An Observational Study on The Epidemiology, Clinical Characteristics, And Outcomes of Neonatal Sepsis in A Pediatric Intensive Care Unit at A Tertiary Care Hospital

Abstract

Neonatal septicemia refers to a clinical syndrome characterized by systemic signs and symptoms due to generalized bacterial infection with a positive blood culture in the first four weeks of life. It continues to remain a leading cause of morbidity and mortality among infants, especially in middle and lower-income countries. The aim is to determine epidemiology & outcome of sepsis in children & objective is to estimate the prevalence, define disease spectrum, identify risk factors, diagnostic criteria, clinical outcomes and to review antibiotic utilization as well as whether the current treatment is in compliance with guidelines. This prospective observational study was carried for a period of six months. All the admitted children were screened for sepsis based on the clinical features and septic screening. Coming to the results part, out of 120 patients, 100 patients met the criteria. The prevalence was found to be 83.33% and males (58%) are more subjected to infections than females. Then results of patients were further divided into various criteria to meet our defined objectives. CRP levels along with other clinical signs & symptoms have a major role in the diagnosis and prognosis of neonatal sepsis. Our present study was formulated as there was a paucity of evidence with respect to the association between neonatal sepsis and CRP as a biomarker for neonatal septicemia. This article concludes early diagnosis and appropriate management improves the outcome in neonatal sepsis.

Keywords

Neonatal sepsis, sepsis spectrum, clinical manifestations, CRP, Antibiotics, WHO prescribing indicators.

Introduction

     
           
       
    Fig.01: Gender Wise Distribution of Sepsis Subjects

In our present study, 100 subjects with suspected sepsis admitted in the SNCU & PICU were enrolled which included 54 males (58%) and 46 females (42%).

       
           
       
Fig.02: Distribution Of Subjects in Different Wards

Coming to the age-wise distribution, patients were divided into 05 groups being kept at intervals of days, months, and years. When looking at the 0-3 days a total of 29 patients were included of which 16 were males (57.14%) and 13 were females (44.82%). At an age interval between 4 to 30 days, 05 were male (41.66%) and 07 were female (58.33%). So, next spotting at 1 month – 12 months, females were 11 (64.7%) and males were 06 (33.3%), and in children of age between 01 years to 07 years, 16 were male (66.6%) and 08 were female (33.4%). Finally, from 7 years to 14 years’ males were 11 (61.1%) and females were 07 (38.9%).

       
           
       
Fig. 03 & 04: Age Interval Wise Distribution

In our study, in the SNCU ward, we have distinguished the types of sepsis among 58 subjects of both genders. Among them, the early onset of sepsis and late onset of sepsis was the same i.e., 29 (50%). Amidst in early onset of sepsis, males were 16(59.25%) & females were 13 (41.93%). In late onset of sepsis, males were 11(40.74%) & females were 18(58.06%).

       
           
       
   
       
           
       
Fig. 05 & 06: Distribution of Onset of Sepsis

During the study period, gravida-wise distribution of patients was taken into consideration. Sepsis is one of the main causes of admission of pregnant women to the intensive care units and of maternal mortality. Among 100 patients, 39% of them belong to primi gravida (G1) constitutes the majority of the patients while 37?long to second gravida (G2), 19 % (G3), and (G4) 5% are third gravida and Fourth gravida respectively.

       
           
       
           
           
       
Fig.07 & 08: Gravida Wise Birth Distribution of Women & Subjects

According to National Neonatology Forum Standards, Babies were considered as Low birth weight if the birth weight is < 2>

       
           
       
          
           
       
Fig.09&10: Gender Wise Weight Distribution

Pregnancies complicated by sepsis are associated with increased rates of adverse obstetric outcomes, including cesarean delivery, postpartum hemorrhage, and pre-term delivery. As pre-term deliveries are much more prone to sepsis in neonates, our study also showed the number of pre-term babies with clinical signs of sepsis was 67 (67%) and the term was 33(33%).

       
           
       
Fig.11: Distribution Of Cases According to The Period of Gestation

Among the 100 subjects, 74 were diagnosed with possible sepsis, 26 were classified as having probable sepsis, and none were identified with proven sepsis.

Early onset sepsis is clearly more prevalent in preterm neonates compared to term neonates, and this finding is statistically significant.

       
           
       
Fig.13: Correlation Between Period Of Gestation And Onset Of Sepsis

Based on the age at the time of clinical presentation subjects were classified as early onset sepsis (EOS) when the age is less than 72 hours and as late-onset sepsis (LOS) when the age is more than 72 hours and categorized based on the clinical stages of sepsis.

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Fig 14: Onset Of Illness Vs Risk Factors In Males

       
           
       
 Fig 15: Onset of Illness Vs Risk factors in females

The most common clinical presentations in this study were cold & cough, tachypnea, chest retractions, incessant crying, abdominal distension, and refusal to suck. The frequency and percentage of occurrence of clinical signs are shown in the following figure.

       
           
       
Fig 16: Clinical Manifestations

The distribution of these clinical signs among the sepsis groups, namely possible, and probable sepsis is shown in table 3. It is evident from this table that the percentage of non-specific clinical signs like refusal to suck, lethargy, and fever is almost equally distributed among the two groups of sepsis so the presence of their signs was of no significance. Whereas frequency of cold & cough, tachypnea, chest retractions, vomiting, abdominal distension, incessant cry were more in clinical sepsis than probable sepsis. Chest x ray shown Broncho pneumonia in 10 neonates and pneumonitis changes in 13 neonates. The signs like chest retractions and abdominal distensions were associated with infections like pneumonia, in most situations. These signs are found in higher percentage in possible sepsis group than probable epsis. It is also found that the occurrence of signs like seizure, moaning & weak cry were found relatively less in both sepsis groups. The most classic sign of sepsis like shock & bulging fontanelle is absent in both groups.

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Among 218 prescribed antibiotics, penicillin’s were 47 (21.55%) followed by cephalosporin’s 74 (33.94%), macrolides      01(0.45%), carbapenems 10(04.58%), aminoglycosides 69(31.65%), tetracycline’s 05(02.29%), glycosides 09(04.12%) and nitroimidazoles 03(01.37%)

       
           
       
Fig.18: Different categories of Antibiotics prescribed in neonatal septicemia

Among 47 penicillin antibiotics prescribed, piperacillin tazobactum combination 35(74.46%) was prescribed high in number than amoxicillin potassium clavulanic acid combination 12(25.53%)

       
           
       
Fig.no.19: Percentage of Penicillin antibiotics prescribed

Coming to Cephalosporin group of antibiotics, 3^rd generation cephalosporin drugs like ceftriaxone 29(39.18%), cefotaxime 19 (25.67%) which were highly prescribed when compared with combination of beta lactamases i.e., ceftriaxone-tazobactum 22 (29.72%), ceftriaxone + sulbactum 03 (04.05%) and 2^nd generation cephalosporin like cefaclor was prescribed very low 01 (01.35%).

       
           
       
Fig.no.20: Percentage of Penicillin antibiotics prescribed

Next the most common group of antibiotics prescribed after cephalosporins was Aminoglycosides which encountered 69 out of 218 antibiotics. Among 69, Amikacin was prescribed more in number i.e., 67(97.10%) than Tobramycin 02 (02.89%).

       
           
       
Fig.no.21: Percentage of Aminoglycosides antibiotics prescribed

After aminoglycoside antibiotics, the most commonly prescribed class of drugs are Carbapenems i.e., Meropenem 10 (04.58%) followed by Glycopeptides group from which Vancomycin 09 (04.12%) then Tetracycline’s group of Doxycycline 05 (02.29%), Nitroimidazoles group of Metronidazole 03 (01.37%) and finally Macrolides like Azithromycin 01 (0.45%) which are very less.

       
           
       
Fig.no.22: Percentage of Other class of antibiotics prescribed

Apart from 218 antibiotic drugs prescribed, 301 drugs account for non-antibiotics which are prescribed to alleviate other systemic problems in neonatal and children with septicemia. The list of all such drugs are shown in below fig no.23.

       
           
       
Fig.no.23: Percentage of non-antibiotics prescribed

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Evaluation of prevalent drugs prescribing practices was analyzed using the WHO drug prescribing indicators. Average number of drugs per encounter was 5.19. Percentage of drugs prescribed by generic name was 39.49%. About 42% of sick newborns were prescribed antibiotics. About 44.31% of sick newborns were given injections. Percentage of drugs prescribed from the NLEM for children was 94.79%.

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Table.06: WHO Indicators

WHO Indicators	Number & Percentage
Total number of drugs prescribed	519
Mean number of drugs per prescription	5.19
Drugs prescribed in generic names	205 (39.49%)
Drugs written in capital letters	50 (09.63%)
Prescriptions with antibiotics	218
Prescriptions encountered with injections	230 (44.31%)
Drugs prescribed from NLEM	492 (94.79%)

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DISCUSSION:

Sepsis is the commonest cause of neonatal morbidity and mortality. It is responsible for about 30-50% of total neonatal deaths. Sepsis related morbidity and mortality is largely either preventable or treatable with rational antimicrobial and supportive therapy. LBW is a strong risk factor for neonatal sepsis due to multiple reasons. Unsafe delivery or unclean delivery at inappropriate place is another important predisposing factor for sepsis. Earliest clinical features of neonatal sepsis are often subtle and non-specific therefore a high index of suspicion is needed for early diagnosis specially so if risk factors are also present. Blood culture is the gold standard diagnosis but it is not available in all the peripheral centers, the cost for the test is also high and results are also not available in early period. Blood culture is often negative in many of the neonates in whom clinical signs and symptoms of sepsis is present. Because of these limitations, quick convenient, affordable, cost effective laboratory method along with clinical parameters is required to evaluate neonatal sepsis. The study was done at Tertiary care Hospital, Kadapa. The prevalence of sepsis in this study was 83.33% i.e., (100/120) which was more when compared with the study done by Abdul Hakeem Abayomi Olorukooba1et al ⁹ where prevalence was 37.6%. Our study can also be comparable with a prevalence of 38.95% was seen from a study in University of Benin Teaching Hospital ¹⁰ which was less with our study. Out of 120 cases collected, 100 newborn babies & children who are suspected to have sepsis were included in the study. Diagnosis of sepsis was arrived based on the clinical examination. In our present study, 100 neonates with suspected sepsis admitted in the SNCU & PICU were enrolled which included 54 males (58%) and 46 females (42%). In a study done by Gomati et al ¹¹ out of 148 neonates in their study 90 neonates (60.8%) were male and 58 (39.2%) were females which is consistent with our study and also male genders are more affected in neonatal septicemia due to X- linked immune-regulatory gene factor contributing the host’s vulnerability to infections in males. In our present study, coming to the age wise distribution, patients were divided into 05 groups being kept at an interval of days, months and years. When looking at the 0-3 days a total of 29 patients were included in which 16 were males (57.14%) and 13 were females (44.82%). At an age interval between 4 to 30 days, 05 were male (41.66%) and 07 were female (58.33%). So, next spotting at 1 month – 12 months, females were 11 (64.7%) and males were 06 (33.3%) and in children of age between 01 years to 07 years, 16 were male (66.6%) and 08 were female (33.4%). Finally, at 7 years to 14 years’ males were 11 (61.1%) and females were 07 (38.9%). In a study done by Michael M. Hermon et al ¹² the majority of study patients were newborns, infants, and toddlers. School children and adolescents comprised 27% of all study patients. More than half of the study population were male (n= 107; 53%). A predominance of male patients was found in the age subgroups of newborns, infants, and school children. Total gender distribution between age subgroups was statistically significant with our present study when compared with study done by Michael M. Hermon et al ¹². In our study, in SNCU ward we have distinguished the types of sepsis among 58 babies in both the genders. Among them, early onset of sepsis and late onset of sepsis was the same i.e., 29 (50%). Amidst in early onset of sepsis, males were 16(59.25%) & females were13 (41.93%). In late onset of sepsis, males were 11(40.74%) & females were 18(58.06%). In a study done by Nithya et al ¹³ number of babies with early onset sepsis was 55.33% and late onset sepsis was 44.67% which accounted less with our study. Also our study is similar to Meharban Singh et al ¹⁴ where there is equal distribution of early and late onset cases. During our study period, gravida wise distribution of patients was taken into consideration Sepsis is one of the main causes of admission of pregnant women to the intensive care units and of maternal mortality. Among 100 patients, 39% of them belongs to primi gravida (G1) constitutes majority of the patient’s while 37?longs to second gravida (G2) and 19 %( G3) and (G4) 5% are third gravida and Fourth gravida respectively. In a study done by Nithya et al ¹³ neonatal sepsis was more common in primi Gravida (48%) followed by second gravida (26%) which is in accordance with the finding that primiparity is a risk factor for sepsis. In a study done by Shah GS et al ¹⁵ reported a higher incidence (72%) of neonatal sepsis in primi gravida which is in consistent with our study. According to National Neonatology Forum Standards, Babies were considered as Low birth weight if the birth weight is < 2> ¹¹, the percentage of culture positive cases in LBW neonates (67%) was higher than in normal birth weight neonates which is similar with our study. This is due to the infection rate which is inversely related to the birth weight of newborn and low immunoglobulin G levels and impaired cellular immunity. Pregnancies complicated by sepsis are associated with increased rates of adverse obstetric outcomes, including cesarean delivery, postpartum hemorrhage, and preterm delivery. As pre term deliveries are much prone to sepsis in neonates, our study also shown the number of pre term babies with clinical signs of sepsis were 67 (67%) and term were 33(33%). Whereas Tessin I et a1¹⁶ in 1990 reported that preterm delivery was a more important risk factor for both morbidity and mortality which was similar with our present study. In our study, among the 100 neonates admitted, 74 neonates were diagnosed with possible sepsis, 26 were with probable sepsis and 0 were with proven sepsis. In a study done by Dr.D.S. jothi et al ¹⁷ .Based on the sepsis results the diagnosis was categorized into 3 group’s viz., possible sepsis, probable sepsis and proven sepsis. So, in their study out of the 250 neonates with possible sepsis 50(20%) are proven sepsis, 84(33.6) are probable sepsis and 116(46.4) are clinical sepsis which recorded low when compared with our study and our study limited with only 2 categories due to lack of blood cultures for proven sepsis. In our study, based on the age at the time of clinical presentation neonates were classified as early onset sepsis (EOS) when the age is less than 72 hours and as late onset sepsis (LOS) when the age is more than 72 hours and categorized based on the clinical stages of sepsis. Whereas in a study done by the same above, early onset sepsis was documented significantly more as compared to late onset sepsis (p < 0> ¹³ the major risk factors for neonatal sepsis were low birth weight (80%) and prematurity (46%) which was consistent but reported rare risk factors like Sp02 & Respiratory rates. Also when compared with the studies done by Nathoo KJ et al ¹⁸ and Tessin I et al ¹⁶ reported poor antenatal care, prolonged rupture of membrane and pre term delivery. Even our study classified risk factors based on the age group wise in neonates in that 00 to 03 days’ neonate age group is greater followed by 01 months to 12 month neonates, 04 to 30 days, 01 years to 07 years compared with children age group 07 – 14 years respectively which was new compared with other studies. The most common clinical presentations in this study were cold & cough (64%), tachypnea (54%), chest retractions (47%), incessant cry (36%), abdominal distension (32%), refusal to suck (31%), vomiting (37%) which were more commonly encountered with possible sepsis than probable sepsis. In a study done by D.S. jothi et al¹⁷ the most common clinical presentations in this study were refusal to suck (91.20%), lethargy (86.40%), weak cry (72%), Tachypnea (63.20%), chest retractions (56.8%) and fever (50.4%). Jain N K et al ¹⁹also reported that common presentations found in neonatal sepsis were respiratory distress (42.6%), lethargy (40%), jaundice (30%), fever (28.3%) and poor feeding (26.7%) which were found similar with our study except with some clinical manifestations like lethargy, jaundice, poor feeding and abdominal distension. With the high frequency of cold & cough, Chest x ray shown Broncho pneumonia in 10 neonates and viral pneumonitis changes in 13 neonates, the most classic sign of sepsis like shock & bulging fontanelle is absent in both groups which was found new in our study. The main hypothesis quotes as an objective in our study was “To find the role of CRP in the evaluation and management of neonates and children with septicemia”. Among the various tests CRP role in neonatal sepsis has been vastly studied when compared with blood cultures with a reason as cultures tests are time consuming, requires well equipped laboratory and trained personnel. It can be false negative due to the small amount of blood drawn from neonates, prenatal antibiotic use or low level of bacteremia.  In our present study, we attempted to determine the best cut-off point for CRP by taking considerations of previous meta-analysis as ? 4.09 ngm/dl which has sensitivity & specificity of 95% and 86% respectively. The levels of CRP were scored high in 0 – 03 days’ age group of neonates (29 ng/dl) compared with 1 month – 12 months (17 ng/dl) and 04-30 days’ age group of neonates (12 ng/dl) respectively of SNCU ward. Also, the levels of CRP were high in 01 -07 years’ age group (24 ng/dl) & 7 years to 14 years of children (18 ng/dl) in PICU ward. Even our present study has sensitivity & specificity of ? 95% & 90% respectively by taking in considerations of previous studies with a cut-off point ? 4.09 ngm/dl when compared with study done by Niza Monga et al²⁰ Out of the total 100 neonates, 47 were blood culture positive from which 40 were positive for CRP also. Among the blood culture negative samples, 30 were CRP positive. The mean value of CRP in blood culture positive neonates was 48.7 mg/l (8.6mg/ L-180.1 mg/L) whereas in blood culture negative neonates were 16.0mg/L (6.6mg/L-44.8mg/L) with a sensitivity and specificity of CRP against blood culture was 85.11% and 43.40% respectively which was even more with our study with only difference of utilizing blood cultures as gold standard test which was not available at our study site. In our present study, the empherical antibiotic treatment for neonatal septicemia was given only based on CRP Levels. Among 519 drugs prescribed, 218 drugs were prescribed as antibiotics which accounts for 42 % and non-antibiotics registered was 301(57.99%). Among 218 prescribed antibiotics, penicillin’s were 47 (21.55%) followed by cephalosporin’s 74 (33.94%), macrolides 01(0.45%), Carbapenems 10(04.58%), aminoglycosides 69(31.65%), tetracycline’s 05(02.29%), glycosides 09(04.12%) and nitroimidazoles 03(01.37%). In a study done by Mirza Shiraz Baig et al²¹ Among the antibiotic combinations amoxicillin - clavunate (38.99%), was most commonly prescribed followed by gentamicin (37.89%) and piperacillin (11.01%). Other antibiotics like, linezolid (0.94%), fluconazole (5.97%), Meropenem (4.42%), vancomycin (0.77%) were also used less commonly in NICU which were more commonly prescribed in both studies except cephalosporin’s which were prescribed high in number. Another study of Pacifici GM et al²², showed that Meropenem exhibits in vitro activity against an impressive number of community - acquired and nosocomial pediatric pathogens which was found similar with our study. Other than antibiotics, remaining drugs are prescribed and their data was also analyzed to treat other systemic infections based on the above mentioned clinical features which is lacking in studies done by different people on neonatal septicemia. In our present study among 100 neonates with sepsis, mortality was correlated with onset of sepsis, type of birth & sepsis sub types into 02 groups in only 06 patients. The mortality was observed mainly in pre term neonates than in normal term neonates. Similarly, in a study done by Dr D.S. Jothi et al ¹⁷ mortality was seen in 3 categories of sepsis of which Significantly higher group of death in LBW babies with pre term delivery with a The overall mortality rate was 10.7%. This is lower with our study. Finally, coming to the list of WHO indicators, of 519 drugs prescribed in our study polypharmacy was 5.19% which can be considered as a normal due to presence of multiple disease conditions in neonates and children. Next, 205 (39.49%) of the drugs were prescribed in generic name. Recently the Government of India and the National Medical Commission have framed rules to prescribe medicines in generic name. This low percentage may be due to doubts on its quality and availability or difficulty in writing combination drugs in generic name. There is need of improvement in awareness regarding benefits of generic medicines in patients, pharmacists and health care providers. In our study the percentage of drugs with generic name was higher when compared with Uma shanker prasad keshri et al ²³ 29.25%. In a study done by Ananya Chakraborty et al²⁴ out of 4800 prescriptions 3408 (71%) of the medications were prescribed in capital letters. In another study conducted by Uma shanker prasad keshri et al ²³, name of all medicines written in capital letters were found in 153 (14.57%) prescriptions and in 171(16.28%) prescriptions written in capital and small letters (mixed) and rest 726 (69.14%) in only small letters. Whereas in our study, only out of 519 drugs prescribed, only 50 drugs were written in capital letters encountering 09.63% which was very low when compared with the above studies.

CONCLUSION:

Neonatal sepsis is one of the leading causes of morbidity and mortality among the newborns in the developing countries. It is a life threatening clinical emergency that demands urgent diagnosis and treatment. Early diagnosis of neonatal sepsis with the aid of biomarkers like CRP may serve as an important tool in reducing the mortality and morbidity among neonates. Appropriate identification of sepsis source, impede antibiotic prescription and hostile management can effectively forestall any adverse outcomes following neonatal sepsis.  The hypothesis quotes as an objective in our study is “To find the role of CRP in the evaluation and management of neonates and children with septicemia” was agreed.  Among the various tests CRP role in neonatal sepsis has been vastly studied when compared with blood cultures with a reason as cultures tests are time consuming, requires well equipped laboratory and trained personnel.  It can be false negative due to the small amount of blood drawn from neonates, prenatal antibiotic use or low level of bacteremia. Blood culture is still the “Gold standard” for the diagnosis of septicemia in neonates and should be done in all cases of suspected septicemia. In view of the changing spectrum of the causative agents of neonatal septicemia and their antibiotic susceptibility patterns from time to time and from one hospital to another, a positive blood culture and the antibiotic susceptibility testing of the isolates are the best guide in choosing the appropriate antimicrobial therapy in treating neonatal septicemia. This article concludes early diagnosis and appropriate management improves the outcome in neonatal sepsis.

Declaration of patient consent:

Written informed consent has been obtained from the patient’s guardian during this study.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.

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