Table 2 Summary of endpoint definitions for pediatric sepsis, severe sepsis, and septic shock

Sepsis

International definitions

9 (33.3)

Schlapbach et al.¹ International Consensus Criteria: Phoenix Sepsis Criteria. Potential life-threatening organ dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems in children with suspected or confirmed infection—2 or more points:

 • Respiratory: PaO₂:FIO₂, mmHg (score 0: ≥ 400 to 3: <100 and IMV) or SpO₂:FIO₂, % (score 0: ≥ 292 to 3: <148 and IMV).

 • Cardiovascular: Vasoactive medication (score 0: none to 2: ≥ 2).

 • Cardiovascular: Lactate, mmol/L (score 0: < 5, 1: 5–10.9, 2: ≥ 11).

 • Age based: MAP, mmHg (score 0 to 2, by age in months and years).

 • Coagulation: Platelets, x10³/µl (score 0: ≥ 100 to 1: < 100).

 • Coagulation: International normalized ratio (score 0: ≤ 1.3 to 1: > 1.3).

 • Coagulation: D-dimer, mg/L FEU (score 0: ≤ 2 to 1: > 2).

 • Coagulation: Fibrinogen, mg/dL (score 0: ≥ 100 to 1: < 100).

 • Neurological: Glasgow Coma Scale (score 0: >10; pupils reactive to 2: fixed pupils bilaterally).

..

Goldstein et al.⁴⁷ International Pediatric Sepsis Consensus Conference. Suspected or present source of infection plus at least two SIRS criteria, one of which must be abnormal temperature or leukocyte count:

 • Core Temperature: > 38.5 °C or < 36 °C.

 • Tachycardia or bradycardia (if < 1 year).

 • Tachypnea or mechanical ventilation.

 • Abnormal leukocyte count or > 10% bands.

7 (25.9)

Rhodes et al.⁴⁸ Surviving Sepsis Campaign Guidelines: Life threatening organ dysfunction caused by a dysregulated host response to infection. The authors using this definition also specify as follows:

 • Signs and symptoms of inflammation.

 • Signs and symptoms of infection.

 • Rectal Temperature: 38.5 °C or 35 °C.

 • Tachycardia.

 • Signs of altered function in at least one of the following organs: mental status, hypoxemia, increased serum lactate levels, or bounding pulses.

1 (3.7)

Unspecified application of Weiss et al.¹⁴ Surviving Sepsis Campaign International Guidelines and Singer et al.²² Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)—SOFA ≥ 2:

 • Respiration: PaO₂:FIO₂, mmHg (score 0: ≥ 400 to 4: < 100 with respiratory support).

 • Coagulation: Platelets, x10³/µl (score 0: ≥ 150 to 4: < 20).

 • Liver: Bilirubin, mg/dL (score 0: < 1.2 to > 4: 12.0).

 • Cardiovascular: MAP, mmHg (score 0: ≥70 to 1: <70).

 • Cardiovascular: Vasoactive medication and dose given (score: 2 to 4).

 • Central nervous systems: GCS score (score 0: 15 to 4: < 6).

 • Renal: Creatinine, µmol/L (score 0: <1.2 to 4: >5.0).

 • Renal: Urine output, mL/d (score 3: < 500 to 4: < 200).

1 (3.7)

Treatment and diagnostic codes

10 (37.0)

Intention-to-treat: decision of senior clinician of sepsis being likely. Treatment with intravenous antibiotics.

1 (3.7)

Scott et al.⁵⁰ Improving Pediatric Sepsis Outcomes Collaborative Investigators. Intention-to-treat criteria.

 • Intravenous antibiotics.

 • ≥2 intravenous fluid boluses or ≥ 1 bolus and a vasoactive agent within 6 hours and a blood culture within 72 hours.

2 (7.4)

Eisenberg et al.⁴⁹ and Scott et al.⁵⁰: Receipt of intravenous anti-infective infusion and either an intravenous vasoactive infusion or one of ≥ 2 boluses of isotonic intravenous fluid, ≥ 35 mL/kg intravenous bolus fluid, or ≥ 2 L intravenous fluid. Diagnostic code for sepsis entered.

1 (3.7)

Infection and organ dysfunction with receipt of intravenous antibiotics and at least two 20 mL/kg boluses of isotonic fluid within 6 hours of presentation; based on the Improving Pediatric Sepsis Outcomes Collaborative expert panel.

1 (3.7)

Disseminated infection with systemic inflammatory response syndrome within 24 hours of emergency department arrival resulting in major or extreme severity of illness: assigned by the 3 M Corporations All Patient Refined—Diagnosis-related Groups algorithm.

2 (7.4)

ICD-10 who had discharge diagnosis of sepsis: systemic inflammatory response syndrome and suspected infection—microbiological culture and antibiotic administration in 72 hours, or antibiotic administration with cultures in 24 hours).

1 (3.7)

ICD-10 combined with intensive care unit transfer.

1 (3.7)

ICD-9-CM and ICD-10-CM R-Codes and explicit microbiological codes for sepsis.

1 (3.7)

Mortality

2 (7.4)

In-hospital mortality and early death (within 72 hours of hospital arrival) or requirement of extracorporeal membrane oxygenation support.

1 (3.7)

Mortality within 30 days of intensive care unit admission, calculated using the length of intensive care unit and hospital stay for those who died in either setting.

1 (3.7)

Other

3 (11.1)

A modified Delphi process by the Pediatric Sepsis Predictor Standardization working group and hospital admission.

1 (3.7)

Vital sign thresholds derived from a multi-centered database of approximately 1.2 million emergency department visits.

2 (7.4)

Severe sepsis

International definitions

5 (18.5)

Goldstein et al.⁴⁷ International Pediatric Sepsis Consensus Conference. Sepsis criteria plus one of:

 • Cardiovascular organ dysfunction.

 • Acute respiratory distress syndrome.

 • Two or more other organ dysfunctions (i.e., Neurologic, Hematologic, Renal, Hepatic).

5 (18.5)

Treatment and Diagnostic codes

2 (7.4)

ICD-9 codes; cardiovascular dysfunction definitions were modified because it was not possible to assign causal attribution for fluid-refractory hypotension, and exam components could not be determined retrospectively.

1 (3.7)

ICD-9-CM and ICD-10-CM R-Codes and explicit microbiological codes for sepsis.

1 (3.7)

Infection and organ dysfunction that is not responsive to intravenous antibiotics or at least two 20 mL/kg of fluid boluses, requiring vasopressors and ongoing resuscitation with more than two 20 mL/kg of fluid boluses with intensive care management; based on the Improving Pediatric Sepsis Outcomes Collaborative expert panel.

1 (3.7)

Other

4 (14.8)

Sepanski et al.⁵¹ screening algorithm results.

 • Modified SIRS: two abnormal measures, one of which must be heart rate (by age) or respiratory rate (by age), and the other one temperature (by neonate or non-neonate age), WBC (by age), or > 10% bands.

 • And one major organ dysfunction (i.e., Respiratory, Cardiovascular).

 • Or at least two minor organ dysfunctions (i.e., Respiratory without mechanical ventilation, Hematologic, Renal, Hepatic).

1 (3.7)

Sepsis with organ dysfunction developing within 48 hours of emergency department arrival. Vital sign thresholds derived from a multi-centered database of ∼1.2 million emergency department visits.

2 (7.4)

Septic shock

International definitions

6 (22.2)

Schlapbach et al.¹ International Consensus Criteria: Phoenix Sepsis Criteria. Potential life-threatening organ dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems in children with suspected or confirmed infection—Sepsis and ≥ 1 cardiovascular point(s).

..

Goldstein et al.⁴⁷ International Pediatric Sepsis Consensus Conference. Sepsis criteria plus cardiovascular organ dysfunction despite adequate fluid resuscitation.

4 (14.8)

Weiss et al.¹⁴ Surviving Sepsis Campaign International Guidelines: a severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion).

1 (3.7)

Singer et al.²² Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3): SOFA ≥ 2 using PELOD-2 cut offs for MAP and creatinine.

 • Respiration: PaO₂:FIO₂, mmHg (score 0: ≥ 400 to 4: < 100 with respiratory support)

 • Coagulation: Platelets, x10³/µl (score 0: ≥ 150 to 4: < 20)

Liver: Bilirubin, mg/dL (score 0: < 1.2 to > 12.0)

 • Cardiovascular: MAP, mmHg (by age in months)

 • Cardiovascular: Vasoactive medication and dose given (score: 2 to 4)

 • Central nervous systems: GCS score (score 0: 15 to 4: < 6)

 • Renal: Creatinine, µmol/L (by age in months)

 • Renal: Urine output, mL/d (score 3: < 500 to 4: < 200)

2- or 6-point rise in PELOD-2:

 • Neurologic: GCS score (score 0: ≥ 11, 1: 5–10, 4: 3–4)

 • Pupillary reaction (score 0: both reactive, 5: both fixed)

 • Cardiovascular: Lactatemia, mmol/L (score 0: < 5.0, 1: 5.0–10.9, 4: ≥ 11.0)

 • Cardiovascular: MAP, mmHg (by age in months)

 • Renal: Creatinine, µmol/L (by age in months)

 • Respiratory: PaO₂:FIO₂, mmHg (score 0: ≥ 61, 2: ≤ 60)

 • Respiratory: PaCO₂, mmHg (score 0: ≤ 58, 1: 59–94, 3: ≥ 95)

 • Respiratory: Invasive ventilation (score 0: No, 3: Yes)

 • Hematologic: WBC count, x10⁹/L (score 0: > 2, 2: ≤ 2)

 • Hematologic: Platelets, x10⁹/L (score 0: ≥ 142, 1: 77–141, 2: ≤ 76)

Adequately fluid resuscitated as per Weiss et al.¹⁴ Surviving Sepsis Campaign International Guidelines: 40 mL/kg of fluids in a 3-hour window or resuscitation target met for MAP at the 5^th percentile or higher for age.

Given vasopressors, serum lactate > 2 mmol/L.

1 (3.7)

Treatment and diagnostic codes

4 (14.8)

Within the first 24 hours after arrival: systolic hypotension and the administration of vasoactive medication or isotonic crystalloids.

2 (7.4)

Eisenberg et al.⁴⁹: Patients with sepsis who received an intravenous vasoactive medication within 24 hours of arrival. Diagnostic code for septic shock entered.

1 (3.7)

Infection and organ dysfunction that is not responsive to intravenous antibiotics or at least two 20 mL/kg of fluid boluses, requiring vasopressors and ongoing resuscitation with more than two 20 mL/kg of fluid boluses with intensive care management; based on the Improving Pediatric Sepsis Outcomes Collaborative expert panel.

1 (3.7)

Mortality

2 (7.4)

In-hospital mortality and early death (within 72 hours of hospital arrival) or requirement of extracorporeal membrane oxygenation support.

1 (3.7)

Mortality within 30 days of intensive care unit admission, calculated using the length of intensive care unit and hospital stay for those who died in either setting.

1 (3.7)