الفهرس 
Introduction
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Abstract
Definition
Sepsis is a common heterogonous entity that is defined by physiological changes known collectively as the systemic inflammatory response syndrome (SIRS) , which occur in response to presumed infectious etiology. (Ephraim and Woods; 2009)
Incidence
Sepsis is ranked as the sixth leading cause of death among neonates and the eighth cause of death among infants in the first year of life. The estimated annual incidence of severe sepsis in newborns is 3 per 1000 live births. The estimated mortality for neonates with severe sepsis is 10.3% with most deaths occurring within the first 48 hours of infection. Although no significant sex difference has been reported, it was noted as early as 1960s that male infant has higher incidence of neonatal sepsis than females, which may be related to X-linked immunoregulatory genes. (Ellen and Patricia; 2010)
In Egypt , septicemia is considered the single most important cause of death accounting for up to 50% of neonatal mortality. (Mona M; 2009)
Pathogenesis
Neonates are highly susceptible to infectious diseases due to immature immune systems and poorly developed skin barrier .Innate immunity, which form the first line of defense against infection is compromised in neonates and result in decreased production of proinflammatory cytokines, tumor necrosis factor particularly interleukin-1,interferon,interleukin-12, antigen presenting cells including monocytes , macrophages , dendritic cells this result in defect in pathogen recognition, activation after stimulation, phagocytic function and bactericidal function. (Wynn and Levy; 2010)
Neonates also exhibit decreased levels of complement proteins and complement mediated opsonic capability compared with adults. They also have decreased level of immunoglobulin except of immunoglobulin G that is transferred across placenta during last trimester. (Wynn and Levy; 2010)
Early and late neonatal sepsis
Neonatal sepsis is categorized as early and late onset neonatal sepsis. Early onset sepsis, often caused by group B streptococcal infection or E-coli occurs in the first 3 days of life and associated with premature rupture of membranes, prematurity and maternal colonization with B streptococcal infection.
Late onset sepsis occurs after the 3rd day of life and among premature infants, it is often caused by gram +ve organisms, it is a common complication of prolonged admission at NICU due to preterm labor. (Downey et al; 2010)
Risk factors
The most important neonatal factor predisposing to infection is prematurity or low birth weight. Preterm infants have a 3- to 10-fold higher incidence of infection than full-term normal birth weight infant. Nosocomial (hospital-acquired) infections are responsible for significant morbidity and late mortality in hospitalized newborns.
The majority of nosocomial infections occur in preterm or term infants who require intensive care. Risk factors for nosocomial infection in these infants include prematurity, LBW, invasive procedures, indwelling vascular catheters, parenteral nutrition with lipid emulsions, endotracheal tubes, ventricular shunts, alterations in the skin and/or mucous membrane barriers, frequent use of broad-spectrum antibiotics, and prolonged hospital stay. Most nosocomial infections are bloodstream infections associated with an intravascular catheter. Other serious infections are pneumonia, meningitis, omphalitis, and necrotizing enterocolitis.
Intrauterine infection is a result of clinical or subclinical maternal infection with a variety of agents by hematogenous transplacental transmission to the fetus. Maternal infection is a necessary prerequisite for transplacental infection Chorioamnionitis results from microbial invasion of amniotic fluid, often as a result of prolonged rupture of the chorioamniotic membrane. Amniotic infection may also occur with apparently intact membranes or with a relatively brief duration of membrane rupture.
After birth, neonates are exposed to infectious agents in the nursery or in the community. Postnatal infections may be transmitted by direct contact with hospital personnel, the mother, or other family members, from breast milk (HIV, CMV) or from inanimate sources such as contaminated equipment. The most common source of postnatal infections in hospitalized newborns is hand contamination of health care personnel. (Nelson; 2008).
Clinical picture:
• Weak or absent cry.
• Skin mottling and tough skin.
• Poor suckling.
• Disturbed conscious level.
• Hypothermia or hyperthermia.
• Tachypnea 60 breaths/minute or more.
• Grunting and sever respiratory distress. (Baqui et al; 2009)
Laboratory diagnosis
1- Cell surface markers:
They are leukocyte surface antigen adhesion proteins on the surface of the neutrophil are known to increase within a few minutes after inflammatory cytokines are activated by bacteria and endotoxins.
These characteristics make it a potential early warning marker for detecting bacterial infections rapidly. A variety of leukocyte surface markers, including CD11b and CD64, have been assessed as markers for neonatal sepsis. The sensitivity and specificity of CD11b for diagnosing early onset neonatal sepsis in two different studies was 96% to 100% and 100%, respectively. CD64 is usually expressed in very low levels by unstimulated neutrophils and is activated by bacterial invasion. CD64 levels have been found to have high sensitivity (95%-97%) and negative predictive value (97%–99%) for early- and late-onset sepsis. (Bhandari et al; 2008)
2- Acute phase reactant:
(A) CRP
The most widely investigated. It is non specific, numerous causes of tissue damage and inflammation may elevate CRP.
CRP is synthesized within six to eight hours of exposure to an infective process or tissue damage, with a half life of 19 hours, and can increase more than 1000-fold during an acute phase response. In a study it was concluded that CRP IL-6 and IgM are helpful in the early diagnosis of Gram-negative neonatal sepsis and CRP continues to be the best single test. ( Khassawneh et al; 2007)
B) Procalcitonin:
It is acute phase reactant produced by monocytes and hepatocytes.It has been recently reported that procalcitonin (PCT), the prohormone of calcitonin, increases markedly in septic conditions and it appears to be a good predictor of infection severity. Furthermore, the finding that PCT is released into the circulation within 3 hrs after endotoxin injection, plateaus at 6 hrs, and remains elevated for 24 hrs makes PCT a promising new indicator for infection. The results of recent studies suggest the usefulness of PCT for early diagnosis of neonatal sepsis. (Perez et al; 2006)
Multiple studies have demonstrated PCT elevation in non-infected patients, including those with heatstroke burns or major trauma, and in those undergoing cardiopulmonary bypass surgeries. Likewise, viral and fungal infections can also lead to elevations in procalcitonin that overlap with the levels seen in systemic bacterial infection. In part because of this variability multiple PCT cut-off values have been proposed to distinguish bacterial from non bacterial infection and even sepsis from non septic conditions.
PCT measurement can detect the onset of infection as well as the Serial response to treatment.(McMaster; 2009)
3- Cytokines:
Cytokines are thought to be endogenous mediators of immune response to bacterial infection. Proinflammatory cytokines as interleukin-1, interleukin-8 and tumor necrosis factor are responsible to initiation and effective defense mechanism against infective pathogens. (Turner et al; 2006)
There is sharp rise in IL6 concentration on exposure to bacterial products, which precedes the increase in CRP. Umbilical cord blood IL6 has consistently been shown to be a sensitive marker for diagnosing early onset neonatal sepsis at the onset of infection compared with other biochemical markers, including CRP, IL1ß and TNFα , but sensitivity is reduced at 24 and 48 hours because IL6 concentrations fall rapidly and become undetectable after 24 hours. The combined measurement of IL6 (early and sensitive) with CRP (late and specific) in the first 48 hours of presumed septic episodes improves the sensitivity compared with either marker alone. (Shalini and Malik; 2010)
4-Molecular biomarkers:
Nucleic acid amplification tests as PCR, used successfully in diagnosis of bacterial, viral and fungal infection in neonates. Studies that have evaluated molecular microbiological methods in the diagnosis of neonatal sepsis show that molecular assays, including PCR and hybridization methods are feasible in neonates and have rapid detection times compared with blood cultures. In neonatal studies, the sensitivity of molecular methods used to diagnose sepsis ranged from 41.1 to 100%, and specificity from 77.2 to 100%. These variations can be attributed to differences in methodology and study design including DNA extraction methods, as well as the characteristics of the population studied (term vs preterm infants).
PCR can be targeted for species detection of bacteria in clinical samples. This technology has also been reported to be a very sensitive and rapid method for detecting potential pathogens in amniotic fluid commonly involved in the pathogenesis of preterm labor and adverse neonatal outcome. (Mohan et al; 2010)
5-Blood culture
Blood cultures are the gold standard in the diagnosis of neonatal sepsis, but suffer from the disadvantages of low sensitivity and reporting delay of 24–72 hrs. The diagnostic capabilities of blood culture systems have improved over the last decade with the advent of automated continuous blood culture monitoring systems. (Puoplo; 2008)
6- White blood cell and differential count
WBCs are less predictive to inflammatory response in neonates with wide individual variation. WBC does have value especially with significant shift to the left. Furthermore, if absolute neutrophil count severely decreased and/or number of immature neutrophil exceeds mature neutrophil with an immature to total neutrophil ratio (I: T) of 0.2 this is suggestive of disseminated infection. (Ellen and Patricia; 2010)
Treatment
After appropriate cultures are taken, early use of broad spectrum systemic antimicrobial therapy based on clinical suspicion is reasonable and impact favorably on morbidity from septic shock. Commonly used antibiotics include a third generation cephalosporin such as ceftriaxone and an aminoglycoside such as amikacin. (Praveen; 2008)
The American College of Critical Care Medicine published guidelines for intervention in neonates, infants, and children who present in septic shock. The goal is the restoration of circulation and perfusion within 60minutes, by 15 minutes from presentation, fluid resuscitation with isotonic or colloid boluses to amaximum volume of 60 ml/ kg should be accomplished. In addition, hypoglycemia and hypocalcemia should be corrected. The appropriate intervention for hypoglycemia is 10% dextrose solution at ml/kg IV push and hypocalcemia may be treated with slow IV administration of calcium gluconate at a dose of 100 mg/kg. The next appropriate step is observation in an ICU setting. If shock persists, central venous and arterial access should be obtained and vasoactive agents should be started, with dopamine as a first-line agent. If after the first hour circulation is not restored with further pressor support concern for adrenal insufficiency should be raised and the need for hydrocortisone therapy should be considered (Daniel et al; 2008).