RU2812594C1 - Method of preventing endothelial damage in critically ill patients - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to intensive care of critical conditions, and can be used to improve the results of treatment of patients with peritonitis, sepsis, and new coronavirus infection. In patients in critical conditions, from the time of registration of multiple organ failure, the volume of infusion is calculated. With a calculated infusion volume of 10 ml/kg/day or less, infusion therapy is carried out with a solution of meglumine sodium succinate at a rate of up to 4.5 ml/min at the calculated dose. When the estimated infusion volume is more than 10 ml/kg/day, infusion therapy is carried out with a solution of meglumine sodium succinate together with crystalloid solutions and/or blood products. A solution of meglumine sodium succinate is administered in an infusion volume of 10 ml/kg/day at a rate of up to 4.5 ml/min through a separate vascular access. The administration of a solution of meglumine sodium succinate is carried out until the symptoms of multiple organ failure are relieved.

EFFECT: method makes it possible to achieve accelerated normalization of the initially elevated level of endothelial cells circulating in the blood in patients with a critical condition, as well as to reduce the severity of multiple organ failure, length of hospitalization, the number of complications, and also increase the chances of patient survival.

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Description

Field of technology

The invention relates to the field of medicine, namely to intensive care of critical conditions. May be applicable, for example, to improve treatment outcomes for patients with peritonitis, sepsis, and new coronavirus infection.

Prior Art

A key aspect of the pathophysiology of critical illness is endothelial dysfunction and damage. At the same time, the severity of damage to this large-scale element of the vascular system in sepsis, severe blood loss, polytrauma, burns, etc. highly correlates with the severity of progressive multiple organ failure syndrome (MODS). The loss of its physiological functions by the vascular endothelium is characterized by the loss of its anticoagulant properties, increased proinflammatory response, and dysregulation of vascular tone. The study of endothelial dysfunction is important in predicting the course, development of complications and outcomes of the disease, assessing the effectiveness of intensive care in critical conditions. Based on the fact that vascular endothelial cells are the first to interact with parenterally administered infusion drugs, one of the options for endothelial protection may be the conscious choice of these media based on assessing the effect of their influence on the severity of endotheliopathy according to its direct and indirect signs. Despite the fact that in conditions of severe endothelial dysfunction the possibility of additional infusion damage cannot be excluded, we have not encountered methods of endothelial protection with infusion solutions used in the intensive care of critical conditions.

There is a known method that describes the anti-apoptotic effect of trimetazidine modified release on endothelial cells (Myocardial cytoprotectors have an anti-apoptotic effect on endothelial cells of the vascular wall / A.I. Inzhutova // Cardiovascular Therapy and Prevention, 2010; 29-32). The method is characterized by the fact that taking modified trimetazidine activates oxidative decarboxylation and enhances aerobic glycolysis, normalizes the functioning of membrane ion channels, preventing the accumulation of intracellular Ca2+, which is manifested by a decrease in the content of apoptotic endothelial cells in the blood.

The disadvantages of this known method are: the need for long-term administration of the drug (3 weeks), which makes it irrelevant for patients in critical condition; lack of proven effect on the function and structure of endothelial cells; lack of a specific point of application in relation to endothelial cells.

There is a known method for correcting endothelial dysfunction using a synergistic therapeutic composition containing the additive meldonium salt of acetylsalicylic acid as a corrector of endothelial dysfunction and a reductase inhibitor HMG-CoA (LV14963 Corrector of endothelial dysfunction).

The disadvantage of this method is that it is aimed at the prevention and/or treatment of thrombosis, as well as thrombotic conditions. At the same time, the proposed drug does not have a direct effect on endothelial cells, their contacts, or their protection. Moreover, the effectiveness of the method was positively assessed in an experimental model of endothelial dysfunction reproduced using a NO synthesis blocker, which is not the key and/or the only factor in the development of endothelial dysfunction.

There is also a known method for preventing the development of endothelial dysfunction in patients suffering from duodenal ulcer complicated by hypertension, including the administration of antibacterial, antihypertensive drugs and a nitric oxide donor - tivortin (Patent UA 44424 Method for prevention of endothelial dysfunction development in patients suffering from the duodenum peptic ulcer complicated with hypertension).

The disadvantages of this method are: restriction of its use only for patients with duodenal ulcer complicated by hypertension, the content of drugs in the treatment regimen, the use of which is unacceptable and contraindicated for patients with other pathologies, the impossibility of using the proposed method for patients with systemic inflammatory response syndrome.

There is a known method of treating endothelial dysfunction by administering dalargin in the form of a sterile crystalloid solution for infusion (patent RU 2657416 C1). The method is characterized by the fact that for the correction of endothelial dysfunction in multiple organ failure syndrome in critical conditions, in severe sepsis and septic shock, in systemic inflammatory response syndrome after heart and vascular surgery, in ischemia-reperfusion syndrome in ischemic stroke and myocardial infarction, in edema lung and acute respiratory distress syndrome, the solution is administered at different time intervals with different durations intravenously at the rate of 50-200 mcg*kg of the patient’s body weight.

The disadvantages of the known method are the impossibility of achieving the concentration of 50-200 mcg*kg indicated in the patent in clinical practice, because dalargin is a peptide drug and is susceptible to the action of endogenous peptidases; according to the literature, it is not detected in the bloodstream half an hour after administration. Thus, to maintain the concentration of dalargin in the blood plasma, its continuous infusion is required at a dose of 50-200 mcg * kg * hour, which is ten times the maximum permitted daily dose (according to the manufacturers' instructions, it is 20 mg)

There is a known method of endothelial protection, described in a group of medical articles covering various aspects of the use of glucocorticosteroids for endothelial protection in experimental and clinical practices (Patterson EK, Cepinskas G and Fraser DD (2022) Endothelial Glycocalyx Degradation in Critical Illness and Injury. Front. Med. 9:898592 doi: 10.3389/fmed.2022.898592 - Brettner F, Chappell D, Nebelsiek T, Hauer D, Schelling G, Becker BF, et al. Preinterventional hydrocortisone sustains the endothelial glycocalyx in cardiac surgery. Clin Hemorheol Microcirc. (2019) 71: 59-70. doi: 10.3233/ CH-180384; - Yanase F, Tosif SH, Churilov L, Yee K, Bellomo R, Gunn K, et al. A randomized, multicenter, open-label, blinded end point, phase 2, feasibility, efficacy, and safety trial of preoperative microvascular protection in patients undergoing major abdominal surgery. Anesth Analg. (2021) 133:1036-47. doi: 10.1213/ANE.0000000000005667; - Lindberg-Larsen V, Ostrowski SR, Lindberg-Larsen M, Rovsing ML, Johansson PI, Kehlet H. The effect of pre-operative methylprednisolone on early endothelial damage after total knee arthroplasty: a randomized, doubleblind, placebo-controlled trial. Anaesthesia. (2017) 72:1217–24. doi: 10.1111/anae.13983; - Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19. JAMA. (2020) 324:1–13. doi: 10.1001/jama.2020.17023). The method involves the use of regular intravenous injections of drugs from the group of glucocorticosteroids for severe and extremely severe COVID-19, which have anti-inflammatory and endothelioprotective properties. The drug begins to be administered immediately upon admission of the patient to the intensive care unit, while dexamethasone is recommended at a dose of 6-20 mg/day intravenously, depending on the severity of the patient’s condition over 1-2 administrations; methylprednisolone at a dose of 60 mg/infusion/intravenously every 6-8 hours. The maximum dose of GCS is used for 3-4 days, and then reduced when the condition stabilizes (relief of fever, stable decrease in CRP levels, ALT and/or AST activity, serum LDH blood). The dose of GCS is reduced by 20-25% per administration/day in the first 2 days, then by 50% every 1-2 days until complete withdrawal.

The disadvantages of the analog include, first of all, the obligate concomitant effects of long-term use of systemic glucocorticoids:

1) From the endocrine system: decreased glucose tolerance, steroid diabetes mellitus or manifestation of latent diabetes mellitus, suppression of adrenal function, Itsenko-Cushing syndrome (moon-shaped face, pituitary-type obesity, hirsutism, increased blood pressure, dysmenorrhea, amenorrhea, muscle weakness, striae), delayed sexual development in children.

2) From the digestive system: nausea, vomiting, pancreatitis, steroid ulcer of the stomach and duodenum, erosive esophagitis, gastrointestinal bleeding and perforation of the wall of the gastrointestinal tract, increased or decreased appetite, indigestion, flatulence, hiccups. In rare cases, increased activity of liver transaminases and alkaline phosphatase.

3) From the cardiovascular system: arrhythmias, bradycardia (up to cardiac arrest); development (in predisposed patients) or increased severity of heart failure, changes in the electrocardiogram characteristic of hypokalemia, increased blood pressure, hypercoagulation, thrombosis. In patients with acute and subacute myocardial infarction - the spread of necrosis, slowing down the formation of scar tissue, which can lead to rupture of the heart muscle.

4) From the nervous system: delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia, increased intracranial pressure, nervousness or anxiety, insomnia, dizziness, vertigo, pseudotumor of the cerebellum, headache, convulsions.

5) From the senses: posterior subcapsular cataract, increased intraocular pressure with possible damage to the optic nerve, tendency to develop secondary bacterial, fungal or viral eye infections, trophic changes in the cornea, exophthalmos, sudden loss of vision (with parenteral administration in the head, neck , nasal turbinates, scalp, deposition of drug crystals in the vessels of the eye is possible).

6) From the metabolic side: increased excretion of calcium, hypocalcemia, increased body weight, negative nitrogen balance (increased breakdown of proteins), increased sweating.

7) Caused by mineralocorticoid activity - fluid and sodium retention (peripheral edema), hypernatremia, hypokalemic syndrome (hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue).

8) From the musculoskeletal system: slower growth and ossification processes in children (premature closure of epiphyseal growth zones), osteoporosis (very rarely - pathological bone fractures, aseptic necrosis of the head of the humerus and femur), rupture of muscle tendons, steroid myopathy, decreased muscle mass (atrophy).

9) From the skin and mucous membranes: delayed wound healing, petechiae, ecchymosis, thinning of the skin, hyper- or hypopigmentation, steroid acne, stretch marks, tendency to develop pyoderma and candidiasis.

Which in general negatively affects the effectiveness of treatment of a critical condition, including those accompanied by a systemic inflammatory reaction.

Known patent RU 2504375 C1 “Pharmaceutical composition for the treatment of diseases associated with endothelial dysfunction”, which describes a pharmaceutical composition for the treatment of diseases associated with endothelial dysfunction. The composition contains as an active ingredient a methylpyridine derivative or a pharmaceutically acceptable salt thereof - 1.0-6.0 wt.%; purine - 10.0-80.0 wt.% and excipients - the rest. Compounds from the group: 3-(N,N-dimethylcarbamoyloxy)-2-ethyl-6-methylpyridine succinate, 3-methylpyridine succinate, 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride, 6-trichloromethyl- 2-chloropyridine (nitrapyrine), 2-ethyl-6-methyl-3-hydroxypyridine succinate. The composition contains inosine, adenosine, and hypoxanthine as purines. The pharmaceutical composition can be made in the form of injections, lyophilisate, hard capsules, tablets, suppositories.

However, 3-(N,N-dimethylcarbamoyloxy)-2-ethyl-6-methylpyridine succinate is toxic. When administered intravenously to mice, its LD50 is 97.94 (91.13-105.3) mg/kg for females and 109.0 (97.0-121.0) for males. With intraperitoneal administration, LD5 0 is 146.4 (135.0-157.0) mg/kg for females and 159.7 (149.2-169.5) mg/kg for males. When administered orally, LD50 for females is 189.7 (161.0-224.0) mg/kg and for males - 197.7 (190.2-204.5) mg/kg, and when administered to rats: intraperitoneally - LD5 0 is 146.8 (124.2-173.5) mg/kg, orally - for females LD5 0 is 181.7 (154.6-213.5) mg/kg and for males 189.5 (168. 1-213.7) mg/kg. This does not allow the drug to be used in doses that have a systemic endothelioprotective effect when used intravenously; oral administration in conditions of developing critical condition, emerging multiple organ failure in patients is often not applicable (due to intestinal paresis, operations on the gastrointestinal tract). In addition, the known pharmaceutical composition makes it possible to reverse the development of endothelial dysfunction and thereby significantly reduce the risk of complications only in acute ischemic lesions of the brain, myocardium after surgery and cerebrovascular insufficiency in various diseases. The use of 3-(N,N-dimethylcarbamoyloxy)-2-ethyl-6-methylpyridine succinate for the purpose of endothelial protection in such critical conditions as, for example, sepsis, severe blood loss, and associated trauma did not demonstrate a significant effect on the severity of endothelial dysfunction in the experiment and clinic. This is primarily due to the insufficiency of the permitted daily and course dose.

Currently, the creation of new highly effective and safe drugs with antihypoxic and cytoprotective effects, which can be used in the treatment of various diseases in the acute and subacute periods for the treatment of endothelial dysfunction, is of great importance.

Currently, no methods have been found in the prior art to prevent endothelial damage in critically ill patients. In known analogues using reamberin (for example, patents RU 2242236 C1 and RU 2324479 C2), therapy is carried out to quickly restore the deficit in circulating blood volume, normalize the chemical composition of plasma and intercellular, cellular fluid, its osmolarity, as well as a positive effect on the reduction of peroxide products lipid oxidation. This is an outdated approach to understanding the goals of critical care critical care. We have another goal - a more tangible, concrete one, namely protection - the preservation of the vascular endothelium in a critical state under conditions of hypoxia and intoxication. In other words, at the dawn of the use of Reamberin, it was believed that a decrease in the severity of organ failure when used is achieved due to the antioxidant effect, the effect associated with improving the utilization of glucose by tissues, the effect of normalizing the disturbed chemical composition of plasma (osmolarity), as well as the effect of reducing plasma toxicity (detoxification Effect). We are talking about the fact that the use of reamberin directly affects vascular endothelial cells, allows you to preserve the integrity of the vascular endothelium, which reduces the severity of endotheliopathy, disturbances in the transport of substances and fluid from the vessels into the intercellular space.

The essence of the invention

The technical objective of the present invention is to prevent disruption of the structure and function of endothelial cells during endothelial dysfunction in patients with critical conditions, without significant negative effects on the immune system and additional toxic effects, for example, a systemic inflammatory response.

The technical result is accelerated normalization of the initially elevated level of endothelial cells circulating in the blood in patients with critical condition, as well as a decrease in the severity of multiple organ failure, length of hospitalization, number of complications, and increased survival.

The technical result is achieved in that the method of preventing endothelial damage in patients in critical conditions, including infusion therapy, is carried out in such a way that the volume of infusion is calculated for the patient from the moment of registration of multiple organ failure. With a calculated infusion volume of 10 ml/kg/day or less, infusion therapy with a solution of meglumine sodium succinate is carried out at a rate of up to 4.5 ml/min at the calculated dose. When the estimated infusion volume is more than 10 ml/kg/day, infusion therapy is carried out with a solution of meglumine sodium succinate together with crystalloid solutions and/or blood products. In this case, a solution of meglumine sodium succinate is administered in an infusion volume of 10 ml/kg/day at a rate of up to 4.5 ml/min through a separate vascular access. The administration of a solution of meglumine sodium succinate is carried out until the symptoms of multiple organ failure are relieved.

The invention is carried out as follows.

From the moment the patient is transferred to the intensive care unit and after registration of multiple organ failure, the level of circulating endothelial cells is determined daily, using a diagnostic test on a flow cytometer, followed by intravenous administration of a solution of meglumine sodium succinate, and then until the symptoms of multiple organ failure are eliminated or its level decreases to the original one. In this case, the primary determination of CEC in blood plasma is carried out at the time the patient is admitted to the intensive care unit, before the start of intensive care, and then with a frequency of once a day until the symptoms of multiple organ failure are relieved.

The introduction of a solution of meglumine sodium succinate is performed as follows:

- For a calculated infusion of up to 10 ml/kg/day, a solution of meglumine sodium succinate is used as an infusion agent with an administration rate of up to 4.5 ml/min.

- With a calculated infusion of more than 10 ml/kg/day, the infusion volume of sodium succinate meglumine solution should be 10 ml/kg/day when administered through a separate vascular access - at a rate of up to 4.5 ml/min. A separate vascular access is an intravenous catheter additionally installed in a central or peripheral vein (or an additional catheter tract) used to prevent mixing of meglumine sodium succinate solution with other parenteral drugs.

The indicated volumes of infusion of meglumine sodium succinate are calculated based on the maximum daily dose of the drug per patient’s body weight, in accordance with the instructions for its use. It was previously noted that the more succinate is used, the greater the endothelial protective effect.

The indicated injection rates were selected based on theoretical and experimental testing for the following reasons:

The first is that at high rates of administration, the amount of unchanged drug in the urine increases, which is subsequently not absorbed.

The second is that if the infusion rate in a critical condition exceeds the specified values, then this leads to the risk of deterioration of the patient’s condition due to possible independent hydrodynamic endotheliopathy.

Example 1

Upon admission of patient M., 58 years old, to the intensive care unit with a diagnosis of Primary disease: Coronavirus infection COVID-19, the virus was identified (U07.1). Severe degree. NEWS 6 points. Complications: bilateral polysegmental viral pneumonia, endotheliocytosis was determined to be significantly increased. Thus, the number of CECs per 3 ⋅ 10 ⁵ leukocytes was 10.47 * 10 ⁵ leukocytes. At the same time, the level of proper values of this indicator is 5±1.67 per 3 ⋅ 10 ⁵ leukocytes. The calculated infusion volume was 10 ml/kg/day. Only meglumine succinate solution was used as an infusion agent at an injection rate of up to 4.5 ml/min, daily, for 7 days of hospitalization. Against the background of prescribed therapy, a significant decrease in the initially elevated level of endotheliocytosis was determined at all stages of observation (p less than 0.031), starting from the second day. The level of endotheliocytosis during this period was determined to be 43.22% lower compared to the baseline, and by day 5 the difference increased and the decrease was 55.36% (p less than 0.03). The initially high level of endotheliopathy we identified in severe cases of the new coronavirus infection (NCI) COVID-19 was described earlier; the authors of these publications, independently of each other, made a similar conclusion based on the assessment of indicators of endothelial dysfunction, such as the level of circulating von Willebrand factor, homocysteine, C-reactive protein, D-dimer, fibrinogen, prothrombin time and platelets. At the same time, some researchers emphasize the relationship between the severity of endotheliopathy and the outcome of the disease and indicate that the manifestations of endotheliopathy are potentially corrected by the use of immunobiological therapy and extracorporeal detoxification methods. However, an unambiguous assessment of the effect of the composition of infusion therapy on the number of CECs in NCI has not yet been found in the literature available to us.

In parallel with the study of endotheliocytosis, we assessed the dynamics of the level of homocysteine (HC), which is an indirect biomarker of endothelial damage. When the patient was admitted to the intensive care unit (ICU), the concentration of GC in the blood plasma was also increased. It was 30.16 µmol/l. The proper value of this indicator in adults ranges from 5-15 µmol/l for men. An analysis of the dynamics of the GC level showed that against the background of infusions of a succinate-containing antihypoxant - reamberin (meglumine sodium succinate), starting from the 4th day of therapy, significant differences with an initially increased level are determined (p less than 0.042). During this period, the GC concentration was 24.71 μmol/L. On the 7th day the indicator was normalized, the differences in the concentration of GC with the initial indicator were even more significant. It was 12.72 µmol/l (p less than 0.014) less than the initial value.

When analyzing the levels of endothelemia and homocysteine in the dynamics of both groups, we studied the linear correlation between them, which revealed a noticeable connection (Pearson's correlation coefficient plus 0.62). This direction of the linear correlation between the levels of endothelemia and homocysteine indicates the significance of the influence of the infusion of succinate containing antihypoxant both on the correction of cellular damage and on the mechanisms causing the increase in GC.

Example 2

Patient S., age 68 years. Diagnosis: Gangrenous cholecystitis. Choledocholithiasis. Cholangitis. Compensated papillostenosis. Complications: limited biliary fibrinous peritonitis. Sepsis. Multiple organ failure.

General history Past, concomitant diseases and operations: acute respiratory infections, acute bronchitis. Gallstone disease for several years, chronic gastroduodenitis, chronic pancreatitis, chronic pyelonephritis, arterial hypertension. Allergic history to previously taken medications, no allergic reactions were noted. There was no blood transfusion.

History of the disease: 08/08/22 operated on for acute calculous cholecystitis - cholecystectomy. 10/13/22 - re-operated for choledocholithiasis: laparotomy, transduodenal papillosphincterolithotomy, common bile duct drainage. 12/20/2022 intense pain in the right hypochondrium. Painkillers, antispasmodics at home. On December 24, 2022, he was hospitalized in the 1st surgical department of the North-Western Regional Scientific and Clinical Center with a diagnosis of perforation of a hollow organ. Peritonitis. Emergency surgery: laparoscopy, revision, adhesiolysis, choledocholithotomy, common bile duct drainage according to Kehr. Sanitation, drainage of the abdominal cavity. Anesthesia: endotracheal anesthesia and mechanical ventilation. Diagnosis: postcholecystectomy syndrome, choledocholithiasis. Cholangitis. Hypertension in the biliary tract with bile leakage in the abdominal cavity. Sepsis. Diffuse bile peritonitis. Complaints upon admission to the intensive care unit: pain in the area of the postoperative wound and drains, aching abdominal pain, general weakness, periodic nausea. There was no vomiting. There was no stool for 4 days, no gas. Urine flow through the Foley urethral catheter, urine output 0.8 l. per day (Lasix stimulation in total - 200 mg) body temperature 37.2 - 37.8°C. General inspection. The condition is very serious, consciousness is stunned, the position is passive. The skin is light yellow and dry. Turgor and elasticity are reduced. The sclera is light yellow, there is a cataract in the right eye. Breathing in the lungs is vesicular-hard, weakened in the lower parts, isolated wheezing. Saturation 94% on oxygen inhalation through a laryngeal mask 6 l/min. Heart sounds are rhythmic and muffled. The abdomen is soft, moderately painful in the epigastrium, hypochondrium, in the area of the postoperative wound and drainage: moderately evenly swollen. Hepatic dullness is preserved. Symptoms of peritoneal irritation are questionable. Peristalsis is single. Blood pressure 90/60, heart rate 102 - norepinephrine 0.15 mcg/kg/min. In the acid-base state of arterial blood, an increase in lactate to 2.7 mmol/l and a deficiency of BE bases (minus 4.7 mmol/l) were noted. Initially, upon admission of the patient, pronounced endotheliocytosis was noted in the blood with a CEC level of 11.7 * 10 ⁵ leukocytes (the limit of reference values is up to 5 * 10 ⁵ leukocytes), a homocysteine level of 17.8 µmol/l (the reference interval for a man is from 6.2 µmol/l up to 15 µmol/l). On the second day after admission: CEC 10.1 * 10 ⁵ leukocytes, homocysteine - 29.1 µmol/l. On the third day of observation in the intensive care unit: CEC 5.7 * 10 ⁵ leukocytes, homocysteine - 25.2 µmol/l. On the seventh day of inpatient treatment in the surgical department: CEC 2.2 * 10 ⁵ leukocytes, homocysteine - 6.9 µmol/l.

Treatment in a surgical hospital:

1. Stationary mode;

2. Diet with enteral tube feeding “Nutricomp Intensive” from the 2nd day of the postoperative period 1.2 g/kg protein;

3. Reamberin (meglumine sodium succinate) 1000.0 ml intravenous drip over 9 hours, with an infusion rate of 1.85 ml/min;

4. Drotaverine 4.0 intravenous drip;

5. Ringer's solution 500.0 KCl 20.0 4% intravenous drip (depending on physiological need and current fluid balance under control of weight and ultrasound of the diameter of the inferior vena cava);

6. Cerucal 4.0 intravenous drip;

7. Clexane 0.4 ml subcutaneously 1 time per day;

8. Octreotide 0.1 subcutaneously 3 times a day;

9. Omez 40 mg. Intravenously 2 times a day;

10. Sulcef and Metranidazole.

Conclusion The patient was in the surgical hospital from 12/24/2022 to 01/21/2023, and in the intensive care ward from 12/24/2022 to 12/28/22. The total number of bed days spent in the hospital was 27. During the stay in the hospital, general and biochemical blood tests, a general urinalysis, chest X-ray, ultrasound of the abdominal organs, SCT of the abdominal cavity, and chest were performed. The final diagnosis was made: postcholecystectomy syndrome. Choledocholithiasis. Cholangitis. Compensated papillostenosis. Complications: internal biliary fistula. Limited biliary fibrinous peritonitis. Sepsis. Multiple organ dysfunction.

The patient was discharged in satisfactory condition.

Example 3

Patient K., a woman aged 65 years, was admitted to the therapeutic department on September 19, 2021 with a diagnosis of community-acquired polysegmental bacterial pneumonia, moderate severity, DN 1. Concomitant: coronary heart disease (atherosclerotic cardiosclerosis, post-infarction cardiosclerosis), arterial hypertension grade 2, risk 4 .

History of illness: fell ill on September 10, 2021, when weakness appeared, body temperature rose to low-grade levels, and dry cough. She took ceftriaxone 1000 mg 2 times a day intravenously. Polymerase chain reaction (PCR test) for NCI dated September 16, 2021 - negative. During treatment, the patient’s health worsened; there was an increase in cough, fever up to febrile levels, and shortness of breath when walking. A computed tomography scan of the chest organs (CT) on October 19, 2021 revealed signs of bilateral polysegmental pneumonia. She was hospitalized in a therapeutic hospital on September 19, 2021. Upon admission, the condition was of moderate severity due to symptoms of intoxication and bronchopulmonary syndrome. A general blood test upon admission revealed a relative leukocytosis of 12.5 ⋅ 10 ⁶ . When assessing the biochemical blood test at the time of admission, no pathological changes were identified. The results of a general urinalysis were within normal limits. When assessing coagulogram parameters, manifestations of hypercoagulation were noted in the form of an increase in the prothrombin index to 142. At the time of admission, SpO2 saturation was 92-93%. From the moment of admission, respiratory support with humidified oxygen was started through a face mask with a flow rate of 6 l/m, syndromic therapy was started in accordance with clinical recommendations. Anticoagulant therapy (Clexane 0.4 ml once a day subcutaneously) and infusion therapy with balanced crystalloid solutions were also prescribed. Against the background of the treatment, positive dynamics were noted in the form of a decrease in signs of respiratory failure, a decrease in dependence on respiratory support with humidified oxygen, an improvement in general well-being, an increase in the level of oxygen saturation to 97-98% against the background of oxygen therapy (5-7 l/min). During the control radiography of the OGK on September 25, 2021, positive dynamics were noted in the form of a decrease in the area of shading of the pulmonary fields. When assessing a general blood test dated September 27, 2021, signs of leukocytosis were noted (leukocytes - 13.5 ⋅ 10 ⁹ ); In the biochemical blood test, normalization of the level of C-reactive protein was noted. When assessing the parameters of a general urine test dated September 29, 2021, no pathological abnormalities were identified. In the coagulogram dated September 29, 2021, against the background of continued anticoagulant prophylaxis using low molecular weight heparins in a prophylactic dosage (Clexane 0.4 mg 1 time per day subcutaneously), the coagulogram parameters returned to normal. Against the background of ongoing therapy and improvement of the condition, on October 1, 2021, the patient suddenly experienced heavy bleeding from the urinary tract during urination, which was accompanied by hemodynamic disturbances of the hypovolemic type: a decrease in blood pressure to 70/30 mm Hg, dizziness, tachypnea, confusion, pallor of the skin. Pain syndrome also occurred in the form of sharp pain in the suprapubic region. At the same time, an enlarged, painful bladder was palpated above the womb. The patient was urgently transferred to the intensive care unit, where hemostatic therapy was started using the drugs etamsylate 2 ml intravenously 3 times a day, Vicasol 1 ml intravenously 3 times a day, tranexamic acid 500 mg 2 times a day intravenously. Anticoagulant therapy was stopped. The patient was examined by a surgeon and urologist, and a urinary catheter was installed, through which a large amount of scarlet blood was released. Infusion therapy was prescribed taking into account physiological losses and electrolyte composition of the blood, transfusion therapy to correct posthemorrhagic anemia (packed red blood cells), and inotropic support with norepinephrine. When assessing the parameters of a biochemical blood test, a decrease in the level of serum iron to 4.0 µmol/l was revealed. In the general blood test, an increase in leukocytosis was noted to 24 × 10 ⁹ ), while the coagulogram parameters remained within normal limits. There were no signs of acute kidney injury, either at the onset of bleeding or during further follow-up (serum creatinine levels ranged from 58 to 67 µmol/l). A general urine analysis revealed gross hematuria, leukocyturia, and proteinuria. Gross hematuria persisted for 5 days during therapy. The patient was repeatedly consulted by a surgeon and urologist. No indications for surgical treatment were identified; conservative hemostatic therapy was continued. During videocystoscopy on October 4, 2021, a large blood clot was found in the lumen of the bladder, making examination difficult. The source of the bleeding could not be identified. As a result of the treatment, positive dynamics were noted in the form of relief of gross hematuria (light yellow urine was released through the urethral catheter). Symptoms of hypovolemia were relieved, inotropic support was discontinued, and the general condition improved somewhat. Blood tests revealed manifestations of posthemorrhagic anemia and the phenomenon of hypercoagulation necessary to stop bleeding. However, against this background, the patient again experienced an increase in the symptoms of respiratory failure, increased shortness of breath, and a decrease in the level of oxygen saturation to 92-93%, which required a re-intensification of respiratory support. When performing radiography of the OGK on October 5, 2021, positive dynamics were noted in the form of a decrease in the area of shading of the pulmonary fields. During a repeat videocystoscopy on November 6, 2021, the edematous mucous membrane of the bladder was visualized with multiple hemorrhages, superficially located dilated vessels, some of which bulged into the lumen of the organ. No pathological space-occupying formations or stones were identified in the bladder cavity. During further treatment, an improvement in the patient's condition was observed; relief of hematuria and pain syndrome, relief of respiratory failure, and a decrease in symptoms of intoxication and bronchopulmonary syndrome were clinically noted. There was a stabilization and improvement of laboratory parameters: normalization of hemoglobin and blood leukocyte levels, increase in serum iron levels, disappearance of signs of hematuria, leukocyturia and proteinuria in a general urine test.

Initially, upon admission, the patient’s blood showed mild endotheliocytosis with a CEC level of 6.7 per 3 ⋅ 10 ⁵ leukocytes (the limit of reference values is up to 5 per 3 ⋅ 10 ⁵ leukocytes, which was apparently associated with polysegmental pulmonary lesions of moderate severity), homocysteine level 15 .1 µmol/l. At the time of manifestation of blood loss and transfer to the intensive care unit: CEC 10.7 per 3 ⋅ 10 ⁵ leukocytes, homocysteine - 14.1 µmol/l.

In order to compensate for severe blood loss, the patient simultaneously underwent infusion-transfusion therapy using several vascular accesses. During treatment, a total of 780 ml of red blood cells, 1690 ml of fresh frozen plasma, and 2000 ml of Ringer's solution were rapidly transfused into the installed central venous catheter. For the purpose of endothelial protection, 800 ml of meglumine sodium succinate (patient weight 80 kg - total daily dose 10 ml/kg/day) was transfused into a separate peripheral vein at a rate of 4.5 ml/min. Thus, the duration of infusion of the daily dose of meglumine sodium succinate was 3 hours.

On the third day of observation and further, against the background of regular infusions of meglumine sodium succinate in the intensive care unit in a volume of 800 ml daily: CEC 3.2 per 3 ⋅ 10 ⁵ leukocytes, homocysteine - 16.0 µmol/l. On the seventh day of hospital treatment: CEC 2.0 per 3 ⋅ 10 ⁵ leukocytes, homocysteine - 4.7 µmol/l.

With a SpO2 saturation level of 97%, on October 10, 2021, the patient was discharged in stable condition as an outpatient. The prognosis of the disease is favorable. Clinical diagnosis. Main: Community-acquired bilateral polysegmental pneumonia, acute course. Respiratory failure of 1-2 degrees. Bleeding from the bladder. Related: Coronary heart disease (atherosclerotic cardiosclerosis, post-infarction cardiosclerosis), arterial hypertension grade 2, risk 4. Urinary tract infection.

Thus, during the declared non-standard therapy of patients in critical conditions, normalization of the CEC level is observed statistically faster and more pronounced than in the standard therapy groups. At the same time, in various types of critical conditions, differently expressed, with different duration and speed, rises in the level of CEC above the norm were observed, but always statistically more significant and faster than standard therapy.

Claims (1)

A method for preventing endothelial damage in patients in critical conditions, including infusion therapy, characterized in that the volume of infusion is calculated for the patient from the moment of registration of multiple organ failure; with a calculated infusion volume of 10 ml/kg/day or less, infusion therapy is carried out with a solution of meglumine sodium succinate at a rate of up to 4.5 ml/min at the calculated dose; with an estimated infusion volume of more than 10 ml/kg/day, infusion therapy is carried out with a solution of meglumine sodium succinate together with crystalloid solutions and/or blood products, while a solution of meglumine sodium succinate is administered in an infusion volume of 10 ml/kg/day at a rate of up to 4.5 ml/min through a separate vascular access; the introduction of a solution of meglumine sodium succinate is carried out until the symptoms of multiple organ failure are relieved.