Neonatology

June 25, 2024
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Neonatology. Lesson 10. Topis:

1.     Generalized infections in neonates. Neonatal sepsis.

Neonatal sepsis.

Background: Neonatal sepsis may be categorized as early or late onset. Eighty-five percent of newborns with early-onset infection present within 24 hours, 5% present at 24-48 hours, and a smaller percentage of patients present between 48 hours and 6 days of life. Onset is most rapid in premature neonates. Early-onset sepsis syndrome is associated with acquisition of microorganisms from the mother. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize in the mother’s genitourinary tract. The infant may acquire the microbe by passage through a colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes.

Late-onset sepsis syndrome occurs at 7-90 days of life and is acquired from the caregiving environment. Organisms that have been implicated in causing late-onset sepsis syndrome include coagulase-negative staphylococci, Staphylococcus aureus, E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, and anaerobes. The infant’s skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization.

Pneumonia is more common in early-onset sepsis, whereas meningitis and/or bacteremia are more common in late-onset sepsis. Premature and ill infants have an increased susceptibility to sepsis and subtle nonspecific initial presentations; therefore, they require much vigilance so that sepsis can be identified and treated effectively.

Pathophysiology: The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common infectious hazards for neonates in the 1950s in the United States. GBS then replaced S aureus as the most common gram-positive agent, causing early-onset sepsis during the next decades. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative S aureus is now observed more frequently. Additional organisms, such as L monocytogenes, Chlamydia pneumonia, Haemophilus influenzae, Enterobacter aerogenes, and species of Bacteroides and Clostridium have also been identified ieonatal sepsis.

Meningoencephalitis and neonatal sepsis syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases and viral diseases, such as gonorrhea, syphilis, herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis, HIV, rubella, toxoplasmosis, Trichomonas vaginalis, and Candida species, have all been implicated ieonatal infection. Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. The colonization patterns iurseries and personnel are reflected in the organisms currently associated with nosocomial infection. Infants with lower birth weight and infants who are less mature in today’s neonatal intensive care units (NICUs) have increased susceptibility to these organisms.

Staphylococcus epidermidis, or coagulase-negative Staphylococcus is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant. It is considered the leading cause of late-onset infections for this population.

The neonate is unable to respond effectively to infectious hazards because of deficits in the physiological response to infectious agents.

 

 

 

 

 

 

 

 

 

 


Fig. 7. Spread of Infection Via the Blood to the Entire Body in an Infant.

 

The fetus has some preimmune immunoglobulin present; however, preimmune immunoglobulin is relatively limited in fetuses compared to adults. The infant receives immunoglobulin G (IgG) prenatally after 16 weeks of gestation; however, the infant born prematurely has less IgG due to the shorter period of placental transmission of immunoglobulin.

Additionally, if the mother is immunosuppressed, it is possible that less IgG can be transmitted to the infant. The neonate is capable of synthesizing immunoglobulin M (IgM) in utero at 10 weeks of gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, thereby stimulating increased IgM production. IgG and immunoglobulin E (IgE) may be synthesized in utero; however, only traces are found in cord blood at delivery. The neonate may receive immunoglobulin A (IgA) from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life.

The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. Skin and mucus membranes are broken down easily in the premature infant. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats.

Scheme of sepsis pathogenesis

                                 pathogen,             toxins,            ferments

                          distortion of hemostasis, changes of immunogenesis

 


macrophages  endothelial  thrombocytes  complement    T, Вlymphocytes  coagulation

                           cells                                          system                                   system

mediators of inflammation: ТNА, interleukinsIL 1,6,8,  NO, prostaglandins,                                           thromboxan А2, prostacyclin

increase of penetrate ability, vasodilatation, blood depot, hypovolemia, metabolic disorders

polyorganic insufficiency

septic shock                          

Mortality/Morbidity: The mortality rate ieonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. Neonatal meningitis, a serious morbidity of neonatal sepsis, occurs in 2-4 cases per 10,000 live births and significantly contributes to the mortality rate ieonatal sepsis; it is responsible for 4% of all neonatal deaths.

Age: Studies have shown that premature infants have an increased incidence of sepsis. The incidence of sepsis is significantly higher in infants with very low birth weight (<1000 g), at 26 per 1000 live births, than in infants with a birth weight of 1000-2000 g, at 8-9 per 1000 live births. The risk for death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates.

Classification of sepsis

1. Time of beginning:

·        antenatal

·        postnatal

o       early

o       late

·        nosocomeal

2. Etiology: streptococcal, staphylococcal, Klebsiellas, Escherichia’s, Candida’s, mixed etiology.

3. Clinical forms: septicemia, septicopyemia.

4. Entrance region: umbilical, pulmonary, bowel, otogenic, cryptogenic.

5. Duration:

o       fulminant few hours1-3 days

o       acute 4-8 weeks

o       prolonged more than 8 weeks

6. Periods: initial, significant clinical signs, recovery, period of rehabilitation.

7. Complications: DICsyndrome, thrombosis, hypotrophy, endomyocarditis, renal failure etc. 

Diagnosis example: postnatal umbilical, staphylococcal sepsis, septicopyemia: (omphalitis, bilateral pneumonia with cardiovascular syndrome, respiratory failure ІІ grade, right shoulder proximal epiphysial osteomyelitis), acute duration, DIC-syndrome.

The risk factors that are associated most highly with neonatal sepsis include:

1.                maternal GBS colonization (especially if untreated during labor),

2.                premature rupture of membranes (PROM),

3.                preterm rupture of membranes,

4.                prolonged rupture of membranes,

5.                prematurity,

6.                and chorioamnionitis.

Predisposing risk factors also are associated with neonatal sepsis. They include:

1.                maternal urinary tract infection, maternal fever greater than 101°F (38.4°C),

2.                poor maternal nutrition, low socioeconomic status,

3.                poor prenatal care,

4.                maternal substance abuse,

5.                recurrent abortion,

6.                difficult delivery,

7.                low Apgar score (<6 at 1 or 5 min), birth asphyxia,

8.                meconium staining,

9.                low birth weight, and congenital anomalies.

An awareness of the myriad of risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing mortality and morbidity.

 

Physical: The clinical signs of neonatal sepsis are nonspecific and are associated with characteristics of the causative organism and the body’s response to the invasion.

·                   Congenital pneumonia and intrauterine infection: Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. This may not be caused by the action of the microorganisms themselves but may be caused by aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Tachypnea, irregular respirations, moderate retracting, apnea, cyanosis, and grunting may be observed. Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.

·                   Congenital pneumonia and intrapartum infection: Neonates who are infected during the birth process may acquire pneumonia through aspiration of the microorganisms during the delivery process. The colonization may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. This damage is partly due to the granulocytes’ release of prostaglandins and leukotrienes. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure with an RDS-like presentation. Vascular congestion, hemorrhage, and necrosis may occur.

o       Klebsiella species and S aureus are especially capable of considerably damaging the lungs, producing microabscesses and empyema.

o       Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue. Coughing, grunting, costal and sternal retractions, nasal flaring, tachypnea and/or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed.

o       On radiography, segmental or lobar atelectasis or a diffuse reticulogranular pattern may exist, much like what is observed in RDS.

o       Pleural effusions may be observed in advanced disease.

·                   Congenital pneumonia and postnatal infection: Postnatally acquired pneumonia may occur at any age. Because these infectious agents exist in the environment, the likely cause depends heavily on the infant’s recent environment. If the infant has remained hospitalized in an NICU environment, especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus or Pseudomonas species. Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the antibiotic-resistance patterns of the hospital.

·                   Cardiac signs: In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia is postulated to occur. These cardiopulmonary disturbances may be due to the activity of granulocyte biochemical mediators, such as hydroxyl radicals and thromboxane B2, an arachidonic acid metabolite. These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when released in pulmonary tissue. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension. The early phase of pulmonary hypertension is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. These late signs of shock are indicative of severe compromise and are highly associated with mortality.

·                   Metabolic signs: Hypoglycemia, metabolic acidosis, and jaundice all are metabolic signs that commonly accompany neonatal sepsis syndrome. The infant has an increased glucose requirement because of sepsis. The infant may also have impaired nutrition from a diminished energy intake. Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. When infants are hypothermic or they are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction.

·                   Neurologic signs: Meningitis is the common manifestation of infection of the central nervous system. It is primarily associated with GBS (36%), E coli (31%), and Listeria species (5-10%) infections, although other organisms such as S pneumoniae, S aureus, Staphylococcus epidermis, Haemophilus influenzae, and species of Pseudomonas, Klebsiella, Serratia, Enterobacter, and Proteus may cause meningitis. Acute and chronic histologic features are associated with specific organisms.

o       Ventriculitis is the initiating event with inflammation of the ventricular surface. Exudative material usually appears at the choroid plexus and is external to the plexus. Then, ependymitis occurs with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Glial bridges may develop by these tufts and cause obstruction, particularly at the aqueduct of Sylvius. The lateral ventricles may become multiloculated, which is similar to forming abscesses. Multiloculated ventricles can isolate organisms in an area, making treatment more difficult. Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts into the arachnoid to affect the cerebral and cerebellar surfaces. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. Ventricular origination of meningitis causes significant treatment problems because the areas are inaccessible. Ventricular obstruction causes an additional problem.

o       Arachnoiditis is the next phase and is the hallmark of meningitis. The arachnoid is infiltrated with inflammatory cells producing an exudate that is thick over the base of the brain and more uniform over the rest of the brain. Early in the infection, the exudate is primarily PMNs, bacteria, and macrophages. Exudate is prominent around the blood vessels and extends into the brain parenchyma. In the second and third weeks of infection, the proportion of PMNs decreases; the dominant cells are histiocytes, macrophages, and some lymphocytes and plasma cells. Exudate infiltration of cranial roots 3-8 occurs. After this period, the exudate decreases. Thick strands of collagen form, and arachnoid fibrosis occurs, which is responsible for obstruction. Hydrocephalus results. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis.

o       Vasculitis extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Occlusion of the arteries rarely occurs; however, venous involvement is more severe. Phlebitis may be accompanied with thrombosis and complete occlusion. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks.

o       Cerebral edema may occur during the acute state of meningitis. The edema may be severe enough to greatly diminish the ventricular lumen. The cause is unknown, but it is likely related to vasculitis and the increased permeability of blood vessels. It may also be related to the cytotoxins of microorganisms. Herniation of edematous supratentorial structures does not occur ieonates because of the cranium’s distensibility.

o       Infarction is a prominent and serious feature of neonatal meningitis. It occurs in 30% of infants who die. Lesions occur because of multiple venous occlusions, which are frequently hemorrhagic. The loci of infarcts are most often in the cerebral cortex and underlying white matter but may also be subependymal within the deep white matter. Neuronal loss occurs, especially in the cerebral cortex, and periventricular leukomalacia may subsequently appear in areas of neuronal cell death.

o       Meningitis due to early-onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneural signs. Neurologic signs may include stupor and irritability. Overt signs of meningitis occur in only 30% of cases. Even culture-proven meningitis may not demonstrate white cell changes in the CSF. Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%). Impairment of consciousness (ie, stupor with or without irritability), coma, seizures, bulging anterior fontanel, extensor rigidity, focal cerebral signs, cranial nerve signs, and nuchal rigidity occur.

o       The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs), an elevated protein level, a decreased CSF glucose concentration, and positive cultures. The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia. Glucose concentration abnormalities are more severe in late-onset disease and with gram-negative organisms. The CSF WBC count is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range CSF protein and glucose concentrations are found in only 15-20%.

o       Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant is also floppy, lethargic, and disinterested in feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs.

·                     Hematologic signs

o                     The platelet count in the healthy newborn is rarely less than 100,000 per mm3 in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur ieonatal sepsis in response to the cellular products of the microorganisms. These cellular products cause platelet clumping and adherence leading to platelet destruction. Thrombocytopenia is generally observed after sepsis has been diagnosed and usually lasts 1 week, though it can last as long as 3 weeks. Only 10-60% of infants with sepsis have thrombocytopenia. Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width (PDW) are shown to be significantly higher ieonatal sepsis after 3 days. Because of the myriad of causes of thrombocytopenia and its late appearance ieonatal sepsis, the presence of thrombocytopenia does not aid the diagnosis of neonatal sepsis.

o                     WBC counts and ratios are more sensitive for determining sepsis than platelet counts, although normal WBC counts may be observed in as many as 50% of cases of culture-proven sepsis. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery. A differential may be of more use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts, taken at the time of symptom onset, are only observed in two thirds of infants; therefore, the neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.

o                     Neutrophil ratios have been more useful in diagnosing or excluding neonatal sepsis; the immature-to-total (I/T) ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis during the first 24 hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs.

·                     Gastrointestinal signs: The gut can be colonized by organisms in utero or at delivery by swallowing infected amniotic fluid. The immunologic defenses of the gut are not mature, especially in the preterm infant. Lymphocytes proliferate in the gut in response to mitogen stimulation; however, this proliferation is not fully effective in responding to a microorganism because antibody formation and cytokine formation is immature until approximately 46 weeks. Necrotizing enterocolitis (NEC) has been associated with the presence of a number of species of bacteria in the immature gut, and bacterial overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of NEC.

Lab Studies:

Blood, CSF, and urine cultures

·                   Aerobic cultures are appropriate for most of the bacterial etiologies associated with neonatal sepsis; however, anaerobic cultures are indicated ieonates with abscess formation, processes with bowel involvement, massive hemolysis, and refractory pneumonia.

·                   A Gram stain provides early identification of the gram-negative or gram-positive status of the organism for preliminary identification.

·                   Bacterial cultures should generally reveal the organism of infection within 36-48 hours; the subsequent initial identification of the organism occurs within 12-24 hours of the growth.

·                   Urine cultures are most appropriate when investigating late-onset sepsis.

·                   Blood and CSF cultures are appropriate for early and late-onset sepsis.

·                   Because of the low incidence of meningitis in the newborn infant with negative cultures, clinicians may elect to culture the CSF of only those infants with documented or presumed sepsis.

A CBC and differential may be ordered serially to determine changes associated with the infection, such as thrombocytopenia or neutropenia, or to monitor the development of a left shift or an elevated I/T ratio. Such serial monitoring of the CBC may be useful in aiding the differentiation of sepsis syndrome from nonspecific abnormalities due to the stress of delivery.

·                   The platelet count in the healthy newborn is rarely less than 100,000 per mm3 in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur ieonatal sepsis, although this sign is usually observed late in the infection. MPV and PDW have been shown to be significantly elevated in infants with sepsis after 2-3 days of life. These measures may assist in determining the etiology of thrombocytopenia.

·       WBC counts and ratios are more sensitive in determining sepsis, although normal WBC counts may be observed in culture-proven sepsis in as many as 50% of cases. Infants who are not infected may also have abnormal WBC counts related to the stress of delivery. A differential may be of more use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts at the time of symptom onset are only observed in two thirds of infants; therefore, neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is also observed with maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.

·       Neutrophil ratios have been more useful in diagnosing neonatal sepsis; the I/T ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis in the first 24 hours is 0.16. In most newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs.

The CSF findings in infectious neonatal meningitis are an elevated WBC (predominately PMNs), an elevated protein level, a depressed glucose level, and positive cultures. The decrease in glucose is not reflective of serum hypoglycemia. The CSF abnormalities are more severe in late onset and with gram-negative organisms. The WBC is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range protein and glucose concentration are found in only 15-20%.

C-reactive protein, an acute phase protein associated with tissue injury, is eventually elevated in 50-90% of infants with systemic bacterial infections. This is especially true of infections with abscesses or cellulitis of deep tissue. C-reactive protein usually rises within 24 hours of infection, peaks within 2-3 days, and remains elevated until the inflammation is resolved. The C-reactive protein level is not recommended as a sole indicator of neonatal sepsis, but it may be used as part of a sepsis workup or as a serial study during infection to determine response to antibiotics, duration of therapy, and/or relapse of infection.

IgM concentration in serum may be helpful in determining the presence of an intrauterine infection, especially if present over a period of time.

Imaging Studies:

·       Chest radiographs may depict segmental or lobar atelectasis, but they more commonly reveal a diffuse, fine, reticulogranular pattern, much like what is observed in RDS. Hemothorax and pleural effusions may also be observed.

·      

A CT

scan may be needed late in the course of complex neonatal meningitis to document any occurrence of blocks to CSF flow, the site where the blocks are occurring, and occurrence of major infarctions or abscesses. Signs of chronic stage disease, such as ventricular dilation, multicystic encephalomalacia, and atrophy, are also demonstrated on CT scan.

·       Head ultrasonograms in neonates with meningitis show evidence of ventriculitis, abnormal parenchymal echogenicities, extracellular fluid, and chronic changes. Serially, head ultrasonograms can demonstrate the progression of complications.

Procedures: Lumbar puncture is warranted for early- and late-onset sepsis, although clinicians may be unsuccessful in obtaining sufficient or clear fluid for all the studies. Infants may be positioned on their side or sitting with support, but adequate restraint is needed to avoid a traumatic tap. Because the cord is lower in the spinal column in infants, the insertion site should be between L3 and L4. If positive cultures are demonstrated, a follow-up lumbar puncture is often performed within 24-36 hours after antibiotic therapy to document CSF sterility. If organisms are still present, modification of drug type or dosage may be required to adequately treat the meningitis. An additional lumbar puncture within 24-36 hours is necessary if organisms are still present.

Complications

1. Septic shock is sepsis with uncorrected hypotension, hypoperfusion of tissues, acidosis, oliguria, conscious changes.

o       Early septic shock is sepsis with hypotension, hypoperfusion of capillaries; which may be corrected in the short period of time by fluids or/and medicine.

o       Refractive septic shock is sepsis with hypotension, hypoperfusion of capillaries; which is not corrected by fluids or/and medicine more than 1 hour; need dopamine, adrenalin or noradrenalin correction.

Septic shock’s stages: І decreasing of blood circulation; ІІ early decompensation; ІІІ late decompensation; IV irreversible (agonizing).

2. DICsyndrome, stages: І hypercoagulation; ІІ hypocoagulation; ІІІ consume coagulopathy; IV restoring.

DIFFERENTIALS These nonspecific clinical signs of early sepsis syndrome are also associated with other neonatal diseases, such as Respiratory Distress Syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery. Therefore, diagnose neonatal sepsis by excluding other disease processes, performing an examination, and testing for more specific indications of neonatal sepsis.

Criteria

 

Meningitis

 

Localized forms of infection

 

Congenital infections

 

Birth trauma

1. Anamnesis:

 

 

 

 

 

 

 

 

Acute and chronic maternal diseases during the pregnancy

 

 

+

 

 

––

 

 

+

 

––

 

Mastitis during breastfeeding period

 

 

+

 

––

 

––

––

 

Umbilical late epithelization

+

 

+

 

––

––

 

Purulent changes of the skin

 

+

 

 

+

 

 

––

––

 

Rapid delivery

 

––

––

––

+

Complicated delivery of shoulders

 

 

––

 

––

 

––

+

 

 Using of forceps, vacuum extraction

––

––

––

+

2.Prolonged intoxication:

 

 

+

 

––

 

+

––

 

-increased body temperature

 

+

 

 

––

 

 

––

––

 

 

loss of appetite

 

+

 

+

 

+

+

 

vomiting,

 

+

 

 

+

+

 

skin color:

 

 

 

 

 

 

 

pale-pink

 

––

 

+

 

––

––

pallor

 

+

––

 

––

+

 

pale-grey

 

+

––

 

+

––

 

yellow

+

––

+

+

weight gain:

slow

 

 

 

 

 

––

 

+

 

––

 

+

 

absent

 

+

––

 

+

––

 

jaundice:

 

+

 

––

 

+

+

 

conjugated

 

––

––

––

+

parenchimatous

+

––

+

––

З.Presence of hematogenous methastatic sites of infection

 

 

+

 

 

––

 

 

+

 

––

 

hepatosplenomegaly

 

+

 

––

 

+

––

 

4.Positive cultures

 

 

 

 

 

 

 

 

blood

 

 

 

 

+

 

––

 

+

––

 

from sites of infection

+

 

+

 

+

––

 

5. CSF:

 

 

 

 

transparent

 

––

 

+

 

––

––

 

muddy

hemorrhagic

pleocytosis

proteinorrhachia

6. Disappearance of the clinical signs during treatment:

slow

rapid

absent

+

––

++

+

 

 

+

––

––

––

––

––

––

––

 

 

––

+

––

––

 

+

––

+

+

 

 

+

––

+

+

––

+

––

––

 

 

+

––

––

––

TREATMENT Medical Care: Initiate treatment immediately because of the neonate’s immunologic weaknesses for fighting infection. Begin antibiotics as soon as diagnostic tests are performed. Additional therapies have been investigated for the treatment of neonatal sepsis; however, no unequivocal proof that these treatments are beneficial exists. These additional therapies include granulocyte transfusion, intravenous immune globulin (IVIG) replacement, exchange transfusion, and the use of recombinant cytokines.

Antibiotic therapy In the United States and Canada, the most current approach to treat early-onset neonatal sepsis syndrome includes combined IV aminoglycoside and penicillin antibiotic therapy. This provides coverage for gram-positive organisms, especially GBS, and gram-negative bacteria, such as E coli. The specific antibiotics to be used are chosen on the basis of maternal history and prevalent trends of organism colonization in individual nurseries.

·                     If infection appears to be nosocomial, direct coverage at organisms implicated in hospital-acquired infections, including S aureus, S epidermis, and Pseudomonas species. Most strains of S aureus produce beta-lactamase, which makes them resistant to penicillin G, ampicillin, carbenicillin, and ticarcillin. Vancomycin has been favored for this coverage; however, concern exists that overuse of this drug may lead to vancomycin-resistant organisms, thereby eliminating the best response to these resistant organisms. Cephalosporins are attractive in the treatment of nosocomial infection because of their lack of dose-related toxicity and adequate serum and CSF concentration; however, resistance by gram-negative organisms has occurred with their use. Do not use ceftriaxone in infants with hyperbilirubinemia because it displaces bilirubin from serum albumen. Resistance and sensitivities for the organism are used to indicate the most effective drug.

·                     Aminoglycosides and vancomycin are both ototoxic and nephrotoxic; have caution when using them. Check the serum level after 48 hours of treatment to determine if levels are above those required for a therapeutic effect. The dosage amount or interval may need to be changed to ensure adequate but nontoxic coverage. A serum level may be warranted when the infant’s clinical condition has not improved to ensure that a therapeutic level has been reached. In addition, perform renal function and hearing screening to determine any short- or long-range toxic effects of these drugs.

·                     If cultures are negative but the infant has significant risk for sepsis and/or clinical signs, the clinician must decide whether to provide continued treatment. Three days of negative cultures should provide confidence in the data; however, a small number of infants with proven sepsis at postmortem had negative cultures during their initial sepsis workup. Management is further complicated if the mother received antibiotic therapy before delivery, especially close to delivery. This may result iegative cultures in the infant who is still ill. Review all diagnostic data, including cultures, maternal and intrapartal risk factors, CSF results, the CBC and differential radiographs, and the clinical picture to determine the need for continued therapy. Treatment for 7-10 days may be appropriate, even if the infant has negative cultures at 48 hours.

·                     The clinician may require different antibiotic choice, dosage, and/or treatment time if the infant has bacterial meningitis. Perform a follow-up lumbar puncture within 24-36 hours after antibiotic therapy has been initiated to determine if the CSF is sterile. If organisms are still present, modification of drug type or dosage is required to adequately treat the meningitis. Continue antibiotic treatment for 2 weeks after sterilization of the CSF or for a minimum of 2 weeks for gram-positive meningitis and 3 weeks for gram-negative meningitis, whichever period is longest. Chloramphenicol or trimethoprim-sulfamethoxazole has been shown to be effective in the treatment of highly resistant bacterial meningitis.

Granulocyte transfusion has been shown to be suitable for infants with significant depletion of the storage neutrophil pool; however, the documentation of storage pool depletion requires a bone marrow aspiration, and the granulocyte transfusion must be administered quickly to be beneficial. The number of potential adverse effects, such as graft versus host reaction, transmission of CMV or hepatitis B, and pulmonary leukocyte sequestration, is considerable. Therefore, this therapy remains an experimental treatment.

Intravenous immune globuline has been considered for neonatal sepsis to provide type-specific antibodies to improve opsonization and phagocytosis of bacterial organisms and to improve complement activation and chemotaxis of neonatal neutrophils; however, difficulties with IVIG therapy for neonatal sepsis exist. The effect has been transient, and adverse effects associated with the infusion of any blood product can occur. Dose-related problems with this therapy decrease its usefulness ieonatal populations.

Recombinant human cytokine administration to stimulate granulocyte progenitor cells has been studied as an adjunct to antibiotic therapy. These therapies have shown promise in animal models, especially for GBS sepsis, but require pretreatment or immediate treatment to demonstrate efficacy. The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) has been studied in clinical trials, but their use in clinical neonatology remains experimental.

The infant with sepsis may require treatment aimed at the overwhelming systemic effects of the disease. Cardiopulmonary support and intravenous nutrition may be required during the acute phase of the illness until the infant’s condition stabilizes. Monitoring of blood pressure, vital signs, hematocrit, and platelets is vital.

Surgical Care: If hydrocephalus associated with neonatal meningitis occurs, and progressive accumulation of CSF is present, placing a ventriculoperitoneal (VP) shunt may be necessary to drain off the excess fluid. The immediate complications of shunt placement are overdrainage, equipment failure, disconnection, migration of catheter, or shunt infection. Abdominal obstruction, omental cysts, and perforation of the bladder, gall bladder, or bowel occur infrequently. The VP shunt may cause long-term neurologic complications, including slit-ventricle syndrome, seizures, neuro-ophthalmological problems, and craniosynostosis; however, the outcome for children with VP shunt placement is generally good with careful follow-up.

Diet: The neonate may need to be given nothing by mouth (NPO) during the first days of treatment because of gastrointestinal symptoms or poor feeding. Consider parenteral nutrition to ensure that the patient’s intake of calories, protein, minerals, and electrolytes is adequate during this period. Feeding may be restarted via a nasogastric tube for the infant with serious compromise. Encourage that breast milk be given because of the immunologic protection it provides.

Activity: The infant with temperature instability needs thermoregulatory support with a radiant warmer or incubator. Also, encouraging parental contact is important to ease the stress for parents and continue the bonding between the parents and child.

Drug Name

Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)

Pediatric Dose

<7 days and <2000 g: 50 mg/kg/dose IV/IM q12h
<7 days and >2000 g: 50 mg/kg/dose IV/IM q8h
7-30 days and <1200 g: 50 mg/kg/dose IV/IM q12h
7-30 days and 1200-2000 g: 50 mg/kg/dose IV/IM q8h
7-30 days and >2000 g: 50 mg/kg/dose IV/IM q6h
>30 days: 100-200 mg/kg/d IV/IM divided q6h; dosage may be doubled with proven meningitis

 

Drug Name

Gentamicin (Garamycin)

Pediatric Dose

0-4 weeks and <1200 g: 2.5 mg/kg/dose IV/IM q18h
<7 days and 1200-2000 g: 2.5 mg/kg/dose IV/IM q12h
<7 days and >2000 g: 2.5 mg/kg/dose IV/IM q12h
>7 days and 1200-2000 g: 2.5 mg/kg/dose IV/IM q8h
>7 days and >2000 g: 2.5 mg/kg/dose IV/IM q8h
IV dosage preferred; IM may be used if IV access difficult

 

Drug Name

Cefotaxime (Claforan)

Pediatric Dose

<7 days: 50 mg/kg/dose IV/IM q12h
>7 days: 50 mg/kg/dose IV/IM q8h

 

Drug Name

Vancomycin (Lyphocin, Vancocin, Vancoled) —

Pediatric Dose

<1 month:
<1200 g: 15 mg/kg/dose IV qd
1200-2000 g: 10 mg/kg/dose IV q12h
>2000 g: 10 mg/kg/dose IV q8h

Drug Name

Metronidazole (Flagyl) — Antimicrobial that has shown effectiveness against anaerobic infections, especially Bacteroides fragilis meningitis.

Pediatric Dose

<4 weeks and <1200 g: 7.5 mg/kg/dose PO/IV q2d
<7 days and 1200-2000 g: 7.5 mg PO/IV qd
<7 days and >2000 g: 7.5 mg/kg PO/IV q12h
>7 days and 1200-2000 g: 7.5 mg/kg PO/IV q12h
>7 days and >2000 g: 15 mg/kg/dose q12h

 

Drug Name

Erythromycin (E-Mycin, Erythrocin) –.

Pediatric Dose

<7 days and <2000 g: 5 mg/kg/dose PO/IV/IM q12h
<7 days and >2000 g: 5 mg/kg/dose PO/IV/IM q8h
>7 days and <1200 g: 5 mg/kg PO/IV/IM q12h
>7 days and >1200 g: 10 mg/kg PO/IV/IM q8h

Drug Name

Piperacillin (Pipracil)

Pediatric Dose

<7 days and 1200-2000 g: 75 mg/kg IV/IM q12h
<7 days and >2000 g: 75 mg/kg IV/IM q8h
>7 days and 1200-2000 g: 75 mg/kg IV/IM q8h
>7 days and >2000 g: 75 mg/kg/dose IV/IM q6h

Drug Category: Antifungals — Fungal infections can masquerade as bacterial infections and/or may appear at the end of prolonged antibacterial therapy.

Drug Name

Fluconazole (Diflucan) — Used to treat susceptible fungal infections, including oropharyngeal, esophageal, and vaginal candidiasis. Also used for systemic candidal infections and cryptococcal meningitis.

Pediatric Dose

0-14 days: Oropharyngeal candidiasis: 6 mg/kg PO/IV initial dose; after 3 d, 3 mg/kg q3d for a total of 14 d
Esophageal candidiasis: 6 mg/kg PO/IV initial dose, followed by 6-12 mg/kg q3d for 21 d
Systemic candidiasis: 6-12 mg/kg/dose PO/IV q3d for 28 d
For acute cryptococcal meningitis, initial dose is increased to 12 mg/kg, and 6-12 mg/kg/dose is administered for 10-12 wk after the CSF cultures become negative

 

Drug Name

Amphotericin B (Amphocin, Fungizone)

Pediatric Dose

Test dose: 0.1 mg/kg/dose IV; not to exceed 1 mg/dose infused over 20-60 min or 0.25 mg/kg infused over 6 h; if tolerated, administer 0.25 mg/kg/d; gradually increase dose by 0.25-mg/kg/d increments until desired daily dose reached
Maintenance dose: 0.25-1 mg/kg/d IV qd infused over 4-6 h; administer total dosage of 30-35 mg/kg over 6 wk

Deterrence/Prevention: The Committee on Infectious Diseases of the AAP recommends that obstetric care include a strategy to manage early-onset GBS disease. Treat women with GBS bacteriuria during pregnancy when it is diagnosed and at delivery. The committee also recommends that women who have previously given birth to an infant with GBS disease be intrapartally treated. Practitioners should use either a strategy based on screening the mother or a strategy based on the presence of intrapartum risk factors to minimize the risk of early-onset GBS disease.

Prognosis: With early diagnosis and treatment, infants are not likely to experience long-term health problems associated with neonatal sepsis; however, if early signs and/or risk factors are missed, the mortality rate increases. Residual neurologic damage occurs in 15-30% of neonates with septic meningitis. Infants with meningitis may acquire hydrocephalus and/or periventricular leucomalacia. They may also have complications associated with the use of aminoglycosides, such as hearing loss and/or nephrotoxicity.

 

 

Management of Neonates With Suspected or Proven Early-Onset Bacterial Sepsis

1.       Richard A. Polin, MD and

2.       the COMMITTEE ON FETUS AND NEWBORN

 

Abstract

With improved obstetrical management and evidence-based use of intrapartum antimicrobial therapy, early-onset neonatal sepsis is becoming less frequent. However, early-onset sepsis remains one of the most common causes of neonatal morbidity and mortality in the preterm population. The identification of neonates at risk for early-onset sepsis is frequently based on a constellation of perinatal risk factors that are neither sensitive nor specific. Furthermore, diagnostic tests for neonatal sepsis have a poor positive predictive accuracy. As a result, clinicians often treat well-appearing infants for extended periods of time, even when bacterial cultures are negative. The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once a pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). Recent data suggest an association between prolonged empirical treatment of preterm infants (≥5 days) with broad-spectrum antibiotics and higher risks of late onset sepsis, necrotizing enterocolitis, and mortality. To reduce these risks, antimicrobial therapy should be discontinued at 48 hours in clinical situations in which the probability of sepsis is low. The purpose of this clinical report is to provide a practical and, when possible, evidence-based approach to the management of infants with suspected or proven early-onset sepsis.

Key Words:

·  Abbreviations: CFUcolony-forming units CRPC-reactive protein CSFcerebrospinal fluid GBSgroup B streptococci I/Timmature to total neutrophil (ratio) PMNpolymorphonuclear leukocyte PPROMpreterm premature rupture of membranes

Introduction

“Suspected sepsis” is one of the most common diagnoses made in the NICU.1 However, the signs of sepsis are nonspecific, and inflammatory syndromes of noninfectious origin mimic those of neonatal sepsis. Most infants with suspected sepsis recover with supportive care (with or without initiation of antimicrobial therapy). The challenges for clinicians are threefold: (1) identifying neonates with a high likelihood of sepsis promptly and initiating antimicrobial therapy; (2) distinguishing “high-risk” healthy-appearing infants or infants with clinical signs who do not require treatment; and (3) discontinuing antimicrobial therapy once sepsis is deemed unlikely. The purpose of this clinical report is to provide a practical and, when possible, evidence-based approach to the diagnosis and management of early-onset sepsis, defined by the National Institute of Child Health and Human Development and Vermont Oxford Networks as sepsis with onset at ≤3 days of age.

Pathogenesis and Epidemiology of Early-Onset Sepsis

Before birth, the fetus optimally is maintained in a sterile environment. Organisms causing early-onset sepsis ascend from the birth canal either when the amniotic membranes rupture or leak before or during the course of labor, resulting in intra-amniotic infection.2 Commonly referred to as “chorioamnionitis,” intra-amniotic infection indicates infection of the amniotic fluid, membranes, placenta, and/or decidua. Group B streptococci (GBS) can also enter the amniotic fluid through occult tears. Chorioamnionitis is a major risk factor for neonatal sepsis. Sepsis can begin in utero when the fetus inhales or swallows infected amniotic fluid. The neonate can also develop sepsis in the hours or days after birth when colonized skin or mucosal surfaces are compromised. The essential criterion for the clinical diagnosis of chorioamnionitis is maternal fever. Other criteria are relatively insensitive. When defining intra-amniotic infection (chorioamnionitis) for clinical research studies, the diagnosis is typically based on the presence of maternal fever of greater than 38°C (100.4°F) and at least two of the following criteria: maternal leukocytosis (greater than 15 000 cells/mm3), maternal tachycardia (greater than 100 beats/minute), fetal tachycardia (greater than 160 beats/minute), uterine tenderness, and/or foul odor of the amniotic fluid. These thresholds are associated with higher rates of neonatal and maternal morbidity. Nonetheless, the diagnosis of chorioamnionitis must be considered even when maternal fever is the sole abnormal finding. Although fever is common in women who receive epidural anesthesia (15%–20%), histologic evidence of acute chorioamnionitis is very common in women who become febrile after an epidural (70.6%).3 Furthermore, most of these women with histologic chorioamnionitis do not have a positive placental culture.3 The incidence of clinical chorioamnionitis varies inversely with gestational age. In the National Institute of Child Health and Human Development Neonatal Research Network, 14% to 28% of women delivering preterm infants at 22 through 28 weeks’ gestation exhibited signs compatible with chorioamnionitis.4 The major risk factors for chorioamnionitis include low parity, spontaneous labor, longer length of labor and membrane rupture, multiple digital vaginal examinations (especially with ruptured membranes), meconium-stained amniotic fluid, internal fetal or uterine monitoring, and presence of genital tract microorganisms (eg, Mycoplasma hominis).5

At term gestation, less than 1% of women with intact membranes will have organisms cultured from amniotic fluid.6 The rate can be higher if the integrity of the amniotic cavity is compromised by procedures before birth (eg, placement of a cerclage or amniocentesis).6 In women with preterm labor and intact membranes, the rate of microbial invasion of the amniotic cavity is 32%, and if there is preterm premature rupture of membranes (PPROM), the rate may be as high as 75%.7 Many of the pathogens recovered from amniotic fluid in women with preterm labor or PPROM (eg, Ureaplasma species or Mycoplasma species) do not cause early-onset sepsis.810 However, both Ureaplasma and Mycoplasma organisms can be recovered from the bloodstream of infants whose birth weight is less than 1500 g.11 When a pathogen (eg, GBS) is recovered from amniotic fluid, the attack rate of neonatal sepsis can be as high as 20%.12 Infants born to women with PPROM who are colonized with GBS have an estimated attack rate of 33% to 50% when intrapartum prophylaxis is not given.13

The major risk factors for early-onset neonatal sepsis are preterm birth, maternal colonization with GBS, rupture of membranes >18 hours, and maternal signs or symptoms of intra-amniotic infection.1416 Other variables include ethnicity (ie, black women are at higher risk of being colonized with GBS), low socioeconomic status, male sex, and low Apgar scores. Preterm birth/low birth weight is the risk factor most closely associated with early-onset sepsis.17 Infant birth weight is inversely related to risk of early-onset sepsis. The increased risk of early-onset sepsis in preterm infants is also related to complications of labor and delivery and immaturity of innate and adaptive immunity.18

Diagnostic Testing for Sepsis

The clinical diagnosis of sepsis in the neonate is difficult, because many of the signs of sepsis are nonspecific and are observed with other noninfectious conditions. Although a normal physical examination is evidence that sepsis is not present,19,20 bacteremia can occur in the absence of clinical signs.21 Available diagnostic testing is not helpful in deciding which neonate requires empirical antimicrobial therapy but can assist with the decision to discontinue treatment.22

Blood Culture

A single blood culture in a sufficient volume is required for all neonates with suspected sepsis. Data suggest that 1.0 mL of blood should be the minimum volume drawn for culture when a single pediatric blood culture bottle is used. Dividing the specimen in half and inoculating aerobic and anaerobic bottles is likely to decrease the sensitivity. Although 0.5 mL of blood has previously been considered acceptable, in vitro data from Schelonka et al demonstrated that 0.5 mL would not reliably detect low-level bacteremia (4 colony-forming units [CFU]/mL or less).23 Furthermore, up to 25% of infants with sepsis have low colony count bacteremia (≤4 CFU/mL), and two-thirds of infants younger than 2 months of age have colony counts <10 CFU/mL.24,25 Neal et al demonstrated that more than half of blood specimens inoculated into the aerobic bottle were less than 0.5 mL.26 A study by Connell et al indicated that blood cultures with an adequate volume were twice as likely to yield a positive result.27 A blood culture obtained through an umbilical artery catheter shortly after placement for other clinical indications is an acceptable alternative to a culture drawn from a peripheral vein.28 The risk of recovering a contaminant is greater with a blood culture drawn from an umbilical vein.29 There are, however, data to suggest that a blood culture drawn from the umbilical vein at the time of delivery using a doubly clamped and adequately prepared segment of the cord is a reliable alternative to a culture obtained peripherally.30

Urine Culture

A urine culture should not be part of the sepsis workup in an infant with suspected early-onset sepsis.31 Unlike urinary tract infections in older infants (which are usually ascending infections), urinary tract infections in newborn infants are attributable to seeding of the kidney during an episode of bacteremia.

Gastric Aspirates

The fetus swallows 500 to 1000 mL of amniotic fluid each day. Therefore, if there are white blood cells present in amniotic fluid, they will be present in gastric aspirate specimens at birth. However, these cells represent the maternal response to inflammation and have a poor correlation with neonatal sepsis.32 Gram stains of gastric aspirates to identify bacteria are of limited value and are not routinely recommended.33

Body Surface Cultures

Bacterial cultures of the axilla, groin, and the external ear canal have a poor positive predictive accuracy. They are expensive and add little to the evaluation of an infant with possible bacterial sepsis.34,35

Tracheal Aspirates

Cultures and Gram stains of tracheal aspirate specimens may be of value if obtained immediately after endotracheal tube placement.36 Once an infant has been intubated for several days, tracheal aspirates are of no value in the evaluation of sepsis.37

Lumbar Puncture

The decision to perform a lumbar puncture in a neonate with suspected early-onset sepsis remains controversial. In the high-risk, healthy-appearing infant, data suggest that the likelihood of meningitis is extremely low.38 In the infant with clinical signs that are thought to be attributable to a noninfectious condition, such as respiratory distress syndrome, the likelihood of meningitis is also low.39 However, in bacteremic infants, the incidence of meningitis may be as high as 23%.40,41 Blood culture alone cannot be used to decide who needs a lumbar puncture, because blood cultures can be negative in up to 38% of infants with meningitis.42,43 The lumbar puncture should be performed in any infant with a positive blood culture, infants whose clinical course or laboratory data strongly suggest bacterial sepsis, and infants who initially worsen with antimicrobial therapy. For any infant who is critically ill and likely to have cardiovascular or respiratory compromise from the procedure, the lumbar puncture can be deferred until the infant is more stable.

Cerebrospinal fluid (CSF) values indicative of neonatal meningitis are controversial. In studies that have excluded infants with “traumatic taps” (or nonbacterial illnesses), the meaumber of white blood cells in uninfected preterm or term infants was consistently <10 cells/mm3.4450 Cell counts 2 standard deviations from the mean were generally less than 20 cells/mm3.46 In a study by Garges et al, the median number of white blood cells in infants who were born at greater than 34 weeks’ gestation and had bacterial meningitis was 477/mm3.43 In contrast, the mediaumber of white blood cells in infants who were born at less than 34 weeks’ gestation and had meningitis was 110/mm3.51 Infants with meningitis attributable to Gram-negative pathogens typically have higher CSF white blood cell counts than do infants with meningitis attributable to Gram-positive pathogens.52 Adjusting the CSF white blood cell count for the number of red blood cells does not improve the diagnostic utility (loss of sensitivity with marginal gain in specificity).53 In addition, the number of bands in a CSF specimen does not predict meningitis.54 With a delay in analysis (>2 hours), white blood cell counts and glucose concentrations decrease significantly.55

Protein concentrations in uninfected, term newborn infants are <100 mg/dL.4450 Preterm infants have CSF protein concentrations that vary inversely with gestational age. In the normoglycemic newborn infant, glucose concentrations in CSF are similar to those in older infants and children (70%–80% of a simultaneously obtained blood specimen). A low glucose concentration is the CSF variable with the greatest specificity for the diagnosis of meningitis.43,51 Protein concentrations are higher and glucose concentrations are lower in term than in preterm infants with meningitis. However, meningitis occurs in infants with normal CSF values, and some of these infants have high bacterial inocula.43,51

Peripheral White Blood Cell Count and Differential Count

Total white blood cell counts have little value in the diagnosis of early-onset sepsis and have a poor positive predictive accuracy.56,57 Many investigators have analyzed subcomponents of the white blood cell count (neutrophil indices)—absolute neutrophil count, absolute band count, and immature to total neutrophil (I/T)ratio—to identify infected infants. Like most diagnostic tests for neonatal sepsis, neutrophil indices have proven most useful for excluding infants without infection rather than identifying infected neonates. Neutropenia may be a better marker for neonatal sepsis and has better specificity than an elevated neutrophil count, because few conditions besides sepsis (maternal pregnancy-induced hypertension, asphyxia, and hemolytic disease) depress the neutrophil count of neonates.58 The definitions for neutropenia vary with gestational age,5861 type of delivery (infants born by cesarean delivery without labor have lower counts than infants delivered vaginally),61 site of sampling (neutrophil counts are lower in samples from arterial blood),62 and altitude (infants born at elevated altitudes have higher total neutrophil counts).63 In late preterm and term infants, the definition for neutropenia most commonly used is that suggested by Manroe et al (<1800/mm3 at birth and <7800/mm3 at 12–14 hours of age).58 Schmutz et al reinvestigated these reference ranges using modern cell-counting instrumentation in 30 254 infants born at 23 to 42 weeks’ gestation.61 Infants with diagnoses known to affect neutrophil counts (eg, those born to women with pregnancy-induced hypertension or those with early-onset sepsis) were excluded. In this study, the lower limits of normal for neutrophil values at birth were 3500/mm3 in infants born at >36 weeks’ gestation, 1000/mm3 in infants born at 28 through 36 weeks’ gestation, and 500/mm3 in infants born at <28 weeks’ gestation. Peak values occurred at 6 to 8 hours after birth; the lower limits of normal at that time were 7500/mm3, 3500/mm3, and 1500/mm3 for infants born at >36 weeks’ gestation, 28 to 36 weeks’ gestation, and <28 weeks’ gestation, respectively.61 It is noteworthy that the study by Schmutz et al was performed at 4800 feet above sea level, whereas that of Manroe et al was performed at 500 feet above sea level.

The absolute immature neutrophil count follows a similar pattern to the absolute neutrophil count and peaks at approximately 12 hours of life. The number of immature neutrophils increases from a maximal value of 1100 cells/mm3 at birth to 1500 cells/mm3 at 12 hours of age.58 Absolute immature counts have a poor sensitivity and positive predictive accuracy for early-onset sepsis.22 Furthermore, if exhaustion of bone marrow reserves occurs, the number of immature forms will remain depressed.64

The I/T ratio has the best sensitivity of any of the neutrophil indices. However, with manual counts, there are wide interreader differences in band neutrophil identification.65 The I/T ratio is <0.22 in 96% of healthy preterm infants born at <32 weeks’ gestational age.66 Unlike the absolute neutrophil count and the absolute band count, maximum normal values for the I/T ratio occur at birth (0.16) and decline with increasing postnatal age to a minimum value of 0.12.58 In healthy term infants, the 90th percentile for the I/T ratio is 0.27.59 A single determination of the I/T ratio has a poor positive predictive accuracy (approximately 25%) but a very high negative predictive accuracy (99%).66 The I/T ratio may be elevated in 25% to 50% of uninfected infants.67

Exhaustion of bone marrow reserves will result in low band counts and lead to falsely low ratios. The timing of the white blood cell count is critical.68 Counts obtained 6 to 12 hours after birth are more likely to be abnormal than are counts obtained at birth, because alterations in the numbers (and ratios) of mature and immature neutrophils require an established inflammatory response. Therefore, once the decision is made to start antimicrobial therapy soon after birth, it is worth waiting 6 to 12 hours before ordering a white blood cell count and differential count.68,69

Platelet Counts

Despite the frequency of low platelet counts in infected infants, they are a nonspecific, insensitive, and late indicator of sepsis.70,71 Moreover, platelet counts are not useful to follow clinical response to antimicrobial agents, because they often remain depressed for days to weeks after a sepsis episode.

Acute-Phase Reactants

A wide variety of acute-phase reactants have been evaluated ieonates with suspected bacterial sepsis. However, only C-reactive protein (CRP) and procalcitonin concentrations have been investigated in sufficiently large studies.72,73 CRP concentration increases within 6 to 8 hours of an infectious episode ieonates and peaks at 24 hours.74,75 The sensitivity of a CRP determination is low at birth, because it requires an inflammatory response (with release of interleukin-6) to increase CRP concentrations.76 The sensitivity improves dramatically if the first determination is made 6 to 12 hours after birth. Benitz et al have demonstrated that excluding a value at birth, 2 normal CRP determinations (8–24 hours after birth and 24 hours later) have a negative predictive accuracy of 99.7% and a negative likelihood ratio of 0.15 for proveeonatal sepsis.76 If CRP determinations remain persistently normal, it is strong evidence that bacterial sepsis is unlikely, and antimicrobial agents can be safely discontinued. Data are insufficient to recommend following sequential CRP concentrations to determine the duration of antimicrobial therapy in an infant with an elevated value (≥1.0 mg/dL).

Procalcitonin concentrations increase within 2 hours of an infectious episode, peak at 12 hours, and normalize within 2 to 3 days in healthy adult volunteers.77 A physiologic increase in procalcitonin concentration occurs within the first 24 hours of birth, and an increase in serum concentrations can occur with noninfectious conditions (eg, respiratory distress syndrome).78 Procalcitonin concentration has a modestly better sensitivity than does CRP concentration but is less specific.73 Chiesa and colleagues have published normal values for procalcitonin concentrations in term and preterm infants.79 There is evidence from studies conducted in adult populations, the majority of which focused on patients with sepsis in the ICU, that significant reductions in use of antimicrobial agents can be achieved in patients whose treatment is guided by procalcitonin concentration.80

Sepsis Screening Panels

Hematologic scoring systems using multiple laboratory values (eg, white blood cell count, differential count, and platelet count) have been recommended as useful diagnostic aids. No matter what combination of tests is used, the positive predictive accuracy of scoring systems is poor unless the score is very high. Rodwell et al described a scoring system in which a score of 1 was assigned to 1 of 7 findings, including abnormalities of leukocyte count, total neutrophil count, increased immature polymorphonuclear leukocyte (PMN) count, increased I/T ratio, immature to mature PMN ratio >0.3, platelet count ≤150 000/mm3, and pronounced degenerative changes (ie, toxic granulations) in PMNs.81 In this study, two-thirds of preterm infants and 90% of term infants with a hematologic score ≥3 did not have proven sepsis.81 Furthermore, scores obtained in the first several hours after birth have been shown to have poorer sensitivity and negative predictive value than scores obtained at 24 hours of age.67 Sepsis screening panels commonly include neutrophil indices and acute-phase reactants (usually CRP concentration). The positive predictive value of the sepsis screen ieonates is poor (<30%); however, the negative predictive accuracy has been high (>99%) in small clinical studies.22 Sepsis screening tests might be of value in deciding which “high-risk” healthy-appearing neonates do not need antimicrobial agents or whether therapy can be safely discontinued.

Treatment of Infants With Suspected Early-Onset Sepsis

In the United States, the most common pathogens responsible for early-onset neonatal sepsis are GBS and Escherichia coli.17 A combination of ampicillin and an aminoglycoside (usually gentamicin) is generally used as initial therapy, and this combination of antimicrobial agents also has synergistic activity against GBS and Listeria monocytogenes.82,83 Third-generation cephalosporins (eg, cefotaxime) represent a reasonable alternative to an aminoglycoside. However, several studies have reported rapid development of resistance when cefotaxime has been used routinely for the treatment of early-onset neonatal sepsis,84 and extensive/prolonged use of third-generation cephalosporins is a risk factor for invasive candidiasis.85 Because of its excellent CSF penetration, empirical or therapeutic use of cefotaxime should be restricted for use in infants with meningitis attributable to Gram-negative organisms.86 Ceftriaxone is contraindicated ieonates because it is highly protein bound and may displace bilirubin, leading to a risk of kernicterus. Bacteremia without an identifiable focus of infection is generally treated for 10 days.87 Uncomplicated meningitis attributable to GBS is treated for a minimum of 14 days.88 Other focal infections secondary to GBS (eg, cerebritis, osteomyelitis, endocarditis) are treated for longer durations.88 Gram-negative meningitis is treated for minimum of 21 days or 14 days after obtaining a negative culture, whichever is longer.88 Treatment of Gram-negative meningitis should include cefotaxime and an aminoglycoside until the results of susceptibility testing are known.87,88

The duration of antimicrobial therapy in infants with negative blood cultures is controversial. Many women receive antimicrobial agents during labor as prophylaxis to prevent early-onset GBS infections or for management of suspected intra-amniontic infection or PPROM. In those instances, postnatal blood cultures may be sterile (false negative). When considering the duration of therapy in infants with negative blood cultures, the decision should include consideration of the clinical course as well as the risks associated with longer courses of antimicrobial agents. In a retrospective study by Cordero and Ayers, the average duration of treatment in 695 infants (<1000 g) with negative blood cultures was 5 ± 3 days.89 Cotten et al have suggested an association with prolonged administration of antimicrobial agents (>5 days) in infants with suspected early-onset sepsis (and negative blood cultures) with death and necrotizing enterocolitis.90 Two recent papers also support this association.91,92

Prevention Strategies for Early-Onset Sepsis

The only intervention proven to decrease the incidence of early-onset neonatal sepsis is maternal treatment with intrapartum intravenous antimicrobial agents for the prevention of GBS infections.93 Adequate prophylaxis is defined as penicillin (the preferred agent), ampicillin, or cefazolin given for ≥4 hours before delivery. Erythromycin is no longer recommended for prophylaxis because of high resistance rates. In parturients who have a nonserious penicillin allergy, cefazolin is the drug of choice. For parturients with a history of serious penicillin allergy (anaphylaxis, angioedema, respiratory compromise, or urticaria), clindamycin is an acceptable alternative agent, but only if the woman’s rectovaginal GBS screening isolate has been tested and documented to be susceptible. If the clindamycin susceptibility is unknown or the GBS isolate is resistant to clindamycin, vancomycin is an alternative agent for prophylaxis. However, neither clindamycior vancomycin has been evaluated for efficacy in preventing early-onset GBS sepsis ieonates. Intrapartum antimicrobial agents are indicated for the following situations93:

1.        Positive antenatal cultures or molecular test at admission for GBS (except for women who have a cesarean delivery without labor or membrane rupture)

2.        Unknown maternal colonization status with gestation <37 weeks, rupture of membranes >18 hours, or temperature >100.4°F (>38°C)

3.        GBS bacteriuria during the current pregnancy

4.        Previous infant with invasive GBS disease

Management guidelines for the newborn infant have been published93 and are available online (http://www.cdc.gov/groupbstrep/guidelines/index.html).

Clinical Challenges

Challenge 1: Identifying Neonates With Clinical Signs of Sepsis With a “High Likelihood” of Early-Onset Sepsis Who Require Antimicrobial Agents Soon After Birth

Most infants with early-onset sepsis exhibit abnormal signs in the first 24 hours of life. Approximately 1% of infants will appear healthy at birth and then develop signs of infection after a variable time period.21 Every critically ill infant should be evaluated and receive empirical broad-spectrum antimicrobial therapy after cultures, even when there are no obvious risk factors for sepsis. The greatest difficulty faced by clinicians is distinguishing neonates with early signs of sepsis from neonates with noninfectious conditions with relatively mild findings (eg, tachypnea with or without an oxygen requirement). In this situation, data are insufficient to guide management. In more mature neonates without risk factors for infection who clinically improve over the first 6 hours of life (eg, need for oxygen is decreasing and respiratory distress is resolving), it is reasonable to withhold antimicrobial therapy and monitor the neonates closely. The 6-hour window should not be considered absolute; however, most infants without infection demonstrate some improvement over that time period. Any worsening of the infant’s condition should prompt starting antimicrobial agents after cultures have been obtained.

Challenge 2: Identifying Healthy-Appearing Neonates With a “High Likelihood” of Early-Onset Sepsis Who Require Antimicrobial Agents Soon After Birth

This category includes infants with 1 of the risk factors for sepsis noted previously (colonization with GBS, prolonged rupture of membranes >18 hours, or maternal chorioamnionitis). GBS is not a risk factor if the mother has received adequate intrapartum therapy (penicillin, ampicillin, or cefazolin for at least 4 hours before delivery) or has a cesarean delivery with intact membranes in the absence of labor.93 The risk of infection in the newborn infant varies considerably with the risk factor present. The greatest risk of early-onset sepsis occurs in infants born to women with chorioamnionitis who are also colonized with GBS and did not receive intrapartum antimicrobial agents. Early-onset sepsis does occur in infants who appear healthy at birth.21 Therefore, some clinicians use diagnostic tests with a high negative predictive accuracy as reassurance that infection is not present (allowing them to withhold antimicrobial agents). The decision of whether to treat a high-risk infant depends on the risk factors present, the frequency of observations, and gestational age. The threshold for initiating antimicrobial treatment generally decreases with increasing numbers of risk factors for infection and greater degrees of prematurity. Suggested algorithms for management of healthy-appearing, high-risk infants are shown in Figs 1, 2, and 3. Screening blood cultures have not been shown to be of value.21

 

 l

FIGURE 1

Evaluation of asymptomatic infants <37 weeks’ gestation with risk factors for sepsis. aThe diagnosis of chorioamnionitis is problematic and has important implications for the management of the newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood cell; Diff, differential white blood cell count.

 

FIGURE 2

Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis. aThe diagnosis of chorioamnionitis is problematic and has important implications for the management of the newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. WBC, white blood cell; Diff, differential white blood cell count.

 

FIGURE 3

Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis (no chorioamnionitis). aInadequate treatment: Defined as the use of an antibiotic other than penicillin, ampicillin, or cefazolin or if the duration of antibiotics before delivery was <4 h. bDischarge at 24 h is acceptable if other discharge criteria have been met, access to medical care is readily accessible, and a person who is able to comply fully with instructions for home observation will be present. If any of these conditions is not met, the infant should be observed in the hospital for at least 48 h and until discharge criteria are achieved. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood cell; Diff, differential white blood cell count.

Conclusions

The diagnosis and management of neonates with suspected early-onset sepsis are based on scientific principles modified by the “art and experience” of the practitioner. The following are well-established concepts related to neonatal sepsis:

1.        Neonatal sepsis is a major cause of morbidity and mortality.

2.        Diagnostic tests for early-onset sepsis (other than blood or CSF cultures) are useful for identifying infants with a low probability of sepsis but not at identifying infants likely to be infected.

3.        One milliliter of blood drawn before initiating antimicrobial therapy is needed to adequately detect bacteremia if a pediatric blood culture bottle is used.

4.        Cultures of superficial body sites, gastric aspirates, and urine are of no value in the diagnosis of early-onset sepsis.

5.        Lumbar puncture is not needed in all infants with suspected sepsis (especially those who appear healthy) but should be performed for infants with signs of sepsis who can safely undergo the procedure, for infants with a positive blood culture, for infants likely to be bacteremic (on the basis of laboratory data), and infants who do not respond to antimicrobial therapy in the expected manner.

6.        The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once the pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed).

7.        Antimicrobial therapy should be discontinued at 48 hours in clinical situations in which the probability of sepsis is low.

 

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