Copy of n.sepsis 2

STUDY OF NEONATAL SEPTICEMIA WITH REFERENCE TO EARLY INDICATORS OF SEPSIS in NICU, PIMSDISSERTATION By Dr. T.CLEMENT MANOHAR.

CLINICAL

Submitted to the NTR UNIVERSITY OF HEALTH SCIENCES, VIJAYAWADA In partial fulfillment of the requirements for the degree of M.D.(PEDIATRICS) Guide Dr. LAXMAN KUMAR .M.D. (AIIMS) Professor Department of Pediatrics,

PRATHIMA INSTITUTE OF MEDICAL SCIENCES KARIMNAGAR, ANDHRA PRADESH.

2012

ACKNOWLEDGEMENT

I express my deep sense of gratitude to Professor, and Head Of The Department of Pediatrics, PIMS and my guide Dr. Ch. LAXMAN KUMAR (M.D Pediatrics, AIIMS), ) whose guidance and encouragement all throughout his periodic assessment and specific corrections, coupled with his rich knowledge and deep interest in the topic, was my constant source of inspiration leading to the success of this study. I express my deep sense of gratitude to Dr. SREERAM REDDY (M.D. Pediatrics), Professor of Pathology, for his cooperation and valuable suggestions through out the period of this study. I am thankful to Dr. Rabindra Kumar Sahoo M.D(Pediatrics),Asst. Professor of Pediatrics PIMS for his support and help in various stages of my work. I am thankful to Dr. Ch. Amith Kumar (Pediatrics) Assistant Professor Of Pediatrics, PIMS and Dr. Sahay Kumar DCh PIMS for their support and help in various stages of my work. I am thankful to my colleagues Dr. P. Rajesh Khanna, Dr. Mohd.Sarfaraz nawaz and my Juniors for their Cooperation in doing my work. Finally I would like to express my gratitude to all the Nursing & Support staff of my Department who helped me. Thank you one and all

Dr. T.CLEMENT MANOHAR.

LIST OF ABBREVIATIONS USEDHb% TC DC B/N CRP m-ESR CSF PPA NNPD EOS : : : : : : : : : : Hemoglobin Total Count Differential count Band Neutrophil ratio C-reactive protein Micro ESR Cerebrospinal fluid Positive predictive accuracy National neonatal perinatal database Early onset sepsis

ABSTRACT

Neonatal septicemia is a major cause of morbidity and mortality in new born infants. Background and Objectives : To study the incidence, predisposing factors, clinical profile, outcome, early indicators of correlation with all clinical aspects, and antibiotic sensitivity pattern of neonatal septicemia. Materials and Methods : The 50 neonates who are showing the well-documented signs of septicemia are included in this study. The blood is subjected to following investigations. 1. 2. 3. 4. 5. 6. 7. Hb, TC, DC with Band neutrophil ratio. Peripheral smear with toxic granules. Micro ESR CRP Blood Culture CSF (when indicated) Urine, Pus (from superficial focus), rectal swab will be subjected to Culture and sensitivity when indicated. 8. Babies will be subjected to radiological investigations when indicated.

Results : Culture was bacteriologically positive in 34% cases. Ciprofloxacin had maximum sensitivity of 88.2%. Leucopenia < 5000/cmm had sensitivity of 47% specificity of 66.67% and PPA of 42.11%, Toxic granulation had 70.56% sensitivity, 63.65%

specificity and 50% PPA. B/N > 0.2 had 88.2% sensitivity 62.4% PPA. m-ESR had sensitivity of 70.56%, specificity of 84.84%, PPA of 70.5%, C-reactive protein had 88.2% sensitivity and 87.8% specificity and 78.95% PPA. Case fatality rate was 28%. Conclusion : Clinical features of neonatal septicemia are non specific and vague. Sepsis screen had good sensitivity, specificity, and PPA. Combination of tests increase the specificity and PPA. As an individual test C-reactive protein has highest sensitivity.

CONTENTSPage No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. INTRODUCTION AIMS AND OBJECTIVES HISTORICAL ASPECTS AND REVIEW OF LITERATURE MATERIALS AND METHODS OBSERVATIONS AND RESULTS DISCUSSION SUMMARY CONCLUSION BIBLIOGRAPHY ANNEXURES a. CLINICAL PROFORMA b. CONSENT FORM c. MASTER CHART d. KEY TO MASTER CHART 1-2 2 3-39 40-42 43-77 78-96 97-100 101 102-110

Clinical study of neonatal septicemia with Reference to early indicators of sepsis.

INTRODUCTION

Neonatal septicemia is defined as a bacterial infection documented by a positive blood culture in the first four weeks of life. Systemic bacterial infection during the first month of life have remained a major cause of infant morbidity and mortality. The early diagnosis of neonatal septicemia still poses great difficulties. Early clinical symptomatology of neonatal septicemia is mimicked by lot of other disorders affecting the newborn. It is a major cause of morbidity and mortality and it accounts for half of all the neonatal deaths in this country. The overall incidence of neonatal sepsis varies between 1-8 cases/1000 live births. Neonatal sepsis can be divided into two subtypes depending upon whether the onset of symptoms is during the first 72 hours of life or later. Although the term early onset sepsis had been used to refer to neonatal

infections occurring as late as one week of age, it should be restricted to those infections with a perinatal pathogenesis, the usual onset of which occur within 72 hours. Early - onset sepsis is caused by organisms prevalent in genital tract or in the labour room. Ascending infection, transplacental hematogenous spreads are important mechanisms of early onset sepsis. After the birth the baby is exposed to the environment contaminated with micro organisms, which start settling or colonising at various places. The organisms enter the body through the umblicus, skin or mucosa. Due to poor immunological

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defence of the new born, even local infections tend to become generalized. Infections are more commonly met with preterm and low birth weight babies. To prevent serious morbidity and mortality caused by untreated or lately treated neonatal septicemia; it is important that the diagnosis is made early and the treatment started as easily as possible. Even though the positive blood culture is diagnostic of neonatal septicemia, the technique of blood culture is time consuming that demands a well equipped laboratory and has a success rate of only 40%, therefore the blood culture has its own limitations. Early treatment with rational antibiotic therapy is possible with the help of certain indirect markers such as leucopenia, toxic granules, band form to neutrophil ratio, micro-ESR and C-reactive protein . This investigation excercise is collectively known as sepsis screen. The early diagnosis of neonatal sepsis by clinical examination is vital. In the presence of predisposing factors, early clinical suspicion coupled with sepsis screen will detect neonatal septicemia earlier, which will enable the clinician to treat the infection timely and adequately, which in turn will help to reduce the neonatal morbidity and mortality.

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AIMS AND OBJECTIVES

I. II.

To study the incidence and predisposing factors of neonatal septicemia. To study the clinical profile and outcome of neonatal septicemia.

III.

To study the early indicators and correlation with all clinical aspects of

neonatal septicemia.

IV.

To study the bacteriology and antibiotic sensitivity pattern of neonatal septicemia.

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HISTORICAL ASPECTS AND REVIEW OF LITERATURE

Knowledge of sepsis

neonatorum progressed slowly. In the recent years a

series of developments have resulted in the emergence of considerable new data by many investigators leading to re-evaluation of this day to day problem. The attention of paediatrician to the problem of neonatal septicemia was brought by Ethel Dunham1 in 1933. This is considered as one of the important milestones in early clinical paediatrics. By the end of the nineteenth century Budin and others had called attention to the four chief sources of infection; the skin, umbilicus, the gastrointestinal and respiratory tracts. Nynan and Fousek1 were able to discover in the records of the New Haven Hospital approximately 5 cases a year from 1933 to 1957. The neonatal septicemia has traditionally been a significant cause of neonatal

morbidity and mortality. The striking importance in the neonatal mortality that has occured over the past 20-25 years stands in marked contrast to the modest gain made in the outcome of infant with proven sepsis. K.C. Buetow et.al. (1965)2 studied septicemia in preterm babies weighing

1000-2500 grams. They concluded that incidence of septicemia was 54.3 per 1000 live preterm births. There was increasing mortality rate with decreasing birth weight. While knowledge of the neonatal sepsis has progressed slowly for a time. In recent years a series of developments have resulted in the emergence of considerable new data by many investigators leading to revaluation of this day to day problem.

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O.N Bhakoo (1980) 3 in his study observed that incidence of primary septicemia was 1.2/ 1000 live births in normal weight infants as compared to 4.7/1000 live births amongst low birth weight babies.

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INCIDENCE : Incidence of neonatal septicemia differs among hospitals, depending on the factors such as obstetric and nursery practices, prenatal care, the health and nutrition of the mother and the incidence of prematurity. But the important factors to be considered is that the overall incidence of sepsis neonatorum, while it may vary from year to year and from place to place, has fairly remained constant over the past 30-40 years (David Wilson) 4 . The overall incidence of neonatal septicemia varies between live births (In Manual of Neonatal Care by Cloherty - 7th Ed.2011. ) 5 . Various authors have given different rate of incidence in their reviews. Freedman et.al. in 19816 reported that the incidence was 2-4 cases / 1000 live births , fairly constant over many years. T.Vesikari in 19857 reported the annual incidence of neonatal septicemia was 3/1000 live briths and the overall mortality was 23%. Lokeshwar in 19888, reported that incidence in the developing countries like ours was much higher, 10-12/1000 live births compared to developed countries 1-10 cases /1000 live births. Moreno et.al. in 19949 observed overall incidence of 3.5 cases /1000 live births. Incidence was high in very low birth-weight and premature babies. Moro et.al. in 199610 found the incidence of nosocomial sepsis in neonatal intensive care units to be 2.9 cases / 100 newborns and 0.2cases / 100 days of stay. Sepsis represented 15.4% of all infections. Dawodu et.al. in 199711 found the incidence of neonatal septicemia 4.9 cases / 1000 live births. 1-8 cases /1000

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Berger et .al. in 199812 found the incidence of neonatal bacterial sepsis 9.8 cases/1000 live births. Mc Cracken et .al.13 reported incidence of septicemia as 1 per 1000 live births and 1 per 230 premature births. According to pooled hospital data based on NNPD survey incidence is around 30 per live births. ( Care of the new born Meharban Singh 7th edition -2010.).

These incidence rates vary from nursery to nursery depending on conditions predisposing to infection.

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PREDISPOSING FACTORS : Multiple risk factors for neonatal septicemia have been identified. Various studies were conducted to find out different predisposing factors so that early diagnosis and institution of prompt and effective therapy would be possible. Multiple risk factors like maternal factors, neonatal factors and environmental factors are identified.

Socio economic status and parental literacy : N.Mehrotra et. al. (1985)14 social and economical factors. concluded that infant mortality is influenced by The incidence of positive blood cultures and

superficial cultures was significantly higher in babies of mother educated up to middle school than those of mother with higher education. Babies of poor, illiterate parents have higher incidence of neonatal infection because they are usually of low birth weight, delivered before 37 weeks of gestation,thus diminishing immunological status of newborns.There is also delay in

appreciating illness and seeking treatment. Besides, most deliveries in poor families are conducted at home under improper aseptic conditions.

Maternal Factors : The fetus and newborn infants are exposed to infection in unique ways. The aminiotic fliuid is bacteriostatic or bactericidal for many organisms with the exception of Group B streptococci, thus most of the babies are sterile at birth (Neonatal Infection by David Isaacs - Ist ED.).

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Bacterial infection in utero and during delivery may occur in following situations. Prolonged rupture of membranes more than 18 hours. Infected birth passage e.g. Group B streptococci, Candida, Listeria, E coli etc. Intrapartum maternal fever of more than 380 C. Preterm labour (less than 37 weeks). Multiple gestation. Premature rupture (less than 37 weeks). Mother with the previous infant with Group B streptococcal infection.

In Manual of Neonatal Care (5th Ed. ) 5 Cloherty evaluated the above criteria while studying neonatal infections. Similar predisposing factors were observed by James C. Overall (1970) 15. N. Mehrotra et.al.in 198514 found a direct correlation between incidence of amnionitis and duration of rupture of membranes. With three fold increase in the incidence of sepsis after 24 hours of rupture of membranes. Ayengar et.al. in 199116 found that vertical transmission of organisms was significantly associated with risk of developing early-onset septicemia.

Kuruvilla et.al. in 1998 17 found the maternal factors significantly associated with early-oneset sepsis. Those were meconium staining of liquor and multiple vaginal examinations.

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Type and place of delivery : The incidence of positive blood culture was least in babies born by normal delivery and maximum in those delivered by caeserian section (Mehrotra)14 Observations of Davies4 are same in this regard. The incidence of positive superficial culture was higher in home delivery than hospital, while positive gastric aspirate culture was higher in the latter. Frequent

superficial infections in the home delivered babies appear to result from many unhygienic surroundings of poor homes and also large number of visitors handling babies. Higher rates of perinatal deaths due to infections, asphyxia and other causes is known with abnormal presentation of difficult labour. Higher incidence of infections in babies delivered by caesarian section appears to result from factors that necessitate it such as obstructed labour prolonged second stage etc.

Neonatal Factors : The most important neonatal factor predisposing to infection is prematurity or low birth-weight. There is 3 to 10 fold higher incidence of infection and sepsis in these infants than in full-term normal birth-weight infants. Males have an approximately two fold higher incidence of sepsis than females.

Sex: Neonatal sepsis is twice frequent in male infants as compared to females (Nelson) 18. Females have greater genetic diversity resulting from random inactivation of one of the two X-chromosome so that in some body cells paternally derived one. Female resistance is due to her heterozygocity for genes of X-chromosomes

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controlling immunoglobulin synthesis and thymic function which results in a greater heterozygocity of antibody response (Robert J. Schlepal et. al. 1969) 19. Gluck (1966) 20 and N. Sinha et. al. (1986) 21 observed that males were more prone to infection than females (ratio of 1.7%). Beutow and Gotoff et. al. 2 agreed for male predominance.Khatua et. al.22

observed male predominance (70.7%) and

concluded that presence of one X-chromosomes in the male confers less immunological protection compared to the female counterpart. Schaffer A.J. 1, Somu et. al. 23, observed neonatal septicemia more common in males ranging from 59 to 82 percent. The risk of sepsis increases markedly in very preterm babies, particularly those weighing < 1000 gm at birth. Bhakoo et.al. in 197424 obseerved that weight below 2500 gm and gestation < 37 weeks has increased the incidence of septicemia. N.Somu et.al. in 197623 observed that incidence of Gram-negative septicemia was higher in babies under 2500 gm at birth. A.R.Nellian et.al. in 198125 found that babies weighing < 2500 gm at birth had higher incidence of neonatal sepsis as compared to higher birth-weight. Sinha et. al. in 198621 studied 82 bacterioogically confirmed cases of neonatal septicemia and observed that male babies with low birth weight predominated (64.9%). Lokeshwar et.al.in 19888 found that risk of sepsis especially nosocomial infection is significantly higher in very low birth-weight neonates, occurring in 25%

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or more of those weighing < 1000 gm & in 14% of those weighing between 10001500 gm. Berger et. al. in 199812 found that the birth-weight 5 days, birth weight < 2500

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gm, transfer from other hospital, total parenteral nutrition, nasogastric tube. Thse risk factor are independently associated with neonatal sepsis. Dawodu et .al. in 199713 found the factors significantly associated with neonatal septicemia were fetal distress, low Apgar score at 5 minute, requirement for mechanical ventilation and umbilical catheterization. Procedure : Resuscitation with contaminated endotracheal intubation, injection, I.V fluids, umblical catheters, exchangetransfusion constitutes important portal of entry of micro organisms. Exposure of new born baby to infected incubators and catheters increases the chances of infection.

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BACTERIOLOGY OF NEONATAL SEPTICEMIA Through the years, there has been a shift in the microorganisms responsible for neonatal septicemia. This is clearly illustrated by the experience at Yale-New Haven Hospital by Freedman et.al. in 19816. During 1930s Group A streptococci were the predominant organisms. In the 1950s Staphylococci became a major cause of nursery outbreaks throughout the

world. Pseudomonas was predominant during the same decade, perhaps because of the introduction of respiratory support system. From the late 1950s onwards, E-Coil has been an important cause of neonatal sepsis. The dramatic rise in incidence of Group B streptococcal infections is notable and has been reflected in other centers as well. Finally Group D streptococci and Klebsiella have been pathogens. relatively recent

The later accounting for a high proportion of antibiotic resistant

organisms that colonize and infect babies in neonatal intensive care units (Goldman et.al. 1978}27.

Streptococci : The Group B streptococcus is the most common Gram-positive organism causing neonatal septicemia. Vertical transmission from mother to infant is the most common route of infection. Nosocomial acquisition of infection has been implicated in some nurseries. The incidence of Group B streptococcus infection has varied widely from place to place and from year to year. The annual incidence has ranged from 0.6 to 3.7 / 1000 live births (Siegal et.al.. 1981) 27.

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Staphylococci :In 1950s phage Group I staphylococcus aureus was the most common bacterial agent causing septicemia in the neonatal units. More recently Coagulase positive staphylococcal disease in nurseries has been caused by organism of the phage II Group. Coagulase negative staphylocci (Staphylococcus epidermidis) may be

identified in blood cultures of babies and are frequently dismissed as contaminants. Repeated isolation of this organisms from blood associated with clinical sings of septicemia should alert the physician to its pathogenic role. They are frequently but not always associated with arterial or venous catheters. Listeria monocytogenes : It is a Gram-positive rod, and is a facultative intracellular parasite found widely in animal kingdom. Infection in man is sometimes seen as a result of contact with domestic animals. E-coli : E-coli are aerobic gram-negative rods found universally in the human intestinal tract and commonly in the human vagina and urinary tract. There are hundreds of different LPS, flagellar and capsular antigenic types of E-coli, but EOS , E coli infections, particularly those complicated by meningitis, are primarly due to strains with the K1-type polysaccharide capsules. E coli with the k1 antigen are resistant to the bacteriocidal effect of normal human serum; strains that possess both a complete LPS and k1 capsule have been shown to specifically evade both complement - mediated bacteriolysis and neutrophil - mediated killing.

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Klebsiella : Klebsiella pneumoniae is a Gram-negative bacteria recently emerged as an important cause of nosocomial sepsis.

Pseudomonas : Pseudomonas aeruginosa is a Gram-negative strictly aerobic bacteria causing neonatal septicemia. Other bacterial pathogens : H. influenzae Enterococci Citrobacter diversus

Nosocomial Infections : Overall incidence of nosocomial infection in neonates is < 5%, but infection rates for individual nurseries have been much higher. Beyond 1 to 2 weeks of life the neonate who has remained in the special care nursery is likely to be colonized with perinatally and nosocomially acquired

flora.This places the neonate at risk of infection due to Coagulase negative staphylococci, Enterococci, Staphylococcus aureus and Gram-negative bacteria. In addition late-onset disease caused by Group B streptococci and Listeria monocytogenes must be considered.

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CLINICAL PRESENTATION : Clinical data which suggests and supports early diagnosis of neonatal septicemia includes detailed history of risk factors these are poor maternal hygiene, no antenatal checkup, repeated P.V.examination, foul smelling liquor, prolonged rupture of membrane, bad obstetrical history of prolonged or difficult labour, forceps application, cord cut with unsterile instrument, resuscitation after birth especially intubation, L.B.W and pre term babies and babies with congenital anomalies. The clinical symptoms and signs of septicemia are vague and nonspecific. The manifestations are different in early-onset and late-onset disease. In general earlyonset sepsis is far likely associated with respiratory distress and babies are more likely to be shocked. Whereas the onset it often, but not always, more incidious in late-onset sepsis. The clinical manifestations of neonatal septicemia includes. Textbook of Paediatrics, 19th ED) 18. (Nelson,

GENERAL : Fever,Hypothermia Poor feeding Not doing well Sclerema.

GASTROINTESTINAL : Abdominal distension Diarrhea, RESPIRATORY SYSTEM : Apnea,Dyspnea Flaring, Grunting Tachypnea,Retraction Cyanosis. Vomiting Hepatomegaly

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RENAL SYSTEM : Oliguria CARDIOVASCULAR SYSTEM : Pallor, Mottling, Cold clammy skin Tachycardia Hypotension CENTRAL NERVOUS SYSTEM : Irritability, Lethargy Hyporeflexia,Hypotonia Irregular respirations High pitched cry HEMATOLOGY SYSTEM : Jaundice Pallor Bleeding. Richard Behrman (Diseases of the Fetus and Infant), Avery (Schaffer Diseases of the newborn), Saul Kraugman (Infectious Diseases of Children) and Klaus and Fanaroff (Care of High-Risk Neonatal) stated similar clinical features. James C. Overall in 197015 evaluated similar clinical features and observed that the higher mortality was in patients who had convulsions. N.Somu et.al. in 197623 revealed that progressive abdominal distension, refusal of feeds, pallor, drowsiness with definitive focus of sepsis almost form the guideline for the clinical diagnosis of septicemia. J.N.Mishra et.al. (1985)28

Bradycardia

Tremors,Seizures Abnormal Moro reflex. Full fontanelle

Splenomegaly Petechiae, Purpura

, Mehrotra et.al. (1985)

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in their study revealed

that jaundice, refusal of feeds, vomiting, lethargy were common manifestations of

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septicemia whereas sclerema,apnea, hypothermia and abdominal distension were associated with high mortality. Khatua et.al. in 198622 observed similar clinical presentation in study of 42 cases and respiratory distress, apnea, convulsions, sclerema were bad prognostic features. S.Kumari et. al. in 198729 in their study of 150 newborns found that one third of infants with bacterial sepsis had significant jaundice. The age of onset of jaundice was slightly early in septicemic babies. Piyush Gupta et.al.in 199330 found that neurological symptoms were common in late-onset disease. Bleeding manifestations, sclerema and granulocytopenia were seen exclusively in preterms. Presence of respiratory symptoms, bleeding, sclerema, shock and granulocytopenia were identified as poor prognostic factor in neonatal Klebsiella septicemia.

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HOST DEFENSE IN NEONATES : Infection is more common in the neonatal period than at any time in life. This is partly attributable to exposure to large number of organisms, but it is also due to a relative failure of the neonatal host defense to clear microorganisms from blood. Most neonatal infections are caused by organisms that are also capable of causing infections in older children and adults, but neonatal infections are usually more severe and more likely to disseminate and fatal.

Humoral immunity : This is particularly important in recovery from infections with extra cellular organisms. B-lymphocytes produce antibodies which coat the surface of

microorganisms and make them more succeptible to phagocytosis. B cells secrete different classes of immunoglobulins.

IgG : Newborn produces relatively little IgG. It remains low until 4-6 months

postnatally. Fetal and neonatal IgG are acquired from the mother transplacentally.

IgA : Newborn is also relatively poor in producing IgA, the antibody present on mucosal surfaces which is important in protection against respiratory and gastrointestinal pathogens. Furthermore IgA does not cross the placenta. But the colostrum and breast milk do contain secretory IgA.

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IgM : The fetus can produce IgM from about 30 weeks of gestation. It also does not cross placenta. IgM unlike IgG, does not activate the classic pathway of complement. Recent work suggest that IgM may have a major role in recovery from Gram-negative organisms.

Monocyte macrophage system : These are the phagocytic cells which ingest the micro-organisms and degrade its proteins to small peptides which are transported to and presented on the cell surface. Thus they act as antigen presenting cells to T - lymphocytes. In newborn infants the number of circulating monocytes in blood are normal but chemotaxis, phagocytosis and antigen processing are all variably diminished.

Cell mediated immunity : T - lymphocytes are responsible for cell mediated immunity. Once an antigen is presented to the T cell, it starts to proliferate. It may then either mature into a memory cell, cytotoxic T cell or helper T cell. Memory cells recognize the same antigen if re-exposed, helper T cells help B cells to produce antibody and cytotoxic T cells are responsible for destroying infected cells. These cytotoxic T cells are important in recovery from infections with intracellular pathogens. T cells production is marginally poorer in neonates.

Neutrophils : Neutrophils are important in phagocytosing extracellular organisms. In neonates there is diminished bone marrow reserve of immature neutrophils. If

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infection leads to peripheral destruction of neutrophils, the neutrophil reserve rapidly becomes depleted resulting in neutropenia.

Complement : The complement system consists of a series of proteins which interact in a sequence or cascade to generate other proteins responsible for important defences to micro-organisms. There are two pathways of complement activation. One is classic pathway while other is alternative pathway. The classic pathway requires the presence of antibody and is best activated by immune complexes. The alternative pathway can be activated by bacterial cell products. Complement levels in the term newborn are approximately one half those of normal adults and preterm babies have even lower levels (Miller - 1978) 27.

Natural killer cells : They kill virus infected cells, some micro-organisms and tumor cells. Their activity is stimulated by interferon and is generally lower in neonates than in adults.

Interferon : There are 3 types of interferons alpha, beta and gamma. The production of alpha and beta is not a specific immune mechanism. Their production is normal in neonatal period. Interferon gamma or immunity produced by T-cells, it has a major role as a modulator of immune response. Macrophages, monocytes and natural killer cells are activated by it. In neonates less interferon gamma is produced.

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Immunological response to bacterial infection : In bacterial infection organisms generally colonize a mucocutaneous surface before invasion. In the neonate the production of secretory IgA and fibronectin which would normally decrease bacterial adherence is relatevily poor. Once the organism is locally established the most important defence mechanism is phagocytosis and killing by neutrophils enhanced by opsonization by specific antibody and complement (Neonatal Infections by David Isaacs 1st ED. ) 27. Saul Krugman31 in Infectious Diseases of Children has stated similar host defence mechanism in newborns. Lokeshwar in 19888 studied immunohaematology of neonatal sepsis. He found that a neonate is relatively immunocompromised and immuno-inexperieced and hence is predisposed to overhelming bacterial sepsis. The main reasons for poor host defence mechanism in the septic neonates are Maternally derived type specific antibodies are less in neonates. Though IgG level in full term babies is equal to that in the mother, in premature babies it is markedly reduced. IgA and IgM levels are less in neonates as they are not transplacentally transmitted. Low levels of complements (50% of adult) and subsequently inability to opsonize bacterial pathogens. Monocytes dysfunction including poor chemotaxis and poor phagocytic activity particularly in neonates with septicemia. In neonates with septicemia exhaution of poor neutrophil storage pool results into neutropenia.

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SEPSIS SCREEN : Exact diagnosis of neonatal septicemia is difficult because there is no definitive diagnostic test. Even blood cultures have an unacceptably low sensitivity. Therefore a clinician must accept that a number of neonates who do not have the disease will have treatment initiated for sepsis. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical and laboratory data can be used together in a management approach to achieve optimal results. A detailed history, examination, laboratory tests, and cultures is presented to guide clinical management. In neonatal septicemia indirect markers of infection such as total leucocyte count, band forms, toxic granules, micro ESR, C-reactive protein when studied collectively, called Sepsis Screen. Sepsis Screen is an extremely reliable index of early neonatal septicemia, with less expenditure and serves as a good guide for initiating antibiotic therapy. When at least two of the indirect markers of infection are positive it gives sensitivity avd specificity of 93% and 88% respectively. It is indicated at birth if an infant born following prolonged rupture of membranes, foul smelling liquor, maternal fever and severe birth asphyxia. After birth if baby develops respiratory distress syndrome or nonspefic features of neonatal sepsis, sepsis screen is indicated to support the clinical supicion so that unnecessary antibiotic usage is curtailed during neonatal period. Philip in 198032 studied sepsis screen with total leucocyte count 0.2, micro-ESR>15mm at the end of 1st hr. and C-reactive protein .> 0.8/100 ml, latex haptoglobin (positive>25 mg/ml) and found 93% sensitivity and 88% specificity, when two or more tests were combined.

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U.K.Namdeo et.al..(1985)

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I their study of

50 neonates with neonatal

septicemia found the usefulness of hematological indices for early diagnosis of neonatal septicemia. They reported that leucopoenia, band to total neutrophil ratio of

>0.3, neutrophil with toxic granulation in >40% and mini-ESR>8mm at the end of 1st hr., were found to be particularly predictive of septicemia with specificity of 98% and positive predictive accuracy of 89%. If more than one of the four tests were positive they becomes more sensitive and sufficiently specific. M.Singh et.al. (1987) 34 I study of 100 babies evaluated that the use of sepsis screen like micro-ESR, gastic aspirate for polymorphs, absolute neutrophil count, band to neutrophil count, band to neutrophil ratio and C-reactive protein in neonatal septicemia. The sensitivity and specificity of these tests was determined. C-reactive protein was found to be most sensitive 80% and specific 91% test. The combination of any two or more positive tests was found sensitive in 86% of cases and specific in 89.6% of cases. Bhandari et.al. in 198835 found in a study of 49 cases of neonatal septicemia and 18 cases of asymptomatic neonatal septicemia, total leucocyte count 0.2 micro-ESR >15 mm at the end of 1st hr.; are the sensitive indicators of neonatal septicemia. The sensitivity and specificity of this screen was 72.7% and 100% respectively. However this sepsis screen was not found suitable for screening cases at birth but these tests are recommended for routine screening of clinically suspected cases of neonatal septicemia. Mishra et.al. in 198936 used the simple haematological tests; total leucocyte count, differential leucocyte count, micro-ESR, platelet count for diagnosis of neonatal septicemia. A band cell to neutrophil ratio of > 0.2 was most sensitive index

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(92%), followed by raised micro ESR of >8 mm at the end of 1 st hr whereas leucopenia 5 x 103 /cmm was most specific index (88%) for the diagnosis of sepsis.Thrombocytopenia of 5000/ cmm, total neutrophil count of < 1000 / cmm, immature to total neutrophil ratio > 0.2, micro_ESR>15 at the end of 1st hr., positive C-Reactive protein. If three of the five tests were abnormal the probability of infection was 90%.

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BLOOD LEUCOCYTE CHANGES IN NEONATAL SEPTICEMIA : Blood leukocytes count in the newborn babies have been considered to be so variable and unpredictable as to be of little value for clinical diagnosis. Leukocyte count varies from 8000 to 20000 per cu,mm during the 1st 28 days of life without demonstrable disease (steigbiggel R.T) 38. Blood leucocyte changes in newborn babies have been considered to be so variable and unpredictable as to be of little value for clinical diagnosis. M.Xanthou in 197039 studied leucocyte blood picture in healthy full term and premature babies during neonatal period. Serial leukocyte counts were done on 15 full term during first 10 days of life and on 14 preterms during first 30 days of life. The

main changes in the leucocyte count during the neonatal period were as follows - an increase in polymorphonuclear neutrophils after birth reaching a peak at 12 hours, thereafter dropping to a figure which remains fairly constant from 72 hours onwards. Xanthou in 1972 in her study of neonatal infection described toxic granulation as an important feature. She felt that toxic granulation was invariably present during sepsis. These changes were never seen in healthy newborn infants (A. Zipursky et. al 1976) 40. A.Zipursky (1976) 40, in study of 49 cases of neonatal septicemia noted that band neutrophil counts were elevated most frequently in proven cases of sepsis. And elevation occured usually within 24 hours of onset of signs of disease. Monroe et .al. in 197941 observed that mild or early-onset of infection caused a significant increase in absolute value of neutrophils. The values were as, high as 17,500/cmm.

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Edward Squire et. al. in 197942 observed that newborns dying with bacterial infection often demonstrated leucopenia, neutropenia and thrombocytopenia usually associated with normal bone marrow cell production. Those with neonatal sepsis frequently had neutrophilia with an increase in absolute band count of infected newborns., 80% showed one or more haematological abnormalities. Alistair G. S. Philip (1980)32

carried a study regarding early diagnosis of

neonatal sepsis. The combination of leucopenia < 5000/cmm and band to neutrophil ratio > 0.2 was particularly predictive of neonatal septicemia. Robert D. Christensen in 198143 found that the band form to neutrophil ratio was more frequently abnormal during neonatal sepsis than the absolute band count. S. N. Parida et. al. (1982) 44 reported that leucocytosis was presen in 25% of both proven as well as suspected cases of septicemia and total percent of neutrophils did not vary significantly (30% and 33.3%) in either group. But 50% of neonates with proven sepsis and 25% of neonates with suspected sepsis had elevated band count respectively. Leucopenia, was observed in 21.6% with 71% mortality rate. The predictive value of elevated band count, leucopenia and simplicity of the test justifies its routine use in early diagnosis of neonatal septicemia. Lokeshwar in 19888 found that the leucopenia in 20% cases, band cell count in 70% cases with band to total neutrophil ratio in 80% of cases. He also found that two or more abnormal parameters in 94% of cases. Mishra et. al. in 198936 found that band cell to neutrophil ratio of > 0.2 was most sensitive index (92%), whereas leucopenia 5 x 103/cmm was most specific index (88%) for the diagnosis of sepsis.

28


Anand et. al. (1991)

45

in study of new born infants with sepcticemia found

haematological evidence of total leucocyte count < 5000 / cmm in those infants and morphological changes in neutrophils such as Dhole bodies, toxic granulations and cytoplasmic vacuolations were also present in those infants. Robert Boyle et.al.(1978)46

also observed the usefulness of absolute

neutropenia and band neutrophil ratio in identifying septic from non septic infants with respiratory distress syndrome.

29


MICRO - ESR : Erythrocyte sedimentation rate is a nonspecific indicator of tissue damage and is known to be elevated in infective states. The rate of increase depends on the severity of the morbid process. Although the values of the ESR has provoked controversy in the past, it can be a very useful test when properly interpreted and applied. Andre D. Lascari in 197247 stated that micro - ESR is low in the newborn which becomes 0-6 mm at the end of 1st hr due to high haematocrit values during neonatal period. In neonatal septicemia micro - ESR values are raised. S. N. Parida et. al. in 198048 found the use of micro - ESR in the diagnosis of neonatal septicemia. The mean value of micro - ESR during neonatal period was 3.02 mm with standard deviation of 2.02 mm. Two standard deviation above mean value gave a value of 7.06 mm. Hence a value of 8 mm and less indicated normality with 95% certainity. They also found that definitely infected neonates had micro - ESR > 8 mm at the end of 1st hr. In their study 74.4% of definetely infected babies and 24% of probably infected babies had elevated ESR. Thus the efficacy of this simple inexpensive test as preliminary procedure to identify the neonate at risk was quite good. Philip et al. in 198032 noted that the micro ESR > 15 mm at the end of 1st hr was the sensitive indicator of neonatal septicemia. Namdeo et. al. in 198533 reported that micro ESR > 8 mm at the end of 1st hr had 89% specificity. Bhandari et .al. in 1988 35 in their study of 49 cases of symptomatic neonatal septicemia and 18 cases of asymptomatic neonatal septicemia reported that micro ESR > 15 mm at the of 1st hr was the sensitive indicator of neonatal septicemia.

30


Mishra et. al. in 198936 in study of 78 cases noted that micro ESR > 8 mm at the end of 1st hr was the sensitive indicator of neonatal septicemia. Anand et .al. in 199145 studied various indicators of neonatal septicemia. The micro ESR > 6 mm in the first three days of life and > 10 mm thereafter was a sensitive indicator of neonatal septicemia. Anita Sharma et. al.49 in study of 65 clinically suspected cases of neonatal septicemia reported the elevated C-reactive protein and elevated micro - ESR compared to controls at the time of diagnosis, but micro - ESR had no prognostic significance and C-reactive protein levels decreased with treatment. J. Chandra et. al. 198750 observed micro-ESR and CRP highly sensitive (100 and 83.3%) in early diagnosis of sepsis. M. Singh (1987) 34 showed micro-ESR as 55% sensitive and 81% specific for diagnosis of sepsis.

31


C-REACTIVE PROTEIN CHANGES IN NEONATAL SEPTICEMIA : C-reactive protein was first discovered in 1930 by Tillet et. al51. They

observed that sera of patients suffering from acute febrile illness precipitated with an extract of pneumococcus i.e., C-Polysaccharide. The substance responsible for reactivity was termed C-precipitin and it was protein. Later it was designated as Creactive protein. C-reactive protein is present in response to variety of inflammatory stimuli.It appears in liver. Normal values in newborn < 0.3 mg/100 ml. Philpson et. al. first described (1950) the presence of C-reactive protein in bacterial infection of neonate. Felix et. al.., Hansen et. al. and Siegel observed increased C-reactive protein more constantly in septicemia. Sabel et. al. studied in cases of neonatal septicemia increased C-reactive protein in 85.7% cases with positive blood culture. Thus the C-reactive protein test is a good diagnostic index of infection as blood culture in case of septicemia (Kalra et. al 1985). Alistair G. S. Philip in 198032 reported efficiency of C-reactive protein in diagnosing early septicemia. It becomes positive when concentration of C-reactive protein is approximately 0.8 mg % and more than this value is significant. This test had specificity of 86%. Sann et. al. in 198452 studied 36 newborn infants with septicemia and early in the acute phase and declines during convalescence.It is synthesized

observed the inverse change in C-reactive protein with infected neonates. The immediate decrease in C-reactive protein reflects effect of treatment. And the later decrease parallels the clinical course of the infection. Thus determination of these tests can help to guide the treatment of infection in newborn.

32


P.Hindocha in 198453 observed 11 out of 12 cases with raised C-reactive protein. He also observed that the C-reactive protein level decreased in many cases after treatment. K. Kalra in 198554 in his study of 76 cases of neonatal infection showed Creactive protein was positive in 69.7% cases. A positive C-reactive protein test in the presence of negative culture after antibiotic therapy seen in 9.2% cases indicated the presence of neonatal infection. S. M. Ali et. al. in 1988 55 studied serial estimation of micro ESR and Creactive protein in assessment of therapy in neonatal septicemia. All cases had significantly elevated micro ESR and C-reactive protein at the time of diagnosis. With treatment C-reactive protein level showed significant decrease as early as 3rd day. Gupta et al in 198956 in a study of 150 newborns, 100 clinically septic, and 50 clinically aseptic cases of newborn infants. Out of 100 clinically septic newborns Creactive protein was positive in 64% and C-reactive protein was found to be the most specific (96%) of neonatal septicemia. Anita Sharma in 199349 studied serial estimation of C-reactive protein in clinically suspected cases of septicemia. She found that significantly increased levels of C-reactive protein in suspected cases as compared to controls. A persistantly positive C-reactive protein tests indicated bad prognosis. With treatment a declining trend of C-reactive protein was seen in survivors but in deteriorating babies the levels kept on increasing. Wagle et. al. in 199457 studied C-reactive protein as a part of sepsis screen. Creactive protein levels of 10mg/L or above was considered abnormal. He concluded that the C-reactive protein level when elevated on day one and / or day two the diagnosis of neonatal sepsis is extremely likely. And when the C-reactive protein

33


level was within normal limit on day one and two of the septic episode, neonatal sepsis can be confidently excluded. In Neonatal Infections by David Isaacs - 1st Ed27 he stated various serum acute phase reactants. C-reactive protein has proved to be most useful in suspected sepsis. It starts to rise within 12-24 hours of the onset of sepsis, earlier than the other acute phase reactants. Serum C-reactive protein was elevated in 15-90% of cases of sepsis and returned to normal within 2-7 days of successful treatment persistant elevation of the serum C-reactive protein may indicate persistant bacterial infection. Cloherty in his manual of neonatal Care, 7th Ed5 2011, stated that positive Creactive protein is significantly associated with neonatal infection. Posen et al in 199858 studied C-reactive protein as an indirect indicator of the presence and resolution of infection C-reactive protein has gained more recent wide spread use. C-reactive protein usually increases in a delayed manner with the onset of inflammation and infection and decreases as inflammation and infection resolves. Sebel et. al. (1974) 59 studied 14 cases of neonatal septicemia and meningitis and compared blood culture with the results of CRP test in these cases they found raised CRP in 85.7% of cases with positive bacterial culture.

34


BLOOD CULTURE IN NEONATAL SEPTICEMIA : Blood culture for detection and typing of organisms remained the most specific investigation in neonatal septicemia since begining. The technique of blood culture is time consuming that demands a well equipped laboratory and has a success rate of nearly 40%. O. N. Bhakoo et al. Staphylococcus pyogenes (1968)24 in study of 70 neonates found that

(32%) was the common organism followed by and E-coli (16%). High fatality rate in Gram23

Pseudomonas pyocyaneus (09%)

negative septicemia has been stressed by Johnson and Sell (1964) Shinefield (1966) 24.

and McCraken and

James C. Overall in 197015 found that the Gram negative enteric bacteria were the most frequent etiologic agent in neonatal bacterial meningitis. N. Somu in 197623 in the study of 725 cases of neonatal septicemia found that Coliform group of organisms were the commonest cause closely followed by Staphylococcus aureus. He also found the other bacteria like Pseudomonas pyocyaneus and Proteus responsible for neonatal septicemia. M.M.Placzek60 and A.Whitelaw in 1983 reported that the Group-B

Streptococcus and E-coli were the commonest causative organisms in early onset septicemia and Staphylococcus epidermidis. Staphylococcus aureus and E-coli were the commonest organism responsible for late - onset septicemia. Mishra et .al. in 198528 studied 120 cases of neonatal septicemia and reported that the Gram-negative organisms were more common (71%) than Gram-positive

organisms (49%) and also reported Gram-negative infection was higher in babies under 2000 gram birth-weight. Common bacteria isolated were E-coli, Pseudomonas, Staphylococci and mortality was high in Pseudomonas (76%) infection.

35


Mehrotra et. al. in 198514 studied 75 symptomatic newborns with septicemia and obsvered E-Coli was the commonest organism on blood culture. Similar observation have been made by Smith et al., Gluck et al. and Gotoff et al. Sinha et .al. in 198621 studied 82 cases of neonatal septicemia, of those Pseudomonas aeruginosa was most common followed by Klebsiella and E-Coli. Khatua et .al. 198622 in a study of 92 cases of neonatal septicemia showed blood culture was positive in 98% cases; of which 76.3% were the main Gram-

negative organisms like Klebsiella, E Coli, Citrobacter, Pseudomonas and 23.7% were Gram-positive organisms predominently Staphylococcus and Streptococcus. Sharma et .al. 198761 found that Gram-negative septicemia was more common in newborn infant. He observed that E-Coli has replaced Klebsiella as the predominant pathogen of neonatal septicemia. Namdeo et. al. in 198762 in the study of 50 neonates with septicemia reported that the Gram-negative organisms were found to be predominant in early onset septicemia and were often fatal whereas Gram-positive organisms were more frequent in late onset septicemia and were associated with favourable outcome. They found predominant organisms were E-Coli, Klebsiella, Proteus, Pseudomonas and Grampositive cocci. P. Chaturvedi. M. Agrawal, P. Narang in 1989 63 found that Gram-negative organisms were more common than Gram-positive organisms. The culture positivity

rate was 73% of those 24.9% cultures were polymicrobial. Among 1059 growths obtained 60.1% were Gram-negative organisms, mainly Klebsiella, E-coli,

Pseudomonas and Gram-positive organisms mainly observed were Coagulase negative staphylococci (24%). An increasing incidence of Coagulase negative Staphylococci and Pseudomonas were observed.

36


Mathur et .al. in 199164 found that the Klebsiella (38.6%), Staphylococcus aureus (21.5%) were the most commonly isolated pathogens with higher mortality in infections with Gram-negative (63.5%) than with Gram-positive organisms (19.1%). Piyush Gupta et al. in 199330 in their study concluded that Klebsiella septicemia continues to be on priority list of nosocomial neonatal infections as evidenced by the rising incidence. Klebsiella septicemia affects the most vulnerable, has more incidence of complications and carries high mortality rate. Moreno et .al. in 19949 in their study of 577 cases with culture proved sepsis found that Gram-negative bacilli particularly species of Klebsiella and E-coli were responsible for 61% of infections, whereas Gram-positive isolates especially Staphylococci and Candida were responsible for 37% and 2% respectively. Case fatality rate was 32%. Mortality was greater in infants with early-onset sepsis than in those with late infection. Koutouby et. al. in 199565 in study of 106 cases of neonatal septicemia found that most common organisms were Group B Streptococcus (23%), E-coli (17%), Staphylococcus epidermidis (18%), Klebsiella pneumoniae (16%). Group B Streptococcus was the most common cause for early-onset sepsis while the Staphylococcus epidermidis was the common cause for late-oneset sepsis. Psedomonas aeruginosa and Klebsiella pneumoniae had highest mortality. Endo et.al. in 199666 found that Klebesiella pnuemonae and E-coli have been replaced by Staphylococcus aureus and Pseudomonas aeruginosa as the predominant isolate in newborn with sepsis. Samanci et.al. in 199767 in their four year study of neonatal septicemia in neonatal intensive care unit concluded that the common causes of neonatal septicemia were Gram-negative bacilli and Staphylococci. Gram-positive micro- organisms were the major causative agents for early-onset septicemia. Since the most common 37


pathogen of neonatal sepsis was Gram- negative bacillus, higher mortality rates were observed in nosocomial sepsis. The overall mortality rate in neonatal sepsis was 44.2% The mortality rate infants in whom nosocomial septicemia developed was significantly higher than in infants in whom early onset septicemia developed. Berger et.al. in 199812 found Coagulase negative Staphylococci, Gramnegative rods and Enterococcus faecalis as the major causative organisms for neonatal septicemia. Group B Streptococcus was the major pathogen of very early onset septicemia (within 24 hrs. of birth). Whereas late-onset infections were most commonly caused by Coagulase negative Staphylococci. Mortality rate was 14%. Kuruvilla et.al. in 1998 17 found that E-coli, E.faecalis were the predominant organisms causing early-onset sepsis, while Klebsiella and E. faecalis were the predominant organisms in late onset sepsis. In Care of Newborn, 7 th Ed 2010. Meharban Singh observed the spectrum of bacterial pathogens analysed from hospital based data collected by Nationa Neonatal Perinatal Database Network from different centers (1995) 68 in our country as follows. Klebsiella pneumonae Staphylococcus aureus E.Coli Pseudomonas aeruginosa Enterobacter species Staphylococcus albus Candida species Acinetobactor Streptococcus viridans Others 29.7% 14.7% 13.9% 09.2% 07.9% 07.2% 04.8% 02.4% 01.4% 08.7%

38


In Manual of Neonatal Care by Cloherty 7th Ed 20115. he stated that group B streptococcus is the most common cause of neonatal sepsis in United States and other bacteria less commonly associated with neonatal septicemia are Gram-positive bacteria including Listeria monocytogens and Enterococcus. K. Chugh et.al. (1987)69

studied 250 sick neonates, 43 blood cultures were positive

Klebsiella species (10%) was the commonest organism followed by Pseudomonas and Staphylococcus aureus and E.coli was the least only 7%.

39


MATERIALS AND METHODS

This study was conducted in PRATHIMA INSTITUTE OF MEDICAL SCIENSES , NAGUNOOR. 50 Neonates below the age of 28 days with clinical suspicion of neonatal

septicemia were included in this study. Neonates admitted in our hospital from out patient department and neonates born in our hospital were included in this study group. After admission detailed history was taken and thorough clinical examination was done. These neonates had the following symptoms and signs which were suspicious of septicemia. Symptoms : Fever Refusal of feeding Vomiting Diarrhea Abdominal distension Irritability Rash Signs : Hypothermia Hyperthermia Tachycardia Bradycardia Tachypnea Apnea

40


Pallor Jaundice Sclerema Petechiae Purpura

All neonates were investigated as follows. Sepsis Screen : i. Total leucocyte count was done by using Neubauers chamber. Leucopenia with count < 5000 / cmm was considered positive for septicemia. ii. Peripheral smear prepared with a drop of blood from heel prick and stained with Leishmans stain. a. The neutrophil is about 10-12 microns in diameter. The cytoplasm contains fine pale violet granules and number of nuclear lobes increase with maturity. b. Toxic granules were identified as a coarse darkly stained granules and its percentage was calculated. iii. Micro - ESR : is simple and inexpensive. It was obtained by collecting capillary blood in standard preheparinised micro haematocrit tube of 75 mm length, 1.1 mm internal diameter and 1.5 mm outer diameter. Fall of erythrocyte column was read after one hour. During neonatal period a value of more than 15 mm at the end of 1st hr was considered as suggestive of infection. iv. C - reactive protein : C-reactive protien was detected by latex

agglutination test - Span CRP kit was for detection of C -Reactive protein.

41


Method : Latex CRP reagent was used for this test. First serum samples and the reagents were brought to room temperature. Then one drop of patients serum diluted with five drops of 0.9% saline. One drop from above solution was taken on the test plate and added one drop of latex CRP reagent. Then mixed them thoroughly with the stirring rod and with the rotating slide. After two minutes agglutination was observed. v. Blood Culture : In all neonates the blood sample was collected from peripheral vein with all aseptic precautions, prior to administration of any antibiotic therapy. 0.5 ml of blood was collected in 5 ml of glucose broth. This sample was

immediately sent to Microbiology Department Three subcultures were observed after 24, 48 and 120 hrs. If no growth was observed after five days culture was reported as negative. If growth was observed material was further analysed for specific organisms. Gram negative organisms showed characteristic colonies on nutrient agar and MacConkey medium. E Coli on MacConkey medium showed pink colonies. On nutrient agar Staphylococci showed colonies of different colours.

42


OBSERVATION AND RESULTS

This study was conducted in PRATHIMA INSTITUTE OF MEDICAL SCIENCES, NAGUNOOR. During study period . 50 neonates below the age of 28 days with clinical suspicion of neonatal septicemia were included in this study.

Table No. 1: Distribution of cases according to Sex. Sex No. of cases Male 33 Female 17 Total 50

Observations : - 33 male babies (66%) were affected by septicemia. - 17 Female babies (34%) were affected by septicemia. - Male babies were more affected by neonatal septicemia than female babies.

Male Female

MALE FEMALE

43


Table No. 2 : Distribution of cases according to age of onset of septicemia. Age of onset No. of cases < 7days 34 > 7 days 16 Total 50

Observations : - 34 Early onset septicemia was present in cases (68%) - Late-onset septicemia was present in 16 cases. (32%) - Early onset septicemia was more common than late onset septicemia.

7 7 days

44


Table No. 3 : Distribution of cases according to birth-weight.

Birth-weight No. of Cases

< 2500 gm 34

> 2500 gm 16

Total 50

Observations : Birth weight < 2500 gm is low birth weight was present in 34 cases (68%). Birth weight >2500 gm was present in 16 cases (32%) Septicemia was more common in low birth weight new newborns i.e.< 2500, gm.> 2000 gm

>2500gms< 2000 gm

37wks

Fullterm (> 37wks )

7 days Total 19 11 30

Maturity Term 15 5 20 Total 34 16 50

Observations : Early onset septicemia was present in 19 preterm babies (63.3%) Early onset septicemia was common in preterm babies.

20 18 16 14 12 10 8 6 4 2 0

19

15

11 < 7 days > 7 days

5

Preterm

Term

47


Table No. 6 : Relation of age of onset with birth weight.

Age of onset 2500 gms 7 days > 7 days Total 20 14 34

Birth weight > 2500 gm 14 2 16 Total 34 16 50

Observations : Early-onset septicemia was presented in 21 cases 58.8% with low birth weight < 2500 gm. Early-onset septicimia was more common in low birth weight babies.

25

20 20

15

14

14 < 7 days > 7 days

10

5 2 0 < 2500 gms > 2500 gm

48


Table No. 7 : Predisposing factor for neonatal septicemia.

Predisposing factor Low birth-weight Prematurity Poor maternal health and hygiene of genitals Prolonged rupture of membranes > 18 hrs. Home delivery Resuscitation after birth Premature rupture of membranes < 37weeks H/o intrapartum maternal infection Bad obstretic history Umblicus discharge No obvious factor detected

No.of cases 34(68%) 30(60%) 29 (58%) 15 (30%) 12(24%) 8 (16%) 7(14%) 4(8%) 3(6%) 3 (6%) 7 (14%)

Observations :

Neonatal risk factors like low birth weight and prematurity were present in 68% and 60% cases respectively.

Maternal risk factors observed were prolonged rupture of membranes > 18 hrs (30%) home delivery 24%, poor maternal health and hygiene of genitals (58%]

In 86% of cases there was one or more predisposing factor present.

49


low birth Low birth-w eight4% 2%2%2% 4% 4% 17% Prematurity

weight

prematurity

Poor maternal health and hygiene of genitals poor maternal health&hygiene Prolonged rupture of membranes > 18 hrs .

6%

PROM Home delivery15%

>18 hrs

Resuscitation after birth

home delivery

Premature rupture of membranes < resuscitation after birth 37w eeks H/o intrapartum maternal infection Bad obstretic history 15% Umblicus discharge H/o intrapartum

PROM 7 days Total Gram-negative 7 7 14 Gram-positive 1 2 3 Total 8 9 17

Observations : Out of 8 culture positive cases of early onset septicemia, Gram-negative organisms were detected in 7 cases (87.5%). Gram-negative organisms were common cause of early onset septicemia.

10 9 9 8 8 7 7 6 6 < 7 days 5 4 3 3 2 1 1 0 Gram staining Gram -negative Gram -positive > 7 days

56


Table No. 13 : Distribution of organisms isolated according to birth weight.

Birth weight Gram-negative < 2000 gm > 2000 gm Total 10 4 14

Gram staining Gram-Positive 2 1 3 Total 12 5 17

Observations : Out of 12 cases of birth weight < 2500 gm Gram-negative organisms were detected in 10 cases (83.3%) Gram-negative septicemia was common in low birth-weight babies i.e., 2500 gm 4 4 2 2 1

0 Gram-negative Gram-Positive

57


Table No. 14 : White blood cell count profile :

WBC Count Bacteriologically Positive < 5000 / cmm > 5000 / cmm Total 8 (47%) 9 (53%) 17

Culture Bacteriologically negative 11 (33.33%) 22 (66.67%) 33 19 31 50 Total

Observations : Sensitivity of the test - 47%

Specificity of the test - 66.67% Positive predictive accuracy of the test - 42.11%

25 22 20

15 < 5000 / cmm 11 10 8 9 > 5000 / cmm

5

0 Bacteriologically Positive Bacteriologically negative

58


Table No. 15 : Cells with toxic granulation profile. Toxic Granulation Bacteriologically Positive Present Absent Total 12 (70.56%) 5 (29.44%) 17 Culture Bacteriologically negative 12 (36.37%) 21 (63.63%) 33 24 16 50 Total

Observations : Sensitivity of the test - 70.56%

Specificity of the test - 63.65% Positive predictive accuracy of the test - 50%

25 21 20

15 12 10 12 Pres ent Abs ent

5 5

0 Bacteriologically Pos itive Bacteriologically negative

59


Table No. 16 : Band neutrophil ratio.

B/N Bacteriologically Positive B/N > 0.2 B/N < 0.2 Total 15 (88.2%) 2 (11.8%) 17




25 21 20

15 15 12 10 B /N > 0 .2 B /N < 0 .2

5 2


60


Table No. 17 : Micro ESR Profile : m-ESR Bacteriologically Positive >15 mm at the end of 1st hr < 15 mm at the end of 1st hr Total 17 33 50 5 (27.4%) 28 (84.84%) 33 12 (70.56%) Culture Bacteriologically negative 5 (15.16%) 17 Total



30

28

25

20 >1 5 m m at the end of 1 s t hr 15 12 10 5 5 5 < 1 5 m m at the end of 1 s t hr


61


Table No. 18 : C-reactive protein profile.

C-reactive protein Bacteriologically Positive Positive Negative Total 15 (88.2%) 2 (11.8%) 17




35 29 30

25

20 Positive 15 15 Negative

10 5 2 0 Bacteriologically Positive Bacteriologically negative 4

62


Table No. 19 : Comparison of sensitivity, specificity and positive predictive accuracy of each test. Test Sensitivity Specificity Positive predictive accuracy WBC Count < 5000 cmm B/N > 0.2 Toxic granulation m-ESR > 15 mm at the end of 1st hr C-reactive protein Observations : C-reactive protein had highest sensitivity (88.2%), specificity (87.8%) and positive predictive accuracy (78.95%) 88.2% 87.8% 78.95% 47% 88.2% 70.56% 70.56% 66.67% 63.63% 63.65% 84.84% 42.11% 62.4% 50% 70.5%

100% 90% 80% 70% WBC Count < 5000 cmm 60% B/N > 0.2 50% 40% 30% 20% 10% 0% Sensitivity Specificity Positive predictive accuracy Toxic granulation m-ESR > 15 mm at the end of 1st hr C-reactive protein

63


Table No. 20 : Combination of two tests C-reactive protein + Toxic granulation.

Toxic granulation + C-reactive protein Positive Negative Total 10 (58.8%) 7 (41.2%) 17 Bacteriologically Positive

Culture Bacteriologically Negative Total

3 (9.11%) 30 (90.9%) 33

13 37 50

Observations : Sensitivity of the combination - 58.8% Specificity of the combination - 90.9% Positive predictive accuracy of the combination - 76.9%

35 30 30 25 20 15 10 10 5 0 Bacteriologically Pos itive Bacteriologically Negative 7 3 Pos itive Negative

64


Table No.21: Combination of two tests-C-reactive protein+m-ESR C-reactive protein + m ESR Positive Negative Total Observations : Sensitivity of this combination - 64.68% Specificity of this combination - 93.93% Positive predictive accuracy of this combination - 84.6% Bacteriologically Positive 11 (64.68%) 6 (35.32%) 17 Culture Bacteriologically Negative 2 (6.07%) 31 (93.93%) 33 13 37 50 Total

35 30 25 20 15 10 5 0 11 6 2

31

Positive Negative

Bacteriologically Positive Bacteriologically Negative

65


Table no. 22 Combination of two tests-Toxic granulation+m-ESR Toxic granulation +m ESR Positive Negative Total Bacteriologically Positive 10 (58.8%) 7 (66.7%) 17 Culture Bacteriologically Negative 4 (12.13%) 29 (87.87%) 33 14 36 50 Total

Observations : Sensitivity of this combination - 58.8% Specificity of this combination - 87.87% Positive predictive accuracy of this combination -71.6%

35 30 25 20 15 10 10 5 0 Bacteriologically Pos itive Bacteriologically Negative 7 4 Pos itive Negative 29

66


Table no.23 Combination of three tests-C reactive protein + Toxic granulation + m ESR Three tests Bacteriologically Positive Positive Negative Total 8 (47.04%) 9 (52.96%) 17 Culture Bacteriologically Negative 2 (5.07%) 31 (93.93%) 33 9 41 50 Total

Observation : Sensitivity of this combination 47.04%

- Specificity of this combination 93.93% Positive predictive accuracy of this combination - 88.8%.

35 30 25 20 15 10 5 0 8 9 2

31

Positive Negative

Bacteriologically Positive Bacteriologically Negative

67


Table No. 24 : Comparision of sensitivity, specificity and positive predictive accuracy of combination of any two or more tests.

Combination tests

of

Sensitivity

Specificity

Positive predictive accuracy

C- reactive protein + Toxic granulation C-reactive protein + m-ESR Toxic granulation + m-ESR C- reactive protein + Toxic granulation + m-ESR

58.8%

90.9%

76.9%

64.68%

93.93%

84.6%

58.8%

87.87%

71.6%

47.04%

93.93%

88.8%

Observations :

Specificity and positive predictive accuracy were increased at the cost of sensitivity, when combination of tests was done.

68


The best combination was C-reactive preoteins + m-ESR followed by Creactive protein + Toxic granulation.

100.00% 90.00% 80.00% C- reactive protein + Toxic granulation 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% Sensitivity Specificity Positive predictive accuracy C- reactive protein + Toxic granulation + m-ESR C-reactive protein + m-ESR ||||||| Toxic granulation + m-ESR

69


Table No 25 : Sensitivity Pattern of Organisms Against Various Antibiotics. The analysis of sensitivity pattern of organisms grown in various culture of 17 neonates was made and the results were observed as under

S.l. No.

Name of Organism

No.of cultures Isolated

Genta Mycin

Amik acin

Ampi cillin

Cloxa Cillin

Cefot axime

Ciproflo xacin

1 2 3

E.coli Klebsiella Staphylococcus Aureus

7 4 3

2 1 _

3 2 1

1 1 1

_ _ 2

1 2 2

6 4 2

4 5

Pseudomonas Proteus Total

2 1 17

1 1 4 (23.52%)

1 1 8 (47.04%)

1 3 17.64%)

_ _ 2 (11.76%)

_ 1 6 (35.28%)

2 1 15 (88.21%}

Observation : In our study shows that Ciprofloxacin had sensitivity of (88.2%), Amikacin had sensitivity of 47.04%, Cefotaxime had sensitivity of 35.28%, Gentamycin had sensitivity of 23.52%, Ampicillin had sensitivity of 17.64%

70


Table No. 26. : Out come Out come No of cases Deaths 14 Surivals 36 Total 50

Observation : Case fatality rate was 28%

28%

deaths survivals

72%

Deaths

Surivals

71


Table No. 27. : Distribution of mortality according to maturity.

Maturity Death Preterm Full-term Total 9 (64.26%) 5 (35.74%) 14

Outcome Survivals 21(58.5%) 15 41.5%) 36 Total 30 20 50

Observations : - Out of 14 deaths 9 deaths (64.26%) occurred in preterm babies. 5 deaths ocured in full-term babies Mortality was higher in preterm babies.

25 21 20

15 15 P re te rm F u ll -te rm 10 9

5 5

0 D e a th S urviva ls

72


Table No. 28 : Distribution of mortality according to age of onset of septicemia.

Age of onset Deaths < 7 days > 7 days Total 10 (71.4%) 4 (28.6%) 14

Outcome Survivals 24 12 36 Total 34 16 50

Observations : 10 deaths (71.4%) occurred in babies with early-onset septicemia. 4 deaths (28.6%) occurred in babies with late-onset septicemia. Mortality was higher in early onset septicemia.

30

25

24

20 < 7 d a ys 15 10 10 12 > 7 d a ys

5

4

0 D e a th s S u rviva ls

73


Table No. 29 : Distribution of mortality according to birth-weight.

Birth - weight Deaths < 2500 gm > 2500 gm Total 9 (64.26%) 5 (35.74%) 14

Out come Survivals 25 11 36 Total 34 16 50

Observations : 9 deaths (64.26%) occurred in babies with weight < 2500 gm 5 deaths (35.74%) occurred in babies with birth weight higher lowbirth weight babies.

30 25 25

20 < 2500 gm 11 10 9 5 5 > 2500 gm

15

0 D e a th s S u rviva ls

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Table No. 30 : Distribution of mortality according to culture positivity. Culture Deaths Bacteriologically Positive Bacteriologically Negative Total Observations : 10 deaths (71.4%) occurred in cases in which culture was bacteriologically positive. 8 deaths (28.6%) occurred in cases in which culture was bacteriologically negative. Mortality was higher in culture positive new born. 14 36 50 4 (28.6%) 28 32 10 (71.4%) Outcome Survivals 8 Total 18

30

28

25

20 Bacteriologically Positive 15 10 10 4 8 Bacteriologically Negative

5

0 Deaths Survivals

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Table No.31 : Distribution of mortality according to Gram-staining of organisms isolated in bacteriologically positive cases.

Gram-staining Deaths Gram negative Gram positive Total 1 (10%) 10 9 (90%)

Out come Survivals 5 (71.43%) Total 14

2 (28.57% 7

3 17

Observations : 9 deaths (90%) occurred in Gram- negative cases 1 deaths (10%) occurred in Gram- Positive cases.

10 9 9 8 7 6 5 5 Gram pos itive 4 3 2 1 1 0 Deaths Survivals 2 Gram negative

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Table No. 32 : Distribution of mortality according to organisms isolated in bacteriologically positive cases. Organisms isolated E.coli Klebsiella Staphylococcus Aureus Pseudomonas Proteus Total Observations : E.coli was detected in 7 cases out of that 4 (57.1%) died and 3 cases survived. Klebsiella was isolated in 4 cases. Out of that 2 died and 2 survived. - Staphylococcus Aureus was detected in 3 cases, out of that 1 died and 2 survived. - Pseudomonas was detected in detected, that case died. 2 cases, both cases died. Proteus, 1 case 2 (100%) 1 10 0 0 7 2 1 17 Deaths 4 (57.1%) 2 (50%) 1 (50%) Outcome Survivals 3 (42.9%) 2 (50%) 2 Total 7 4 3

4 .5 4 4 3 .5 3 3 2 .5 2 2 1 .5 1 1 0 .5 0 0 De a th s S u r v iv a ls 0 1 2 STAPH E.c o li K le b s ie lla S ta p h y lo c o c c u s A u r e u s Ps e u d o mo n a s Pr o te u s

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DISCUSSIONThis study was conducted in PRATHIMA INSTITUTE OF MEDICAL SCIENCES NAGUNOOR , KARIM NAGAR 50 neonates below the age of 28 days with clinical suspicion of neonatal septicemia were included in this study. In this study clinical profile, sepsis screen, outcome of neonatal septicemia was studied.

Clinical Profile : Clinical profile of neonatal with signs and symptoms of neonatal septicemia was as below Table I shows distribution of cases according to sex 33 male babies(66%) and 17 female babies (34%) were affected by neonatal septicemia. Nelson18 stated that males have an approximately two fold higher incidence of sepsis than females. Piyush Gupta et.al30. observed male predominance (64.7%) in neonatal

septicemia.. N. Somu et. al23, Philip et.al32. observed that males were affected more than females. Khatua et. al22. found that males were affected in (70.7%) of cases. N. Sinha et al21. observed that the male to female ratio was 52:30 in 1.73:1. In this study male babies with low birth weight predominated (64.9%) H..David wilson4 stated that increased incidence of sepsis neonatorum in male infants in probably related to the higher incidence of congenital anomalies of the urinary tract in the males, resulting in primary urinary tract infection and secondary sepsis.

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Placzek et. al60. in their study found 41 males and 24 females out of 65 cases of neonatal septicemia .The male to female ratio was 1.70 : 1. Wash Burn and colleagues31 observed male to female ratio of 2.02 : 1. They postulated the genetic origin for these sex differences that related to the females possession of two X chromosomes in contrast to males possession of a single X chromosome. Table No-II shows distribution of cases according to age of onset of

septicemia. Early onset septicemia is < 7 days was present in 34 cases (68%) andonset septicemia is > 7 days was present in 15 cases (32%). So early-onset septicemia was more common than late-onset septicemia. Our

findings are consistant with other studies. Piyush Gupta et. al30. found that 76.4 % of cases occured in < 7 days i.e, early onset type. T. Vesikari et. al7. reported early onset in most of the patients with neonatal sepsis. In 410 cases studied onset < 7 days was found in 370 cases. Khatua et. al22. observed that 70% cases developed early onset septicemia J.N.Mishra et al. observed that early-onset septicemia was in 71.7% cases. In our study the early onset septicemia was more common because of maternal risk factors like prolonged rupture of membranes, home delivery, H/o intrapartum maternal infection, poor maternal health and hygiene of genitals and neonatal risk factors like prematurity and low birth weight. Table No. III shows distribution of cases according to birth weight low birth weight i.e, < 2500gm was present in 34 cases (68%). These findings are consistant with other studies.

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Nellian et. al25, N Mehrotra et. al, Piyush Gupta et. al, Agarwal et. al, Khatua et. al. and Koutociby et. al. observed that low birth weight new born have higher in cidence of neonatal septicemia. N. Sinha et. al21. observed that babies with low birth weight predominanted (64.9%). Nelson18 and Cloherty5 stated that the low birth-weight was the single most important factor in neonatal septicemia. There was 3-10 fold higher incidence of septicemia in these infants than in normal birth-weight infants. Philip et .al32. observed that low birth-weight was present in 18 cases out of 30 proven cases of sepsis is 60%. Moreno et. al9. observed that 58% patients were of low birth-weight Anand. et al. found that more than 2/3 cases of neonatal sepsis were low birth- weight. Table No. IV shows distribution of cases according gestational age 30 preterm babies (60% ) were affected. So preterm babies were more affected than full term babies by neonatal septicemia ,Our observations are consistant with other studies. Anand et. al45. observed that 62% preterm babies were affected. Khatua et. al22. observed that out of 92 babies with neonatal septicemia 58 were preterm in 56.52%. Fanaroff et. al26., Koutouby et. al65., Piyush Gupta et.. al30., N. Mehrotra et. al14. found that preterm babies were more affected than full-term babies by neonatal sepsis. Higher incidence of many complications of labour and resuscitation are more common in preterm babies than full term neonates. Premature babies are relatively immunocompromised and immuno-inexperienced. These factors predispose them to infection.

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Table No V shows relation of age of onset of septicemia with maturity.Early onset septicemia was present in 19 preterm babies (63.3%). Table VI shows relation of age of onset of septicemia with birth weight. It shows that early-onset septicemia was present in 21 cases (58.5%). Table No. VII shows various predisposing factors detected in neonatal septicemia. In 86% of cases predisposing factors were present. Common neonatal factors observed were prematurity (60%) and low birth weight (68%). Agarwal et. al70, N Sinha et. al21, Philip et. al32, Anand et. al45, N. Mehrotra et. al14, Piyush Gupta et. al30, Khatua et. al22. and Nellian et. al25. observed low birth weight as important factor. Piyush Gupta et. al30, Fanaroff et. al26, N. Mehrotra et. al14, Khatua et. al22, Anand et. al45, and Koutouby et. al65. found increase in incidence of neonatal septicemia in preterm babies. Nelson18 and Cloherty5 stated that the prematurity and low birth weight are the most important predisposing factors in neonatal septicemia. Common maternal factors observed were poor maternal health and hygiene of genilats (58%), prolonged rupture of membranes (31%), Home delivery (23%) premature rupture of membranes (15%), H/O intrapartum maternal infection (9%). Udani et.al. and Kishor et. al. have reported high incidence of vertical transmission and sepsis in babies born to mothers with prolonged rupture of membrane. Anand et. al45. observed prolonged rupture of membranes in 29.3% of cases. N. Mehrotra14 noted three fold increase in the incidence of sepsis after prolonged rupture of membranes.

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James.C. Overall et. al15. observed that unsterile delivery provides an obvious source of inoculation of the new born with potentially pathogenic organisms. N Mehrotra et. al14. observed that superficial infections were more frequent in home and also larger number of visitors handling babies. N. Mehrotra et. al14. observed influence of socio-economic factors. Babies of poor illiterate parents have higher incidence of neonatal infection because they are usually low birth weight, delivered before 37 weeks of gestation, thus diminishing immunological status of newborns. There is also delay in appreciating illness and

seeking treatment. Besides, most deliveries in poor families are conducted at home under improper aseptic conditions. Faranoff26 stated that maternal socio-economic status, health and vaginal flora are important factors in determining the incidence neonatal sepsis. Smith and associates found a correlation between maternal pyrexia and neonatal infection. Berman71 and Banker and Duport and Thamdrup emphasized the important role of maternal infection in pathogenesis of neonatal infection. Pryles and associates in controlled study of infants born after premature rupture of membranes, maternal infection, umbilical cord vasculitis and neonatal sepsis. James. C. Overall et. al15. observed that maternal infections, particularly of the uterus and urinary tract also significantly predispose to neonatal infection. Zilliacus and Totterman noted a more than 6 fold greater incidence of internal infection in neonates born with mothers with urinary tract infection at the time of delivery than in ones born to mother without such infection. Neonates may acquire the pathogens from their mothers either in utero (ascending infection) or intrapartum during their passage through contaminated birth canal. During the birth the usually sterile fetus encounters bacteria from maternal of

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vagina, perineum, feces, and skin and gets colonized. The fetal skin, mucous membranes and gastrointestinal and respiratory tracts are colonized by organisms from contaminated amniotic fluid or from vaginal secretions swallowed or aspirated either before birth or during passage through the birth canal. In our study resuscitation after birth important factor in neonatal septicemia. Dawodu et. al11. found that requirement of mechanical ventilation was important risk factor. Agarwal et. al70. found that birth asphyxia was common predisposing factor. Moro et. al10. observed that mechanical ventilation for >5 days was significantly associated with neonatal sepsis. Under normal condition the infants skin and mucus membrane prevent bacterial invasion and colonization proceeds uneventfully over a period of several days. Invasion of micro-organisms and subsequent infection may occur when the normal defence mechanism of the skin and mucous membrane are compromised. Thus mucosal abrasions or cutaneous defects associated with birth defects, fetal monitoring obstretical manipulation and /or vigorous resucitation predispose to bacterial invasion and infection. Similarly, the use of indwelling catheters, which are routinely used in low birth-weight infants to monitor vital signs and for blood sampling and infusions, provides sites for bacteria which normally contaminate and (17%) was observed as one of the

colonize normally contaminate and colonize the new born skin. Venous catheters are most dangerous in this regard. Fanaroff 26 stated that asphyxiated infants requiring resuscitative procedures including mechanical ventilation and catheterization are at high risk of developing sepsis. Table VIII shows various clinical features observed in our study.

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Commonly observed clinical manifestations were refusal to feeds

(56%)

temperature abnormality (47%), sclerema (45%), jaundice (41%) Pallor (36%), not doing well (24%), rash (21%) and convulsions (17%). Khatua et. al22. observed that refusal of feeds, lethargy, diarrhea, temperature abnormality, abdominal distension, jaundice and vomiting were most common presenting features. Mishra et. al28. observed that common clinical presentations were juandice, lethargy, refusal of feeds, vomiting and respiratory distress. Agarwal et. al70. observed that refusal to suck, sluggish activity, fever, jaundice were common clinical features.Gupta et. al30. observed that lethargy , feeding problems, abdominal distension, respiratory distress, hypothermia apnea and irritability were the most common presenting features. Somu et. al 23.. observed that abdominal distention, diarrhea,refusal fo feeds, lethargy, vomiting, pallor were

common presenting features. Anand et. al 45. observed that refusal of feed, lethargy, temperature changes, sclerema were predominant clinical features. All these studies show that clinical features of neonatal septicemia are non specific and m

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