Wednesday, January 11, 2012

Neonatal sepsis

Author :
David J. Hackam, MD, PhD
Attending Pediatric Surgeon, Children’s Hospital of Pittsburgh
Associate Professor of Surgery
University of Pittsburgh School of Medicine
Co-Director, Fetal Diagnosis and Treatment Center, Children’s Hospital of Pittsburgh


Neonatal Sepsis : When Little Babies Get Very Sick
  • Neonatal sepsis refers to a condition characterized by distinct physical and laboratory findings that occur within the first 30 days of life, in the setting of infection.
  • Septic neonates may be classified into three groups: congenital, early-onset, and late-onset. Infants within each group have specific causative organisms and risk factors.
  • Neonatal sepsis is associated with a high risk for morbidity and mortality. Treatment should be directed towards maintaining blood pressure and perfusion to organ systems, while treating the specific infective agent.  

Introduction:  what is neonatal sepsis?

Although the term “sepsis” has been around since ancient times, modern definitions of “sepsis” were described in detail in the early 1990s, at a consensus conference convened by the American College of Chest Physicians and the Society of Critical Care Medicine. At that time, “sepsis” was described as a systemic response to a physiologic insult – including infectious and other etiologies – that lead to the development of further organ injury, ultimately culminating in multiple organ dysfunction syndrome[1]. Neonatal sepsis, also termed Sepsis neonatorum, refers to a group of physical and laboratory findings that occur in response to invasive infection within the first 30 days of life. As will be discussed below, there are various infectious causes of neonatal sepsis; however, the pattern of presentation is quite similar in all cases, as is the approach to treatment. The importance of neonatal sepsis as a diagnosis is found in the fact that this diagnosis occurs in between 1 to 8 children per 1000 live births in the United States, and may be associated with a fatality rate of up to 30%[2]. As such, it is essential that caregivers that are involved with the management of neonates have a reliable approach to the diagnosis and treatment of infants with sepsis, and that appropriate intervention be instituted in a timely manner.

What are the causes of sepsis in neonates, and who is at risk?

Neonatal sepsis can occur in any infant. However, the diagnosis is significantly more common in pre-term infants than full term infants, and can affect up to 30 to 1000 live births in the pre-term population. Sepsis is also more common in males than females, and in developing countries. Other risk factors include infants born after prolonged rupture of membranes (see below) or maternal infection[3].

The causes of neonatal sepsis are best classified into three time periods as displayed in Figure 1:
1) infections that occur during pregnancy (so called “congenital infection”); 2) infections that occur early after delivery (“early-onset infection”); and 3) infections that occur later on, such as after the infant is discharged from the hospital (“late-onset infection”). The division between early- and late- onset infection is thought to be between 2 to 5 days, although a longer period of time has also been suggested[4].  A summary of the most common pathogens during these phases of infection is provided below.
a. Congenital infection:

Congenital infection is thought to occur during the pregnancy, either across the placenta or via ascent up the birth canal. The principal organisms that account for congenital infection leading to neonatal sepsis include syphilis, human immunodeficiency virus (HIV), Toxoplasma, and cytomegalovirus. Risk factors for the development of congenital infection include a maternal infection with these organisms (which then leads to infection of the fetus), or prolonged rupture of membranes (leading to ascending infection).

b. Early-onset infection:

Early onset infection is thought to occur during passage of the fetus through the birth canal. The principal organisms that account for early-onset infection include predominantly group B streptococcus (GBS), as well as Escherichia coli (E. coli) in the remainder[5]. Since early-onset infection is thought to occur during parturition, it is not surprising that the major risk factor for this phase of neonatal sepsis is the asymptomatic colonization of the maternal gastrointestinal or genitourinary tracts[6]. The maternal GI or GU tracts are colonized by GBS in up to 30% of pregnant women. Risk factors for higher colonization rates include African American descent and diabetes[7]. Additional risk factors for early-onset infection include prolonged rupture of membranes, prematurity, male gender, low birth weight, maternal infection, and poor prenatal care[8].

As will be discussed below, treatment of the mother with antibiotics against GBS has resulted in a decreased incidence of GBS-induced neonatal sepsis, and a corresponding increase in sepsis from other organisms, in particular Gram-negative organism including E. coli and Klebsiella species[9].

c. Late-onset infection:

Late-onset infection is thought to occur well beyond the early delivery phase, and as such reflects organism that may be acquired in the hospital setting or at home. As such, infants with late-onset neonatal sepsis develop infections from common hospital pathogens, including bacteria (coagulase negative staphylococcal species), viruses, and fungi (candida species)[10]. Patients that are on antibiotics for any length of time are at increased risk for the development of late-onset infection, as are those infants that have any centrally placed intravenous catheter. Such lines may include a Broviac or percutaneously-inserted central catheter (PICC-line), an umbilical arterial line, or an umbilical venous line. Indeed, neonates that are on ventilators for reasons other than sepsis may acquire an infection in the hospital, a so-called nosocomial infection[4].

Late-onset neonatal sepsis can also occur in infants after they leave the hospital. In these cases, organisms that are similar to those causing early-onset sepsis i.e., GBS, E. coli and other Gram-negative species predominate[11].

Why are neonates at particularly increased risk for the development of sepsis?

There are several key features of neonates that place them at increased risk for the development of sepsis[12]. Neonates have a relatively immature immune system, and the effects on the immune system are more pronounced in more premature neonates. Such defects include a loss of protective maternal antibodies, as well as non-specific alterations in macrophage phagocytosis and clearance of invading pathogens, impaired T-cell and B-cell responses, and altered production of complement and antibodies [13]. In addition, the newborn infant – particularly the preterm infant – has relatively permeable mucosal surfaces that allow for the trans-epithelial passage of bacteria and other pathogens. The frequency with which preterm neonates undergo invasive procedures, that themselves result in the introduction of potential pathogens, also increases the specific risk to the neonate of the development of sepsis. The presence of co-morbidities, such as impaired cardiac function, anatomic defects of the gastro-intestinal or urinary tract, and abnormalities in glucose metabolism worsen the neonate’s ability to withstand infection, and lead to an increased risk for the development of neonatal sepsis.

How do infants with sepsis present? Consider the case of baby Sarah.

In order to illustrate the typical presentation of neonatal sepsis, consider the following case, that describes the story of baby Sarah: 

Sally and Jim were so excited for the arrival of their newborn daughter, Sarah, that when she arrived three weeks early, they assumed (as Jim’s mother had told them) that she was just as excited to meet them as they were her. And considering that this was her first delivery, Sarah came out pretty uneventfully – if you consider an hour of straight pushing as uneventful. Sally’s pregnancy had had its ups and downs – she certainly had more than her fair share of nausea, and had needed to take some antibiotics in pregnancy for a culture of her vagina that had come back positive. But when they first laid eyes on Sarah, all they could focus on was how perfectly beautiful she was. Jim’s mother had, of course, thought she was beautiful too, but she couldn’t help but notice that she had a funny way of breathing – it was a little fast, and she tended to make an occasional gasping sound. On Sarah’s first night in the hospital, Jim’s mother became even more concerned – her nostrils seemed to flare, and from time to time that gasping sound became more noticeable. When the nurse’s aide came in to check Sarah’s temperature, he found Sarah to be cold (35.9oC) and suggested that they add an extra blanket and turn up the room temperature. Jim’s mom would have none of it. Requesting that a doctor see the child immediately, Sarah was now found to be in real respiratory distress – gasping for air, and breathing in such a way that her ribs seemed to retract with each shallow breath. Sarah was transferred down to the neonatal intensive care unit (NICU) where she was immediately started on oxygen, and given an intravenous line for the administration of antibiotics and fluids. After a few days of treatment – including a short stint on a ventilator - Sarah started to improve. The nurse in the NICU told Sally and Jim that Sarah had a blood culture that was positive for “Group B strep”, which accounted for how sick she became. Sarah was transferred out of the NICU after about a week, and after another few days up on the floor, she was breast feeding like a professional, with no evidence that she had ever been sick. Now Sally, Jim - and his mother - could spend their time focusing on how perfectly beautiful she was. 

What are the signs of sepsis in neonates?

Neonates with sepsis present with a variety of subtle clinical findings that individually may not point to a specific infectious etiology, but together should alert the caregiver to the fact that the infant is septic. These signs include subtle changes in respiration, including apnea and / or tachypnea. There may be associated changes in heart rate, including frequent episodes of bradycardia and/or tachycardia. The reasons that sepsis leads to changes in ventilation and cardiac rate are not completely understood, but they remain highly useful as markers for the presence of sepsis. In addition, neonates with sepsis commonly exhibit alterations in core body temperature, as manifested by fever and or hypothermia. Changes in skin perfusion commonly accompany sepsis, as manifested by mottling, cooling of the extremities, and a general “ill look” to the baby overall. Other subtle findings of sepsis include the development of feeding intolerance, vomiting, or diarrhea.

In more advanced stages, infants with sepsis may show signs of petechiae - small areas of hemorrhage within the skin – as evidence for the platelet consumption that frequency is seen in sepsis. In association with these signs, more advanced sepsis is associated with evidence of global impaired tissue perfusion, characterized by reduced urine output and decreased systemic blood pressure. Secondary pulmonary hypertension may develop in more severe cases of sepsis, leading to impaired gas exchange in the lungs[14]. This can result in progressive tissue hypoxia and increased work of breathing.

It is important to point out that the clinical course of septic patients is unpredictable. There may be the gradual onset of tachypnea, nasal flaring and fever, or the rapid, striking development of cardio-respiratory shock. The specific course depends to some degree on the infectious agent, the overall health of the neonate, including gestational age and birthweight, and the presence of specific co-morbidities. However, it is fairly safe to predict that in the absence of aggressive treatment that is directed at maintaining tissue perfusion, supporting the function of the cardio-respiratory system and treating the underlying infection, septic neonates can be expected to have a dramatic downward spiral, characterized by systemic inflammation and multiple organ dysfunction. Fortunately, aggressive early therapy is highly successful in treating sepsis in the majority of cases (see below).
The specific focus of sepsis may affect the presentation to some degree. Infants with pneumonia typically develop pulmonary symptoms first (nasal flaring followed by increased oxygen requirements and respiratory failure). Infants with meningitis may manifest bulging fontanelles. However, in general, the signs of sepsis are subtle and do not point to the precise infectious location or agent.

How is neonatal sepsis diagnosed?

The diagnosis of sepsis requires careful clinical suspicion, detailed physical examination, and a combination of lab tests and x-rays15. Although there isn’t one single test that can reliably diagnose sepsis in all neonates, the above combination will establish the diagnosis in most. 

a. Physical examination:

On physical examination, a head-to-toe evaluation is necessary in order for the diagnosis of sepsis to be established. After obtaining vital signs (temperature, heart rate, respiratory rate), the infant is examined first to assess the extent of hydration – the fontanelle is examined for evidence of dehydration (sunken) or bulging (occasionally seen in meningitis). Nasal flaring is assessed, as is the presence of sunken or bulging orbits (evidence of dehydration vs. meningitis). The skin is carefully palpated, and evidence of petechiae are noted, as are signs of poor perfusion, including mottling, pallor, and coolness to the extremities. The lungs are auscultated, and evidence of pneumonia (asymmetrical breath sounds) or crackles (evidence of fluid leakage) is noted. The heart tones are examined for evidence of murmur (patent ductus arteriosus), and the heart rate and strength of the heart tones are noted (decreased with pericardial effusion). Examination of the abdomen will detect evidence of distention, tenderness, or erythema, as may be seen in the setting of ileus (which may accompany neonatal sepsis) or necrotizing enterocolitis (discussed in another Knol). Evidence of peripheral edema (seen in more advanced sepsis) and other signs of skin infection (redness, warmth) should also be noted. Although the physical findings do not point to a specific etiology, they should raise the suspicion for sepsis, and lead to the acquisition of additional tests.

b. Laboratory tests:

The laboratory work-up of septic neonates begins with a complete blood count, including leukocyte count with differential, and platelet count. Evidence of decreased circulating white blood cells may be noted (leucopenia), as may signs of increased white blood cells (leukocytosis). Leucopenia is probably more common than leukocytosis in cases of neonatal sepsis. Neonatal sepsis may also be associated with an increase in the release of immature white blood cells into the circulation, as manifest by an increase in circulating band forms. A decrease in platelet count may also be noted, a manifestation of the formation of small blood clots within the tissue or impaired production in the bone marrow 16. Additional tests of note include abnormalities in serum electrolytes, including increased or decreased sodium concentrations, both of which are evidence of the free water imbalance that accompanies sepsis. Septic infants may also manifest hyper- or hypo-glycemia.

Obtaining accurate cultures of all body fluids is the most important step in establishing the diagnosis of sepsis. This includes a blood culture, as well as a culture of the urine and the cerebrospinal fluid. When obtaining a blood culture, it is important to avoid drawing blood from intravenous catheters or central lines. It is particularly important to be able to recognize the presence of common contaminants in blood cultures, especially coagulase-negative staphylococcus or viridans streptococci. The practice of obtaining cultures from two clean sites facilitates this task. It is noteworthy that neonatal endotracheal cultures are often not very helpful in establishing the diagnosis of neonatal sepsis, given the frequency and speed with which endotracheal tubes become colonized with microbes.

In certain cases, a viral etiology will be suspected, particularly in cases of congenital neonatal sepsis. Rapid viral testing may be available, especially in cases in which herpes simplex virus infection is suspected.

There is not an individual x-ray that will reliably diagnose neonatal sepsis, although many tests may provide supportive information. For instance, the chest x-ray may illustrate evidence of diffuse infiltrates and poor overall aeration (Figure 2). Pneumonia may also be seen.

There is great interest in the use of markers of systemic inflammation to diagnose systemic sepsis in neonates. Such markers include C-reactive protein, tumor necrosis factor, interleukin-1, and interleukin-6. Initial results with these markers show some promise in selected patients [17].

How is neonatal sepsis treated?

a. Maintenance of vital signs:

The treatment of infants with sepsis must begin before a specific infectious agent is identified. In all cases, attention is placed on stabilization of the airway, maintenance of adequate breathing, restoration of intact circulation, followed by treatment with broad spectrum anti-microbial agents to cover likely pathogens. In cases in which oxygenation is inadequate, supplemental oxygen should be administered. This can be accomplished using techniques that include nasal cannulas, external oxygen in the form of blow-by, or endotracheal intubation with mechanical ventilation. Systemic perfusion is maintained by administering fluid boluses using either crystalloid, colloid, or blood products as needed. In cases in which sepsis has progressed to the point at which hypotension has developed – i.e., a condition termed septic shock – systemic pressure is inadequate to maintain tissue perfusion. In these cases, inotropic support will typically be necessary[18]. Useful agents for the treatment of neonatal septic shock include combinations of epinephrine, dopamine, dobutamine, or milrinone. Platelet infusions may be required for the treatment of sepsis-induced thrombocytopenia. Early nutritional support is necessary, and may be safely administered using total parenteral nutrition[19]. Careful glycemic control is mandatory, as wide fluctuations in serum glucose are commonly seen in neonates with sepsis.

b. Antimicrobial therapy:
In addition to the maintenance of systemic vital signs, treatment of neonatal sepsis requires specific antimicrobial therapy. The specific antimicrobial agent is influenced by the particular “phase” of neonatal sepsis, as characterized in Figure 1. For instance, early-onset neonatal sepsis is treated with a combination of agents that treat group B streptococcus as well as Gram-negative species. Useful agents include ampicillin and gentamicin, or ampicillin plus cefotaxime. These agents in combination cover a broad spectrum of the most common pathogens in early-onset sepsis, and have excellent penetration into the central nervous system. There is evidence to support the use of ampicillin and gentamicin in the treatment of early-onset neonatal sepsis [20]. When gentamicin is used, close monitoring of renal function is required. It is important to note that the pharmacy of an individual nursery will greatly facilitate the choice of antibiotics, based upon the prevailing antibiotic sensitivity spectra against these and other known antibiotics.

For late-onset sepsis, the choice of antibiotic therapy should be based, in part, on the prevailing flora of the individual NICU, and the infection history of a particular infant. In general, the same empiric treatment as for early-onset sepsis may be used (i.e., ampicillin and gentamicin), unless micro-organisms with resistance to these agents are identified. In instances in which a central line is present, treatment should be instituted to cover S. aureus and coagulase-negative staphylococci. There is increasing incidence of methicillin-resistant S. aureus or MRSA in infants with line infections. In view of this, a reasonable first-line antimicrobial choice is vancomycin, in addition to an aminoglycoside such as gentamicin, for empiric coverage of Gram-negative bacilli while awaiting the results of cultures. Persistent bacteremia, or evidence of progressive sepsis despite adequate antimicrobial coverage, necessitates the urgent removal of the infected line. Similarly, the presence of fungemia in the setting of an infected central line necessitates line removal. In neonates who are admitted to the NICU from the community, antibiotic selection should include treatment of meningitis. Empiric choices include a third-generation cephalosporin (i.e., cefotaxime or ceftriaxone) plus ampicillin.

c. Severe neonatal sepsis and the role of ECMO.
It is worth noting that in cases of neonatal sepsis that are refractory to conventional ventilatory and inotropic support, extracorporeal membrane oxygenation (ECMO) may be indicated[21]. This approach involves placing the infant on a “heart-lung” bypass circuit, such that perfusion is achieved using a pump, and oxygenation is provided using an oxygenation membrane. While effective in selected cases of neonatal sepsis, this treatment should be reserved for the sickest of infants, given the complications associated with ECMO. These include, but are not limited to, bleeding, intracerebral hemorrhage, supra-infection, and renal failure. Prior to placing an infant on the ECMO circuit, it is important to obtain a recent head ultrasound, as well as an echocardiogram to exclude the presence of cardiac anomalies. We have shown that ECMO has been used nationally in smaller and smaller infants with acceptable outcomes, and should therefore be considered a part of the treatment armamentarium in the management of neonatal sepsis[22].

How long should treatment be continued?

In general, empiric treatment of neonatal sepsis should be continued for 7-10 days, providing there is improvement in the overall condition of the patient. In many cases, the neonate will have all the clinical features of sepsis and will have improved after institution of antimicrobial therapy but will fail to yield a positive culture. In these instances it is appropriate to continue a full course (7-10 days) of antibiotics, despite the absence of a specific organism. Longer durations (up to 3 weeks) of antibiotic therapy may be used in cases of pneumonia or meningitis. 

Can neonatal sepsis be prevented?

Because early-onset sepsis develops upon exposure of the fetus to the colonized uro-genital or gastrointestinal tract of the mother (Figure 1), attempts have been made to reduce the extent of bacterial exposure using intrapartum antibiotics. Based upon the consensus recommendations from the US Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics, all pregnant women are now screened with a vaginal and rectal swab at weeks 35 to 37, and maternal intrapartum chemoprophylaxis is administered [23, 24]. Typical prophylaxis regimens include intravenous penicillin G every 4 hours until delivery. In cases in which penicillin allergy is documented, cefazolin may be used unless anaphylaxis to penicillin is a risk. Other choices include clindamycin or vancomycin in pregnant women with severe penicillin allergies. There is evidence in favor of the use of ampicillin instead of penicillin for GBS prophylaxis given the frequency and severity of ampicillin-resistant E. coli neonatal sepsis after maternal antibiotics [25].

The strategy of intrapartum treatment has been shown to be highly effective[26]. Since the widespread adoption of intrapartum treatment strategies, the incidence of early-onset sepsis has decreased by 75%, from 1.7 per 1,000 live births in 1993 to 0.35 per 1,000 in 2003 27, 28. It is noteworthy that in association with the decrease in early-onset GBS infection, there is an increase in early-onset neonatal sepsis due to E. coli.

Prevention of late-onset neonatal sepsis includes care and attention to limit nosocomial infection. Measure such as hand washing techniques, sterile techniques for any procedure, care and attention to central line access, and avoidance of exposure of at-risk infants to neonates with known infections can all limit the incidence of late-onset neonatal sepsis[29].

What is the outcome of treatment for neonatal sepsis?

Most infants with neonatal sepsis have an excellent prognosis without lasting deficits. This is truly a miracle of modern neonatal medicine, and is attributed to a more in depth appreciation of the subtle findings of sepsis, rapid institution of antimicrobial therapy, early use of fluid boluses and inotropic support, and judicious ventilatory strategies. However, despite advances in neonatal care overall, there is still a significant mortality rate. Specifically, the mortality rate for early-onset infection is estimated to be 5% to 10% and for late-onset disease from 2% to 6% [2]. Infants that develop meningitis are at greater risk for the development of long term sequelae, including issues of global mental retardation, motor anomalies (i.e., spastic quadriplegia), seizures, cortical blindness, and deafness[30]. The outcome of patients with late-onset neonatal sepsis may be influenced, in part, by the presence of associated anomalies to a greater extent than the septic episode itself. There is also the possibility of recurrent neonatal sepsis in both early- and late- onset varieties, likely due to persistent mucosal colonization with pathogens such as GBS. Death from neonatal sepsis is somewhat more likely for early-onset disease and for infants born prematurely. Mortality from early-onset GBS disease has fallen from 55% in the 1970s to 10% to 15% in the 1980s, to a current rate of 3% to 5%. Mortality from late-onset GBS is approximately 5% to 7%.

Summary and conclusions

In summary, neonatal sepsis is a common cause of morbidity and mortality in infants. The disease presents with a constellation of quite subtle findings, include mild apnea and temperature instability, yet can rapidly progress to fulminant organ dysfunction and death. Neonatal sepsis can be classified as congenital, early onset, and late onset, each differing by the mode of infection and the type of organism involved. Treatment includes attention to the maintenance of normal cardiorespiratory function, as well as specific antimicrobial therapy. Although there is still a significant mortality rate associated with neonatal sepsis, most infants respond fully to treatment without any sequelae of this potentially devastating disease.


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