RU2634471C2 - Method for local treatment of postpartum endometritis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for the local treatment of postpartum endometritis. To do this, complex therapy is carried out, which includes intrauterine injection of ultrasonically cavity medicated solutions. For uterine cavity ultrasonic treatment, a solution containing 1 μg of Betaleukin preparation and 400 ml of 0.9% saline is used. Two procedures are performed every other day at a frequency of ultrasonic oscillations of 25 kHz, the amplitude of ultrasonic waveguide instrument oscillations is 60-120 mcm, drug solution consumption is 100-150 ml/min, exposure is 3-5 min, infusion volume is at least 300 ml.

EFFECT: reduced duration of treatment, reduced likelihood of severity, recurrence and chronicization of the inflammatory process and the need for subsequent surgical treatment due to rapid and persistent reduction of the inflammatory process and cytokine imbalance at the local level.

2 cl, 1 ex

Description

The invention relates to medicine, in particular to obstetrics and gynecology, and relates to methods and devices intended for the treatment of inflammatory diseases of the uterus, namely postpartum endometritis, using ultrasound devices for treating the uterine cavity with drug solutions.

Among postpartum infectious diseases, the most common postpartum endometritis (PE). Its frequency is 40-50% of all postpartum infectious diseases.

Often, postpartum endometritis is the cause of chronic endometritis, leading to impaired fertility in women, which is associated with irrational therapy. In the structure of the causes of chronic endometritis, postpartum inflammatory complications account for about 30%, which indicated the need for a further search for methods of treatment and prevention of acute postpartum endometritis.

There are various methods of treating postpartum endometritis, which include the appointment of antibacterial agents, uterotonics, infusion therapy, intrauterine installations, the use of immunocorrective drugs. To reduce the drug load on the patient’s body and improve the effectiveness of treatment, local treatment methods are widely used using physiotherapy and physiotherapy, in particular: intrauterine irrigation with ozonated distilled water, antiseptic solutions; carrying out intrauterine installations with a proteolytic enzyme; electrophoresis with 1% solution of emoxipin on the hypogastric region; carrying out plasmapheresis with laser irradiation of blood and laser irradiation of blood with hyperbaric oxygenation; intracavitary administration of a hydrogel of chitosan hydrochloride containing metronidazole and dioxidine; local treatment of postpartum endometritis with intrauterine insufflation of gel sorbents (see RF Patents No. 2086275; 2267327; 2309744; 2342173). As the closest analogue of the claimed invention, the selected "Method of local treatment of inflammatory diseases of the uterine cavity and device for its implementation" (see RF Patent No. 2537779, A61N 7/00. Publ. 10.01.2015), in which the ultrasound treatment is carried out with a solution of furatsilina 1: 5000 or 1% dioxidine solution at a 1:40 dilution with 0.9% saline.

However, the above methods of treating PE are not always effective, because they do not allow for complete rehabilitation of patients, due to the fact that they mainly use solutions of antiseptics or enzymes, not taking into account the development of cytokine imbalance at the local level. This necessitates the search for new effective methods of treatment that make it possible to stop the inflammatory process with a high probability, and prevent its recurrence and chronicity.

The objective of the invention is to develop a method of local treatment of postpartum endometritis, taking into account the development of cytokine imbalance, with the aim of increasing the effectiveness of treatment, persistent relief of inflammation, reducing the treatment time for this pathology, preventing recurrence and chronicity of the inflammatory process.

The task is achieved by the use of basic therapy with antibiotics according to the testimony of irrigation of the uterine cavity with a solution of the Betaleikin immunomodulator immunotherapy modulator, cavitated by low frequency ultrasound 2 times every other day, and the uterine cavity is treated with a cavitated solution containing 0.9% saline 400.0 ml, with a Betaleikin immunomodulator drug 1 μg, with an exposure of 3-5 minutes and a flow rate of a drug solution of 100-150 ml / min, with a frequency of ultrasonic vibrations of 25 kHz, with a volume astvora not less than 300 ml per procedure using an apparatus AUZH-100- "FOTEK".

The method provides for the destruction of bacterial films, removal of purulent, pathological plaque from the uterine cavity with minimal damage to healthy tissues and impregnation of the Betaleikin immunomodulator preparation into the mucosa, correcting the cytokine imbalance, which provides an antimicrobial, antiseptic and anti-inflammatory effect, reducing the drug load on the body of a nursing mother, and prevents the chronicity of the inflammatory process.

Technically, the method consists in introducing an ultrasonic instrument into the uterine cavity with an internal irrigation channel of small diameter in a protective casing. A “voiced” (cavitated) drug solution is supplied through the channel of the instrument. Method parameters: frequency of ultrasonic vibrations of 25 kHz, flow rate of the drug solution 100-150 ml / min, exposure 3-5 minutes, the volume of the solution is not less than 300 ml per procedure, the amount of the drug was selected empirically according to the results of experiments. A device for implementing this method of treatment, the device AUZH-100- "FOTEK" (manufacturer of LLC "FOTEK") contains: an ultrasonic generator, an acoustic unit, a waveguide-tool with an internal irrigation channel, a protective casing of a special form with drainage holes and an infusion system for supplying a drug solution. The device allows you to locally affect the endometrium and myometrium with a “voiced” solution of the injected drug, spraying it into the uterine cavity and effectively acting on the microbial agent and biological tissue, while ensuring constant circulation of the solution inside the uterus.

Patients with clinical signs of postpartum endometritis, who noted changes such as leukopenia with a stab shift, relative lymphocytopenia, decreased activity of the cytokine status (in serum and lochia), decreased levels of α, γ-interferons, were treated 2-3 times every other day the cavity of the postpartum uterus with a cavitated solution, including 0.9% physiological saline 400.0 ml, with Betaleikin 1 μg, using the ultrasonic therapy apparatus AUZX-100-FOTEK.

The method is as follows: in the treatment room 3-4 days after delivery in a gynecological chair before administering the medicine, the external genitalia are sanitized with an antiseptic solution, the cervix is treated with an antiseptic with a cotton swab, the cervix is taken from the front lip by bullet forceps, into the cavity the uterus through the cervical canal introduces the tip of an ultrasound instrument with an internal irrigation canal of small diameter in the protective casing, through the tip is fed "voiced" (cavitated) fishing line saline solution: 0.9% saline 400.0 ml + Betaleikin 1 mcg. The device for implementing the treatment method AUZH-100- "FOTEK" (manufacturer of LLC "FOTEK") is protected by utility model patent No. 125853, A61N 7/00 "Device for the local treatment of inflammatory diseases of the uterine cavity." The apparatus allows washing tissues from purulent and pathological plaque, destruction of bacterial films, deep impregnation of drugs into the mucosa due to irrigation of tissues with a directed cavitation stream and cavitation bubbling of the solution in the cavity (mixing the solution in the cavity with cavitation vesicle flows), which increases the susceptibility of tissues and microbial drug agents.

The immunomodulating drug Betaleikin ® is a medicine based on recombinant human interleukin-1β (IL-1β), a complete analogue of the human protein IL-1β, produced by genetic engineering (see RF Patent No. 28706, A61K 38/20. Publ. 04.10. .1999). Pharmacotherapeutic group - Cytokine. Reg. No. Р№000222 / 01 dated 12/20/2007. Previously, the Betaleikin drug was used to treat tuberculosis, as a means of emergency radiation therapy by intravenous or subcutaneous administration. In gynecology and obstetrics, the use of the drug was not detected.

Immunosubstitution therapy with cytokines is a new step, since the use of genetically engineered endogenous immunomodulator compares favorably with the use of cytokine and interferon inducers. Their effectiveness is often low due to the reduced ability of body cells to respond to external stimulation in immunodeficiency states. Immunosubstitution therapy, IL-1, on the contrary, is especially effective in immunodeficiency conditions that accompany many infectious diseases, or when a local infection develops against the background of an existing immunodeficiency. IL-1 is one of the first cytokines produced by cells when pathogens are introduced, however, despite the synthesis of endogenous IL-1, in some cases this is not enough to effectively fight the infection. Against this background, the additional administration of the Betaleikin IL-1 drug from the outside can have a decisive effect on the adequate course of protective reactions and the elimination of the pathogen. Using Betaleikin, it becomes possible to regulate the cytokine imbalance, compensating for the lack of IL-1β. In contrast to the methods of immunostimulation with cytokine replacement therapy, there is no need for additional induction of the production of immune factors by our own defense systems in the focus of inflammation, adequate protective reactions and elimination of the pathogen are ensured, which is the novelty of the proposed method.

To substantiate the proposed method in the first series of experiments, 45 patients aged from 20 to 39 years, distributed in 3 groups, were examined and treated.

The first group consisted of 15 patients with mild PE, who, according to the clinical protocol for treating PE (basic therapy), underwent antibacterial, uterotonic, antianemic, anti-inflammatory therapy according to indications, as well as vacuum aspiration of the contents of the uterine cavity.

The 2nd group included 2 subgroups: 2a - 15 patients with a mild PE who were treated with a cavitated antiseptic solution (1% dioxidine 10.0 ml + 0.9% saline 400.0 ml) using the AUZH-device 100- "FOTEK"; 2b - 15 patients with mild PE who underwent treatment of the uterine cavity with a cavitated solution with the addition of Betaleikin (1 μg Betaleikin per 400 ml of 0.9% saline) - the proposed method. Also, the second group of patients underwent antibacterial, uterotonic, antianemic, anti-inflammatory therapy according to indications.

Diagnosis of PE was based on complaints, clinical and laboratory data, microbiological examination of Lochia, ultrasound examination of the pelvic organs, uterine involution rate, determination of interleukins (IL-1, IL-4, IL-6), tumor necrosis factor - alpha (TNF-α). Evaluation of the effectiveness of the above methods was based on the rate of decrease in the clinical manifestations of PE, normalization of the level of leukocytes, C-reactive protein (CRP), IL (interleukins), ultrasound monitoring of changes in the size of the uterus, and changes in the microbiological composition of the lochia.

In patients with mild PE, the disease was diagnosed 3-5 days after birth on the basis of complaints (unexpressed pain in the lower abdomen, hyperthermia up to 37.5), an increase in the level of leukocytes up to 10-15 thousand per cubic millimeter of blood, and an increase in C- reactive protein to 66-90 g / l, lowering hemoglobin of blood to 90-100 g / l, increasing levels of IL-1, IL-4, IL-6 and TNF-α, on day 3 according to ultrasound echo signs of uterine subinvolution , lochiometers, microbiological examination of Lochia revealed the presence of: Escherichia coli 10 ³ -10 ⁶ CFU / ml, Enterococcus faecalis 10 ⁵ -10 ⁶ CFU / ml, Proteus mirabilis 10 ⁵ CFU / ml.

Patients of the 1st group were prescribed antibiotics (cephalosporins or penicillins) according to the clinical protocol, uterotonics, antianemic and anti-inflammatory therapy according to indications, as well as vacuum aspiration of the contents of the uterine cavity.

Patients of the 2nd group were prescribed antibiotics (cephalosporins, penicillins), uterotonics, antianemic and anti-inflammatory therapy according to indications. In subgroup 2a, 3 procedures were performed daily for treating the uterine cavity with a solution of 1% dioxidine 2.0 ml + 0.9% nat. 400.0 ml solution, cavitated with a low-frequency ultrasonic device AUZX-100- "FOTEK"; patients of 26 subgroups underwent treatment of the uterine cavity with a cavitated solution using the Betaleikin drug 1 μg, diluted with 0.9% physical. solution, 2 procedures every other day.

Evaluation of the effectiveness of treatment:

Group 1: relief of pain, normalization of temperature, change in the nature of lochia was observed on the 4th day after treatment in 82% of patients, normalization of the level of leukocytes, C-reactive protein, and the level of interleukins on 6-7 days from the start of treatment.

Subgroup 2a: pain relief, temperature normalization, change in the nature of lochia was observed on the 3rd day after treatment in 92% of patients, normalization of the level of leukocytes, C-reactive protein, interleukin level on the 5th day from the start of treatment, after the 3rd ultrasound procedure, the size of the uterus 10 ± 1.5 weeks, the uterine cavity is closed, without pathological inclusions.

Subgroup 2b: relief of pain, normalization of temperature, change in the nature of lochia were observed on the 3rd day after treatment in 95% of patients, normalization of the level of leukocytes, C-reactive protein, the level of interleukins at 4-5 days from the start of treatment, after the 2nd ultrasound procedure the size of the uterus is 10 ± 1.5 weeks, the uterine cavity is closed, without pathological inclusions.

When conducting an immunohistochemical study of the endometrium in patients 6 months after birth, a chronic endometritis marker CD 138 in 1 group was detected in 60% of patients, in group 2a in 15%, and in group 2b no marker of chronic endometritis was found, which shows an unobvious effect of the proposed method in the form of a complete cure for PE in patients of this group.

Clinical example No. 1. Patient B., 28 years old, was hospitalized in GBUZ MO Moscow Regional Perinatal Center 02/18/14 with a diagnosis of Second timely delivery in the head presentation. Chronic fetal hypoxia. Early discharge of amniotic fluid. Hypotonic bleeding. Manual examination of the uterine cavity. Anemia of the 1st degree. Gestational pyelonephritis. In the anamnesis: in 2009, ureaplasmosis was treated, the number of pregnancies was 4, of which 2 births (including real ones), 2 spontaneous miscarriages in the period of 9 and 8 weeks of gestation. On the 2nd day after childbirth, body temperature increased to 37.5 ° C, hemorrhagic lochia with an unpleasant odor is determined. A gynecological examination revealed: the uterus is enlarged to 15-16 weeks, palpation is moderately painful, discharge from the uterine cavity is hemorrhagic with an unpleasant odor. Ultrasound scan of the small pelvis: the uterine cavity is expanded throughout from 15.6 to 17.2 mm with heterogeneous hypoechoic inclusions and hyperechoic contents. In a clinical blood test, hemoglobin is 98 g / l, white blood cells are 5.0⋅10 ⁹ / l, stab shift to the left, erythrocyte sedimentation rate (ESR) is 58 mm / h. C - reactive protein - 55 μg / l. In blood serum, IL-1 - 510.63 pkg / ml, IL-6 - 96.63 pkg / ml, IL-8 - 231 pkg / ml. When determining IL-1 in the lochia of the postpartum uterus, a decrease to 29.63 pkg / ml was established. When examining the vaginal discharge by the bacterioscopic method (Gram stain), the following were found: epithelial cells in moderation, leukocytes 45-50 in the field of view, moderately positive cocci. Bacteriological culture of uterine aspirate: growth of Enterococcus faecalis 10 ⁵ CFU / ml. Given the complaints, the data of a clinical and laboratory examination of a patient from a high-risk group for the development of purulent-septic complications, the diagnosis of postpartum endometritis is established. The basic treatment was carried out: cefotaxime 1.0 g. - 2 times a day intramuscularly for 5 days, oxytocin 1.0 ml. 2 times a day intramuscularly for 3 days, sorbifer 1 t. 2 times a day and additionally treatment of the uterine cavity according to the proposed method with a cavitated solution using the Betaleikin preparation (0.9% saline solution 400.0 ml + Betaleikin 1 mcg) 2 treatments every other day.

After the treatment, the patient noted a short-term rise in body temperature to 38 ° C. The body temperature returned to normal on the 2nd day, the mild nature of the goof, on the 4th day after treatment with a gynecological examination, the size of the uterus corresponds to the postpartum period, palpation is painless, clinical blood count on the 4th day: white blood cells 8.1⋅10 ⁹ / l, ESR - 20 mm / h, hemoglobin - 102 g / l, C-reactive protein - 15 μg / l, smear normalization for microflora: 10 epithelial cells in the field of view, single white blood cells, Gram (+) sticks. Ultrasound on the 6th day of the postpartum period - without pathology, bacterial culture of the separated cervical canal - there is no growth of pathological flora. In the study of IL-1 interleukins - 270.13 pkg / ml, IL-6 - 53.63 pkg / ml, IL-8 - 71 pkg / ml.

A follow-up examination after 6 months revealed no pathology, a vaginal smear corresponds to the 1st degree of purity of the vagina, an immunohistochemical study of the endometrial biopsy - there are no markers of chronic endometritis, bacterial culture of the detachable cervical canal without pathology. The proposed method has confirmed its effectiveness.

Clinical example No. 2. Patient G., 33 years old, was hospitalized in GBUZ MO MOPTS 03/15/14 with a diagnosis of First timely operative delivery in the pelvic presentation. Pregnancy after IVF. Polyhydramnios. Gestational diabetes. Pfannenstiel laparotomy, cesarean section in the lower uterine segment. The patient had a history of infertility of 8 years, in 2012, laparoscopy, bilateral tubectomy for hydrosalpinges, the number of pregnancies was 1-real after IVF, during pregnancy, she was diagnosed with gestational diabetes mellitus - a diet, candidiasis colpitis in the 3rd trimester during 24 weeks. On the 3rd day after childbirth, body temperature increased to 37.6 ° C, scanty hemorrhagic lochia with an unpleasant odor was determined. Gynecological examination revealed: the uterus is enlarged to 15 weeks, palpation is moderately painful, discharge from the uterine cavity is hemorrhagic with an unpleasant odor. Ultrasound of the pelvis: the uterine cavity is expanded throughout up to 18 mm with heterogeneous hyperechoic inclusions.

In a clinical blood test, hemoglobin is 112 g / l, leukocytes 4.9 910 ⁹ / l, stab shift to the left, ESR - 48 mm / h, C-reactive protein - 60 μg / l. IL-1 - 787.33 pg / ml, IL-6 - 81.33 pg / ml, IL-8 - 631 pg / ml, when determining IL-1 in the lochia of the postpartum uterus, a decrease to 17.35 pg / ml was established. When examining the vaginal discharge by the bacterioscopic method (Gram stain), the following were found: epithelial cells in moderation, 70 leukocytes in sight, moderately positive cocci. Bacteriological culture of uterine aspirate: growth of Enterococcus faecalis 10 ⁵ CFU / ml, Escherichia coli 10 ⁶ CFU / ml.

Given the complaints, clinical and laboratory examination data, a patient from the high-risk group for the development of purulent-septic complications was diagnosed with postpartum endometritis. The treatment was carried out: cefotaxime 1.0 g (2 times a day IM 5 days), oxytocin 1.0 ml (2 times a day IM 3 days) and treatment of the uterine cavity with a cavitated solution using Betaleikin (0 , 9% saline solution 400.0 ml + Betaleikin 1 mcg) 2 procedures every other day.

After the treatment, the patient did not complain, the body temperature returned to normal on the 2nd day, the character of the lochia returned to normal, on the 4th day after treatment with a gynecological examination, the size of the uterus corresponds to the postpartum period, the palpation is painless, the parameters of the clinical blood test on the 4th day : leukocytes 7.8⋅10 ⁹ / l, ESR - 20 mm / h, hemoglobin - 115 g / l, C-reactive protein - 10 μg / l. In the study of IL-1 interleukins - 370.13 pkg / ml, IL-6 - 33.23 pkg / ml, IL-8 - 49 pkg / ml.

Normalization of the smear on the microflora: 10 epithelial cells in the field of view, single white blood cells, gram-positive rods. Ultrasound on the 6th day of the postpartum period - without pathology, bacterial culture of the separated cervical canal - there is no growth of pathological flora.

A follow-up examination after 6 months revealed no pathology, a vaginal smear corresponds to the 1st degree of purity of the vagina, an immunohistochemical study of the endometrial biopsy - there are no markers of chronic endometritis, bacterial culture of the detachable cervical canal without pathology.

The novelty of the invention is the use of the well-known Betaleukin immunomodulator preparation for ultrasonic treatment of the uterine cavity for a new purpose and route of administration - for the treatment of inflammatory diseases of the uterus in the course of treatment in the form of a solution with physiological solution when the mixture is fed through the working channel of an ultrasound instrument, which leads to the restoration of the epithelial layer in the uterus, allows you to adjust the cytokine imbalance, compensating for the lack of IL-1β in contrast to the known methods, which is not idnym effect of the proposed method.

Thus, the use of ultrasonic cavitation irrigation of the uterine cavity with postpartum endometritis with a solution of the Betaleikin immunomodulator drug with physiological saline at a ratio of 1 μg Betaleikin drug per 400 ml of 0.9% saline allows the inflammatory process to be quickly and persistently reduced, leading to a significant reduction treatment time, reduces the likelihood of weighting, relapse and chronic inflammation and the need for subsequent surgical treatment of women, which This allows you to recommend a way for the introduction of health facilities.

Claims (2)

1. A method of local treatment of postpartum endometritis, including complex therapy, which includes the intrauterine administration of ultrasonically cavitated drug solutions, characterized in that for ultrasonic treatment of the uterine cavity, a solution of the Betaleukin immunomodulator drug with 0.9% saline is used at a ratio of 1 μg the preparation per 400 ml of physiological saline, at the same time 2 procedures are performed every other day at a frequency of ultrasonic vibrations of 25 kHz, an amplitude of vibrations of the ultrasonic waveguide-inst rumen 60-120 microns, the flow rate of the drug solution 100-150 ml / min, exposure exposure 3-5 minutes, the infusion volume of at least 300 ml. 2. A method of local treatment of postpartum endometritis according to claim 1, characterized in that for carrying out ultrasound treatment of the uterine cavity, an ultrasound therapy device AUZX-100- "FOTEK" of the company "FOTEK" LLC in Yekaterinburg is used, which allows performing an action on the endometrium with a cavitation stream, supplemented with cavitation bubbling of the drug solution in the uterine cavity with the constant circulation of the solution inside the uterus.