Abstract
Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial and immune system dysfunction. We searched the PubMed and EMBASE databases from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject heading terms and text words related to concepts of pediatric organ dysfunction. Electronic searches were conducted by medical librarians. Studies were eligible for inclusion if they reported original data collected in critically ill children, evaluated performance characteristics of scoring tool(s) or clinical assessments for organ dysfunction, and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction employing iterative voting and discussion. While the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.
Keywords: organ dysfunction, critical illness, children
Table of Contents Summary:
We present evidence-informed, consensus criteria for organ dysfunction in critically-ill children, following systematic reviews of the literature on organ dysfunction clinical assessments and scoring tools.
Introduction
Pediatric critical care largely focuses on preventing, stabilizing and hastening resolution of dysfunctional organ systems. Even in the best pediatric intensive care units (PICUs), recalcitrant multiple organ dysfunction syndrome (MODS) represents the most common antecedent for death.1–3 Multiple investigations have ascertained that risk for mortality in the PICU is associated with number of dysfunctional organs in a dose-response fashion.1,4–9 More recently, risks for short and long-term morbidity following pediatric critical illness, assessed as functional status or health-related quality of life, were strongly associated with intensity and duration of organ dysfunction.4,9,10
Although the history of pediatric MODS is rich with theory and controversy, confirmation of a unifying mechanism(s) for MODS as an underlying feature of critical illness pathophysiology remains elusive.11–13 Clinical phenotypes, with individual treatment approaches, have been proposed for pediatric MODS14,15 A recent survey of parents and care providers of critically ill children reported that following survival and functional status/health-related quality of life, duration of organ dysfunction was identified as the next most important outcome for a hypothetical interventional trial enrolling critically ill children.16
Despite its paramount importance in the practice of pediatric critical care, clinicians and researchers have relied on historical expert consensus definitions of organ dysfunctions that were derived in 2004 for the conduct of the RESOLVE trial of activated protein C (Xigris, Lily) for pediatric septic shock.17 Results of this consensus conference were published in 2005 as a supplement to Pediatric Critical Care Medicine and represent the most frequently cited reference for this journal.18 Accordingly, in March 26–27, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) convened a group of nearly 30 experts (clinicians, basic scientists, bioengineers, and others) in Rockville, Maryland, to discuss a research agenda for pediatric MODS with an ultimate goal of improving outcomes for children who experience this common syndrome. The workshop was sponsored by the Office of Science Policy, Analysis and Communication of the NICHD. A summary of this first Pediatric MODS Workshop was subsequently published as a supplement to Pediatric Critical Care Medicine in 2017.19
In addition to the development of new program announcements related to pediatric MODS (Research to Advance the Understanding and Management of MODS in Children, PAR-18–091, etc), the other immediate, clear directive that emerged during this workshop, was the organization of a grassroots, Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Collaborative. The PODIUM Collaborative focused on the notion that in order to advance knowledge related to pediatric MODS, the field required clearer, updated definitions and common data elements for MODS overall, as well as for individual organ dysfunction, particularly given the wealth of novel data that had been published on this subject over the preceding decade.
The PODIUM Collaborative addressed the key question, “What are the performance characteristics of currently used scoring tools and clinical assessments to screen for single and multiple organ dysfunction among critically ill children?” The long-term goal of the PODIUM Collaborative is to improve outcomes for children with MODS. The overall objectives of this work are to widely disseminate validated contemporary definitions of single and multiple pediatric organ dysfunction.
This executive summary describes the methodology and presents the final set of evidence-based pediatric organ dysfunction criteria. Additional details are provided in the accompanying manuscripts published as a Supplement in Pediatrics.refPODIUMOrganSpecificSystematicReviews The feasibility and the roadmap for the PODIUM project were established in 2016 in consultation with methodologists from the Johns Hopkins Evidence-based Practice Center (KAR) and informed by targeted evidence assessment by the Scientific Resource Center for Agency for Healthcare Research and Quality (AHRQ)’s Effective Health Care (EHC) Program. The methods for development of criteria characterizing organ dysfunction in critically ill children consisted of several predefined phases: 1) conduct twelve systematic reviews including identification, assessment, and synthesis of published literature on scoring tools and clinical assessments used for single and multiple organ dysfunction; 2) develop criteria indicating single organ dysfunction, including rationale and supporting evidence for each; and 3) undertake iterative voting for consensus building.
Definitions
Critically ill children were defined as admitted to an intensive care unit or cared for in an emergency department or hospital ward and at risk for admission to an intensive care unit. Pediatric age was defined as birth to <18 years, excluding critically ill premature babies (<37 weeks gestation) cared for in a neonatal intensive care unit. There are several available methods to identify organ dysfunction in critically ill children. We therefore did not require a specific definition for individual organ dysfunction, as we were interested in capturing a broad range of clinical, laboratory, physiological and imaging scoring and assessment tools utilized to screen for and identify organ dysfunction.
Selection and Organization of Panel Members
The selection of panel members was initiated by experts invited to participate in the aforementioned NICHD Pediatric MODS Workshop in 2015. Invitations were extended to experts based on their record of publication on organ dysfunction topics, and their leadership and participation in multicenter pediatric critical care clinical research studies during the prior five years. Two co-chairs were identified (MMB and JJZ) who were responsible for coordination of in-person meetings, conduct of educational webinars, overview of the systematic review and voting processes, and proofreading and editing of manuscripts for journal submission. Chair(s) for each subgroup were then identified and were charged with coordination of subgroup meetings and discussions, supervision of the subgroup’s progress in the conduct of their respective systematic review, evaluation of evidence for their subgroup’s topic, and oversight of the subgroup’s identification of criteria for organ dysfunction, accompanying rationales, any revisions needed based on voting results, and manuscript drafting. Subgroups were formed by subtopic, as follows: MODS as a unifying diagnosis; individual organ dysfunction: neurologic, respiratory, cardiovascular, gastrointestinal, hepatic, renal, hematologic, coagulation, endocrine, immune, and endothelial; and data analysis and validation.
A total of 92 panelists were identified based on their record of peer reviewed publications on the subtopic of interest, with 4 eventually withdrawing due to time constraints. The final list of 88 panelists representing 47 institutions and 7 countries constituted the PODIUM Collaborative. Conflict of interest disclosures were sought from all panelists before the start of the systematic reviews, and again at the time of journal submission. All work was conducted voluntarily, without compensation.
Systematic Reviews and Data Synthesis
We set out to answer two key questions (KQ): “What are the performance characteristics of currently used scoring tools and clinical assessments to screen for 1) single and 2) multiple organ dysfunction in critically ill children?” We identified 11 subtopics for KQ1 and one topic for KQ2. The subtopics for KQ1 were specific to the following organ systems: neurologic, respiratory, cardiovascular, gastrointestinal, hepatic, renal, hematologic, coagulation, endocrine, immune, and endothelial. We developed Population, Intervention, Comparators, and Outcomes (PICO) questions specific to each of the 11 organ systems as well as for multiple organ dysfunction as listed in Table 1 of the Effective Health Care Pediatric MODS Topic Brief.20 The 12 systematic reviews are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.21 The protocol for the 12 systematic reviews was registered on PROSPERO (CRD42018090500).
Table 1.
PODIUM: Criteria for organ dysfunction in pediatric critical illness
| Organ system | Criterion for organ dysfunction | Suggested thresholds | Conditions | Severity |
|---|---|---|---|---|
| Neurologic | GCS | ≤8 | None | Not graded |
| GCS-m | ≤4 | None | Not graded | |
| CAPD | ≥9 | None | Not graded | |
| EEG background attenuation and suppression; electrographic seizure activity | NA | Not applicable in patients with history of seizures or acute neurological injury on admission | Not graded | |
| Respiratory | PaO2/FiO2 | ≤ 300 | If on HFNC (≥ 1.5 L/kg/min or ≥ 30 LPM), NIV, non-rebreather, or venturi; FiO2 ≥ 0.4 in all modes of support | Non-severe |
| SpO2/FiO2 | ≤ 264 | •→ If on HFNC (≥ 1.5 L/kg/min or ≥ 30 LPM), NIV, non-rebreather, or venturi; FiO2 ≥ 0.4 in all modes of support •→ When 80% ≤ SpO2 ≤ 97% |
Non-severe | |
| Ventilatory failure (obstructive lung disease, e.g. asthma, without oxygenation failure) | NIV | If on HFNC (≥ 1.5 L/kg/min or ≥ 30 LPM), NIV, non-rebreather, or venturi; FiO2 ≥ 0.4 in all modes of support | Non-severe | |
| Invasively ventilated | If invasively ventilated | Non-severe | ||
| OI = (FiO2 × MPAW × 100)/PaO2 | ≥ 4 to < 16 | If invasively ventilated | Non-severe | |
| ≥ 16 | If invasively ventilated | Severe | ||
| OSI = (FiO2 × MPAW × 100)/SpO2 | ≥ 5 to < 12.3 | •→ If invasively ventilated •→ When 80% ≤ SpO2 ≤ 97%) |
Non-severe | |
| ≥ 12.3 | •→ If invasively ventilated •→ When 80% ≤ SpO2 ≤ 97%) |
Severe | ||
| ECLS for any respiratory failure | NA | If invasively ventilated | Severe | |
| CVa | Venoarterial ECLS, temporary or durable LVAD or RVAD support | NA | None | Severe |
| Cardiac Arrest | NA | None | Severe | |
| Heart rate (HR) | >2SD above normal for age •→ 0–7 days: HR>180 •→ >1 week – 1 m: HR>180 •→ >1 m – <1 y: HR>180 •→ >1 y – <6 y: HR>160 •→ 6 y – <13 y: HR>150 •→ 13 y – <18 y: HR>130 |
If present at the same time as any of the other criteria for CV organ dysfunction | Not graded | |
| Systolic blood pressure (SBP) | More than 2SD below normal for age •→ 0–7 days: SBP<50 •→ >1 week – 1 m: SBP<70 •→ >1 m – <1 y: SBP<75 •→ >1 y – <6 y: SBP<75 •→ 6 y – <13 y: SBP<80 •→ 13 y – <18 y: SBP<80 |
If present at the same time as any of the other criteria for CV organ dysfunction | Not graded | |
| Vasoactive-Inotropic Scoreb | ≥5 | If present at the same time as any of the other criteria for CV organ dysfunction | Not graded | |
| Serum lactate | ≥3 – <5 mmol/L | If present at the same time as any of the other criteria for CV organ dysfunction | Non-severe | |
| ≥5 mmol/L | If present at the same time as any of the other criteria for CV organ dysfunction | Severe | ||
| Serum troponin I | 0.6 – 2.0 ng/mL | If present at the same time as any of the other criteria for CV organ dysfunction | Non-severe | |
| >2.0 ng/mL | If present at the same time as any of the other criteria for CV organ dysfunction | Severe | ||
| Central venous oxygen saturation | <70% | If present at the same time as any of the other criteria for CV organ dysfunction •→ In patients without cyanotic congenital heart disease •→ Ideally sampled from right atrium or pulmonary artery in a patient without intracardiac abnormalities, but proximal SVC and IVC acceptable. •→ Whole blood laboratory assay as standard, but consider validated continuous invasive monitoring |
Not graded | |
| Echocardiographic estimation of left ventricular ejection fraction | 30% – <50% | If present at the same time as any of the other criteria for CV organ dysfunction | Non-severe | |
| <30% | If present at the same time as any of the other criteria for CV organ dysfunction | Severe | ||
| Renal | Urine outputc | <0.5 mL/kg/hr for ≥6 hours | Concomitant serum creatinine increase 1.5–1.9 times baselined OR ≥0.3 mg/dL (≥26.5 μmol/L) increase | Not graded |
| <0.5 mL/kg/hr for ≥12 hours | None | Not graded | ||
| Serum creatinine | Increase 1.5–1.9 times baselined OR ≥0.3 mg/dL (≥26.5 μmol/L) increase | Concomitant urine outputc <0.5 mL/kg/h for ≥6 hours | Not graded | |
| Increase ≥2 times baselined | None | Not graded | ||
| eGFR | Decrease to <35 mL/min/1.73m2 | Excludes neonates <30 days of age | Not graded | |
| Initiation of RRT | NA | Initiation of RRT for any reason other than toxic ingestion or hyperammonemia | Not graded | |
| Fluid overloade | 20% | Measured starting 48 hours after ICU admission | Not graded | |
| GI | Bowel ischemia | Bowel perforation OR pneumatosis intestinalis OR ischemia present on gross inspection (surgical) or by plain abdominal film, CT, or MRI Sloughing of gut |
None | Severe |
| Hepaticf | AST | >100 IU/L | Absent hemolysis or myopathy (Wilson disease is an exception as severe Coombs-negative hemolysis may be present) Presence of liver-based coagulopathy coupled with hepatic encephalopathyg |
Not graded |
| ALT | >100 IU/L | Absent hemolysis or myopathy (Wilson disease is an exception as severe Coombs-negative hemolysis may be present) Presence of liver-based coagulopathy coupled with hepatic encephalopathyg |
Not graded | |
| GGT | >100 IU/L | Absent biliary obstruction Presence of liver-based coagulopathy coupled with hepatic encephalopathyg |
Not graded | |
| Total bilirubin | >5 mg/dL (>85.5 μmol/L) | Absent suspected Gilbert’s disease Presence of liver-based coagulopathy coupled with hepatic encephalopathyg |
Not graded | |
| Direct or conjugated bilirubin | >2 mg/dL (>34.2 μmol/L) | Absent biliary obstruction Presence of liver-based coagulopathy coupled with hepatic encephalopathyg |
Not graded | |
| Liver-based coagulopathy coupled with hepatic encephalopathy | PT ≥15 seconds or INR ≥1.5 accompanied by clinical hepatic encephalopathy For those with a PT ≥20 seconds or INR ≥2.0, HE is not required, but should be assessed. Hepatic encephalopathy is determined by age specific grading scales (Tables 2 and 3 in the PODIUM Online Supplement, Acute Liver Dysfunction Section) (refPODIUMSupplement) |
Presence of: AST >100 IU/L OR ALT >100 IU/L OR GGT >100 IU/L OR Total bilirubin >5 mg/dL (>85.5 μmol/L) OR Direct or conjugated bilirubin >2 mg/dL (>34.2 μmol/L) To ensure vitamin K deficiency is not a principal component of the coagulopathy, a single dose of intravenous vitamin K (1 mg for infants up to 10 mg in adults) is administered with repeat PT/INR determined 6–8 hours later. |
Not graded | |
| Hematology | Platelet countg | <100,000 cells/μL | Patients without underlying hematologic or oncologic diagnoses | Not graded |
| <30,000 cells/μL | Patients with underlying hematologic or oncologic diagnoses | Not graded | ||
| 50% decrease from baselineh | Patients with baseline thrombocytopenia regardless of etiology (i.e., baseline platelet count <100,000 cells/ μL) | Not graded | ||
| Leukocyte count | <3,000 cells/μL | None | Not graded | |
| Hemoglobin | 5 - <7 g/dL | None | Non-severe | |
| < 5 g/dL | None | Severe | ||
| Coagulationi | Platelet count | <100,000 cells/μL | •→ Absent liver dysfunction •→ Presence of at least one additional coagulation dysfunction criterion |
Not graded |
| International normalized ratio | >1.5 | •→ Absent liver dysfunction •→ Presence of at least one additional coagulation dysfunction criterion |
Not graded | |
| Fibrinogen | <150 mg/dL (<4.41 μmol/L) | •→ Absent liver dysfunction •→ Presence of at least one additional coagulation dysfunction criterion |
Not graded | |
| D-dimer | >10x the upper limit of normalj or above the assay’s upper limit of detection if this limit is below 10x upper limit of normal | •→ Absent liver dysfunction •→ Presence of at least one additional coagulation dysfunction criterion |
Not graded | |
| Endocrine | Blood glucose | ≥150 mg/dL (≥8.3 mmol/L) | None | Not graded |
| <50 mg/dL (<2.8 mmol/L) | None | Not graded | ||
| Serum total thyroxine (T4) | <4.2 mcg/dL (<54 nmol/L) | Not applicable for patients with pre-existing primary or central thyroid disease | Not graded | |
| Serum cortisol levels pre and post ACTH stimulation test | Peak <18 mcg/dL (500 nmol/L) and/or increment of <9 mcg/dL (250 nmol/L) post ACTH stimulation | Post stimulation cortisol level should be measured at 30 min following a low dose test and 1 hour following a high dose testing. Testing should only be considered in patients with clinical suspicion of primary adrenal insufficiency (e.g., unexplained hyponatremia, hyperkalemia, hypoglycemia and hemodynamic instability). |
Not graded | |
| Immune | Peripheral absolute neutrophil count | <500 cells/μL | None | Not graded |
| Peripheral absolute lymphocyte count | <1,000 cells/μL | None | Not graded | |
| CD4+ T-lymphocyte count | <750 cells/μL | Age <1 y | Not graded | |
| <500 cells/μL | Age 1 y – 5 y | Not graded | ||
| <200 cells/μL | Age ≥6 y | Not graded | ||
| CD4+ T-lymphocyte percentage of total lymphocytes | <26% | Age <1 y | Not graded | |
| <22% | Age 1 y – 5 y | Not graded | ||
| <14% | Age ≥6 y | Not graded | ||
| Monocyte HLA-DR expression (where clinically available)l | < 30% | None | Not graded | |
| Ex vivo LPS-induced TNFα production capacity (where clinically available)k | Below manufacturer provided thresholds | None | Not graded |
GCS, Glasgow Coma Score; GCS-m, Glasgow Coma Score motor response; CAPD, Cornell Assessment of Pediatric Delirium; EEG, electroencephalography; HFNC, high flow nasal cannula; LPM, liters per minute; NIV, non-invasive ventilation; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; OI, oxygenation index; OSI, oxygenation saturation index; MPAW, mean airway pressure; PaO2, partial pressure of oxygen in arterial blood; SpO2, pulse oximetry oxygen saturation; ECLS, extracorporeal life support; CV, cardiovascular; SD, standard deviation; m, month; y, year; SVC, superior vena cava; IVC, inferior vena cava; LVAD, left ventricular assist device; RVAD, right ventricular assist device; CT, computed tomography; MRI, magnetic resonance imaging; eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; PT, prothrombin time; INR, international normalized ratio; ACTH, adrenocorticotropic hormone; HLA-DR, Human Leukocyte Antigen – DR isotype; LPS, lipopolysaccharide; TNFα, tumor necrosis factor alpha
Criteria for cardiovascular dysfunction in patients who have cardiovascular dysfunction in the setting of critical illness, excluding patients: 1) with underlying cyanotic congenital heart disease, and 2) those who underwent cardiopulmonary bypass (CPB) during the episode of care (i.e., the ICU admission). These criteria are not intended to assess or grade post-CPB impaired cardiac output or inflammatory state.
Vasoactive Inotropic Score = dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 10 × milrinone dose (μg/kg/min) + 10,000 × vasopressin dose (units/kg/min) + 100 × norepinephrine dose (μg/kg/min)
Consider ruling out obstructive uropathy in the setting of low urine output
Use the lowest serum creatinine value available in the 3 months prior to admission as the baseline serum creatinine. If a prior serum creatinine is unavailable, baseline creatinine should be extrapolated from a normal eGFR for age and an appropriate estimating equation. In many critically ill children, heights are unavailable, making a height-independent equation preferential. The table in supporting documents, providing estimated baseline creatinine values based on a height-independent equation and normal reference eGFR for age. These creatinine values are derived from a healthy pediatric population1 and have been validated in critically ill children2.
Fluid overload can be defined by input/output or weight-based calculations. For weight-based determination, FO = [(Current weight − ICU admission weight)/ICU admission weight] × 100. For input/output based determination, FO = {[Sum of daily (fluid in − fluid out)]/ICU admission weight} × 100. Use of weight-based formula for fluid overload is preferential if weight data are available.
Condition that has to be met for all acute liver dysfunction criteria: no known evidence of chronic liver disease with duration of symptoms <8 weeks
For the purposes of defining hematologic failure, thrombocytopenia should exist in the absence of coagulation dysfunction (i.e., presence of at least 2 of the 4 PODIUM Coagulation Dysfunction criteria).
For patients with underlying hematologic or oncologic disease and baseline thrombocytopenia, both <30,000 and 50% decrease from baseline criteria must be met.
We propose that in the absence of acute liver dysfunction as defined by PODIUM, at least 2 of the 4 criteria should be present to define coagulation dysfunction. However, it should be noted that studies investigating combinations of these criteria are not available. The clinical context should be taken into account when applying these criteria in defining coagulation dysfunction. Furthermore, the proposed criteria have not been validated in children on mechanical circuits (extracorporeal life support/ventricular assist device/continuous renal replacement therapy/cardiopulmonary bypass) and, as such, may not be useful in these populations due to the effects of the circuit and associated anticoagulation therapy.
Foaud HM, Labib JR, Metwally HG, El-Twab KM. Plasma D-dimer as a Prognostic Marker in ICU Admitted Egyptian Children with Traumatic Brain Injury. J Clin Diagn Res. 2014 Sep;8(9):PC01–6.
These tests may be clinically available outside the U.S.
We searched the PubMed and Embase databases from 1992 to October 2017, with an update conducted in January 2020, using a combination of medical subject heading terms and text words for concepts of organ dysfunction specific to each subtopic, and outcomes.20 Electronic searches were conducted by medical librarians at the William H. Welch Medical Library, Baltimore, MD. Search strategies, dates conducted, and number of resulting citations are detailed in Data Supplement, Supplemental Table 1.
Studies were eligible for inclusion if they reported original data collected from critically ill pediatric patients (<18 years), evaluated the performance characteristics of scoring tool(s) or clinical assessments for organ dysfunction, and assessed an included outcome: mortality (e.g., PICU mortality, 28-day mortality, hospital mortality, mortality post-discharge), functional outcomes/residual morbidity (e.g., neurofunctional, cognitive, adaptive behavioral, depression, post-traumatic stress disorder, or acute stress disorder), organ-specific outcomes/residual morbidity (e.g., tracheostomy, gastric tube insertion, renal replacement therapy at hospital discharge), outcomes related to MODS (e.g., duration of new or progressive MODS, composite time to complete resolution of organ dysfunction), cost of medical care, and other patient-centered outcomes (e.g., quality of life, symptom improvement, quality of dying, spillover effect of a patient’s health care on loved ones).20
Studies were excluded if the study population consisted of infants born preterm (<37 weeks gestation) or adults (all participants ≥18 years of age, or mixed pediatric and adult population with inability to separate data for patients <18 years). Other exclusion criteria included: animal-only studies, not original data (e.g., editorials, commentaries, meeting proceedings, etc.), case reports or case series with sample size ≤10 participants, abstract-only, and non-English language publications with inability to determine eligibility.
Two independent reviewers identified studies meeting criteria for inclusion, with differences resolved by a third reviewer. PRISMA flowcharts are presented for each PODIUM organ-specific systematic review.refPODIUMOrganSpecificSystematicReviews
Risk of Bias Assessment, Data Abstraction and Synthesis of Included Studies
Risk of bias for included studies was assessed using the Quality in Prognosis Studies (QUIPS) tool.22 Key data elements were extracted from each study using an electronic form developed in REDCap23 and exported into evidence tables. Graphical summaries of the risk of bias assessments and evidence tables for each subtopic are presented for each PODIUM organ-specific systematic review.refPODIUMOrganSpecificSystematicReviews Data synthesis was conducted by organ dysfunction assessment or scoring tool within each subtopic. Quantitative analysis was not pursued due to high heterogeneity among included studies.
Drafting and Developing Agreement for Criteria Indicating Organ Dysfunction
After completion of the systematic reviews, each subgroup proposed a set of criteria for organ dysfunction specific to their subtopic, accompanied by a rationale and supporting literature as identified through the review. In addition, suggested threshold(s), any conditions that would need to be met prior to applying a criterion in a clinical scenario, and severity grading were provided, as applicable. Proposed criteria, accompanying rationales and evidence tables were then disseminated to 60 PODIUM voting members (minimum of 3 from each subgroup), using an online tool that ensured anonymity of responses (Qualtrics, Provo, UT). Each set of criteria was scored using the Research and Development/UCLA Appropriateness scale, ranging from 1 (strongly disagree) to 9 (strongly agree).24 Scores of 1–3 represented disagreement, 4–6 represented equipoise, and 7–9 represented agreement. A comment box was optional for scores in the agreement range, and mandatory for scores in the equipoise and disagreement ranges. The a priori level of agreement was set at ≥80% of PODIUM voters rating organ dysfunction criteria as 7–9. Criteria that did not reach at least 80% agreement were reviewed by the subgroup they originated from, along with comments justifying disagreement or equipoise. They were revised by the subgroup (with justification for revisions) over a period of two weeks. Revised criteria were resent to all PODIUM voters for a second round of voting. The same process was then followed in a third and final round of voting. The three rounds of voting took place between October 18, 2019 to October 31, 2019 (round 1), November 19, 2019 to December 3, 2019 (round 2), and December 18 to December 31, 2019 (round 3). Inter-voting periods were used for revision of criteria that did not meet at least 80% agreement. After review of additional evidence from the January 2020 literature review update, none of the subgroups required revision of already-proposed criteria, however risk of bias and evidence tables were updated accordingly.
In their evaluation of evidence supporting specific scoring tools or clinical assessments of organ dysfunction, each subgroup was instructed to discuss feasibility and usability of each proposed criterion (e.g., is a laboratory test routinely obtained in the intensive care unit, are there cost limitations, is the test/assessment tool invasive, resource intensive, or difficult to interpret).
Lastly, each PODIUM subgroup identified knowledge gaps during the process of the literature review and proposed priorities for future preclinical and clinical research. Research priorities were submitted to the full PODIUM membership for ranking on a five-tier priority scale.
PODIUM Organ Dysfunction Criteria
Based on evidence assessed through each organ-specific systematic review of currently used scoring tools and clinical assessments to screen for single organ dysfunction, organ dysfunction criteria were proposed for all individual organ systems, with the exception of endothelial dysfunction. Following the systematic review of the literature on endothelial dysfunction assessment tools, no published assessment tools or biomarkers were identified that adequately screened for or identified endothelial cell activation (i.e., acquisition of new cellular functions to restore homeostasis) or dysfunction (i.e., loss or inappropriate exaggeration of cellular functions worsening pathologic changes) in critically ill children.
A total of 40 criteria were proposed initially. Eight criteria were added and five were removed during voting rounds #2 and #3 based on feedback from PODIUM membership. There were 43 criteria remaining after the iterative voting process described above. Median agreement scores (IQR, range) and percent agreement for each of the three voting rounds are detailed in Data Supplement, Supplemental Table 2.
The organ dysfunction scoring tools and clinical assessments proposed by PODIUM are summarized in Table 1 of this executive summary. The evidence tables and rationale supporting each criterion are presented in each PODIUM organ-specific systematic review.ref12PODIUMOrganSpecificSystematicReviews
The top two priorities for future research identified by each PODIUM organ subgroup, and further prioritized through voting across the entire voting PODIUM membership, are summarized in Table 2 of this executive summary.
Table 2.
PODIUM: Research Priorities for the Study of Organ Dysfunction in Critically Ill Childrena
| PODIUM: Research Priorities |
|---|
| Develop and validate tools that use routine clinical data from the electronic health record that allow for automated and longitudinal calculation of scores to be made available for “real-time” clinical assessment |
| Develop scores to predict – rather than diagnose or describe – organ dysfunction |
| Identify trajectories or early warning signs of cardiovascular dysfunction in critical illness for prediction of clinical deterioration to cardiopulmonary arrest or institution of mechanical circulatory support. Can these be used to target early intervention in this high risk population? |
| Validate urinary biomarkers of AKI/renal dysfunction: a) appropriate thresholds in children, in particular non-cardiac populations, b) use of biomarkers to derive and target MODS-AKI phenotypes, c) development of a clinical renal function panel |
| Compare the epidemiology and outcomes of MODS as a syndrome versus co-existing, but pathobiologically distinct, multiple concurrent organ dysfunctions |
| Identify biomarkers (e.g. proteomic and/or transcriptomic signatures) of immune system dysregulation in critically ill children; to develop high-throughput, rapid-turnaround tests for these biomarkers; and to move them to clinical laboratory and/or the bedside for the diagnosis and management of immune system failure in critically ill children |
| Validate objective scoring systems for neurologic dysfunction in pediatric MODS that can be used longitudinally to detect a) patients at risk for neurologic injury, b) progression of injury, and c) resolution/repair of the injury |
| Ascertain impact of bundled care for AKI (e.g. use of balanced fluids, nephrotoxin avoidance, diuretics) |
| Identify and prognosticate according to existing and emerging technology (somatic and cerebral NIRS, analyses of cardiac index, echocardiographic parameters) in the assessment of cardiovascular dysfunction in critical illness. Can any be associated with improvement in clinical status with therapy? |
| Correlate biomarkers to physiological function and measured clinical parameters is also important. Unbiased, large scale analysis, so called “-omics" approaches, should be employed to monitor multiple variables simultaneously and provide novel insights into disease pathology |
| Evaluate host-microbial interactions in the gastrointestinal tract |
| Define coagulation dysfunction using different combinations of the laboratory tests included in the proposed criteria in children off and on mechanical circuits is a high research priority |
| Expand the definition of respiratory failure in MODS beyond gas exchange. Oxygenation and ventilation are nonspecific, affected by cardiac function, and do not address pathophysiology. Biomarkers of lung epithelial and endothelial disruption may provide additional structural and pathophysiologic information. Can biomarkers of pulmonary damage improve the definition of respiratory MODS? |
| Investigate the performance of von Willebrand factor, antithrombin, thrombomodulin, mean platelet volume, thromboelastography/thromboelastometry to further define coagulation dysfunction |
| Explore correlation with critical illness outcomes and consider implications for clinical research for markers of adrenal axis function at the cellular level |
| Facilitate high-throughput, rapid-turnaround tests of leukocyte function (e.g. HLA-DR expression, cytokine production capacity) to the clinical laboratory and/or the bedside for clinical use for the diagnosis and management of immune system failure in critically ill children |
| Determine if effective minute ventilation via invasive or non-invasive measures improve the definition of respiratory MODS. |
| Consider if the definition of hematologic failure should include abnormal function in addition to abnormal quantity of cells/cellular components. |
| Identify mechanistic links between neurological dysfunction and other organ dysfunctions (e.g., exosomes released from liver triggering neurologic involvement, sepsis pathophysiology mechanisms and neurologic dysfunction, etc). |
| Develop a more fundamental understanding of how endothelial cells from various organs and vascular segments differentially respond to stimuli associated with critical illness, focused on human cell models with defined properties of specific vascular segments or organs |
| Develop reliable clinical score and/or biomarkers of feeding intolerance |
| Explore correlation of copeptin (an indirect measure of ADH/vasopressin concentrations) with critical illness outcomes |
| Characterize acute-on-chronic liver failure in children in order to provide a foundation to develop consensus guidelines |
| Determine if red cell distribution width is a clinically relevant biomarker of hematologic failure |
| Characterize disseminated intravascular coagulation in the setting of acute liver failure. |
Abbreviations: PODIUM, Pediatric Organ Dysfunction Information Update Mandate; AKI, acute kidney injury; MODS, multiple organ dysfunction syndrome; NIRS, near infrared spectroscopy; HLA-DR, Human Leukocyte Antigen – DR isotype; ADH, antidiuretic hormone
In descending order of priority based on PODIUM membership ranking
In summary, the PODIUM Collaborative was convened to review published literature on performance characteristics of multiple and single organ dysfunction scoring tools and clinical assessments, and to develop contemporary, evidence-based criteria for organ dysfunction in critically ill children. These goals were achieved by conducting systematic reviews of the literature for single and multiple organ dysfunction scoring tools and assessments, and by building consensus for the resulting criteria. The PODIUM criteria for organ dysfunction are meant to serve as a foundation to researchers to further validate, refine, and combine criteria to: accurately identify patients with single or multiple organ dysfunction; identify patterns of organ dysfunction combinations and temporal trends that constitute unique phenotypes associated with worse outcomes; and serve either as entry criteria or as outcome measures for clinical trials, depending on the nature and scope of the intervention(s) tested.
The PODIUM project has several strengths and limitations. This is the first large-scale summary of existing evidence related to performance characteristics of scoring tools and assessments for organ dysfunction in critically ill children. Previously proposed criteria have been based on expert opinion, with potential bias inadvertently introduced by panel members. All systematic reviews conducted for PODIUM were rigorous, transparent and fully reproducible; the search strategy is published along with this executive summary, thus facilitating regular updates as new evidence and novel tests for organ dysfunction emerge. Special emphasis was placed on developing organ dysfunction criteria that are strongly supported by published studies, and not by expert opinion. In addition, whenever possible, we took into consideration issues of a) feasibility (i.e., tests or clinical assessments that can be conducted routinely in most critically ill children); b) safety (i.e., noninvasive or minimally-invasive tests preferable to invasive tests even if the latter have better performance characteristics); c) equity (i.e., tests or clinical assessments that can be conducted in intensive care units including those with limited resources); d) limitations for timing of assessment (i.e., generalizable to the entire intensive care unit or hospital stay vs studied only on specific days such as day of admission to the intensive care unit); e) barriers to accurate organ dysfunction assessments (i.e., difficult-to-interpret tests or tests requiring high level of training and specialization); f) operationalization (i.e., tests or clinical assessments routinely recorded in electronic medical records that will facilitate future development of clinical decision support tools).
Limitations are related to available data as well as the PODIUM process. There is extreme heterogeneity in categorization of various patient populations among pediatric critical care studies, and in definitions of common data elements (including “basic” data elements such as age categories). This rendered quantitative evaluation of performance characteristics of individual scoring and assessment tools in the form of meta-analyses inappropriate. While the PODIUM Collaborative emphasized diversity of institutions and diversity of age and gender among participating members, initial membership was dictated by participation in the 2015 NIH/NICHD symposium. We acknowledge that, while membership was broadened and included members from seven countries, it is still primarily representative of academic North American pediatric intensive care units.
Conclusions
The PODIUM criteria for organ dysfunction provide a foundation for clinicians and researchers to diagnose and study single and multiple organ dysfunction in critically ill children. These criteria will require further validationNL S-P, et al PODIUM evaluation manuscript and refinement followed by implementation in the clinical environment using bioinformatics tools. The PODIUM process is transparent and reproducible, and thus renders itself to serial updates as new evidence and novel criteria for organ dysfunction emerge.
Supplementary Material
Data Supplement, Supplemental Table 1. PODIUM Organ Dysfunction Criteria: Search Strategies for Systematic Reviews
Data Supplement, Supplemental Table 2. PODIUM Organ Dysfunction Criteria: Voting Results by Subtopic
Funding/Support:
Publication costs for this manuscript were supported by the Johns Hopkins University Discovery Award (MMB), The Richard J. Traystman Endowed Chair at the Johns Hopkins University, and Seattle Children’s Hospital. NIH/NINDS R01NS106292 (MMB).
Abbreviations:
- PODIUM
Pediatric Organ Dysfunction Information Update Mandate
Footnotes
Conflict of Interest Disclosures (includes financial disclosures): The authors have no conflicts of interest to disclose.
The guidelines/recommendations in this article are not American Academy of Pediatrics policy, and publication herein does not imply endorsement.
References
- 1.Leclerc F, Leteurtre S, Duhamel A, et al. Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children. Am J Respir Crit Care Med. 2005;171(4):348–353. [DOI] [PubMed] [Google Scholar]
- 2.Watson RS, Crow SS, Hartman ME, Lacroix J, Odetola FO. Epidemiology and outcomes of pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med. 2017;18(3_suppl Suppl 1):S4–S16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ferreira AM, Sakr Y. Organ dysfunction: General approach, epidemiology, and organ failure scores. Semin Respir Crit Care Med. 2011;32(5):543–551. doi: 10.1055/s-0031-1287862 [doi]. [DOI] [PubMed] [Google Scholar]
- 4.Typpo KV, Petersen NJ, Hallman DM, Markovitz BP, Mariscalco MM. Day 1 multiple organ dysfunction syndrome is associated with poor functional outcome and mortality in the pediatric intensive care unit. Pediatr Crit Care Med. 2009;10(5):562–570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kutko MC, Calarco MP, Flaherty MB, et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med. 2003;4(3):333–337. [DOI] [PubMed] [Google Scholar]
- 6.Leteurtre S, Martinot A, Duhamel A, et al. Validation of the paediatric logistic organ dysfunction (PELOD) score: Prospective, observational, multicentre study. Lancet. 2003;362(9379):192–197. [DOI] [PubMed] [Google Scholar]
- 7.Proulx F, Fayon M, Farrell CA, Lacroix J, Gauthier M. Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest. 1996;109(4):1033–1037. [DOI] [PubMed] [Google Scholar]
- 8.Wilkinson JD, Pollack MM, Glass NL, Kanter RK, Katz RW, Steinhart CM. Mortality associated with multiple organ system failure and sepsis in pediatric intensive care unit. J Pediatr. 1987;111(3):324–328. [DOI] [PubMed] [Google Scholar]
- 9.Typpo K, Watson RS, Bennett TD, et al. Outcomes of day 1 multiple organ dysfunction syndrome in the PICU. Pediatr Crit Care Med. 2019;20(10):914–922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zimmerman JJ, Banks R, Berg RA, et al. Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock. Crit Care Med. 2020;48(3):319–328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Carcillo JA, Podd B, Aneja R, et al. Pathophysiology of pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med. 2017;18(3_suppl Suppl 1):S32–S45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Leteurtre S, Duhamel A, Salleron J, et al. PELOD-2: An update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013;41(7):1761–1773. [DOI] [PubMed] [Google Scholar]
- 13.Lacroix J, Cotting J, Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Severity of illness and organ dysfunction scoring in children. Pediatr Crit Care Med. 2005;6(3 Suppl):126. [DOI] [PubMed] [Google Scholar]
- 14.Carcillo JA, Halstead ES, Hall MW, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med. 2017;18(6):513–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sanchez-Pinto LN, Stroup EK, Pendergrast T, Pinto N, Luo Y. Derivation and validation of novel phenotypes of multiple organ dysfunction syndrome in critically ill children. JAMA Netw Open. 2020;3(8):e209271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Merritt C, Menon K, Agus MSD, et al. Beyond survival: Pediatric critical care interventional trial outcome measure preferences of families and healthcare professionals. Pediatr Crit Care Med. 2018;19(2):e105–e111. [DOI] [PubMed] [Google Scholar]
- 17.Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: A multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–843. [DOI] [PubMed] [Google Scholar]
- 18.Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2–8. [DOI] [PubMed] [Google Scholar]
- 19.Tamburro RF, Jenkins TL. Multiple organ dysfunction syndrome: A challenge for the pediatric critical care community. Pediatr Crit Care Med. 2017;18(3_suppl Suppl 1):S1–S3. [DOI] [PubMed] [Google Scholar]
- 20.Veazie S, Winchell K, Relevo R, Kondo K, Helfand M. Pediatric multiple organ dysfunction syndrome (MODS). https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/TND-0845-170203.pdf. Updated 2017. Accessed October 28, 2020.
- 21.Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ. 2009;339:b2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280–286. [DOI] [PubMed] [Google Scholar]
- 23.Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Fitch K, Bernstein SJ, Aguilar MD, et al. The RAND/UCLA appropriateness method user’s manual. https://Www.rand.org/pubs/monograph_reports/MR1269.html. also available in print form. Santa Monica, CA: RAND Corporation; 2001. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Supplement, Supplemental Table 1. PODIUM Organ Dysfunction Criteria: Search Strategies for Systematic Reviews
Data Supplement, Supplemental Table 2. PODIUM Organ Dysfunction Criteria: Voting Results by Subtopic