RU2563175C1 - Method for preoperative stimulation of erythropoiesis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: if intraoperative blood loss makes 25% of circulating blood volume, chemotherapeutic preparations are used: 3 days before the operations, the preparations are administered in a single dose: aranesp in a dose of 1 mcg/kg subcutaneously and sorbifer in a dose of 10 mg/kg orally; one day before the operation, sorbifer is administered in a dose of 10 mg/kg; folic acid is administered orally in a dose of 6 mg/day; for 3 days, cyanocobalamin (vitamin B₁₂) is administered intramuscularly in a dose of 0.2 mg. If intraoperative blood loss exceeds 25% of circulating blood volume, the above chemotherapeutic treatment is added with donor-specific transfusion intraoperatively and on the 1^st or 2^nd day, however the administered donor blood volume is expected to reduce to 70-74% of the blood loss volume.

EFFECT: invention enables reducing the necessity of the postoperative blood transfusion.

2 tbl, 2 ex

Description

The invention relates to medicine, namely to pharmacology, resuscitation, hematology, and can be used in surgical operations.

Until recently, it was believed that the best method of replenishing blood loss is a transfusion of donated blood. In recent years, the attitude towards allogeneic blood transfusion has radically changed due to the constant threat of the development of infectious complications (AIDS, hepatitis B, C), the high cost of blood transfusion media, a sharp decrease in the number of donors, a change in their social status, as well as the refusal of patients from blood transfusion by religious considerations [Zhiburt, EB Textbook of transfusiology / E.B. Jiburt. - 2002. - 733 p.].

A high risk of complications associated with blood transfusion was the reason for the search for alternative methods to exclude the use of donated blood. One of the promising methods to exclude transfusion of donated blood is the use of chemotherapeutic drugs in the preoperative period to stimulate erythropoiesis. As a result of chemotherapy, there is a decrease in blood loss during surgical interventions.

As drugs that stimulate erythropoiesis, vitamins, iron preparations and hormones are used. Iron preparations and vitamins B ₆ , B ₁₂ , folic acid, contribute mainly to plastic support of erythropoiesis, without affecting the initial stages of differentiation of erythropoiesis progenitor cells. This limits their use due to their low efficiency in systemic disorders of erythropoiesis. Hormonal drugs (androgens, anabolic hormones) act on the differentiation and proliferation of erythroid cells, but their use violates the endocrine status of the body, and therefore side effects occur.

Based on the foregoing, in order to reduce blood loss during surgery, a promising direction is the development of new and improvement of known methods for stimulating erythropoiesis in the preoperative period.

There is a method of harvesting the required amount of autoblood before surgery using chemotherapeutic drugs (patent RU No. 232321515 from 08/10/2008). The proposed method has the following disadvantages: it is not taken into account that the active stimulation of erythropoiesis in combination with blood sampling in a short time (7 days) is accompanied by a stressful reaction of the body with the development of a systemic neuroendocrine response due to fluctuations in the volume of circulating blood (BCC), pain and emotional effects (especially in patients of childhood and adolescence), activation of the adrenal system, vasoconstriction, the predominance of catabolism over metabolism, increased consumption of oxygens fabrics.

A method for stimulating hematopoiesis in the postoperative period [patent RU No. 2245720 of 02/10/2005] using epocrine is described. When using this method, it is not taken into account that intraoperative autologous blood sampling (especially in children) is accompanied by sharp fluctuations in bcc, instability of hemodynamic parameters during surgery. In addition, with the stimulation of erythropoiesis, latent iron deficiency is possible, which affects the dynamics of the restoration of hematological parameters and the effectiveness of its implementation. The use of replacement infusion therapy does not exclude the likelihood of developing vasovagal reactions to temporary blood loss. Intraoperative harvesting of autologous blood does not eliminate the risk of bacterial infection and the risk of technical errors.

Enterol-250 was proposed to stimulate erythropoiesis [RU patent No. 2189826 from 09/27/2002]. At present, the proposed preparation cannot be widely introduced into practical public health due to the technical difficulties of the preparation of the preparation, inaccessibility for patients, and sufficiently effective erythrohemoglobin correction, treatment of infectious diseases in patients is a prerequisite.

Nikolenko V.V. and Abduev V.B. They suggested using autologous blood taken before surgery, and leading the patient before suturing the wound. The replenishment of blood loss was carried out by crystalloids. To ensure intraoperative normovolemia, Gelofusin and Reamberin were introduced [RU patent No. 2336898 from 10.27.2008]. The described method has the following disadvantages: preoperative harvesting of autologous blood does not eliminate the risk of bacterial contamination, leads to perioperative anemia and increases the need for transfusion. Drug-controlled hypotension does not exclude the development of formidable complications from the brain, heart and kidneys.

As a prototype of the selected method S.N. Bocharova et al. [RU patent No. 2409395 of 01.20.2011]. It was proposed that iron preparations be administered in a therapeutic dose within 5 preoperative days, 500 mg of 12.5% dicinone, 5% glucose solution, 500 ml of 6% hydroxyethyl starch (HES) are administered 40 minutes before the operation. With blood loss of 15-30% of the BCC, HES and prednisone are additionally administered. The proposed method does not affect the initial stages of differentiation of erythropoiesis progenitor cells, since only iron preparations are used, which leads to low efficiency of the erythropoiesis stimulation process. It is not taken into account that ineffective stimulation of erythropoiesis in combination with blood sampling in a short time (5 days) is accompanied by a stressful reaction of the body. The use of replacement infusion therapy does not exclude the likelihood of developing vasovagal reactions to temporary blood loss. Intraoperative autologous blood harvesting does not eliminate the risk of bacterial infection.

The objective of the present invention is to improve methods for stimulating erythropoiesis in the preoperative period.

The technical result is achieved in that the stimulation of erythropoiesis is carried out using various chemotherapeutic drugs in a certain sequence and at different times before surgery.

The technical result is simple, not requiring large material costs and is based on the use of erythropoietin, which enhance the proliferation of progenitor cells of the erythroid series - CFU-E, as well as all capable of dividing erythroblasts, accelerates the synthesis of hemoglobin in all erythroid cells, including reticulocytes. Erythropoietin, being a mitogenic factor and differentiation hormone, promotes the formation of red blood cells from partially determined erythropoiesis progenitor cells, and “triggers” the synthesis of mRNA in sensitive cells for the formation of enzymes involved in the formation of heme and globin. The hormone also increases blood flow in the vessels surrounding erythropoietic tissue in the bone marrow, and increases the release of reticulocytes from its sinusoids into the blood. The rate of incorporation of iron (59Fe) into cells specifically stimulates erythropoiesis without affecting leukopoiesis.

The use of vitamin B ₁₂ and folic acid is necessary for the synthesis of nucleoproteins, maturation and fission of cell nuclei. With their deficiency in erythroid tissue, disorders arise associated with the formation and slowed down maturation rate in the bone marrow of huge nucleated erythroid cells - megaloblasts. Large red blood cells formed from them - megalocytes have a sharply shortened period of life. These disorders lead to slow entry and rapid destruction of red blood cells in the blood.

The technical result is achieved by the fact that, according to the invention, for hemorrhages during the operation, constituting up to 25% of the BCC, the following chemotherapeutic drugs are used: 3 days before the operation, the drugs are administered once: Aranesp ™ at a dose of 1 μg / kg subcutaneously and sorbifer at a dose of 10 mg / kg orally, 1 day before the operation, sorbifer is administered orally at a dose of 10 mg / kg, folic acid is administered orally at a dose of 6 mg / day, and cyanocobalamin (vitamin B ₁₂ ) at a dose of 0.2 is administered daily intramuscularly for 3 days mg; with blood loss during the operation from 25% or more of the BCC, donor blood transfusion is additionally noted above for transfusion of blood donated intraoperatively and 1-2 days after surgery, but the volume of donated blood is reduced to 70-74% of the volume of blood loss.

The proposed method is as follows. Before surgery, all patients are stimulated with erythropoiesis with a full clinical and paraclinical examination: an ionogram is determined, a blood chemistry test, a general blood count, a general urinalysis, coagulation, iron, folic acid, vitamin metabolism, and the initial level of the hormone erythropoietin are performed. Of the functional examinations, it is mandatory: ultrasound, ECG, CT of the brain. According to the results of surveys and with baseline indicators that are within the age limits, the proposed method is carried out.

For hemorrhages during the operation, constituting up to 25% of the BCC, the following chemotherapeutic drugs are used: 3 days before the operation, the drugs are administered once: Aranesp ™ at a dose of 1 μg / kg subcutaneously and sorbifer at a dose of 10 mg / kg orally, 1 day before operations are administered orally sorbifer in a dose of 10 mg / kg, folic acid orally in a dose of 6 mg / day, and cyanocobalamin (vitamin B ₁₂ ) at a dose of 0.2 mg is administered daily intramuscularly for 3 days; with blood loss during the operation from 25% or more of the BCC, donor blood transfusion is additionally noted above for transfusion of blood donated intraoperatively and 1-2 days after surgery, but the volume of donated blood is reduced to 70-74% of the volume of blood loss.

In the early postoperative period and before the patient is discharged, a control clinical and laboratory examination is performed (OAK, OAM, biochemical blood test, a coagulogram, an ionogram, iron, folic acid metabolism, erythropoietin hormone are determined).

Examples of practical use of the proposed method

Example 1. Patient Sh. At the age of 3 months, weight 6 kg, was operated on with a diagnosis of "Scaphocephaly" (premature fusion of the sagittal suture of the skull). At the hospital stage, a clinical and laboratory examination was performed: a biochemical blood test, a general blood test, a general urinalysis, an ionogram, a coagulogram, indicators of the exchange of iron, folic acid, vitamins, the initial level of the hormone erythropoietin, ultrasound, ECG, and CT of the brain were determined. The initial data were erythrocytes (Er) 3.07 × 10 ⁹ , hemoglobin (Нb) 91 g / l, reticulocytes (Rt) 3.43 ‰, and the level of serum iron (Fe) 4 μvel.

In patients with a diagnosis of “Scafocephaly”, blood loss during surgery is 8–25% of the total circulating blood volume; therefore, only chemotherapeutic stimulation of erythropoiesis is prescribed to the patient. 3 days before the operation, the drugs were administered once: Aranesp ™ at a dose of 1 μg / kg subcutaneously and sorbifer at a dose of 10 mg / kg orally, 1 day before the operation, sorbifer was administered orally at a dose of 10 mg / kg, folic acid was administered orally at a dose of 6 mg / day, and for 3 days, cyanocobalamin (vitamin B ₁₂ ) was administered intramuscularly at a dose of 0.2 mg.

During surgery, blood loss amounted to 12% of the BCC. During the operation and in the early postoperative period, blood transfusion was not performed. In the early postoperative period, an increase in the absolute blood indices was noted: Er 3.45 × 10 ⁹ , Нb 109 g / l, Rt 10.43 ‰, Fe 20 mcvel. The patient stayed in the hospital for 6 days. Discharged in satisfactory condition. Before discharge: Er 3.96 × 10 ⁹ , Hb 121 g / l, Rt 12.43 Fe, Fe 30 mcvel. No side effects from the use of these drugs have been reported.

Example 2. Patient V., aged 12 months, weight 12.7 kg, was operated on with a diagnosis of trigonocephaly (premature fusion of the metopic seam of the skull). At the hospital stage, they conducted a clinical and examination: an ionogram, a biochemical blood test, a general blood test, a general urine test, a coagulogram, indicators of the exchange of iron, folic acid, vitamins, the initial level of the hormone erythropoietin, ultrasound, ECG, and CT of the brain. The initial data are Er 4.0 × 10 ⁹ , Hb 116 g / L, Rt 2.67 ‰, Fe 4.5 μvel. 3 days before the operation, the drugs were administered once: Aranesp ™ at a dose of 1 μg / kg subcutaneously and sorbifer at a dose of 10 mg / kg orally, 1 day before the operation, sorbifer was administered orally at a dose of 10 mg / kg, folic acid was administered orally at a dose of 6 mg / day, and for 3 days, cyanocobalamin (vitamin B ₁₂ ) was administered intramuscularly at a dose of 0.2 mg.

In patients diagnosed with Trigonocephaly, blood loss during the operation amounted to 25-35% of the total circulating blood volume, therefore, the patient was prescribed chemotherapeutic stimulation of erythropoiesis with transfusion of donated blood. During surgery, blood loss amounted to 28% of the BCC. During the operation, the patient received a blood transfusion, but the volume of transfusion was reduced by 50%. In the early postoperative period, an increase in the absolute blood indices was noted: Er 5 × 10 ⁹ , Нb 133 g / l, Rt 12.6 ‰, Fe 25 μvel. The patient stayed in the hospital for 6 days and was discharged in satisfactory condition. Before discharge: Er 3.65 × 10 ⁹ , Hb 121 g / l, Rt 10.43 Fe, Fe 23 μvel. No side effects from the use of these drugs have been recorded.

The examples given illustrate the possibility of using this method to stimulate erythropoiesis in the preoperative period and decide on the need for transfusion of donated blood in the postoperative period.

The method of stimulating erythropoiesis in the preoperative period was tested on the basis of the Federal Center for Neurosurgery, Tyumen. There were 20 patients under observation, of which, after stimulation, erythropoiesis was not required in 16 patients in the postoperative period of donated blood transfusion. Table 1 presents the statistically processed data - the results of the application of the proposed method. The advantages of the proposed method compared to the prototype are presented in table 2.

The proposed method is easily reproducible, does not require large material costs and reduces the need for postoperative blood transfusion in 85% of operated patients.

The overall economic effect per 100 operated patients compared to the prototype is 350 thousand rubles.

Table 1 Dependence of the volume of transfused donated blood on the BCC, the volume of blood loss and the age of the patients Age of patients The amount of blood loss during surgery (in ml) The percentage of blood loss from bcc The volume of transfused donated blood in% of BCC Up to 6 months (n = 10) 69.0 ± 23.2 20.8 ± 3.2 Not carried out From 6-12 months (n = 5) 103.3 ± 98.6 28.6 ± 2.2 35 Older than 1 g. (N = 5) 94.8 ± 59.1 30.5 ± 3.4 10

table 2 The positive effect of the proposed method compared with the prototype The main features of the methods Prototype The proposed method The use of car donation is used Not used The risk of bacterial infection in violation of the technique of taking blood tall absent Blood transfusion Not used Is used Drainage fluid return is used Not used Stimulation of erythropoiesis Not carried out Effective Duration of preoperative preparation Within 5 days Within 3 days Use of drugs during surgery to lower blood pressure applies Not applicable Economic effect when conducting 100 operations compared to the prototype - 350 thousand rubles

Claims (1)

The method of stimulation of erythropoiesis in the preoperative period, characterized in that the following chemotherapeutic drugs are used for hemorrhage during the operation, constituting up to 25% of the BCC: 3 days before the operation, the drugs are administered once: aranesp ™ at a dose of 1 μg / kg subcutaneously and sorbifer at a dose of 10 mg / kg orally, 1 day before the operation, sorbifer is administered orally at a dose of 10 mg / kg, folic acid is administered orally at a dose of 6 mg / day, and cyanocobalamin (vitamin B ₁₂ ) is administered daily intramuscularly for 3 days 0.2 mg; with blood loss during the operation from 25% or more of the BCC, donor blood transfusion is additionally noted above for transfusion of blood donations intraoperatively and 1-2 days after surgery, but the amount of donated blood is reduced to 70-74% of the volume of blood loss.