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Future Directions in the Evaluation and Management of Neonatal Sepsis

Future Directions in the Evaluation and Management of Neonatal Sepsis

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DOI: 10.1542/neo.13-2-e1032012;13;e103
AlexanderMicah Bhatti, Alison Chu, Joseph R. Hageman, Michael Schreiber and Kenneth
Future Directions in the Evaluation and Management of Neonatal Sepsis
 http://neoreviews.aappublications.org/content/13/2/e103located on the World Wide Web at:The online version of this article, along with updated information and services, is
ISSN: .60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Printthe American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,it has been published continuously since . Neoreviews is owned, published, and trademarked byNeoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,
 at Health Internetwork on February 7, 2012http://neoreviews.aappublications.org/ Downloaded from 
FutureDirections in the Evaluation andManagement of Neonatal Sepsis
Micah Bhatti, MD, PhD,*Alison Chu, MD,* JosephR. Hageman, MD,
Michael Schreiber, MD,*Kenneth Alexander, MD,PhD*Author DisclosureDrs Bhatti, Chu,Hageman, Schreiber,and Alexander havedisclosed no financialrelationships relevantto this article. Thiscommentary does notcontain a discussion of an unapproved/investigative use of a commercial product/device.
 Although sepsis is one of the important etiologies of illness in hospitalized infants, it isoften dif 
cult to determine if an infant is truly infected and, moreover, how to treat these infections. To address the
rst issue, researchers have begun to examine techni-ques to shorten the amount of time it takes to culture and identify organisms. Onthe clinical side, the development of biomarkers may help physicians to better identify infants who are likely ill from infection versus those infants who are unstable fromother processes. The ability to distinguish between these cohorts will help to curtailexcessive use of empirical antibiotics. Even if infants are determined to truly have in-fection on the basis of a positive culture, it is becoming more challenging to appropri-ately treat causative organisms, as multidrug resistance becomes more prevalent.Furthermore, it becomes more important to evaluate strategies to prevent these infec-tions before they occur.
After completing this article, readers should be able to:1. Understand new developments in serum biomarker research.2. Recognize the steps in identifying infectious organisms and how current research intonew laboratory techniques may be able to expedite this process.3. Understand the uses and limitations of less well-known antimicrobial agents intreating multidrug-resistant infections.4. Understand the importance of hand hygiene and careful central catheter use inpreventing neonatal infection.5. Become familiar with recent research on the utility of nutrition, including earlyenteral feeding, human milk, and lactoferrin, in the prevention of infection.
One of the most challenging aspects of neonatal sepsis is determining if an infant who isclinically unstable is truly infected. To improve our ability to accurately detect sepsis, re-search has been conducted assessing the use of various biomarkers. In addition, advance-ments in medical microbiology have led to faster detectionof pathogens in blood samples. Another challenge to themanagement of critically ill infants is the emergence of multidrug-resistant (MDR) organisms that will require neo-natologists to use unfamiliar antibiotics with well-known tox-icities.InthewakeofMDRorganismsandlimitedantibiotics,hospitals have implemented rigorous prevention programs. We will review advances in the prevention and diagnosis of neonatal sepsis and the treatment of MDR infections.
Advances in Sepsis Detection
Clinical sepsis is de
ned as a whole-body in
ammatory state(systemic in
ammatory response syndrome) and the pres-ence of a known or suspected infection. (1) This seemingly 
central line
associated bloodstream infections
C-reactive protein
early onset sepsis
group B streptococcal
heart rate characteristics
late onset sepsis
polymerase chain reaction
whole-cell mass spectrophotometry 
*Pritzker School of Medicine, University of Chicago, Chicago, IL.
Department of Pediatrics, NorthShore University Health System, Evanston, IL, and Professor Emeritus of Pediatrics, FeinbergSchool of Medicine, Northwestern University, Chicago, IL.
infectious diseases
Vol.13 No.2 February 2012
 at Health Internetwork on February 7, 2012http://neoreviews.aappublications.org/ Downloaded from 
straightforward de
nition poses two major challenges.First, although many clinicians almost automatically as-cribe neonatal systemic in
ammatory response syndrometo infection, the causes of this syndrome are myriadand include many noninfectious processes. Second, thesensitivity of blood cultures for identifying pathogenicbacteria may be lower in neonates than in adults becauseof previous antibiotic treatment, small specimen vol-umes,andlow-gradebacteremia.(2)(3)Complicatingmat-ters, it can take up to 48 hours to detect an organism onthe basis of blood culture by using current methods (4)and then an additional 24 to 48 hours before the iden-tity and antibiotic sensitivities are known. During thistime, empirical antibiotics are administered.To improve the diagnosis of neonatal sepsis, new tech-nologies are being introduced in clinical laboratories that  will reduce the time required to identify a potential patho-gen. In addition, various biomarkers and heart rate charac-teristics(HRC)monitoringarebeingassessedtodetermine whether it is possible to rapidly identify infected neonates.
HRC Monitoring
Research into cardiac electrical patterns has revealed that reduced variability and transient decelerations in heart rate may be early indicators of clinical instability and arehypothesized to be mediated by the cholinergic anti-in
ammatory pathway. (5) The HRC index is a statisti-cally derived interpretation of the beat-to-beat variationin a patient. (6) A low index indicates normal variation,but as normal variation is lost, the index rises, as does therisk of clinical deterioration. A recent randomized con-trolled trial of 
3,000 very low birth weight infants re- vealed that the use of HRC monitoring signi
cantly decreased the 30-day mortality rate after a septic-likeevent without a signi
cant increase in antibiotic days.(5) The mechanism by which mortality is decreased inthemonitoredcohortremainsunclear. In aseparatestudy,neonates with culture-proven sepsis had a statistically higher HRC during the 24 hours leading up to the septicepisode compared with healthy controls. (6) However,neonates with culture-negative, septic-like events had astatistically similar rise in HRC. Therefore, HRC is ableto serve as an early warning of impending clinical insta-bility, and additional research is needed to determine if it can differentiate between true sepsis versus a culture-negative, septic-like event.
Serum Biomarkers
 Although a positive blood culture remains the standardfor diagnosing neonatal sepsis, many investigators haveassessed measuring the host response as an adjunct toculture-based diagnosis. The goal of serum biomarkerresearch is to identify a means by which an infectedchild can be identi
ed rapidly, before the onset of life-threatening symptoms. A good diagnostic host markerfor sepsis with a high negative predictive value wouldreduce the inappropriate use of antibiotics, health carecosts, and lengths of hospital stays. (7) An ideal bio-marker should be elevated early in the course of infec-tion and stay elevated for a suf 
cient period to provideopportunity for sampling. The biomarker should have well-de
ned values to differentiate infected from non-infected infants, with a very high sensitivity and negativepredictive value. (8) It also is helpful if its values re
ect the progression of disease and response to therapy. (8)Several serum biomarkers have been evaluated as poten-tial indicators of neonatal sepsis.C-reactive protein (CRP), the most commonly usedbiomarker, is synthesized within 6 hours of exposureto an infectious process and usually becomes abnormal within 24 hours. (7) Because CRP takes up to 24 hoursafter the onset of an infection to become abnormal, it haslittle utility in assisting in the early detection of sepsis. CRPisalsolimitedinthatotherprocessesinadditiontoinfectioncan result in elevation, including trauma and ischemia. (7)It does have a high speci
city, between 93% and 100%;thus,anormalCRPinaseptic-appearingneonateisunlikely to be ill because of an infectious process. Levels generally remain elevated until the infection is controlled; therefore,CRP can serve as a marker of successful treatment.Procalcitonin (PCT) is a 116
amino acid peptideprecursor to calcitonin that rises in response to most infections and some in
ammatory processes. (9) Theincrease of PCT in sepsis seems to correlate with theseverityandmortalityofdisease,andincreasesinPCToc-cur more rapidly than increases in CRP. (10) A meta-analysis of 22 studies found that PCT was more accuratein the diagnosis of late onset sepsis (LOS) than CRP. (9) A separate meta-analysis included 29 studies and founda pooled sensitivity and speci
city of 81% and 79%, re-spectively. (11) In the neonate, PCT is increased duringthe
rst 2 days of life and is theorized to be secondary toperipartum proin
ammatory changes, making it less diag-nostic during this time period. (12) Levels can also beelevatedininfantswithnoninfectiousprocesses,suchasre-spiratory distress syndrome, hemodynamic failure, andperinatal asphyxia, as well as postresuscitation. (10)Other immunologic markers are being studied fortheir utility in the detection of neonatal sepsis. Proin
am-matory cytokines such as interleukin-6 and interleukin-8 were initially thought to be excellent markers for detect-ing infection, but the very short half-life of circulating
infectious diseasesfuture of neonatal sepsis
Vol.13 No.2 February 2012
 at Health Internetwork on February 7, 2012http://neoreviews.aappublications.org/ Downloaded from 

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