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PEDIATRICS
INVENTION
Patent of the Russian Federation RU2191031

METHOD OF TREATMENT OF PNEUMONIA IN DEEP-CONDITIONED CHILDREN IN ARTIFICIAL VENTILATION OF LUNGS

METHOD OF TREATMENT OF PNEUMONIA IN DEEP-CONDITIONED CHILDREN IN ARTIFICIAL VENTILATION OF LUNGS

The name of the inventor: Dementieva GM; Kushnareva MV; Koval GS; Ryumina I.I.
Name of patent holder: Moscow Research Institute of Pediatrics and Pediatric Surgery
Address for correspondence: 127412, Moscow, ul. Taldom, 2, Moscow Research Institute of Pediatrics and Pediatric Surgery
Date of commencement of the patent: 2001.01.10

(EN) The invention relates to medicine, in particular to pediatrics, namely neonatology, can be used to treat pneumonias in preterm infants who are on artificial ventilation. Enter broad-spectrum antibiotics and intravenously immunoglobulin-pentaglobin, which alternate every other day with intravenous injection of fresh frozen plasma. This method significantly improves the effectiveness of treatment of pneumonia in the declared category of children.

DESCRIPTION OF THE INVENTION

The invention relates to the field of medicine, in particular to pediatrics and neonatology.

The work is based on the idea of ​​the possibility of complex treatment of pneumonia in premature newborn babies, which includes antibacterial and immunocorrective therapy.

Methods for the treatment of pneumonias in children with deep respiratory distress syndrome and respiratory distress syndrome (IVF), including the administration of broad-spectrum antibiotics (cefotaxime, ceftazidime, amikacin, tobramycin, netromycin and others) are combined with intravenous immunoglobulins - octagam, sandoglobulin, Intraglobin, pentaglobin [Bonanno Conti M. Immunoglobuline intravenose in neonati a rischio settico. Efficacia comparative di preparazioni 7Se5S // Minerva pediatr. 1990. - Vol. 42, Nl-2. - P. 15-18; Jenson HB, Pollock BH The role of intravenous immunoglobulm for the prevention and treatment of neonatal sepsis // Semin. Perinatal. - 1998. - Vol.22, N1. - P.50-63; Chen JY Intravenous immunoglobulin in the treatment of full term and prematu N11. - P. 839-844].

As an analogue, a method for treating severe pneumonia in premature infants is proposed, which involves the appointment of broad-spectrum antibiotics from the group of cephalosporins and aminoglycosides in combination with intravenous pentaglobin at a dose of 5 ml per kg of body weight once a day for at least 3 consecutive days [Hellwege N. N. Et al. J. of Neonatology. - Vol. - P. 44].

The disadvantage of this method is that intravenous immunoglobulin preparations can reduce the immunoregulatory index of CD4 / CD8 due to a sharp increase in the number of T-suppressors (CD8), causing a significant decrease in the proliferative activity of lymphocytes and the NST of monocytes [Aukrust P., Meuller F. et al . Modulation of lymphocyte and monocyte activity after intravenous immunoglobulm administration in vivo // Cliv. Exp.ImmunoL - 1997. - Vol. 107, Nl. - P.50-56], it is essential to inhibit the activity of natural killer cells [Ruiz JE, Kwak JY et al. Intravenous immunoglobulm inhibits NK cell activity in vivo in women with recurrent spontaneous abortion // Am. J. Reprod. Immunol. - 1996. - Vol. 35, N4. - Р.370-375], to reduce the synthesis of human leukocytes by tumor necrosis factor-alpha and interleukin-6 [Toungouz M., Denis S., Dupont E. Inhibition of HLA-DR mediated cytokines production by intravenous immunoglobulins // Brit. J. Haematol. - 1994.- Vol.87, Suppl. Nl. -P.206., Aukrust P., Hestdal K. et al. Effects of intravenous immunoglobulin in vivo on abnormally increased tumor necrosis factor-alpha activity in human immunodeficiency virus type 1 infection // J. Infect. Dis. - 1997. - Vol.176, N4. -P.913-923]. Moreover, immunoglobulin antibodies to gamma interferon can block gamma interferon production and lymphocyte proliferation in recipients, and the large aggregates in immunoglobulin preparations bind complement to 79-100% [Denys C., Toungouz M., Dupont E. Increased in vitro immunosuppresive action of anti-CMV and anti-HBS intravenous immunoglobulins due to higher amounts of interferon-gamma specific neutralizing antibodies // Vox Sang. - Vol.72, N4. - 1997. - P.247-250]. In addition, there is literature data on the lack of any clinical effect in the treatment of severe "fan-associated infection" with intravenous immunoglobulins in newborn infants [Adhikari M., Wesley AG, Fourier PB Intravenous immunoglobulin prophylaxis in neonates on artificial ventilation // S. Afr . Med. J. - 1996. - Vol.86, N. 5. - P. 542-545].

The above circumstances require the search for a new approach to immunocorrective therapy in the complex treatment of deep-infertile children with severe pneumonia, which will reduce or eliminate the immunosuppressive effect that occurs with the use of intravenous immunoglobulin.

The aim of the invention is to develop a new method for treating pneumonia in preterm infants who are on artificial ventilation. The goal is achieved by the use of broad-spectrum antibiotics in combination with intravenous pentaglobin, the introduction of which alternates with fresh-frozen plasma.

Pentaglobin is a human immunoglobulin preparation for intravenous administration enriched with IgM (Biotest Pharma, Germany). The content of human plasma proteins in a 1 ml solution of the drug for infusions of 50 mg, including IgM 6 mg, IgA 6 mg, IgG 38 mg.

Fresh frozen plasma (FFP), obtained from the blood of healthy donors, contains the main complex of biologically active substances present in the blood, including immunoglobulins, lysozyme, complement components, cytokines of various classes (interferons, tumor necrosis factor), albumin, electrolytes, Etc. Fresh-frozen plasma possesses good opsonizing properties, anti-viral and antibacterial activity, detoxication action [Gorodetsky VM Ways to reduce the use of homologous blood and its components. - "Hematology and transfusiology." - 1995, - N1. - P. 27-28; Samsygin S.A. "Immunocorrection" (chapter in the monograph: Krasovskaya TV, Beloborodova NV Surgical infection in newborns - M., 1993. - 224 pp.) Introduction of fresh frozen plasma between infusions of pentaglobin allows to compensate for the low content of cytokines and components Complement, caused by the suppression of their production by high concentrations of immunoglobulins and activates the phagocytosis of neutrophils.

Description of the method of treatment. In the presence of clinical and radiologic signs of pneumonia in deep-infertile children with respiratory distress syndrome located on the IVL, treatment begins with the appointment of combined antibacterial therapy in the form of a combination of third generation cephalosporins with aminoglycosides at age doses intravenously (in the absence of effect for 3 days - Tienam and meronem), the introduction of intravenous immunoglobulin - pentaglobin. The introduction of pentaglobin 5 ml / kg once a day every other day (at least 3 times) alternates on days with intravenous injection of fresh-frozen plasma at 10 ml / kg.

To identify the effectiveness of the proposed method of treating severe pneumonia, 3 groups of deep-inferior children with severe pneumonia developed against the background of ventilation used for respiratory distress syndrome were examined and analyzed:

1 group - children who received pentaglobin and freshly frozen plasma (FFP) in combination with antibacterial therapy of the third generation cephalosporins and aminoglycosides, in some cases with carbapenem therapy or antibiotics of other groups (vancomycin, metgil, lincomycin and others), taking into account the etiology of the disease (27 Children);

Group 2 - children who received only intravenous immunoglobulin, against antibiotic therapy, similar to the first group (8 children).

Group 3 - children who received FFP without intravenous immunoglobulin for 3 consecutive days in combination with antibiotic therapy similar to the first group (30 children);

All children were evaluated for the dynamics of the clinical state (the severity and duration of toxicosis, the state of respiratory function, physical changes in the lungs, the presence of foci of inflammation on the roentgenogram). In addition, the indicators of clinical studies of the gas composition and acid-base state of blood, urine, the results of microbiological cultures of the separated respiratory tract and other loci, the immunological parameters of blood and respiratory tract contents were analyzed.

Combined use of pentaglobin and FFP as part of complex antibacterial therapy in children of the first group contributed to a faster and more effective treatment of pneumonia than in the 2nd and especially the 3rd groups (Table 1). In particular, the duration of infectious toxicosis decreased, the duration of antibiotic therapy, the foci of infectious inflammation were quickly stopped. The proposed comprehensive treatment of severe pneumonia in the deep-seated children allowed to reduce the lethality by 30% in the department of resuscitation of newborns, to reduce the outcome of the disease by 2 times in sepsis and to reduce the incidence of bronchopulmonary dysplasia 2 times compared with the period when the treatment included antibacterial and posindrome therapy in combination With the introduction of FFP.

When treating intravenous immunoglobulins without FFP, the clinical state of children was intermediate: the clinical effectiveness of immunotherapy was higher than in group 3, but less pronounced than in the first.

With the introduction of pentaglobin in combination with FFP, the elimination of pathogens from pneumonia occurred 1-2 weeks earlier than with the separate application of these drugs. A good clinical and microbiological effect from the use of immunopreparations was achieved as a result of the creation of a high level of immunoglobulins in the inflammatory focus, which was significantly higher after the administration of pentaglobin (Table 2).

A faster subsequent decrease in the concentration of immunoglobulins to the baseline level was noted in the group of children who received FFP (after 2.1 ± 0.2 days). After the administration of pentaglobin, an increased content of IgG and IgM persisted longer (3.4 ± 0.2 days, p <0.02).

In children of the 2nd group who received intravenous immunoglobulin preparations, from the end of the acute period to the end of the second month of life, a pronounced depression of immunological reactions is observed: inhibition of oxygen-dependent metabolism, microbicidal activity and other phagocytic functions of neutrophils, and suppression of alpha interferon secretion (19 ± 3 ME) and gamma-interferon (11 ± 4 ME). Until the end of the first month of life in these children, the relative content of T-lymphocytes (E-ROC) and the "active" T-population of lymphocytes (Ea-ROC) is reduced. Although the level of IgG in the blood plasma remained high until the end of the neonatal period, at the age of 8-9 weeks its concentration dropped sharply and was 2-2.5 times lower than in groups 1 and 3. This indicates the inhibition of IgG synthesis in the body of preterm infants who received only intravenous immunoglobulin in the neonatal period.

Combined administration of pentaglobin and FFP facilitated the rapid improvement of the phagocytic functions of neutrophils and improved their oxygen-dependent metabolism, a stable level of subpopulations of lymphocytes with an increase in helper activity and B-lymphocyte activity. In this group of children, the level of interferon alpha was 30.1 ± 2.1 (norm - 32 ± 8.9 ME) and gamma-interferon - 34.2 ± 4.4 ME (-38.8 ± 12 ME). Elevated levels of IgG in these children were noted up to 2-3 weeks of life, which provided the necessary anti-infectious protection and antibacterial effect of complex treatment. At the age of 8-9 weeks of life, the level of the main classes of immunoglobulins was within the normal range. IgG at this stage was lower than in children treated with freshly frozen plasma, but higher than in the group of children receiving intravenous immunoglobulin.

Thus, combined use of pentaglobin and FFP on the background of antibacterial therapy, allows to significantly improve the effectiveness of treatment of pneumonia in the deep-seated children who are on ventilator. Introduction FFP eliminates the negative consequences of the use of intravenous immunoglobulin drugs associated with the development of immunodepression.

Clinical examples of the specific performance of the method.

Example 1. Child Chernyshev Ilya. History of the disease N 1666.

Diagnosis: bilateral draining heavy pneumonia, omphalitis, phlebitis of umbilical vessels, perinatal encephalopathy of posthypoxic genesis, anemia. Prematurity is 13 weeks.

The baby was born with a body weight of 1177 g and a body length of 36 cm at the 28th week of pregnancy. In the anamnesis of the mother, endometrium, uterine myoma. The first pregnancy ended with premature birth, from 2 nd to 6 th pregnancy - medical abortion at the request of a woman. The present pregnancy is the 7th, which was taking place with severe toxicosis in the 1st half, giving birth in the breech presentation. The condition of the child at birth was severe, an Apgar score of 4/5 points. Symptoms of cerebral circulation of the 2nd degree (oppression syndrome), skin-hemorrhagic syndrome, respiratory distress syndrome were noted, because of which ILV was carried out for 11 days. In the first day of life, conjunctivitis was diagnosed, and on the third day - pneumonia, confirmed by roentgenology. On the 12th day of life, manifestations of catarrhal omphalitis and phlebitis of the umbilical vessels were noted.

From the first day of life, the child received antibacterial therapy with cephalosporin series and aminoglycoside for 24 days, and the rate of metrozhil and lincomycin for 6 days. On the 6th, 8th and 10th days of life, the child was intravenously injected with pentaglobin, and on the 7th, 9th and 11th days - FFP. The condition of the child in the first 7 days of life was very severe, but on the 8th day it stabilized, the body temperature dropped from 37.8 o C to 37.0 o C, and from the 11th day it normalized, not exceeding 36.8 o C. In the following weeks the state of the child with a slow but positive dynamics. Independently to suck the child became at the age of 1 month 18 days, a stable increase in body weight was observed from 1 month 21 days. At the same time, the child was transferred from the kuvez to the crib. Clinically and radiologically the phenomena of pneumonia stopped at the age of 1 month, and omphalitis and phlebitis - 26 days. At the age of 1 month and 27 days the child was discharged in satisfactory condition with a body weight of 1840 g.

Microbiological seeding of tracheo-bronchial aspirate on the 6th day of life revealed the presence of Stapylococcus epidermidis (with hemolytic properties) in the number of Ig6 colony forming units / ml (CFU / ml), Candida albicans - Ig4 CFU / ml, Mycoplasma hominis-Ig5 CFU / Ml and Bacteroides fragilis - Ig3 CFU / ml. After completion of the course of pentaglobin and FFP (11th day of life), there were no bacteroids in TBA and there was a marked inhibition of the growth of epidermal staphylococcus and candida, which were detected in the amount of Ig1 CFU / ml. Sanitation of the respiratory tract was observed on the 16th day of life. The study of local respiratory immunity on the 5th day of life showed the absence of sIgA, IgG and IgM. One day after the first administration of pentaglobin in TBA, immunoglobulins of the main classes were detected in concentrations: sIgA 0.01 mg / mg albumin (mg / mg), IgG 1.01 mg / mg IgM 0.38 mg / mg. The level of immunoglobulins in TBA remained high for another 2.5 days after the end of the course of immunotherapy.

On the 6th day of life, immunological blood counts indicated an active inflammatory process in the child's body: an increase in the intensity of phagocytosis was revealed - PHYSI = 4.5 (norm 2 ± 0.24) and the number of phagocytic neutrophils - FVCD = 54% (norm 26 ± 9 %). And there was an increase in the relative number (in%) of the major subpopulations of lymphocytes: CD4 - 54, norm - 34 ± 4.8; CD8 - 34 (norm - 22,5,5) and CD 16 - 16 (the norm is 10 ± 1,1). The level of immunoglobulins class A and G was rather low - IgA - 0.2, g / l IgG - 3.2 g / l, and IgM - increased - 0.5 g / l. At the age of 8 weeks the immunological parameters corresponded to the age norm (PHYO-2, FCH-40%, CD3-49, CD4-30, CD8-27, CD22-15, CD16-18, CD22-2).

In the clinical analysis of blood on the 6th day of life before the appointment of pentaglobin, pronounced leukocytosis (leukocyte count reached 44 · 10 9 / l!) And a shift of the formula to the left (myelocytes - 1%, stab neutrophils - 10%, segmented neutrophils - 68% Lymphocytes - 16%, monocytes - 4% and eosinophils - 1%). However, in the dynamics of complex treatment, the blood picture improved already on the 11th day of life: the leukocytes were 15.6 × 10 9 / l, the stab neutrophils were 3%, the segmented neutrophils were 67%, the lymphocytes 24%, monocytes 4%, eosinophils 2 %. Completely hemogram normalized at the age of 1 month 3 days.

In urinalysis before 23 days of life, bacteriuria due to epidermal staphylococcus in the amount of Ig6 CFU / ml was recorded. However, the clinically infectious-inflammatory process in the urinary tract was not realized.

Thus, the use of the proposed method of treatment for a prematurely born child with severe pneumonia that developed against the background of respiratory distress syndrome and artificial ventilation allowed the patient to quickly stop the symptoms of the disease, prevent the development of complications (in particular bronchopulmonary dysplasia) and the formation of immunodepression, and translate into physiological Nursing.

Example 2. Child of the Deaf St. Gregory. Case history N210.

Diagnosis: bilateral pneumonia in the background of pneumopathy (disseminated atelectasis), obstructive tracheobronchitis. Asphyxia in childbirth. Condition after pulmonary hemorrhage. Perinatal encephalopathy (hyperexcitability syndrome). Conjugation jaundice 1 st degree. Prematurity is 12 weeks.

The child of Deaf Gregory, the second of twins, gestational age of 28 weeks, was born with a body weight of 1260 g and a length of 37 cm in a woman of 23 years. In the anamnesis of the mother gastritis and ulcer of the duodenum, food allergy and bronchitis with an asthmatic component. The present pregnancy was the first, with toxicosis in the first trimester and with the threat of miscarriage at the 11th week, in connection with which seams were placed on the cervix. In the 2nd trimester, anemia of pregnant women developed. Childbirth proceeded swiftly. The child was born in asphyxia with an Apgar score of 4/7 points. The condition at birth is severe due to respiratory distress syndrome type I and intrauterine infection. Since the birth of the child was carried out mechanical ventilation, which lasted 14.5 days. Until the 12th day of life, the child's condition remained very serious, then positive dynamics were noted. The body temperature was increased to 37.2 ° C - 38.0 ° C for 5-12 days of life. From the 24th day of life, the child began to add to the mass, and his condition was regarded as moderate. Symptoms of tracheobronchitis stopped by the 18th day of life, and pneumonia - by day 28. From 1 month 18 days the child's condition is satisfactory. The child received antibacterial therapy: cephalosporins in combination with aminoglycosides 10 days, vancomycin + fortum - 15 days and diflucan 12 days. On the 8th, 10th and 12th day of life the child was administered pentaglobin, alternating with the management of FFP on the 9th, 11th and 13th days. Immediately after the course of immunoglobulin and plasma, normalization of body temperature and improvement of the general condition of the child were noted.

TBA cultures showed that the causative agents of pneumonia were Klebsiella pneumonia, Candida albicans, Enterococcus, which were sown in an amount of Ig 4-6 cfu / ml. After the course of pentaglobin and FFP, only Enterococcus and Klebsiella in the amount of Ig1 CFU / ml were detected in the respiratory tract in the presence of antibiotic therapy. On day 22 of life, the airways were completely sanitized.

On the 8th day of life before the administration of pentaglobin, IgG was detected in TBA in the amount of 0.04 mg / mg and IgM - 0.15 mg / mg. One day after the first injection of intravenous immunoglobulin, the level of IgG increased to 0.5 mg / mg, and IgM - 0.15 mg / mg.

Thus, a comparative analysis of the results of the survey by groups and the presented clinical examples suggest that the proposed method for treating pneumonia in the deep-infertile children with respiratory distress syndrome and being on the ventilator is adequate and highly effective.

CLAIM

The method of treatment of pneumonias developing on the background of artificial ventilation in deep-infertile children with respiratory distress syndrome, conducted by broad-spectrum antibiotics, characterized by the addition of a combination of intravenous immunoglobulin-pentaglobin and fresh frozen plasma by alternating their administration.

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Date of publication 06.01.2007gg