Supplemental Table 1: Sepsis definitions used
Lead author, Year, (n) Sepsis definition: specific information Definition
N = 3
Horan et al, 2008, CDC HAIs, (n/a)35
Recognized pathogen cultured from 1 or more blood cultures and at least 1 of the following signs: fever (>38°C), chills, or hypotension
● <1 year of age: at least 1 of the following: fever (>38°C, rectal), hypothermia (<37°C, rectal), apnea, or bradycardia
Clinical sepsis may be used only to report primary BSI in neonates and infants and must meet all of the following:
● At least 1 clinical sign with no other recognized cause [fever (>38°C rectal), hypothermia (<37°C rectal), apnea or bradycardia]
● Blood culture not done or no organisms detected in blood
● No apparent infection at another site, and
● Physician institutes treatment for sepsis Goldstein et al 2005,
Pediatric consensus definition, (n/a)7
SIRS in the presence of or as a result of suspected or proven infection
SIRS is defined as the presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count:
● Core temperature of >38.5°C or <36°C
● Tachycardia, defined as a mean heart rate >2 SD above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise unexplained persistent elevation over a 0.5- to 4-hr time period -OR- for children <1 yr old: bradycardia, defined as a mean heart rate <10th percentile for age in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease; or otherwise unexplained persistent depression over a 0.5-hr time period
● Mean respiratory rate >2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia
● Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or 10% immature neutrophils
Vermont-Oxford Network Database Manual of Operations, Data Definitions, release 17.1, 2013, (n/a)
Positive blood and/or CSF culture
Diagnostic N = 8
Auriti et al, 2012, (n=762)12
Positive blood culture (confirmed) or negative blood culture (suspected)
● Postnatal signs of sepsis included fever (> 38°C, rectal), hypothermia (< 36°C, rectal), tachycardia (HR > 180 beats/min) or bradycardia (HR < 100 beats/min), apnea, lethargy, feeding problems, mottled skin,
convulsions, hypotonia; -OR- at least 2 of the following laboratory findings: leukopenia (WBC < 5,000 mm3), leukocytosis (WBC > 20,000 mm3), thrombocytopenia (< 100,000 mm3), CRP > 15 mg/L, fibrinogen > 150 mg/dL, or metabolic acidosis (base excess of <7 mmol/L); and a positive blood culture result
● Episodes of suspected sepsis were those in which the neonate had at least 2 clinical or laboratory signs suggestive of infection, along with a negative blood culture result
Wu et al, 2013, (n=44)13 Positive blood culture and/or antibiotic therapy for >5d in infants with clinical signs of infection such as persistent cardiorespiratory instability, neutropenia, immature-to-total granulocyte ratio >0.2, and elevated CRP concentrations (value not reported)
Newman et al, 2010, (n=67623)40
Positive blood culture
In many cases, the infants were asymptomatic and the tests were obtained because of maternal risk factors Griffin et al, 2005,
(n=678)37
Positive blood culture (bacteria not ordinarily considered to be a contaminant), antibiotic therapy of > 5d, physician suspected diagnosis
Ng et al, 2010, (n=154)19 Positive bacterial or fungal blood culture
Screening was performed in infants with non-specific signs:
● Unstable temperature (< 36.5°C or > 37.5°C on two occasions within 12h)
● Hemodynamic instability [sudden increase or decrease in HR or persistent tachycardia (> 160/min) or bradycardia (< 100/min), poor peripheral circulation with prolonged capillary refilling time > 3 sec, systemic hypotension or unexplained increase in requirement of vasopressor support to maintain an acceptable MAP]
● Respiratory compromise (progressive increase in FiO2 requirement or ventilatory setting in a previously stable infant, apneic spells, sudden increase in RR or persistent tachypnea (> 60 breaths/min), and central cyanosis due to splinting of diaphragm by the distended abdomen and
● Unexplained metabolic parameters [persistent metabolic acidosis (base deficit ≥ 10) or hyperglycemia (> 10 mmol/L)]
● Probable clinical sepsis-infants presented with at least 3 clinical signs plus evidence of hematologic or metabolic derangements despite negative bacterial culture, was also considered to have sepsis based on strong circumstantial background of the clinical course and laboratory results
Chaaban et al, 2009, (n=573)24
Positive blood culture-Evaluation for sepsis done at the discretion of the neonatal providers for maternal risk factors and signs of sepsis
Ottolini et al, 2003, (n=1665)22
Positive blood culture or culture negative clinical sepsis
● Signs: fever; hypothermia; lethargy; tachypnea; apnea/bradycardia; cyanosis; and hypoglycemia (not explained by other diagnosis)
● Ninety-one percent of the neonates with the diagnosis of sepsis had more than 1 sign, and 77% had > 3.
Three percent (8/300) of infants with sepsis had positive blood cultures with organisms not considered contaminants
Dutta et al, 2010, (n=601)23
Positive blood culture with clinical signs of sepsis -OR- positive blood culture in an asymptomatic baby who was started on prophylactic antibiotics
Intervention N = 7
Kuhn et al, 2009, (n=102)14
Sepsis: Positive blood culture with the same pathogen and increased CRP (> 10 mg/L)
● Possible: clinical “signs” without positive blood culture or increased CRP (> 10 mg/L)
● Pneumonia: increase in the requirements for ventilator support in an intubated neonate, new onset of purulent tracheal aspirates with a predominant organism in cultures, and 2 chest radiographs showing new and persistent infiltrates, plus increased CRP (>10 mg/L)
INIS Collaborative group, 2011, (n=3493)1
Positive blood culture (proven) or suspected serious sepsis with at least one of the following characteristics:
● BW < 1500 g
● Evidence of infection in blood culture, CSF, or usually sterile body fluid; or
● Need for respiratory support through an endotracheal tube.
● Evidence of infection in blood culture, CSF, or normally sterile body fluid [present in 42% of patients in each treatment group (IVIg and placebo)]
Manzoni et al. 2009, (n=321)20
Clinical signs, presence of laboratory findings consistent with sepsis, and isolation of a causative organism from blood (peripheral) or CSF or peritoneal fluid. Diagnostic criteria used but not given
● For Staphylococcus species, diagnosis required 2 positive culture results from peripheral blood drawn within 48 hours or only 1 positive culture result accompanied by a concomitant positive culture result from the CVC (or blood drawn from the CVC) for the same organism. In the case of Staphylococcus aureus, only 1 positive result was required
Poindexter et al, 2004, (n=1433)25
Positive blood or CSF culture (bacteria or fungi) in the presence of compatible clinical signs of septicemia Lin et al, 2008,
(n=434)26
Positive blood culture with clinical signs Weisman et al, 1992,
(n=753)27
Clinical signs consistent with sepsis in association with isolation at autopsy of a causative organism from either blood/CSF culture or a sterile site (e.g., liver, spleen, meninges, lung)
Fanaroff et al, 1994, (n=2416)28
Positive blood culture for bacteria or fungi from an infant with signs compatible with infection.
● CoNS required 2 positive blood cultures obtained no more than 4d apart, either from a central catheter and a peripheral venipuncture or two peripheral venipunctures.
● Probable sepsis: antibiotic treatment for >3 days who had one positive blood culture for a commensal organism and either no subsequent cultures or a negative subsequent culture. The diagnosis of meningitis required a positive culture of CSF.
Outcomes N = 7
Klinger et al, 2010, (n=15839)29
Positive blood culture, defined clinically Been et al, 2009,
(n=301)15
Positive blood or CSF culture (proven) in the first 2 months of life
● Clinical sepsis was a clinical presentation of sepsis with raised CRP (value not reported) Stoll et al, 2004,
(n=6093)6
Positive blood culture and antibiotic therapy for >5d (proven)
● Culture-negative clinical infection: antibiotic therapy for >5d Wynn et al, 2013,
(n=34396)38
Positive blood culture (bacterial or fungal) obtained and antibiotic therapy for >5d or death <5d while receiving therapy
Tita et al, 2009, (n=13258)30
Proven (positive cultures of blood, CSF, or urine obtained by catheterization or suprapubic aspiration;
cardiovascular collapse; or an unequivocal radiograph confirming infection in a neonate with clinical sepsis)
● Suspected (with clinical findings suggesting infection) Bassler et al, 2009,
(n=944)68
Positive blood culture (bacteria, fungi, or viruses)-the decision to obtain blood for culture was at the discretion of the local clinicians
Mitha et al, 2013, (n=2665)39
Confirmed infection of maternal origin on the basis of medical records. Postnatally acquired infection treated with antibiotics for >7d
Observational N = 17
Madan et al, 2012, (n=6)17
Positive blood culture plus SIRS (defined as ≥2 of the following):
● Temperature >38.5°C or <36°C,
● Tachycardia (mean HR >2 SD above normal)
● Tachypnea (mean respiratory rate >2 SD above normal OR mechanical ventilation) and
● Leukocyte count (elevated or depressed)]
Strunk et al, 2012, (n=838)31
Combination of (1) suggestive clinical signs, (2) a positive blood culture (for the diagnosis of CoNS sepsis: only single-organism blood cultures were included),and (3) appropriate antibiotic treatment of ≥5 days
Wynn et al, 2011, (n=17)18
Pediatric consensus criteria for septic shock-from Goldstein et al 20057 [sepsis and cardiovascular organ dysfunction (despite administration of isotonic intravenous fluid bolus >40 mL/kg in 1 hr
● Decrease in BP (hypotension) <5th percentile for age or systolic BP <2 SD below normal for age -OR-
● Need for vasoactive drug to maintain BP in normal range (dopamine >5ug/kg/min or dobutamine, epinephrine, or norepinephrine at any dose)
-OR-
● Two of the following
Unexplained metabolic acidosis: base deficit >5.0 mEq/L Increased arterial lactate >2 times upper limit of normal Oliguria: urine output <0.5 mL/kg/hr
Prolonged capillary refill: >5 secs Core to peripheral temperature gap >3°C
Mercer et al, 2012, (n=417)32
Suspicious clinical findings AND
● Positive blood or CSF culture -OR- Evidence of cardiovascular collapse requiring volume expansion or pressor agents
Weston et al, 2011, (n=658)69
Positive blood or CSF culture (bacteria) Bizzarro et al, 2005,
(n=647)70
Positive blood culture (traditional neonatal pathogen or a commensal species)
● Cultures that yielded CoNS, were reviewed using modified specific criteria of the CDC. Timing sepsis according to the infant’s age when the positive blood culture was obtained as early onset (4d of life), late onset (5–30d), and late, late onset (30d)
Hornik et al, 2012, (n=37826)42
Positive culture [blood, urine collected by catheterization or suprapubic tap or CSF)]
● Definite CoNS = 2 positive cultures drawn on the same day
● Probable CoNS infection as 2 positive cultures within a 4d period, 3 positive cultures within a 7d period or 4 positive cultures within a 10d period
Cohen-Wolkowiez et al, 2009, (n=119130)47
Positive blood culture
● Definite CoNS sepsis as 2 positive blood cultures for CoNS drawn on the same day
● Probable CoNS sepsis as 2 positive blood cultures for CoNS within a 4d period, 3 positive blood cultures for CoNS within a 7d period, or 4 positive blood cultures for CONS within a 10d period;
Escobar et al, 2000, (n=18299)71
Positive culture from a normally sterile site
● Probable infection: clinical course strongly suggested that infection was present, culture results negative
● Possible infection: negative cultures and equivocal clinical findings-infection could not be excluded Kermorvant-Duchemin
et al, 2008, (n=48)36
Hypotension and/or need for intravenous fluid administration or vasoactive drugs, in the presence of proven or highly probable infection
Stoll et al, 2002, (n=6215)16
Positive blood culture
● Definite CoNS infection: 2 positive blood cultures drawn within 2 days of each other or 1 positive blood culture and elevated CRP within 2 days of blood culture
● Possible infection: 1 positive blood culture and patient treated with vancomycin, oxacillin, or a semisynthetic antistaphylococcal agent for >5 days
Hornik et al, 2012, (n=104676)46
Positive culture (blood, urine obtained by suprapubic tap or in-and-out catheterization, or CSF)
● Definite CoNS sepsis as 2 positive cultures on the same day
● Probable CoNS sepsis as 2 positive cultures for CoNS within a 4d period, 3 positive cultures for CoNS within a 7d period, or 4 positive cultures for CoNS within a 10d period
Kingsmore et al, 2008, (n=72)33
Acutely ill presentation
Sixty-three percent of clinically infected samples were associated with positive microbiological culture results.
Ninety-two percent of clinically infected samples were collected while on antibiotics.
Benitz et al, 1998, (n=1002)21
Positive blood, CSF, or urine culture (pathogenic bacteria)
● Probable sepsis if: clinical, radiographic, and laboratory findings were consistent with this diagnosis but cultures were negative
Vergnano et al, 2011, (n=443)72
Positive culture collected from a normally sterile site (blood, CSF, and supra-pubic aspirate) for which clinicians prescribed > 5d of antibiotic treatment
Puopolo et al, 2011, (n=350)73
Positive blood or CSF culture (pathogenic bacteria)
● If CoNS, only considered real if the treating physician considered the infant infected, as evidenced by antibiotic treatment that lasted for 5d or until neonatal death
Fanaroff et al, 1998, (n=2416)34
Positive blood culture (bacteria or fungi) from an infant whose signs were compatible with infection
Abbreviations: SIRS-Systemic inflammatory response syndrome, SD-standard deviation, CSF-Cerebrospinal fluid, HR-heart rate, WBC-White blood cell, CRP-C-reactive protein, D-day, MAP-mean arterial pressure, FiO2-fraction of inspired oxygen, BW –birth weight, IVIg-Intravenous immune globulin, CVC- central venous catheter, CoNS-Coagulase negative Staphylococcus
