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1、新生儿脓毒症,Neonatal Sepsis,Most common cause of neonatal mortality in developing countries.Up to 20%of neonates develop sepsis and 1%die of sepsis related causes.Incidence of systemic infection is 3%(India)with septicemia(75%)and pneumonia(25%)NNP Network,2005,Early and Late-onset Sepsis,NeoReviews,Vol.
2、11,No.8,August 2010,Neonatal Sepsis,SepticemiaPneumoniaMeningitisArthritisOsteomyelitisUrinary tract infection NNP Network,2005,Neonatal Sepsis,Intramural admissions-Klebsiella pneumoniae(32.5%)-Staphylococcus aureus(13.6%)Extramural admissions-Klebsiella(27.5%)-S aureus(38%)Sankar et al.Indian j Pe
3、diatr.2008;75:261-6,Neonatal Sepsis-Definitions,Probable sepsis(any one criteria):-Maternal fever or foul smelling amniotic fluid-PROM(24 hrs)or gastric polymorphs(5 hpf)-Positive sepsis screen(any two criteria)-Total WBC count(0.2)-Total WBC count 1mg/dl,micro ESR 10 mm-first hour-Radiological evid
4、ence of pneumonia NNF,India,Neonatal Sepsis-Definitions,Culture positive sepsis-Isolation of the pathogen from blood,CSF,urine or abscess 72 hours of age Pathological evidence of sepsis on autopsy,NNF,India,Neonatal Sepsis-Incidence,Incidence of EOS is 1-2 cases/1000 live births.This incidence is 10
5、 fold higher in the VLBW infants.Incidence of early onset GBS has declined 80%from 1.7 cases/1000 live births(1993)to 0.34/1000 live births(2005)due to intrapartum antibiotic prophylaxis.Mortality 2.6%in term and 35%in VLBW infants.Survivors of EOS may have severe neurologic sequelae attributable to
6、 meningitis,hypoxemia,septic shock,PPHN etc.,Puopolo KM.NeoReviews 2008;9:e571-579,Neonatal Sepsis-Classification,Early onset sepsis(24 hours)More than three vaginal exam during laborProlonged and difficult delivery with instrumentationPerinatal asphyxia(apgar 4 at 1min)or difficult resuscitation(pr
7、esence of 3-treat,Presence of 2-sepsis screen),Aggarwal et al.India j Pediatr.2001;68:1143-7,Neonatal Sepsis-Classification,Late onset sepsis(72 hours)usually nosocomial or community acquired)Risk factors:NICU admissionPoor hygieneLow birth weightPoor cord carePrematurityBottle feedingInvasive proce
8、dureSuperficial infection(pyoderma,umbilical sepsis)VentilationAspiration of feeds,Puopolo,K.,NeoReviews 2008,9;571-e579,Organisms Causing Neonatal Early-onset Sepsis,Organisms Causing Early-onset Sepsis in Very Low-birthweight Infants,Puopolo,K.,NeoReviews 2008,9;571-e579,Risk Factors for All Cause
9、s of Early-onset Sepsis in Infants Weighing Less than 2000 g at Birth in the Era of Intrapartum Antibiotic Prophylaxis,Puopolo,K.,NeoReviews 2008,9;571-e579,Risk Factors for Early-onset GBS Sepsis in the Absence of IAP,Puopolo,K.,NeoReviews 2008,9;571-e579,“Early”Pathogens(first week),Group B Strep(
10、GBS)Incidence used to be 4-6/1000 live births(0.4%)Now 0.1%after prenatal screening guidelinesE.coliEvery few decades flips back and forth with GBS as most common causeGram negative rods(esp.in urine)Occasional Salmonella sepsisListeria monocytogenesHerpes SimplexEnterovirus,“Late”Pathogens(1-2 week
11、s),GBS or group A strepEnterics/Enterococcus in urineHSVEnterovirus,RSV,Flu,Community Acquired(after 4-6 weeks),PneumococcusMeningococcusGABHSHaemophilus influenzae(HIB)not really a problem anymore,Signs/Symptoms,Temperature irregularityFeverHypothermiaTone and BehaviorPoor toneWeak suckShrill cryWe
12、ak cryIrritability,SkinPoor perfusionCyanosisMottlingPallorPetechiaeUnexplained jaundice,Most by themselves mean little,but three(or two)strikes and you are Out!,Signs/Symptoms,Feeding ProblemsVomitingDiarrheaAbdominal distensionHypo or Hyperglycemia,CardiopulmonaryTachypneaRetractionsTachycardia fo
13、r ageBradycardia in first few days of lifeHypotension for ageLow PO2,Signs/Symptoms,Sunken fontanelleBulging or pulsating fontanelleNeck stiffness CAN NOT be usedBabies can be bacteremic but look wellPresence of a“cold”does not change anything,PIDJ April 2005,Study in India found that any two of the
14、se signs had an almost 100%sensitivity for sepsis and over 90%mortality,Reduced suckingWeak cryCool extremitiesVomitingPoor toneRetractions,Neonatal Sepsis-Investigations,Blood culture(1ml sample adequate)possible to detect growth in 24 hours using BACTEC or BACT/ALERT systemsTotal WBC count(0.2CRP
15、1mg/dl or Micro-ESR 15mm/hrLP(incidence of meningitis 0.3-3%)In EOS LP is indicated in the presence of+blood culture or symptoms of septicemiaIn LOS,LP should be done in all infants prior to starting antibiotics,Neonatal Sepsis-Investigations,LP should not be done in the following cases:-Asymptomati
16、c babies investigated for maternal risk factors-Premature babies with RDS-Critically ill and hemodynamically unstable babies,Normal CSF Values in the Newborn,Neonatal Sepsis-Investigations,Urine culture should not be part of sepsis evaluation in the first 72 hours of life.In LOS urine culture should
17、 be obtained by suprapubic puncture or catheterization.UTI diagnosis:10WBC/mm in a 10 ml centrifuged sample 10 organisms/mL in catheterized specimen Any organism in a suprapubic specimen,Neonatal Sepsis-Investigations,Chest X ray in case of respiratory distress or apneaAbdominal X Ray if suspecting
18、necrotizing enterocolitis,Neonatal Sepsis-Newer Diagnostic Tests,Acute phase reactantsCell surface markersGranulocyte colony stimulating factorCytokinesMolecular geneticsMol cell proteomics,Acute Phase Reactants,These endogenous peptides are produced by the liver as part of immediate response to inf
19、ection or injuryC-reactive proteinProcalcitoninFibronectinHaptoglobinLactoferrinNeopterinOromucosoid,Human C-reactive Proteincomplexed with Phosphocholine,Five identical subunits(protomers)that are arranged around a central pore,NeoReviews,2005;6:e508-515,What is CRP?,Non-type-specific somatic polys
20、accharide fraction extracted from Streptococcus pneumoniae.“Fraction C”as it was called was precipitated by sera of acutely infected patients and sera of convalescent patients lost the ability to cause precipitation.Acute phase reactant protein composed of five identical nonglycosylated polypeptide
21、subunits.It is synthesized in hepatocytes,regulated at the transcription level by interleukin(IL)-6 and IL-1-beta.The exact function of CRP is not known.CRP activates complement and has a functional effect on phagocytic cells and play an important role in the first line of host defense.CRP may be a
22、key component in lipid metabolism and contribute to the pathogenesis of atherosclerosis and myocardial infarction.,CRP Values in the Blood,In healthy adults:0.8mg/LIn infants:10mg/LStarts with in 4-6 hours after stimulation and peaks around 36-48 hours.Biologic half life is 19 hours with 50%reductio
23、n daily after the acute phase stimulus resolves.Measuring CRP concentration in CSF is unreliable.,Cell Surface Markers and Granulocyte Colony Stimulating Factors,Neutrophil CD 11b and CD 64 appear to be promising markers.CD 64 had sensitivity of 80%and specificity of 79%in culture proven sepsis.CD 1
24、1b had a sensitivity of 96-100%and specificity of 81-100%in culture proven sepsis.GSF,mediator produced by the bone marrow facilitates proliferation of neutrophils in sepsis.A concentration of 200pg/ml has a sensitivity of 95%and specificity of 99%.,Procalcitonin(PCT),PCT is produced by the monocyte
25、s and hepatocytes and is propeptide of calcitonin.PCT rises 4-6 hours after exposure to bacterial endotoxin peaking at 6-8 hours.Half life of PCT 25-30 hours.Elevated concentrations are found in RDS,IDM and hemodynamically unstable infants.PCT values of 2.3ng/ml and CRP 30mg/L indicates a high likel
26、y hood of late onset sepsis.,CRP Concentration in Sepsis(Sensitivity,Specificity,Predictive Values),Serial measurements in early and late onset sepsis showed the best cut off value of 10mg/L(Stanford)CRP concentration was normal in 30%of all sepsis episodes.PPV was 5%for culture proven early onset s
27、epsis and 43%in late onset sepsis.Greater elevation in CRP concentrations were associated with higher probability of infection.Negative predictive value was highest both for early and late onset sepsis after three values(99.7 and 98.7)Two CRP concentration 10mg/L obtained 24 hours apart makes sepsis
28、 unlikely.,Benitz et al.Pediatrics.1998;102:e41,C-reactive Protein:rate Nephalometry,NeoReviews,2005;6:e508-515,Light scattered isProportional to concentration of antigen,Factors That Can InfluenceCRP Values,Mode of delivery Gestational age Type of organism causing sepsis Granulocytopenia Surgery Im
29、munizations Severe viral infections(eg,herpes simplex virus,rotavirus,influenza),NeoReviews,2005;6:e508-515,Cytokines in Sepsis,Cytokines mediate communication between cells of the body by binding to specific cellular receptors and transducing signals in to different target cells with biologic effec
30、ts that play a role in the pathogenesis of sepsis.Interleukin-6(mononuclear phagocyte)has been consistently shown to increase in early onset sepsis,but sensitivity is reduced at 24-48 hours as the concentration rapidly falls and becomes undetectable at 24 hours(Normal plasma concentration of IL6 is
31、10pg/mL)Combined measurement of IL6(early sensitive)with CRP(late and specific)in the first 48 hours improves sensitivity compared to either marker alone.,Mehr et al.pediatr Infec Dis J.2000;19:879-87,Cytokines in Sepsis,IL8 is proinflammatory cytokine(mononuclear phagocyte)that is considered to be
32、an accurate marker with sensitivities ranging from 80-91%and specificities 76-100%.A combination of IL8(70pg/ml)and CRP(10mg/L)showed a sensitivity of 80%and a specificity of 87%.TNF and median IL6 values were significantly higher in patients with sepsis compared to controls.,Franz et al.Pediatrics
33、2004;114:1-8,Molecular Genetics in Sepsis,Polymerase chain reaction(PCR)analysis relies on the fact that bacteria specific 16S rRNA gene is conserved in all bacterial genomes and is a useful method for identification of bacteria in clinical samples.PCR assay is challenging due to small amount of res
34、idual DNA present reagents resulting in false positivity.Detection by PCR does not yield the antimicrobial pattern of the pathogen.Real time PCR combined with DNA Micro Array technology will allow identification and antimicrobial sensitivity of the organism.Proteomics:Significant alterations in the
35、levels of eight serum proteins were found in infected neonates.,Start Parenteral Antibiotic(Ab)Send Cultures(report in 72 hrs.),Culture-ve,Clinically well(Stop Ab),Clinically ill(Cont Ab x 7-100),Culture+ve,Pneumonia,Sepsis(Cont Ab x 7-100),Meningitis,Osteomyelitis(Cont Ab x 3-6 wks),CRP Guided Deci
36、sion for Early Onset Sepsis,NeoReviews,2005;6:e508-515,CRP Guided Decision for Late Onset Sepsis,NeoReviews,2005;6:e508-515,Antibiotic Therapy,Early onset sepsis:-Ampicillin and Gentamicin or CefotaximeHospital acquired infection:-Vancomycin/Oxacellin/Cefotaxime(6070%of Gm negative organisms are res
37、istant)MRSA:-Vancomycin/Ciprofloxacin/AmikacinEnterococus:-Ampicillin and Gentamicin Psuudomonas:-Piperacilli-tazobactam with Amikacin Penicillin resistant staphylococcus:Cloxacillin,Nafcillin or Methicillin,Adjunctive Therapy,Intravenous Immune Globulin(IVIG):There is insufficient evidence to suppo
38、rt the routine use of IVIG in suspected or proven sepsis.Granulocyte colony stimulating factor(G-CSF):Insufficient evidence to support the use of G-CSF.Exchange transfusion:Has not been well studied in neonatal sepsis.May be used with caution in certain situations(DIC,severe metabolic acidosis)Pentoxifylline:This is a methylxanthine that has been postulated to modulate the activity of RES and decrease the neutrophil activation that contributes to acute injury.,Tripathi S et al.Internet Journal of medical update 2010;5:45-54,
