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,NeoRev
2、iews, Vol.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%) Sa
3、nkar et al. Indian j Pediatr.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 E
4、SR 10 mm-first hour -Radiological evidence 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-
5、2 cases/1000 live births.This incidence is 10 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 EO
6、S may have severe neurologic sequelae attributable to 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 instrumentationPerin
7、atal asphyxia (apgar 72 hours) usually nosocomial or community acquired) Risk factors:NICU admissionPoor hygieneLow birth weightPoor cord carePrematurityBottle feedingInvasive procedureSuperficial infection (pyoderma, umbilical sepsis)VentilationAspiration of feeds,Puopolo, K., NeoReviews 2008, 9;57
8、1-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 Causes of Early-onset Sepsis in Infants Weighing Less than 2000 g at Birth in the Era of Intrapartum Antibiotic Prop
9、hylaxis,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 (GBS)Incidence used to be 4-6/1000 live births (0.4%)Now 1mg/dl or Micro- ESR 15mm/hrLP (incidence of m
10、eningitis 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: -Asymptomatic babies investigated for maternal risk
11、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 be obtained by suprapubic puncture or
12、 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 necrotizing enterocolitis,Neonatal Se
13、psis-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 infection or injuryC- reactive proteinPr
14、ocalcitoninFibronectinHaptoglobinLactoferrinNeopterinOromucosoid,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 polysaccharide fraction extracted fr
15、om 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 subunits.It is synthesized in
16、 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 key component in lipid m
17、etabolism 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% reduction daily after the a
18、cute 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 11b had a sensitiv
19、ity 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 monocytes and hep
20、atocytes 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 likely ho
21、od 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
22、 sepsis 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 70pg/ml)and CRP (10mg/L) showed a sensi
23、tivity 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 2004;114:1-8,Molecular Genetics in Sepsis,Polymerase chain reaction (PCR) analysis relies on the fact that bacteria specific 16S rRNA gene
24、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 residual DNA present reagents resulting in false positivity.Detection by PCR does not yield the antimicrobial pattern of the pathogen.Real t
25、ime PCR combined with DNA Micro Array technology will allow identification and antimicrobial sensitivity of the organism.Proteomics: Significant alterations in the levels of eight serum proteins were found in infected neonates.,Start Parenteral Antibiotic (Ab)Send Cultures (report in 72 hrs.),Cultur
26、e - 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 Decision for Early Onset Sepsis,NeoReviews, 2005;6:e508-515,CRP Guided Decision for Late Onset Sepsis,NeoReviews, 2005;6:e508-515,An
27、tibiotic Therapy,Early onset sepsis: -Ampicillin and Gentamicin or CefotaximeHospital acquired infection: -Vancomycin/ Oxacellin/Cefotaxime (6070% of Gm negative organisms are resistant)MRSA: -Vancomycin/Ciprofloxacin/ AmikacinEnterococus: -Ampicillin and Gentamicin Psuudomonas: -Piperacilli-tazobac
28、tam with Amikacin Penicillin resistant staphylococcus: Cloxacillin, Nafcillin or Methicillin,Adjunctive Therapy,Intravenous Immune Globulin (IVIG): There is insufficient evidence to support the routine use of IVIG in suspected or proven sepsis.Granulocyte colony stimulating factor (G-CSF): Insuffici
29、ent 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,
