Episode Transcript
Hi and Welcome to Clerkship Ready - Pediatrics - A podcast aimed at helping you excel during your clinical clerkship in Pediatrics.
I am Dr. Davis , and I am a General Pediatrician at the University of Virginia.
Today, we will be reviewing what you need to know before your first sepsis work-up in a young infant.
During your pediatrics inpatient rotation and even during your newborn nursery rotation, you will likely encounter at least one infant being evaluated and/or treated for neonatal sepsis.
In this episode, we will define neonatal sepsis, talk about the presentation of sepsis, what a sepsis workup entails, how to make the diagnosis and treatment of neonatal sepsis.
Let’s first talk about what sepsis is.
Sepsis is a clinical syndrome in which an infection leads to an inflammatory response throughout the body that rapidly progresses to organ dysfunction or even death.
Neonatal sepsis is defined as sepsis in a term – meaning more than 37 weeks gestation - or late preterm - meaning 34-37 weeks gestation - infant in the neonatal period – which is within the first 28 days of life. Neonatal sepsis can further be broken down into early onset sepsis, which occurs within the first 72 hours after birth, or late onset sepsis, occurring after 72 hours of life. Although the term “neonatal sepsis” technically refers to the first 28 days of life, infants continue to be at increased risk of infection in their first few months of life due to their developing immune systems. So for the purposes of our discussion today, we will talk about evaluation of infants in their first two months of life.
Worldwide, neonatal sepsis affects 2,202 infants per 100,000 live births, and has a mortality rate of >11%. In the United States, early onset sepsis affects 50 in 100,000 live births, with a mortality rate of about 3%. So it’s a big problem that we don’t want to miss. It’s also a problem that may be hard to detect, because as we’ll talk about, young babies only have a few ways to tell you that they’re sick – so symptoms like crying, sleeping too much, not waking for feeds may mean a lot of different things. Parents – and clinicians – may not recognize sepsis quickly. Also, because young babies who are sick can also deteriorate rapidly, we have to have a high index of suspicion and react quickly.
Let’s talk a little bit about how these infants present:
If it’s early onset sepsis, most term infants will have signs and symptoms within the first 24 hours after birth.
Symptoms include respiratory distress, tachycardia, temperature instability, irritability, poor feeding, apnea or pauses in breathing greater than 20 seconds, hypotonia, and lethargy. With regards to temperature instability, while some babies will develop a fever – which is defined as a temperature of greater than 100.4 Fahrenheit or 38 degrees Celsius, many babies will become hypothermic – meaning a temperature of less than 97.7 Fahrenheit or 36.5 Celsius. Development of seizures or bulging fontanelles are very concerning signs that suggest meningitis, or spread of the infection into the cerebrospinal fluid.
Again, these symptoms can be vague, so it is important to always have a high index of suspicion.
Fortunately, we do have tools that can help us assess risk. While you are in the newborn nursery, you will often reference the Kaiser Neonatal Early-Onset Sepsis Score – also known as the neonatal sepsis calculator, to calculate an individual infant’s risk of developing EOS. I’ve put the link to the sepsis calculator in the Show Notes. This tool takes into account specific risk factors for neonatal sepsis:
- gestational age - the earlier the baby is born, the higher the risk of sepsis
- maternal antepartum temperature – meaning the temperature of the birth parent during labor and delivery. If the parent was febrile, that increases the risk of sepsis in the baby
- hours from rupture of membranes to delivery – the longer the time since rupture, the higher the risk
- whether the parent received antibiotics intrapartum (or during delivery) – if the answer is yes, this decreases the risk, and
- maternal Group B Strep status – if this is positive, this increases the risk. We’ll talk about Group B strep screening in a minute.
The sepsis calculator will give you a score. You will use both the sepsis score and the infant’s appearance to determine the infant’s risk of early onset sepsis. If an infant is well appearing, meaning it has no abnormalities in heart rate, respiratory rate, temperature, or work of breathing, the risk score will be lower than if the infant has clinical signs of illness. However, don’t forget that, while this is a great tool, it can always be over-ruled by clinical judgement. If you have concern that an infant may have sepsis, even if the early onset sepsis risk score is low, you should still proceed with a sepsis work up of the infant.
Infants with late onset sepsis will usually present to the pediatrician’s office – sometimes because parents have a concern but sometimes for their routine newborn follow up, or directly to the emergency department.
Infants with Late Onset Sepsis usually present in one of 2 ways:
1. The ill appearing neonate – with symptoms such as respiratory distress, tachycardia, temperature instability, irritability, lethargy, poor feeding, apnea, and so on. OR
2. The well- appearing neonate with no evident source of infection, and an isolated fever or hypothermia
When you have a baby that you are worried might have sepsis, how do you make the diagnosis? You will do a quick physical –
- First, assess their vital signs. Look at temperature, heart rate and respiratory rate (if abnormal, reassess these during your exam), and weight. Remember it is normal for an infant to lose up to 10% of their birthweight in the first few days of life before they gradually return to birth weight by two weeks of life. Excessive weight loss could be a sign of poor feeding or could be due to infection.
- When I examine a baby, I like to look, listen, then feel. First look at the baby overall, are they awake and alert? Actively breast feeding? Sleeping, but easily arousable? These are all normal findings. If the baby is asleep, and very difficult to arouse even with rigorous stimulation like a sternal rub, we consider that lethargic, which is a highly concerning sign that suggests sepsis. Conversely, if the infant is crying inconsolably despite soothing measures like swaddling, swaying, shushing sounds, and sucking on a finger or pacifier, that is considered irritability, and is an equally concerning finding.
- While I am looking at the baby, I feel their fontanelle, or “soft spot” on the top of their head. It should feel soft and flat. Fullness or bulging or sunken fontanelles are all abnormal and concerning for meningitis.
- I then watch and listen to the baby’s breathing pattern, looking for any signs of increased respiratory effort, like nasal flaring, tracheal tugging or subcostal retractions, or belly breathing. While you are watching, you can start listening with your stethoscope to their heart and lungs. Remember babies’ heart rates are much faster than adults (normal ranges from 90-180), so it can sometimes be hard to hear any murmurs. I recommend listening to as many infants as possible on your pediatric rotation, so that you can learn what “normal” sounds like.
- I then work my way down from the chest, feeling their belly, paying close attention to the liver, to feel for any hepatomegaly, which could indicate heart failure.
- I feel the inguinal pulses and pedal pulses and assess capillary refill. It can be normal in the first day or two of life for a neonate to have some acrocyanosis (blue hands or feet that have slowed capillary refill). But it is never normal to have delayed capillary refill over the chest, which we call central cyanosis. Normal capillary refill is less than 2-3 secondsXXXX.
- Finally, look at the baby from head to toe to assess for any rashes, particularly small fluid filled vesicles on an erythematous base, which could be neonatal Herpes Simplex Virus. These can be scattered on the body or around mucous membranes like the eyes, nares, mouth, and anus.
Based on your exam findings, you will decide whether it is appropriate to do what we call a sepsis workup.
But before we talk about the sepsis workup, let’s talk about the primary pathogens – and the types of infections that you need to worry about.
Early Onset Sepsis is primarily caused by bacteria and viruses that colonize the maternal genitourinary tract and then contaminate the amniotic fluid, placenta, fetus, and fetal membranes. Most of these infections result from ascending bacteria from the lower vaginal tract
The two most common bacterial pathogens are Group B Strep, also known as Strep agalactiae or GBS, and E coli – depending on what study you’re looking at, these 2 make up 60-70% of all infections. Strep viridans is another fairly common organism. Other organisms found in the genitourinary tract, such as Klebsiella or Enterococcus, can also cause sepsis.
Listeria has historically been one of the most common organisms for early onset sepsis, however, it now accounts for only about 1% of infections.
Because GBS has historically been the most common cause of neonatal Sepsis, the American College of Obstetricians and Gynecologists (ACOG) now recommends universal GBS culture-based screening at 36 0/7 to 37 6/7 weeks of pregnancy. Approximately 30% of pregnant persons have vaginal-rectal colonization with GBS, and 50% of them will transmit the bacteria to the infant. Of those infants, 1-2% will develop GBS early onset sepsis if antibiotic prophylaxis is not administered during labor. Therefore, if the GBS culture is positive, antibiotic prophylaxis will be given. The recommended antibiotic treatment for prophylaxis is penicillin or ampicillin. If the mother has a penicillin allergy with low risk of anaphylaxis, a first-generation cephalosporin should be administered. If she has a severe allergy with high risk of anaphylaxis, clindamycin or vancomycin can be used. Antibiotic prophylaxis for GBS is most effective if given at least 4 hours prior to delivery. Because the exact time of delivery is unpredictable, antibiotics are initiated upon hospital admission for labor or at the time of rupture of membranes, and repeated every 4 hours until time of delivery.
E. coli is becoming a more common cause of bacteremia in young infants and is usually associated with a urinary tract infection. Therefore, it is important to do a urinalysis, followed by a urine culture if the urinalysis is abnormal.
Herpes Simplex Virus, or HSV, is another pathogen that you have to worry about in this age.
HSV-1 and HSV-2 commonly infect the face and genitalia. HSV can remain latent for periods of time and then reactivate to cause an active infection, which can then be transferred to the infant. The risk of transmission to the infant is highest if the maternal infection is a primary genital infection and the infant is born vaginally. Mothers with a known history of recurrent genital herpes should be offered suppressive antiviral therapy, such as acyclovirXXX, beginning at 36 weeks gestation to help decrease the risk of transmission.
Approximately 85% of HSV infections in neonates occur during the intrapartum period – meaning during delivery, and about 10% occur postnatally – or after delivery.
Neonatal HSV presents in 1 of 3 forms:
1. Approximately 25% will have disseminated infection,
2. 30% will have central nervous system infection, and
3. 45% will have mucocutaneous infection of the skin, eyes, and mouth
For every neonatal sepsis evaluation, it is crucial to identify the maternal HSV status. Find out if the laboring parent had lesions at the time of delivery, whether they were treated, and if it was a primary or recurrent infection. Also examine the baby for any rashes as described during the physical exam. Although it is important to note that many infants with Neonatal HSV will not have a visible rash, so this cannot be used to rule-out HSV as a potential source of infection.
OK, let’s now talk about types of infection.
Bacteremia – a bacterial infection in the blood stream – is the primary cause of neonatal sepsis – and is present in about 82% of documented cases. Pneumonia accounts for another 5%, and meningitis for about 4%. You might be asked by your resident or attending: if more than 80% of sepsis is from bacteremia, is a blood culture enough? Of course, the answer will be no. Not only will you be missing 20%, you also have to remember that a blood culture alone cannot serve as the sole means of diagnosis, as many cultures can be negative due to low colony count, use of antenatal maternal antibiotics, and small blood volumes collected. Remember that you often cannot get much blood from a newborn.
Let’s talk about what a sepsis workup entails. You will get the following:
- Serial CBC’s with differential – in particular, assess the WBC count, absolute neutrophil count, and percentage of immature cells
- Blood culture
- Lumbar puncture for cerebrospinal fluid – or CSF- should be considered and discussed. As previously mentioned, only 4% of infants with early onset sepsis have meningitis, so in some cases, obtaining CSF can be deferred. However, you also don’t want to miss it because it can be devastating. Certainly if the blood culture is positive, if the infant is not improving with antibiotic therapy, or if the infant becomes lethargic, irritable, or has clinical seizures, CSF should be obtained without delay and antibiotic dosing should be adjusted to dosing for meningitis.
- In many centers, inflammatory markers, such as a C-reactive protein or procalcitonin, are also done.
- Urinalysis and urine culture
- Chest xray if there are respiratory symptoms
- If you have concern for HSV infection, your labs will also include surface swabs of the eyes, nares, mouth, and anus, cerebrospinal fluid, and blood to send to the lab for HSV PCR testing.
Now that we know our main pathogens: GBS, E coli, strep viridans, Listeria, and possibly HSV, we can select our antimicrobial coverage.
Ampicillin (a B-lactam) paired with gentamicin (an aminoglycoside) is the classic combination. Ampicillin will provide coverage for GBS, Strep viridans, and Listeria. Gentamycin covers E coli and other gram negative organisms. Additionally, as was discussed in the episode about choosing antibiotics, this combination provides bactericidal synergism to cover our most common bacterial pathogens. Another commonly used option is Ampicillin and an expanded spectrum cephalosporin, like Cefotaxime.
Acyclovir should be added for HSV coverage as appropriate.
With regards to treatment,
For an ill-appearing neonate, obtain labs and CBC, CRP, and appropriate cultures immediately, and start antibiotics without delay.
For a well appearing neonate with isolated fever and no evident source of infection, the approach is more nuanced. You will want to reference the American Academy of Pediatrics Clinical Practice Guidelines for evaluation and management of a well-appearing febrile infant 8 to 60 days old for your next steps. I’ve put the link in the Show Notes, and it may be helpful to pull up these guidelines when you have a patient for whom you’re worried about sepsis, as the clinical guideline algorithms can be somewhat complex.
The first thing you will want to identify is the patient’s age in days. Treatment for a 8-21 day old will differ from that of a 22-28 day old or a 29-60 day old, based on the incidence rates and risk stratification by age. In essence, the guidelines are stricter for younger infants, given an increased incidence of sepsis before 21 days of life, and become more liberal as the infant gets closer to 60 days.
For infants 8-21 days, the management is most conservative. Presume sepsis until proven otherwise. Obtain blood cultures, urinalysis, urine culture, and CSF, evaluate for risk of HSV, and start empiric antimicrobials. Urine should be obtained by in-and-out catheter, to ensure the sample is not contaminated. If urinalysis is abnormal, send urine cultures as well.
Empiric antibiotic coverage in this age range is still ampicillin and an aminoglycoside (like gentamicin) or ampicillin and an expanded spectrum cephalosporin (such as cefotaxime or cefepime) for coverage of E. coli, GBS, Listeria, and Enterococcus. However, local antibiotic susceptibility patterns should always be considered.
If the infant is 22-28 days old, you may pause before obtaining a lumbar puncture. Get urine, blood cultures and inflammatory markers first. Again, urine should be obtained by in-and-out catheter, to ensure the sample is not contaminated. If urinalysis is abnormal, send urine cultures as well. If inflammatory markers are abnormal, a lumbar puncture is necessary and antimicrobials should be started. If all labs are normal, you can consider watching and waiting and observation rather than immediately performing a lumbar puncture and obtaining CSF cultures. However, watchful waiting does mean careful observation, almost always in the hospital either on the pediatric inpatient unit or in the neonatal ICU.
One of the most important take-home messages from this podcast is that if you are ever concerned enough about a young infant to obtain blood cultures, you should monitor them for any changes in vital signs or clinical exam for at least 36-48 hours while monitoring for blood culture results. This means admitting the infant to the hospital for monitoring for at least that duration of time.
The guidelines for 29-60 day old infants are similar. Obtain urinalysis, blood culture, and inflammatory markers. If inflammatory markers are increased, proceed with urine culture, lumbar puncture, and start empiric antibiotics. If inflammatory markers are normal, but urinalysis is positive, obtain urine culture and start appropriate antibiotics for treating a UTI. In this case, you do not have to obtain CSF unless the infant changes clinically or if the infant’s blood culture is positive. If both inflammatory markers and urinalysis are normal, you can defer further testing and monitor clinically without initiation of antibiotics while blood cultures are processing. If they remain without growth for 36-48 hours, and the infant continues to be well appearing, you can discuss safe discharge of the infant home with a plan for close follow up with their PCP.
In conclusion, remember that infants in the first 2 months of life are at high risk for sepsis. So if a young infant has fever, temperature instability, or is acting irritable or lethargic, you need to think about sepsis.
OUTRO:
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