Prevention and Therapy of Bacterial Complications with Recombinant Granulocyte Colony-Stimulating Factor in Newborns with Respiratory Pathology and Perinatal Damage to the Central Nervous System

The dissertation is devoted to the study of the role of recombinant granulocyte colony-stimulating factor (filgrastim) in the prevention and therapy of bacterial complications in newborns with respiratory pathology and perinatal damage to the central nervous system who are on mechanical ventilation. The research is aimed at justifying clinico-immunological criteria for the prescription of rh-G-CSF, optimal doses and regimens of its use, as well as at evaluating the influence of the drug on the frequency of development of neonatal sepsis, mortality, duration of mechanical ventilation, and length of hospital stay. Special attention is given to the immune status of newborns with neutropenia developing against the background of severe respiratory pathology, and the dynamics of pro- and anti-inflammatory cytokine indicators, the subpopulation composition of leukocytes, and biochemical indicators during therapy with recombinant G-CSF.

Relevance of the Topic:

The introduction of modern methods of therapy for respiratory pathology and perinatal damage to the CNS in newborns into clinical practice has made it possible to significantly reduce the level of perinatal mortality. However, the growth of bacterial complications remains an important problem in intensive care and resuscitation departments, as septic infection still occupies one of the leading places in the structure of childhood mortality. According to data from various authors, mortality from neonatal sepsis currently ranges from 13 to 50%, which substantially diminishes the achievements of modern pediatric science (M. Ericsson, R. Bennett, 1998; Yu. F. Isakov, N. V. Beloborodova, 2001).

Low tolerance of newborns on mechanical ventilation to the development of bacterial complications is determined by a whole complex of factors. These include: the severity of the patients' condition due to primary and concomitant diseases, features of the immune system of the newborn, the necessity of using invasive diagnostic and laboratory monitoring methods, the duration of mechanical ventilation, as well as changes in the etiological structure of infecting microorganisms and the emergence among them of strains resistant to most antibiotics used in clinical practice. These circumstances indicate the need to develop other methods of prevention and intensive therapy of bacterial complications, as the high mortality rate in neonatal sepsis indisputably proves that traditional programs are virtually exhausted.

It is known that the development of neutropenia in newborns with severe respiratory pathology is an unfavorable symptom indicating the addition of bacterial complications (G. P. Bodey, Y. S. Sathe, 1996). This justifies a more in-depth study of immune status indicators in newborns with this pathology. From a clinical-diagnostic standpoint, unquestionable interest lies in the comparison of levels of pro- and anti-inflammatory cytokines, activation factors of immunocompetent cells, and the subpopulation composition of leukocytes during the development of severe bacterial complications in newborns.

A number of authors and the clinical experience of our department have indicated therapeutic efficacy of the use of human recombinant granulocyte colony-stimulating factor (filgrastim) in neonatology for the correction of neutropenia, as well as in the prevention and therapy of sepsis (Gilan et al., 1994; Schibler et al., 1998). The development of clinico-immunological criteria for the prescription of rh-G-CSF in newborns with neutropenia arising as a consequence of severe respiratory pathology and perinatal damage to the CNS, optimal doses and regimens of the drug's use, evaluation of its influence on the occurrence, development, and outcome of bacterial complications, as well as assessment of the safety of its use in this category of patients, determine the relevance of the present research.

Goal and Objectives of the Research:

The goal of the present research was to reduce the frequency of development and increase the efficacy of therapy of bacterial complications in newborns with respiratory pathology and perinatal damage to the CNS on mechanical ventilation, through the use of rh-G-CSF in standard intensive therapy.

To achieve this goal, the following tasks were set:

1. To conduct a controlled randomized clinical trial of rh-G-CSF in newborns with neutropenia having respiratory pathology and perinatal damage to the CNS.

2. To determine the influence of rh-G-CSF on the main medical-statistical indicators (frequency of development of bacterial complications, mortality, duration of mechanical ventilation, and length of hospital stay) in newborns with severe respiratory pathology and perinatal damage to the CNS.

3. To study the immune status in newborns with neutropenia, severe respiratory pathology, and perinatal damage to the CNS.

4. To study the influence of rh-G-CSF on the plasma level of certain interleukins, the subpopulation composition of lymphocytes, and certain biochemical indicators in newborns with neutropenia and severe respiratory pathology combined with perinatal damage to the CNS.

5. To develop clinico-immunological criteria for the prescription and optimal dosing of rh-G-CSF in this category of patients.

Scientific Novelty of the Work:

As a result of the research, for the first time, a theoretical and clinico-laboratory justification of the safety and efficacy of the use of rh-G-CSF in the prevention and therapy of bacterial complications in newborns with respiratory pathology and perinatal damage to the CNS on mechanical ventilation was provided.

The following theses are submitted for defense:

1. The development of neutropenia in newborns with severe respiratory pathology and perinatal damage to the CNS is accompanied by changes in the activity of pro- and anti-inflammatory interleukins of the plasma and the subpopulation composition of lymphocytes of the blood. 2. The use of rh-G-CSF in standard intensive therapy will reduce the frequency of development of neonatal sepsis and mortality in newborns with respiratory pathology and perinatal damage to the CNS on mechanical ventilation. 3. The therapeutic activity of the drug is based on its ability to increase the number of leukocytes, alter their population composition, and influence the activity of pro- and anti-inflammatory interleukins.

Practical Application of the Obtained Results:

Based on the dissertation materials, 26 printed works have been published. The following inventions were completed:

Method of Clinical Diagnosis of Sepsis in Newborns with Respiratory Disorders and Perinatal Damage to the CNS" (No. 2185628 dated 20.07.2002).

Method of Early Diagnosis of Sepsis in Newborns" (No. 2180119 dated 27.02.2002).

Method of Prognosis of the Outcome of Bacterial Infections in Newborns" (No. 2246729 dated 20.02.2005).

The results of the conducted research were used in lectures at republican and regional seminars and advanced training courses for physicians in intensive care and resuscitation.

Practical recommendations arising from the research materials have been implemented in the practice of the resuscitation department of the RNIIAП. The work was carried out in the resuscitation department and the immunology and bacteriology laboratory of the Rostov-on-Don Research Institute of Obstetrics and Pediatrics.

Validation of the Work:

The materials of the dissertation were presented at the Russian Congress on Pediatric Anesthesiology, Resuscitation, and Intensive Therapy (Moscow, 2001), the I Scientific-Practical Conference of Anesthesiologists and Resuscitologists of the South of Russia "Actual Problems of Pediatric Anesthesiology, Resuscitation, and Intensive Therapy" (Rostov-on-Don, 2002), the Scientific-Practical Conference of Pediatricians of the South of Russia "Actual Questions of Pediatrics" (Rostov-on-Don, 2003), and the thematic seminar for physicians of the Southern Federal District "New Diagnostic and Therapeutic Technologies" (Rostov-on-Don, 2003).

The main provisions of the work were heard at the meeting of the Academic Council of the Rostov Research Institute of Obstetrics and Pediatrics of the Ministry of Health and Social Development of the Russian Federation on March 3, 2005. Protocol No. 2.

Structure of the Work:

The dissertation is presented on 144 pages of typed text and consists of an introduction, a literature review, a chapter describing the scope and methods of research, three chapters presenting the results of original research, a conclusion, conclusions, and practical recommendations. The bibliography includes 138 primary sources, of which 63 are by domestic authors. The work is illustrated with 44 tables, 17 figures, and one scheme.