Download Bacterial infections

STATE ESTABLISHMENT «DNEPROPETROVSK MEDICAL ACADEMY
OF MINISTRY OF HEALTH UKRAINE »
“Сonfirmed;”
at methodical meeting
of hospital pediatrics №1 department
Сhief of department
professor _____________V. A. Kondratyev
“______” _________________
METHODICAL INSTRUCTIONS
FOR STUDENTS` SELF-WORK
WHILE PREPARING FOR PRACTICAL LESSONS
Educational discipline
module №
Substantial module №
Theme of the lesson
Course
Faculty
pediatrics
2
9
Bacterial infections in the newborn
5
medical
Dnepropetrovsk, 2013.
1. Theme urgency:
During the last years the problem of sepsis has got a special urgency. It is caused by the application
of modern methods of treatment and occurrence persistent to antibiotics gram negative flora
(intrahospital) that has led to increase of disease and death rate from this serious illness.
2. Specific goals:
А. Student should know:
1. Definition of the term "sepsis".
2. Classification of purulent-septic diseases and sepsis at children.
3. Etiopathogenesis of sepsis.
4. Clinical signs of "minor" purulent-septic diseases at newborns.
5. Clinical signs of sepsis at children. Additional methods for confirming the diagnosis.
6. Features of the course of septicemic and septicopyemic septic forms.
7. Principles of treatment of purulent-septic diseases and sepsis at children of early age.
8. Principles of rendering the urgent help at an infectious-toxic shock.
9. Consequences of purulent-septic diseases and sepsis at children.
10. Dispensary supervision over children who have suffered sepsis.
В. Student should be able::
1
2
3
4
5
6
7
8
To diagnose clinical signs of pyoinflammatory process, including sepsis in the child.
To appoint investigation to the child for confirming the diagnosis.
To diagnose "sepsis" according to classification.
To evaluate additional methods of investigation.
To carry out differential diagnostics of sepsis with other purulent-septic diseases.
To make the plan of investigation of person having sepsis.
To make the plan of treatment of person having sepsis.
To apply deontological receptions during gathering of complaints and the anamnesis.
3. Tasks for students` self-dependent work during preparation for the classes.
3.1. List of main terms, parameters, characteristics, which students has to
master preparing for the classes.
The term
Definition
1. Syndrome of the systemic inflammatory
answer
Complex of symptoms which includes the
general intoxication, signs of respiratory
insufficiency (tachypnea, apnea), tachycardia,
clinical manifestations of perinatal
encephalopathy, leucocytosis or leucopenia,
increase in level of C-reactive protein..
2. Septic shock
Occurs in the case of decompensation of
haemodynamics at patients with the syndrome of
the systemic inflammatory answer.
3. Multiple organ failure
Simultaneous disorders of function of two and
2
more organs and systems as a result of the
syndrome of the systemic inflammatory
answer.
4. Staphylodermia
Pyoinflammatory damage of the skin of
staphylococcal aetiology.
3. Septicemia
Clinical variant of sepsis without formation of
foci of purulent inflammation. General toxic
manifestations predominate.
4. Septicopyemia
Clinical variant of sepsis with the formation of
not less than two local pyoinflammatory
sites (pneumonia, otitis, omphalytis,
meningitis, etc.)
5. Passive immunotherapy
Administaration to the child specific or not
specific antibodies. This method is used
predominantly at children.
6. Active immunotherapy
Administaration to the child agents which
stimulate production of own antibodies
3.2. Theoretical questions for classes:
1. Definition of the term "sepsis".
2. Definition of the term "minor" purulent-septic diseases
3. Etiopathogenesis of sepsis and purulent-septic diseases.
4. Sepsis classification.
5. Clinical manifestations of purulent-septic diseases (vesiculopustulosis, impetigo neonatorum,
Ritter`s exfoliative dermatitis, conjunctivitis, omphalytis, umbilicytis, osteomyelitis, etc.).
6. Clinical manifestations of septicopyemic and septicemic septic forms.
7. Features of the course depending upon the causative agent.
8. Laboratory diagnostics of purulent-septic diseases and sepsis at children. Value of the blood
count, urinalysis, inoculation of pathological material, blood inoculation on sterility, biochemical
and immunological blood tests.
9. Treatment and prophylaxis of purulent-septic diseases and sepsis at children.
10. Prophylaxis of purulent-septic diseases and sepsis at infants.
4.3 . Practical works (tasks) which are performed on occupation:
1 To collect complaints, case history and personal (life) history
2. To inspect the child consistently
3. To reveal early symptoms of sepsis and other pyoinflammatory diseases at children
4. To reveal the signs of the complications of sepsis and other pyoinflammatory diseases at children
5. To evaluate the condition of the child and available clinical symptoms.
6. To evaluate the results of the additional methods of investigation
7. To make the clinical diagnosis according to classification.
8. To make the treatment plan.
9. To make recommendations of dispensary supervision.
.
7. Maintenance of the subject:
3
Staphyloderma.
Vesicle pustulesis – a disease which can begin in the middle of the early neonatal period:
on the skin of buttocks, hips, natural folds, the head there are the small superficially located
vesicles up to several millimeters in size filled at first with transparent, and then with muddy
content. Morphological substratum of the disease is inflammation in the site of openings of sweat
glands. Course of a disease, as a rule, is benigh. Vesicles burst in 2-3 days, on its place small
erosions are formed which become covered by dry thin skin, without leaving the scars or
pigmentation after falling away. Local treatment: 1-2% solution of iodine, powder of xeroform.
Pemphigus of the newborn can manifest in two forms: benigh and malignant. Benigh
form is characterized by occurance among erithematose spots of vesicles and small bullas (to 0,51 cm in the diameter), filled with serous and purulent content.
The malignant form of pemphigus of the newborn is characterized by occurance on skin of
a large number of sluggish vesicles, mainly of big size - to 2-3 cm in the diameter. Nikolsky's
symptom can be positive. Condition of children is severe, the expressed symptoms of
intoxication are evident. Temperature increases to the febrile.
Treatment of pemphigus of the newborn consists from antibacterial, desintoxication,
immunocorrecting therapy
Ritter's exfoliative dermatitis – the most severe form of staphylococcal piodermiya of the
newborns which can be considered as septic variant of the pemphigus. It is caused by hospital
strains of Staphilococcus aureus which produces exotoxin - exfoliatin. Disease begins at the end of
the 1st, the beginning of the 2nd week of life with emergence of reddening, moist skin and
formation of rhagades in umbiclical region, inguinal folds, round a mouth. The early beginning is,
as a rule, characterized by severe course of disease. For several hours bright erythema extends on
the skin of abdomen, trunk, extremities. Further on various sites of the body there are sluggish
vesicles, rhagades, shedding of epidermis which leaves big erosion. Nikolsky's symptom is the
positive at the majority of children. The newborn looks like "scalded by boiled water". Treatment
is carried out by the principles of treating septic patients.
Necrotic phlegmon of the newborn. This type of the inflammation of subcutaneous fat is
observed predominantly on the first month of life owing to the developed net of lymphatic vessels.
Typically manifested with acute beginning, high fever, enxiety, decreased appetite. Local changes
have phasic character, process is more often localized at sacral and coccygeal area, at the breast
and neck. At first on the big surface of skin there is a dense spot of hyperemia which for several
hours increases in size. Over time the skin above the center of affection becomes cyanotic with its
softening which defines purulent process of subcutaneous fatty cellulose. Then skin over the
damaged area exfoliates, wounds are evident, necrotic tissues are discharged through fistula. The
necrosis can extend deeply to the bones.
At the adequate treatment which is carried out in a surgical hospital, reparation stage occurs
with development of granulations and an epithelisation of wound surface, formation of scars.
Omphalitis. Omphalitis is defined as inflammatory process in the umbilical wound and
neighbouring tissues, caused mainly by Staphylococcus aureus. It is accepted to distinguish simple,
phlegmonose and necrotic forms of omphalitis.
Simple (catarrhal) omphalitis is characterized by long-standing healing and wetting of a
umbilical wound, presence of serous or purulent discharge that dries up with formation of a crust.
Terms of the wound epitelization increase. The hyperemia and infiltration of edges of umbilical
wound can be observed. The general condition of newborns is, as a rule, satisfactory, children
active, quite well gain weight..
At phlegmonose form in process, except for the umbilical ring, nearby subcutaneous fatty
cellulose and vessels are involved. When pressing the umbilicus purulent exudates are discharges.
Edema and hyperemia of edges of the wound, a thickening of the skin round an umbilicus are
noted, subcutaneous fatty cellulose is infiltrated, the umbilicus is located over the surface of the
anterior abdominal wall. There can be symptoms of phlebitis and lymphangitis. There are
4
intoxication symptoms, child becomes enxious or sluggish, appetite decreases, temperature
increases.
Eructions are noted, the weight curve becomes flat or decreases. Formation of an ulcer of an
umbilicus is possible. Phlegmonose omphalitis also complicates by thrombophlebitis and
tromboarteriitis, umbilical sepsis.
Necrotic omphalitis occurs as the complication of the phlegmonose form at preterms and
immature children. Process extends deeply with the necrosis of the skin, subcutaneous fatty
cellulose, muscles, intestinal eventration is possible.
Osteomyelitis.
Anatomical and physiological features of the newborns have a great value in the
development of osteomyelitis. So, epiphyseal parts of bones consist mainly of chondral tissue and
are vasculated trough independent vascular system of final type which predisposes to the delay of
blood flow, fixing of pathogenic microorganisms and the development of pyoinflammatory
process. In case of the affection of the epiphyses of tubular bones the smoothness of contours of
the corresponding joint, edema, consolidation of soft tissues, loss of active movements in
extremities (paresis), restriction and pain are noted at movements associated with expressed
intoxication and pronounced inflammatory changes in peripheral blood. Radiological changes at
osteomyelitis in the form of destruction appear in 2 weeks.
Sepsis of the newborn
Sepsis is an acyclic disease caused by system inflammatory answer to the infectious agent
which is located in blood.
Sepsis is one of the important causes of morbidity and mortality of newborns and infants,
especially prematurely born with intrauterine growth restriction.
Infection at sepsis can occur during the antenatal period, while delivery process and by
contamination after the birth. Antenatal acquisition of infection is possible through transplacental,
hematogenous and ascending intramnial ways. In the development of sepsis of the newborns the
great value has viral and bacterial infection of the placenta.
Etiology.
Among etiologic factors the frequency of grampositive and gramnegative flora are
approximately equal. It is caused by increase of the role of such bacteria, as Streptococcus spp.,
Enterococcus spp. and S. epidirmidis. Among Staphylococcus which cause sepsis, the steady
increase in metitsilinresistant strains is observed. Frequency of sepsis which is caused by not
fermenting gramnegative bacteria (Pseudomonas aeruginosa and Acinetobacter spp) and also
Klebsiella pneumoniae and Enterobacter cloacae is increasing. As a rule, these microorganisms act
as causative agents of hospital sepsis at patients of resuscitation and intensive care departments.
Frequency of sepsis which is caused by fungal infection increased. On section of the children
generalized candidiases are diagnosed in 10-15% of cases of sepsis.
Epidemiology.
Infection source – affected mother, the service personnel, affected child.
Way of transmission - airborne (from the patient or the carrier), and also - contact,
nosocomial infection. The infection extends through hands, medical instruments, suctions devices,
etc. Humidifiers of the device for the mechanical ventilation, incubators, connecting tubes of the
devices can be the source of Pseudomonas aeruginosa..
Most often entrance gate of the infection are intestines, umbilical wound, rarely - skin,
lungs.
Pathogenesis.
Three main components predispose for the development of sepsis: microorganism vitulence,
volume of affection, reactivity of the macroorganism. As a result of the number of researches it
became obvious that the development of organ and system affection, first of all, is caused by
uncontrollable distribution of pro-inflammatory mediators from primary center of the infectious
5
inflammation with the following activation of macrophages in other organs and tissues and
liberation of similar endogenous substances.
The syndrome of the systemic inflammatory answer is the complex of symptoms which includes the
general intoxication, signs of respiratory insufficiency (tachypnea, apnea), tachycardia, clinical
manifestations of perinatal encephalopathy, leucocytosis or leucopenia, increase in level of Creactive protein. According to the concept of sepsis pathogenesis as the syndrome of the systemic
inflammatory answer, there are three stages of its course:
1. Local production of inflammatory mediators (TNF, IL-1,IL-6) and ita antagonists (IL-4,
IL-10, IL-11, antagonists of IL-1 receptors, growth B-factor) for the control of inflammatory
reaction and restoration of homeostasis.
2. If the local homeostasis and balance between inflammatory mediators which passed into
systemic circulation, in the first stage wasn't restored, inflammatory cytokines cuses clinical
symptoms of sepsis, shock and organ dysfunction. Increase of level of persistent anti-inflammatory
mediators can lead to the anergia or to the immune imbalance.
3. Systemic disorder of homeostasis with formation of the individual course of antiinflammatory or proinflammatory reaction.
In case of haemodynamical decompensation at patients with a syndrome of the systemic
inflammatory answer septic shock occurs. Criteria of the development of multiorgan insufficiency
- simultaneous disorders of function of two and more organs and systems associated with the
syndrome of the systemic inflammatory answer. The most widespread is the combination of organ
disturbances at sepsis of the newborns, the DIC-syndrome, respiratory distres-syndrome, acute
renal feilure, CNS disorders.
Classification of sepsis of newborns depends upon the term and way of an infection, an
etiology, entrance gate of the infection, main clinical signs and syndromes, a phase of the course
of the disease.
1) According to the occurrence of the first clinical manifestations of the disease the
sepsis of the newborns is divided into early and late. In the early sepsis the first manifestations of
the disease occur during first 3 days of life. Clinical manifestations of late sepsis of the newborns
observe after the 3rd day of life. Disease occurrence after 14 days of life is caused in most cases by
nosocomial infection.
2) Etiological identification of sepsis. The sepsis is divided into gram - positive and
gram - negative. After detection of the causative agent exact etiologic identification of the form of
the disease is possible (staphylococcal, streptococcal, collibacillar, pseudomonad, fungoid, etc.).
3) Sepsis of the newborns can be classified by entrance gate of an infection - umbilical,
pulmonary, intestinal, otogenous, cryptogene and others.
4) According to the form: septicemic, septicopyemic
5) According to the leading septic focus: enterocolitis, pneumonia,
meningoencephalitis, etc.
6) According to the current: fulminant - from several hours to 1-3 days; acute - 4-6
weeks; subacute - more than 6 weeks.
7) According to the severity of the course of the disease and leading clinical
syndromes: bacteremia, syndrome of the systemic inflammatory answer, sepsis, severe sepsis,
septic shock, polyorganic insufficiency.
8) According to the period of the disease: initial, manifected, restoration, rehabilitation.
9) According to the complications (trombotic, insufficiency of organs and systems,
anemia, intestinal dysbacteriosis, etc.)
Clinical manifestations.
Symptoms: intoxication, CNS disorders, haemodynamical, microcirculatory and metabolical
disturbances, in combination with the presence of the inflammatory focuses. Anamnestic data that
should be taken into account: mother’s health condition, feature of the delivery, in particular
duration of the waterless period; characteristic changes in behavior of the child - weakness, refusal
from breastfeeding; decreased weight in the absence of a hypogalactia, eruction, vomiting; loss of
physiological reflexes, fever, pathological jaundice, respiratory and cardiovascular disorders.
6
In case of fulminant form as the result of the excess of bacterial exotoxins and endotoxins,
massive emission of mediators occurs which causes fever, toxicosis, hyperexcitability or CNS
depression, microcirculation disorders - a marble skin colour with hemorrhages and bleeding from
the places of injections (DIC-syndrome), cardiovascular failure, oliguriya, neurologic disorders.
Especially severe condition develops at the adrenal hemorrhages with the unfavorable prognosis at
most patients within several days.
Acute sepsis (lasting 4-6 weeks) has clinical manifestations in the form of septicopiemia or
a septicemia. The septicopiemic form is characterized by the hectic fever which, expressed
intoxication, purulent focuses. At the initial stage the purulent focus can be single. At umbilical
sepsis in umbilical vessels - thrombophlebitis or thrombarteritis. Further metastases (osteomyelitis,
meningitis, microbic destruction of lungs, etc.) occur. Severe complication sepsis –necrotic
enterocolitis.
Septicemiya - a clinical form of sepsis with expressed symptoms of bacterial toxicosis in
the absence of the metastatic centers of a purulent inflammation. At slowly progressing subacute
(till 8 weeks) course of sepsis in the initial stage of the illness local symptoms of the purulent
center at the entrance gate of infection appear: intestinal dysfunction, omphalitis, purulent
discharge from the umbilical wound, tension of the muscles of the anterior abdominal wall, fever,
weak sucking reflex, vomiting, lack of the weight increase, and then decreased weight, pallor of
the skin with a gray or icteric shade, a lymphadenopathy, acrocyanosis, tachycardia, dyspnea,
decreased tones of the heart, abdominal distension, enlargement of liver and spleen. There can be
hemorrhagic rash, bloody discharge from the umbilical wound.
Features of sepsis at the prematurely born. At prematurely born and children with IUGR
sepsis develops much more often than at children that were born in term and with normal weight.
The immune system of this group of children has a feature of critically low lg level in serum which
predisposes such children to the bacterial infections. This group of children has not manifested
clinical picture of the sepsis caused by weak inflammatory reaction in tissues. Sometimes infectious
agent is found in blood or liquor that complicates establishment of the diagnosis.
Infectious-toxic shock.
The most widespread infectious agents of extrahospital septic shock at children older than 1
month without immunodeficiency are: meningococcus, pneumococcus, hemophilus influenza type
B. At intrahospital septic shock the most widespread infectious agents are the gramnegative
enterobacteria, staphylococcus, enterococcus, fungi. Development of the septic shock is caused by
activation of mediators of the systemic inflammatory answer after contact of the immune cells with
endotoxins of gramnegative enterobacteria. At first stage hyperthermia, circulatory hyperdinamia,
tachycardia, a vasodilatation, arterial hypotension with high level of delivery of oxygen occurs.
Further development of shock leads to reduction of heart output owing to the hypovolemia
(extravasation and blood deposition) or to the myocardium depressions, or to the combination of
these factors. Blood pressure critically decreases, perfusion of tissues deteriorates, vascular
resistance sometimes increases, metabolic lactate acidosis increases, symptoms of organ
dysfunction are evident (acute respiratory distress-syndrome, acute renal failure, DIC-syndrome,
septic hepatitis, etc.).
Clinical features of sepsis depending upon the infectious agent.
Gramsnegative sepsis is characterized by the symptoms of toxicosis with CNS depression –
weakness, anorexia; microcirculatory disorders – pallor, fast cooling, scleredema, hypothermia
(fever occurs only at colli-sepsis). Characteristic signs are high affection of brain membranes, lungs
and intestines, tendency to the DIC-syndrome, minimal local inflammatory reaction (delay of
healing of the umbilical wound, puffiness of tissues in the bottom segment of the umbilical ring)
and inflammatory changes in peripheral blood. Purulent disorders of skin and subcutaneous
cellulose, liver and spleen enlargement usually are not evident.
Local purulent affection of the skin and subcutaneous cellulose, umbilicus, lungs, bones
(osteomyelitis), the ears, the expressed inflammatory changes of peripheral blood are typical for
staphylococcal sepsis.
Diagnostic criteria. Goals of objective examination:
7
1. Assessment of the nervous system (presence of disorders of consciousness, focal neurologic
symptoms, signs of irritation of brain membranes, signs of traumatic damage)
2. Assessment of the condition of perfusion (time of capillary filling), other signs of disorders of
microcirculation, urination.
3. Assessment of the condition of hydration (condition of skin and mucous membranes, turgor of
the skin, big fontanel, pulsation and dilatation of subcutaneous veins).
4. Assessment of breathing (frequency, pathological types of breathing, tachypnea, dispnea,
hyperpnea, objective data that points to the possibility of the infectious focus in lungs, pleural
cavity, upper respiratory tract (retropharyngeal abscess, epiglottitis) or development of the
respiratory distress-syndrome).
5. Assessment of the cardiovascular system (heart rate, bllod pressure, heart borders, signs of
primary disorder of cardiovascular system).
6. Assessment of the gastrointestinal (presence of diarrhea, gastrointestinal bleeding, liver size,
pathological masses in the abdominal cavity).
7. Assessment of the lymphatic system (lymphoadenopathy, lymphadenitis, lymphangitis, spleen
size, tonsils inspection).
8. Assessment of the uriogenital system (congenital pathology, pathological discharge from
genitals).
9. Assessment of the skin and mucous membranes (exanthemas, enanthemas, dry necroses,
pyodermia, gangrenose ectima, candidiasis manifestations, burns).
10. Assessment of the bones and joints (trauma, bone pain, local hyperemia and edema round the
joints, tubular bones, other symptoms of arthritis and osteomyelitis).
Paraclinical examination
1. Complete blood count.
2. Urinalysis.
3. Blood type and Rhesus factor.
Urgent bacterioscopy of pathological discharge which can contain the causative agent of the disease
(blood, sputum, etc.)
4. Bacteriological investigations (blood, liquor, sputum, urine, discharge from wounds, etc.) with
determination of the sensitivity of microflora to antibiotics.
5. Stool examination.
6. Biochemical blood test (hematocrit, general protein, glucose, urea, creatinine, coagulograme,
hepatic enzymes, bilirubin, amylase, osmolarity, serum electrolytes: sodium, potassium, calcium,
chlorides).
7. Immunological investigation (parameters of cellular and humoral immunity, phagocytosis,
circulating immune complexes, complement).
8. Definition of blood gases and parameters of the acid-base balance in the arterial (capillary) or
venous blood.
9. Radiological investigation – thoracic organs and other systems, depending upon the possible
localization of the source of sepsis.
10. Ultrasonic investigation of the central nervous system, internal organs, cardiovascular system
with calculation of parameters of central haemodynamics.
11. Measurement of the breathing rate, heart rate, blood pressure with calculation of average blood
pressure, central venous pressure.
12. Electrocardiography.
13. Inspectios and consultations of consultants, depending upon the possible etiology of sepsis
(surgeon, traumatologist, otholaryngologist, neurologist, infectiologist, etc.)
The diagnosis of septic shock is defined in the presence of two or more symptoms of the
systemic inflammatory answer namely:
1. fever (higher than 37,2 (C) or hypothermia (lower than 35,2 (C),
2. tachycardia (heat rate is higher than age normal parameters),
3. tachypnea (frequency of breathing is higher than age normal parameters),
4. leucocytosis (more than 12x109/l) or leucopenia (less than 4x109/l)
8
5. ledt shift of the leukocyte formula - increase in the quantity of immature forms of
neutrophils over 10%;
and following symptoms of disorders of haemodynamics and perfusion:
1. Blood pressure at two measurements below age normal parameters more than on 1/3;
2. Preservation of hypotonia despite carrying out infusion therapy of 20 ml/kg by colloid or
crystalloid solutions;
3. Necessity of inotropic or vasopressor support (with the exception of dopamin less than 5
mcg/kg/min.);
4. Combination of hypotonia with criteria of severe sepsis (disorders of consciousness, oliguria).
Treatment of sepsis of newborns includes etiotropic treatment (antibacterial, antiviral,
antifungal therapy) and the pathogenetical actions directed on ensuring haemodynamical stability
and oxygenation of tissues, support of normal parameters of the homeostasis, immunotherapy, if
necessary – surgical treatment of the infectious focuses.
Relevance of empirical selection of antibiotics is explained by the need of a timely initiation
of treatment and to receiving results of bacteriological investigation. According to the
recommendations of the International Septicological Association (Maastricht, 1995), at septis of
moderate severity for the "starting" antibacterial therapy combination of cephalosporins of the 3rd
generation (cephtazidim, cephtriacson, cephoperason) and aminoglycosides of the 3rd generation
(amikacin, netromycin) are recommended. At severe sepsis, septic shock, polyorgan insufficiency
treatment should be started with cephalosporins of the 4th generation (cephypim), monobactams
(aztreonam), carbapenems (imepenem/celastin, meropenem).
At identification of the infectious agent the choice of the scheme of antibacterial therapy is
defined by its sensitivity
Monitoring standards during intensive therapy:
Monitoring of an electrocardiogram, heart rate, systolic, diastolic and average blood pressure
(invasive or noninvasive),
Measurement of the central venous pressure (4 times per day in 6 hours, or are more often if
indicated),
Control of the weight (4 times per day in 6 hours),
Thermometry (desirable a skin and rectal gradient),
Pulsoxymetria,
Capnometria,
Hourly control of diuresis,
Above listed laboratory investigations should be evaluated at least than once per day, or more often,
depending on the clinical situation, character of pathological disorders and dynamics of the
condition of the patient.
Treatment of septic shock should be carried out only in resuscitation and intensive care units, but it
is necessary to begin treatment where this condition is diagnosed (somatic, surgical, infectious
departments, an ambulance car, etc.)
INTENSIVE THERAPY IN THE UNSPECIALIZED DEPARTMENTS, OR AT THE PREHOSPITAL STAGE
1. Ensuring upper respiratory airways potency;
2. Oxygen therapy (if indicated - mechanical ventilation);
3. Ensuring of reliable venous access, beginning of infusion therapy by isotonic solutions,
crystalloids 20 ml/kg in 20 minutes;
4. If the etiology of sepsis is established (meningococcemia) – intravenous administration of
cephtriacson or cephotaxim 50 mg/kg;
5. Anticonvulsive therapy (if seizures are present);
6. Administration of symptomatic preparations (antipiretics, analgetics).
INTENSIVE THERAPY IN THE INTENSIVE CARE UNITS
1. Ensuring upper respiratory airways potency, oxygen therapy by the humidified oxygen;
2. Ensuring reliable venous access (accesses), the beginning of infusion therapy with isotonic
crystalloid salt, in volume up to 60 ml/kg in the first hour, or colloids (6-10% hyproxiethylamylum
9
200) up to 20 ml/kg in the first hour, with determination of further rate and composition of infusion
therapy according to the condition of the patient and perfusion indicators, dyuresis, heart rate,
arterial and central venous pressure. In the absence of a hypernatremia and hyperosmolarity the
starting solution for the infusion therapy at children older than 1 month should be a combination of
7,5%-10% of sodium chloride with a synthetic colloid (preferably 6-10% hyproxiethylamylum 200)
in the ratio 1:1 at the dose of 6-8 ml/kg in 5-15 minutes with the following infusion of crystalloids.
Further infusion therapy has to provide correction of electrolytes (sodium, calcium), parameters of
acid-base balance (correction of metabolic acidosis at рН less than 7,2 and absence of effect from
the previous infusion therapy), hemostasis parameters (at fibrinogen level less than 1,5 g/l and
protrombin index less than 50% - a transfusion of fresh frozen plasma, 10-20 ml/kg with heparin
40-50 U per 1 kg of weight), the oxygen capacity of blood (a transfusion of erythrocytes till the
level of hemoglobin reaches 100 g/l). Correction of potassium level has to begin after restoration of
diuresis. Administration of glucose solutions should be started only at confirmed hypoglycemia.
Criteria of efficiency of infusion therapy are: improvement of perfusion, microcirculation, increase
of diuresis, tachycardia resolution, normalization of parameters of preloading (central venous
pressure, final diastolic volume of the left ventricle), increase in PO2 to 33-53 mm hg. and SatO2 to
64-75%.
3. Antibacterial therapy (children over 1 month of age).
• Outhospital development of septic shock in children with absence of signs of
immunodeficiency – ingibitorprotected penicillin, cephalosporins of the ІІ generation
(cefuroxim), at symptoms of the neuroinfection (meningitis, meningococcemia) –
cephalosporins of the ІІІ generation (cefotaxim or ceftriaxon).
• Outhospital development of septic shock in children with neutropenia or other signs of
immunodeficiency - carbapenems (tienam, or meronem) or a combination of ceftazidim with
antipseudomonase aminoglikosides (tobramycin, netylmicin, amikacin).
• Outhospital development of septic shock at children with asplenia - cefotaxim or ceftriaxon.
• Syndrome of staphylococcal toxic shock - oxacillin or cefazolin.
• Syndrome of streptococcal toxic shock - benzylpenicillin + clyndamicin, or macrolid /
cefotaxim + clyndamicin.
• Intrahospital development of septic shock - a choice depends upon microbiological hospital
flora. In the presence of the central venous catheter - vancomicin or teicoplanin, at burns and
neutropenia - vancomicin or teicoplanin in a combination with carbapenems or cefalosporins of
the ІІІ-IV generation.
• Antibacterial therapy (children younger than 1 month) – cefalosporins of the ІІІ generation
(cefotaxim) + ampicillin.
4. Inotrops and sympathomimetics (all preparations to administer by infusion pumps).
5. Begins after the beginning of infusion therapy and preloading restoration
6. Dopamine 5-25 mcg/kg/min. intravenously, a dose is titrated depending upon the desirable
effect (inotropic or vazokonstriction).
7. If dopamine is inefficient (hypotonia persists) - noradrenalin, as adrenaline 0,1-0,2
mcg/kg/min. intravenously, a dose is titrated from the minimal to the effective (increase in
blood pressure, diuresis).
8. At low heart output dobutamin is indicated in a dose of 5-20 mcg/kg/min. intravenously.
9. Use of the combination of noradrenalin and dobutamin is possible. The purpose of inotropic
support is ensuring heart output at the level of 4-5 l/min./sq.m and oxygen delivery at the
level of not less than 600-700 ml/min./sq.m; the goal of sympatomymetics administration is
ensuring sufficient average arterial pressure and perfusion of life important organs.
10. In the absence of the effect from sympatomymetics hydrocortisone 50 mg each 6 hours
intravenously, or prednisone in equivalent doses should be used with correction of acidosis
and electrolytes.
11. Absence of effect from infusion inotropic support and antibacterial therapy for 1-2 hours
and development of acute respiratory distress-syndrome are indications for the mechanical
ventilation.
10
12. In the presence of the infectious focus was the source of development of septic shock
(abscess, phlegmon, peritonitis, empyema of pleurae and other remote purulent centers),
urgent surgery for the drainage and local sanitation of the purulent centers is indicated in
combination with syndromic therapy.
13. During treatment of septic shock it is necessary reduce affection of gastrointestinal mucous
(decompression, stimulation of intestinal motility, administration of gastrocytoprotectors venter).
14. In the absence of effect from the offered complex of intensive therapy alternative methods
of treatment (extracorporeal methods of a detoxication, auxiliary blood circulation,
immunocorrection, glycosides and other inotropic agents, inhibitors of proteases, naloxon, etc.) can
be considered
Additional materials for the self-control
А. Clinical cases
Case 1
The 3200 g term newborn female delivered via normal spontaneous vaginal delivery to a 25
year old G1P0 syphilis non-reactive, group B strep (GBS) negative, rubella immune, hepatitis B
surface antigen negative mother with early preeclampsia and thrombocytopenia (platelet count
80,000). Rupture of membranes occurred 11 hours prior to delivery with clear fluid. Intrapartum
medications included 3 doses of butorphanol (narcotic opioid analgesic). The last dose was
administered within 1 hr of delivery. There was no maternal fever. Apgars were 8 and 9.
In the newborn nursery, vital signs are: HR 140, T 37, BP 47/39, RR 54. Oxygen saturation
is 98-100% in room air. The infant appears slightly pale and mottled. She is centrally pink with
persistent grunting, shallow respirations, and lethargy. Her fontanelle is soft and flat. Heart exam is
normal. Lungs show good aeration. Abdomen is soft and without masses. Pulses are 1+ throughout
with 3-4 sec capillary refill. Neuro exam shows decreased tone and a weak, intermittent cry.
Labs: CBC with WBC 3,200, 6% segs, 14% bands, 76% lymphocytes, Hgb 15, Hct 43,
platelets 168,000. Blood glucose 52. The chest x-ray is rotated with fluid in the right fissure, diffuse
streakiness on the left, and a normal cardiac silhouette. CBG (capillary blood gas) pH 7.31, pCO2
43, pO2 44, BE-4. CSF: 2430 RBCs, 20 WBCs, 1% PMN, 17% lymphs, 82% monos, glucose 39,
protein 133, gram stain shows no organisms.
Questions
1. What other tests would you obtain?
2. What would your assessment be for this infant
3. What would your recommendations be (if any) for further evaluation or treatment?
4. How long would you treat her?
Case 2.
A female infant is delivered by spontaneous vaginal delivery at 29 weeks of gestation. Her
Apgar scores are 8 at 1 minute and 9 at 5 minutes. Her weight is 1,300 g, length is 38 cm, and head
circumference is 27 cm. The mother is a 20-year-old primiparous African American female
who had one previous live term pregnancy and one abortion. Her past medical and surgical histories
are otherwise unremarkable. She had adequate prenatal care, and her prenatal laboratory test results
were normal, including a negative screen for group B Streptococcus and normal findings on
prenatal ultrasonography. She experienced premature contractions at 27 weeks, at whichtime a dose
of betamethasone was administered. At 29 weeks of gestation, she went into labor. Clear amniotic
fluid was drained after artificial rupture of membranes just prior to delivery. At the time of delivery,
the mother did not have fever or tachycardia, although she had a white blood cell count of
16.9_103/mcL (16.9_109/L), with 58% neutrophils, 12% bands, 15% lymphocytes, and 12%
monocytes by manual differential count. The mother did not receive antibiotics during the
intrapartum period.
11
The baby is admitted to the neonatal intensive care unit (NICU) due to prematurity and is treated
with intravenous ampicillin and gentamicin for 48 hours until cultures are negative and the baby
remains clinically stable. She begins oral feedings with expressed human milk (EBM) on the second
day after birth. Small amounts of residue are present periodically after feedings. She otherwise
remains clinically stable, breathing comfortably in room air. On day 13 after birth, she develops
abdominal distention and vomits once. Greenish material is aspirated via the orogastric gastric
A complete blood count revealed a white blood cell count of 30.7_103/mcL (30.7_109/L),
with a differential count of 62% neutrophils, 1% bands, 20% lymphocytes, 11% monocytes, 4%
eosinophils, and 2% basophils; hematocrit of 34.2% (0.342); and platelet count of 294_103/mcL
(294_109/L). A plain abdominal film revealed distended bowel loops without signs of obstruction
or pneumatosis.
Questions
5. What other tests would you obtain?
6. What diseases do you include in the differential diagnosis?
7. What is the presumable source of infection?
8. How to treat this disorder?
Case 3
Thirteen-day-old African-American twin boys are brought to the ED because of fussiness
and inconsolable crying for several hours. Twin A’s signs began first, with decreased feedings and
one episode of nonbilious, nonbloody emesis of formula. Neither infant has a history of fever. Both
are having normal stool and urine frequency, without evidence of blood or mucus in the stool.
Delivery was by urgent caesarean section at 36 weeks’ gestation for "poor blood flow" to twin B,
which was noted on routine ultrasonography. The mother had no symptomatic infections during her
pregnancy. She recalls that studies were performed to look for infection but did not know the
results.
Physical examination of twin A reveals a mildly fussy infant who cries during the
examination; he is consolable with a pacifier, but takes it somewhat reluctantly. Twin A cries and
draws up his legs during palpation of his abdomen, which is soft and not distended. Twin B also
appears somewhat fussy but consolable, makes good eye contact, and falls asleep easily. The
remainder of the examination findings, including vital signs, is normal for both twins.
A CBC on twin A shows a WBC count of 21.1x103/mcL (21.1x109/L) (65% neutrophils, 5% bands,
15% lymphocytes, 14% monocytes, 1% eosinophils); Hgb of 14.7 g/dL (147 g/L); and platelet count
of 330x103/mcL (330x109/L). A blood culture is drawn. An abdominal radiograph of twin A is read
as normal. Because of the poor feeding, crying, and 36-week gestation, twin A is admitted for
observation. Twin B also is admitted for further observation.
The following morning, the Gram stain of the blood culture from twin A showed numerous
gram-positive cocci in pairs and chains on direct smear. Shortly thereafter, twin A developed a fever
to 100.9°F (38.3°C); a lumbar puncture was performed, and the CSF also showed this organism.
Considering the increased risk of nosocomial and perinatal infection in twins, a similar evaluation
was undertaken in twin B, which revealed similar-appearing bacteria in the blood and CSF. The
organism later was identified as beta-hemolytic group B Streptococcus (GBS). Both infants were
started on antibiotics after their lumbar punctures. There was no initial evidence of meningitis in
either twin, as evidenced by cell count, glucose concentration, or protein value in the initial CSF. A
repeat lumbar puncture on both infants after 48 hours of antibiotics showed a significant cellular and
chemical response.
The following morning, the Gram stain of the blood culture from twin A showed numerous
gram-positive cocci in pairs and chains on direct smear. Shortly thereafter, twin A developed a fever
to 100.9°F (38.3°C); a lumbar puncture was performed, and the CSF also showed this organism.
Considering the increased risk of nosocomial and perinatal infection in twins, a similar evaluation
was undertaken in twin B, which revealed similar-appearing bacteria in the blood and CSF. The
organism later was identified as beta-hemolytic group B Streptococcus (GBS). Both infants were
started on antibiotics after their lumbar punctures. There was no initial evidence of meningitis in
either twin, as evidenced by cell count, glucose concentration, or protein value in the initial CSF. A
12
repeat lumbar puncture on both infants after 48 hours of antibiotics showed a significant cellular and
chemical response.
Questions
1. What is the definitive diagnosis?
2. Write down confirmation of the diagnosis.
3. How to treat this disorder?
B. Tests
Question 1. A 22-day-old infant is noted by his mother to have a rectal temperature of
38.3°C. She reports that he has been acting normal and appears generally well. He was born at 37
wk of gestation, went home with his mother at 24 hr of life, and has done well since. There is no
known underlying illness. The physical examination is normal. The infant's WBC count is
19,500/mm3 and the absolute band count is 850/mm3. There are 4 WBCs/mm3 in an unspun urine
sample, and results of a Gram stain of the urine are negative. This infant fails to meet criteria for
low risk of serious bacterial infection because:
A. He was born prematurely.
B. The WBC count is elevated.
C. The absolute band count is elevated.
D. There is a urinary tract infection.
E. He is less than 1 mo of age.
Answer B. Explanation: Infants younger than 3 mo with fever who appear generally well; who have
been previously healthy; who have no evidence of skin, soft tissue, bone, joint, or ear infection; and
who have a total white blood cell (WBC) count of 5,000-15,000/μL, an absolute band count of
<1,500/μL, and normal urinalysis results are unlikely to have a serious bacterial infection. The
negative predictive value with 95% confidence of these criteria for any serious bacterial infection is
>98%, and for bacteremia, >99%. Neonates are at higher risk of sepsis and meningitis caused by
group B streptococci and other organisms.
Question 2. A newborn develops sepsis and shock. The pathogen that most commonly causes
systemic and focal infections in the newborn is:
A. Staphylococcus aureus
B. Group A streptococci
C. Group B streptococci
D. Escherichia coli
E. Herpes simplex virus
Answer C. Explanation: Group B streptococcal organisms are the major cause of severe systemic
and focal infections in the newborn. Coagulasenegative staphylococcal infections are the most
common nosocomial infections in the neonatal intensive care unit.
Question 3. All of the following statements concerning perinatal group B streptococcal
neonatal infections are true except:
A. Approximately 20-40% of pregnant women are colonized.
B. Colonization rates are increased in women older than 40 yr, in whites, and in higher
socioeconomic groups.
C. Pregnant women who are colonized are usually asymptomatic.
D. Approximately 40-70% of infants born to colonized women become colonized.
E. Approximately 0.5-2% of colonized infants become infected.
Answer B. Explanation: Group B streptococcal colonization rates are increased in women younger
than 20 years of age, in African Americans, and among lower socioeconomic groups.
13
Question 4. The recommended regimen for selective intrapartum prophylaxis for group B
streptococcal infection is:
1. Penicillin G 5,000,000 units IV to the mother at the onset of labor
2. Penicillin G 5,000,000 units IV to the mother at the onset of labor, followed by 2,500,000 units
IV every 4 hr until delivery
3. Penicillin G 5,000,000 units IV to the mother at the onset of labor, followed by continuous
infusion of 500,000 units per hour until delivery
4. Crystalline penicillin G 50,000 units IM to the newborn
5. Procaine penicillin G 150,000 units IM to the newborn
Answer B. Explanation: For group B streptococcal prophylaxis, the AAP and CDC recommend
administration of penicillin G, 5,000,000 units IV, to the mother at the onset of labor, followed by
2,500,000 units IV every 4 hr until delivery. Ampicillin is an alternative. For penicillin-intolerant
women, cefazolin may be used. For penicillin-allergic women at high risk for anaphylaxis,
clindamycin or erythromycin should be used.
Question 5. Regarding early-onset versus late-onset neonatal infection, all of the following are true
except:
A. Group B streptococci are the most common cause of early-onset infection.
B. Early-onset disease usually presents within the first 7 days of life, whereas late-onset disease
presents after 7 days.
C. Maternal chemoprophylaxis has led to striking decreases in both early-onset and late-onset
disease.
D. Early-onset disease is often associated with maternal obstetric complications, whereas late-onset
disease is not.
E. Early-onset disease usually presents as sepsis and pneumonia, whereas late-onset disease usually
presents as bacteremia and meningitis.
Answer C. Explanation: In the 1990s, widespread implementation of maternal chemoprophylaxis
led to a striking 65% decrease in the incidence of early-onset neonatal group B streptococcal
disease in the United States, from 1.7 per 1,000 live births to 0.6 per 1,000 live births, while the
incidence of late-onset disease remained essentially stable at approximately 0.4 per 1,000.
Question 6. The risk of early-onset group B streptococcal infection in an infant of a 34- yr-old
mother is increased with all of the following except:
A. Heavy maternal vaginal or rectal colonization with group B streptococci
B. Prolonged rupture of membranes (greater than 18 hr)
C. Maternal fever with temperature greater than 38°C
D. Maternal bacteriuria with group B streptococci during her last pregnancy
E. Previous infant with invasive group B streptococcal infection
Answer D. Explanation: Risk factors for early-onset disease include heavy maternal vaginal or
rectal colonization with group B streptococci, prolonged rupture of membranes, intrapartum fever,
prematurity, maternal bacteriuria during pregnancy, and previous delivery of an infant who
developed group B streptococcal disease.
Question 7. Which of the following pregnant women should receive prophylaxis against
group B streptococci?
A. A woman who tested positive for group B streptococci at 37 wk of gestation and is having a
planned cesarean section (without rupture of membranes)
B. A woman who tested negative for group B streptococci at 35 wk of gestation and goes into
spontaneous labor at 36 wk
C. A woman whose group B streptococcal status is unknown and who had a previous infant at home
with invasive group B streptococcal infection
14
D. A woman who tested negative for group B streptococci at 37 wk and has had prolonged rupture
of membranes (>20 hr) when she delivers at 39 wk of gestation
Answer C. Explanation: Any woman with a positive prenatal screening culture, group B
streptococcal (GBS) bacteriuria during pregnancy, or a previous infant with invasive GBS disease
should receive intrapartum antibiotics.
Question 8. All of the following infants routinely require a sepsis evaluation (at least a
complete blood count with differential, and blood culture) except:
A.An infant born at 36 wk whose mother had not been tested for group B streptococci
B. An infant born at 38 wk whose mother had a culture that was positive for group B streptococci
and who was delivered 2 hr after the mother received her first dose of antibiotics
C. An infant born at 40 wk whose mother had a culture that was negative for group B streptococci
but was treated for suspected chorioamnionitis
D. An infant born at 38 wk whose mother had a culture that was positive for group B streptococci
and had spontaneous rupture of membranes but then delivered by cesarean section for failure to
progress
E. An infant born at 39 wk whose mother had a culture that was negative for group B streptococci
Answer A. Explanation: Guidelines from the Centers for Disease Control and Prevention (CDC)
provide an algorithm for the empirical management of a newborn whose mother received
intrapartum antimicrobial agents for prevention of early-onset group B streptococcal disease or
suspected chorioamnionitis.
Question 9. Which of the following is the most significant risk factor for fungal sepsis in a
premature infant?
A. Meconium aspiration
B. Intravenous lipid infusion
C. Previous administration of vancomycin
D. Postconceptional age
E. Heavy colonization with Candida
Answer E. Explanation: The inability of the newborn infant to localize Candidacolonization
facilitates overgrowth of Candida on mucocutaneous surfaces, which is a major predisposing factor
for neonatal Candida
infections.
Question 10. A premature newborn on broad-spectrum antibiotics with a central venous catheter
appears to be in shock, and you suspect either bacteria or Candida. The recommended culture
studies for this patient include:
A. Blood cultures using only routine blood culture media
B. Routine blood cultures and also fungal cultures using Sabouraud culture media
C. Routine blood cultures and also fungal cultures using brain-heart infusion media
D. Routine blood cultures and also fungal cultures using Bordet-Gengou culture media
E. Only fungal cultures, because the newborn is on antibiotics
Answer A. Explanation: Candida grows readily on routine blood culture media, and therefore
special media are unnecessary. Cultures should also include the possibility of antibiotic-resistant
bacteria.
Question 11. The term 3-day-old infant at various skin surfaces has erythema, erosions, rhagades,
epidermal desquamations. The infant looks, as if scalded by boiled water that were absent at time of
delivery. Nikolsky's symptom is positive. Extreme anxiety, hyperesthesia, febrile are observed
temperature. What is the most probable diagnosis in this case?
15
A Exfoliative dermatitis
B Phlegmon of the newborn
C Figner`s pseudofurunkulesis
D Pemphigus of the newborn
E Mikotic erythema
Question 12. The child is 2 day old. He was born term with signs of intrauterine infection,
antibiotics were administered. Specify, why the interval between introduction of antibiotics at
newborn children is longer in comparison with children of older age and adults, and doses - lower?
A Newborns have lower level of glomerular filtration
B Newborns have lower concentration of protein and albumin in blood
C Newborns have decreased activity of glucuronile transferase
D Newborns have decreased blood рН
E Newborns have higher hematocritis
Question 13. The infant on the 40th hour after delivery has hyperesthesia, CNS depression and
decreased appetite. There is the suspicion of sepsis. What is the differential diagnosis?
A Hypoglycemia
B Hypocalcemia
C Hyperbilirubinemia
D Hyperkalemia
E Hypomagniemia
Question 14. The term infant on the 6th day after delivery has erythema, inactive bubbles, erosive
surfaces, cracks, epidermal shadding at various skin surfaces which looks like after scalding of
boiled water. Nikolsky's symptom is positive. The general condition of the child is severe. The
anxiety, hyperesthesia, febrile temperature are evident. What is the most probable diagnosis in this
case?
A Ritter`s exfoliative dermatitis
B Phlegmon of the newborn
C Figner`s pseudofurunkulesis
D Pemphigus of the newborn
E Epidermolisis
Question 15. Mother of the newborn child suffers from chronic pyelonephritis, before labour had
acute respiratory virus infection. Labour is urgent, prolong waterless period. At the 2 day
erythematous rash has appeared, further - bubbles at the size about 1 сm, filled with serousepurulent content. Nikolsky's symptom is positive. After opening the bubbles the erosions are
evident. The child is weak. Body temperature is subfebrile. What is the most probable diagnosis?
A Pemphigus of the newborn
B Vesikulopustulesis
C Pseudofurunkulesis
D Sepsis
E Ritter`s dermatitis
Question 16. Newborn infant has purulent discharge from umbilical wound, skin round the
umbilicus is edematous. The skin is pale, with a yellow-gray shade, generalised hemorrhagic rash.
Body temperature is hectic. Which of the listed diagnoses is the most probable?
A Sepsis.
B Haemorrhagic disease of the newborn
C Haemolytic illness of the newborn
D Trombocytopathy.
E Omfalitis.
16
Question 17. The infant on the 6th day after delivery at the occipital region, at neck and buttocks
has vesicles, filled with serous-purulent content, which densely cover a skin, that were absent at
time of delivery. The general condition of the child is satisfactory. What disease should we think
about?
A Vesisulopustulosis
B Pemphigus of newborns
C Miliaria
D Impetigo
E Bullous epidermolis
4. LITERATURE FOR STUDENTS
1. Nelson Textbook of Pediatrics. - 18th ed. / Ed. by R. Kliegman et al.-Philadelphia: Saunders Co,
2007.- 3146 p.
2. Pediatry. Guidance Aid / За ред. О.В. Тяжка; О.П. Вінницька, Т.І. Лутай – К. : Медицина,
2007 . – 158 с.
3. Current Pediatric Diagnosis & Treatment (CPDT). - 18th ed./ Ed. By W.W.Hay et al. - The
McGraw-Hill Companies. – 2006.
4. Current pediatric therapy -18th ed. / Ed. by F.D.Burg et al. - Elsevier Inc. – 2007.
5. Nelson Essentials of Pediatrics -5th ed. / Ed. by B.S.Siegel, J.J.Siegel. - Elsevier Inc. – 2007.
6. Examination of the Newborn. A Practical Guide / Ed. by Helen Baston and Heather Durward. the Taylor & Francis e-Library. - 2005.
7. Fetal and neonatal secrets. - second edition . / Ed. by R.A.Polin, A.R.Spitzer. - Elsevier.- 2006.
8. Key Topics in Neonatology / Ed. by R.H. Mupanemunda, M. Watkinson. - Oxford Washington
DC. -1999.
Performed by ass. Shiricina M.V., ass. Tkachenko N.P.
Approved “_____”____________20____y.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
Reconsidered
Approved “_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
Reconsidered
Approved ““_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
Reconsidered
Approved “_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
17
Reconsidered
Approved ““_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
Reconsidered
Approved “_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
Reconsidered
Approved ““_____”____________20____р.
Сhief of the department, professor
Protocol №_____
V. A. Kondratyev
18