multiple organ failure develops. Under conditions of intoxication and hypoxia in patients with ASIO, mitochondrial respiratory chain loses its property to receive electrons from other substrates except succinic acid which is intermediate compound of Krebs cycle. Additional exogenic admission of succinic acid enriches energy deficiency in human body [1].

The objective of this research was to study Reamberin solution effects with its antioxidant, antihypoxant and indirect hepatoprotective properties on clinical sings of ileus and morphological liver status.

Materials and methods

Results of 232 patients’ examination were analyzed including 202 patients with ASIO at the age of 30 to 80 years who were treated at Central City Hospital of Ivano-Frankivsk, Ukraine. The patients included 98 men (48.5%), 104 women (51.5%) and 30 apparently healthy individuals. ASIO reasons included strangulated hernia in 56 (27.7%) patients, including postoperative hernia in 22 (10.8%) patients; strangulated intestinal obstruction in 44 (21.7%) patients, adhesive obstruction in 63 (31.1%) patients, obturation intestinal obstruction in 17 (8.4%) patients. Clinical and biochemical parameters of the functional state of organism as well as histomorphologic parameters of resected section of small intestine were investigated at the preoperative period and on the 1st, 5th and 14th postoperative day.

The material for the study (small intestine of 13 patients) was sampled during small intestine resection. Small intestinal fragments were used as a control. They were taken during autopsy in 9 patients after 3-9 hours of death from diseases not associated with gastrointestinal tract disorders.

The patients were divided into two groups: main group – 102 persons, and control group – 100 patients. In order to correct metabolic disorders 400-800 ml of Reambein (“POLISAN”) solution (depending on severity) was introduced to patients of the main group 2 times a day i.v. with the speed of 90 drops per minute before the surgery and during the first 5 days of the postoperative period. Reamberin has antioxidant action causing a positive effect on aerobic processes in the cell reducing the production of free radicals and restoring cells energy potential [2]. The drug is licensed for use by State Pharmacology Center of MPH of Ukraine.

The experimental studies were conducted in the vivarium of Ternopil State Medical University named after I. Gorbachevsky during 2011-2012 years on 40 Vietnamese pigs weighing 15-25 kg. All interventions, care and euthanasia of animals was performed in compliance with the substantive provisions of the Convention on the protection of vertebrate animals used in experiments and other scientific purposes from 18.03.1986; the EU Directive № 609 from 24.11.1986, the order of Ministry of Health of Ukraine No 690 from 23.09.2009.

Surgical restoration of intestinal patency was performed in 12, 24, 36, 48 and 72 hours after disease modeling by resection of the affected area applying side-to-side interintestinal anastomosis. Anesthesia of surgical procedures and euthanasia were performed through i.v. administration of thiopental sodium in a dose calculated according to body weight of the animal after preliminary sedation. At the postoperative period, the animals of II group were additionally administered Reamberin solution i.v. twice a day for 5 days, in a dose of 10 ml per kg of body weight. Morphological and ultrathin body structure, the degree of endogenous intoxication and the balance of pro- and antioxidant systems by identifying ceruloplasmin (CP) were studied to assess liver state in the dynamics of the course and treatment of diseases. Blood serum of healthy and intact animals was used as a control.

Statistical processing of the results was performed using mathematical program complex for computer based on Microsoft Windows 1985-2005 as well as programs for statistical analysis Analys+Soft, 2007. Verification of samples distribution for normality was performed using Shapiro-Wilk test. Student-Fischer test for normally distributed samples and Wilcoxon-Mann-Whitney test for samples with distribution different from the normal were used to test the hypothesis of averages equality.

Results and discussion

Intensive augmentation of endotoxemia in the body of both patients and animals on the background of intestinal passage violation was established to depend on AOI duration (Table 1).

Table 1

Indices of oxidative-antioxidative balance and EI in patients with ASIO and in animals under experimental conditions (M±m)

Groups
Stages of
Examination
Indices
CP, IU
MWM, IU
DC, IU
MDA,
mcmol/l
А) Patients with ASIO
Norm (control n=8)
29.12±1.04
0.24±0.04
0.38±0.04
3.69±0.16
ASIO before the treatment
*25.47±0.85
**0.46±0.05
**0.53±0.04
***5.22±0.39
After treatment without Reamberin
1-2 days
***23.33±1.02
***0.54±0.06
***0.68±0.07
***5.72±0.61
5-6 days
26.68±2.05
***0.50±0.02
***0.78±0.03
**1.01±0.52
11-12 days
***22.29±1.33
***0.54±0.04
**0.57±0.05
***4.86±0.23
After treatment with Reamberin
1-2 days
23.96±0.95
0.69±0.03
0.64±0.10
5.51±0.64
5-6 days
°°34.45±1.15
°0.44±0.03
°°0.60±0.04
°5.12±0.25
11-12 days
°°28.13±1.77
°0.45±0.03
°0.40±0.02
°3.75±0.30
B) Experimental animals
Norm (n=10)
36.34±1.19
0.20±0.01
0.33±0.02
2.46±0.14
ІІ (n=20) without Reamberin 12
24
36
48
72
*89.74±2.31
***47.86±1.91
34.26±1.37
***25.28±1.01
***21.09±1.24
**0.29±0.02
***0.27±0.03
***0.33±0.03
***0.33±0.03
0.46±0.06
0.40±0.06
*0.52±0.06
***0.75±0.10
**0.81±0.12
***0.52±0.04
**4.32±0.62
*3.45±0.41
***4.56±0.40
***5.76±0.47
*3.05±0.15
ІV (n=20) with Reamberin
12
24
36
48
72
34.97±2.31
°54.70±1.56
°°°40.52±1.14
°°33.51±1.46
°°26.75±0.72
0.29±0.04
0.24±0.07
°°0.26±0.01
0.24±0.04
°0.34±0.01
0.40±0.06
0.50±0.06
°°°0.47±0.03
°0.50±0.05
0.56±0.08
3.64±0.43
3.20±0.52
3.56±0.33
°4.51±0.28
°3.59±0.18

Note.

Difference compared to norm:

* - p<0.05;

** - p<0.01;

*** - p<0.001.

Difference compared to type of treatment:

° - p<0.05;

°° - p<0.01;

°°° - p<0.001

In AOI clinical picture and AOI experimental model we detected the same changes of oxidation-antioxidant balance, EI, depending on the background of observations.

The table shows that CP activity in the serum of patients with ASIO before the treatment and especially in the experiment (II group) compared to the control decreased with further increase and subsequent decrease to critical level on 11th-12th days after curative therapy of patients and 72 hours of observations in experiment (III group). This CP dynamics is believed to be the result of increased enzyme rate due to the increase in the substrate of its action with further increase in synthesis of “acute phase protein” liver. Progressive reduction of CP level which occurred in the course of ASIO (II group) without the use of Reamberin is a bad prognostic sign. After ASIO surgery CP level had a slight tendency to normalization.

In some periods CP level in animals of III group exceeded by 6-7 IU the same compared to the second group of animals, and its significant decrease lower than the control indices was observed only after 72 hours of ASIO. After ASIO surgery its activity in the serum approached to the normal range on background of Reamberin.

The research of primary (DC) and secondary products of lipid peroxidation (MDA) in serum indicates lipid peroxidation process intensification during the course of ASIO surgery. Toxicity of blood serum correlated with the level of lipid peroxidation products. One of its manifestations is the initiation of free radical oxidation in target organs, especially in the liver [3]. The levels of DC and MDA were higher than the normal level in patients and in experiment at the period of clinical recovery.

Reamberin use for therapeutic purposes caused reduction of lipid peroxidation intensity in ASIO. We observed the typical changes in the liver in cases of ASIO in patients as in the experiment and were approximately in the same direction. Enlargement of the central veins and capillaries, tissue swelling, dyscomplectation of hepatocytes beams with all kinds of degenerative changes and focal necrosis surrounded by histio-lymphocytic infiltrates in the cytoplasm were noted during autopsy in 13 persons who died after surgery for ASIO.

Ultra-thin liver structure was studied in 5 patients with ASIO. Profound changes in the liver parenchyma was established to correlate with disease stage and duration of intestinal obstruction and indicated necrobiotic changes development in all components of the body. Large electron-transparent spaces in hepatocytes cytoplasm were observed. Organelles remains and thin granular substance were occasionally noted there and smooth endoplasmic reticulum was missing. Granular endoplasmic reticulum in the form of short tubules often extended was scattered in the locations of organelles that remained. Hepatocytes nuclei were in a state of pycnosis with density of parietal component. Mitochondria were swollen with structure loss and Disse’s spaces were completely destroyed. Necrosis was also observed in endothelial cells and Kupffer sinusoid cells.

Morphological changes and ultra-thin structure of liver in experimental animals had a lot in common with those of ASIO patients. Liver of animals responded to laparotomy with central venous hyperemia and adiemorrhysis, and dyscomlectation of hepatic beams, degenerative changes in hepatocytes which stabilized on 4th-5th days of the experiment. Part of mitochondria tended to swell with partial lysis of cristae in 24 hours of the experiment. Granular endoplasmic reticulum in most cells was disorganized and represented by single small tubules, decrease was observed until smooth endoplasmic reticulum disappearance, Golgi apparatus was atrophied, Disse’s spaces were sharply narrowed with hyalinization symptoms. Liver sinusoids were filled with blood elements. Degenerative changes in hepatocytes increased in 48 hours. Cells nuclei were with different introsusceptions, others were swollen, almost empty. Most mitochondria in cells dramatically increased in size with almost absent cristae, and they appeared almost empty in some parts of the cell. Granular endoplasmic reticulum was presented by degranulated small tubules. Most of the cytoplasm was empty or filled with fragments of some organelles. Smooth endoplasmic reticulum and Golgi apparatus were atrophied and detection of their structure was not possible. Many hepatocytes were in a state of necrobiosis and some of them were necrotic. Described changes were expressed in somewhat lesser degree on the background of Reamberin solution additional use.

In 72 hours after intestinal patency restoration without Reamberin solution prescription, ultrathin elements structure of liver worsened compared to the data before surgical treatment and their partial recovery was observed only in some isolated groups of parenchymal cells. Normalization of the fine structure of hepatocytes majority was observed during the same period in case of Reamberin inclusion to the complex treatment.

The data of morpho-dynamics and ultra-thin structure of liver in patients with ASIO corresponded to the so-called nonspecific reactive hepatitis, the extent of which increased with increase in of EI products levels.

Conclusions

  1. Correlation between stages of pathological morphological changes of liver in case of ASIO and intensification of endogenous intoxication in human body and during experiment was established.

  2. Additional use of Reamberin caused energy potential activation in cells, acceleration of intestinal passage and significant decrease in endotoxicosis degree, intensive decrease in morphology and functional changes in liver and level of endogenous intoxication.

Prospects for further research

Inclusion of pathogenesis-based therapy to protocols of comprehensive surgical treatment of patients with ASIO will be proposed based on the research results.

References

1 

IYa Dziubanovskyi, KH Poliatsko. Profilaktyka pohlyblennia enteralnoi nedostatnosti ta endohennoi intoksykatsii u khvorykh na hostru neprokhidnist tonkoho kyshechnyka. In: Proceedings of scientific conference of surgeons of ternopillia. Ternopil; 2002. p. 38-40.

2 

MG Romantsov, TV Sologub, AL Kovalenko. Reamberin 1,5% dlia infusiy - primenenie v klinicheskoi prakrike: rukovodstvo dlia vrachei. The Pharma Innovation Journal. 2000;158.

3 

M Mates. Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology. 2000;153 (1-3):83-104.

4 

AS Loginov, LI Aruin. Klinicheskaya morfologiya pecheni. Moskow: Meditsina; 1985. 240.

5 

K Ito, H Ozasa, S Horikawa. Edaravone protects against lung injury induced by intestinal ischemia/reperfusion in rat. Free-Radic-Biol-Med. 2005;38 (3):369-374.

6 

Leenwen PA Van, MA Boermeester, AP Houdijk, et al. Clinical significance of translocation. Gut. 1994;35 (1):28-34.



Copyright (c) 2017 V. D. Skrypko, O. I. Deltsova, A. O. Klymenko, M. H. Gonchar, P. I. Sheviak

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