Hematologic Dysfunction Criteria in

Critically Ill Children: The PODIUM

Consensus Conference
Jennifer A. Muszynski, MD, MPH,a Jill M. Cholette, MD,b Marie E. Steiner, MD, MS,c Marisa Tucci, MD,d Allan Doctor, MD,e

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Robert I. Parker, MD,f on behalf of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Collaborative

CONTEXT:
Studies of organ dysfunction in children are limited by a lack of abstract
consensus around organ dysfunction criteria.
OBJECTIVES:
To derive evidence-informed, consensus-based criteria for hematologic
dysfunction in critically ill children.
DATA SOURCES:
Data sources included PubMed and Embase from January 1992 to
January 2020.
STUDY SELECTION:
Studies were included if they evaluated assessment/scoring tools
to screen for hematologic dysfunction and assessed outcomes of mortality, functional status,
organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature
infants, animal studies, reviews/commentaries, small case series, and non-English language
studies with inability to determine eligibility were excluded.
DATA EXTRACTION:
Data were abstracted from each eligible study into a standard data
extraction form along with risk of bias assessment.
RESULTS:Twenty-nine studies were included. The systematic review supports the
following criteria for hematologic dysfunction: thrombocytopenia (platelet count <100000
cells/mL in patients without hematologic or oncologic diagnosis, platelet count <30000 cells/
mL in patients with hematologic or oncologic diagnoses, or platelet count decreased $50%
from baseline; or leukocyte count <3000 cells/mL; or hemoglobin concentration between 5
and 7 g/dL (nonsevere) or <5 g/dL (severe).
LIMITATIONS:
Most studies evaluated pre-specified thresholds of cytopenias. No
studies addressed associations between the etiology or progression of cytopenias overtime
with outcomes, and no studies evaluated cellular function.
CONCLUSIONS:
Hematologic dysfunction, as defined by cytopenia, is a risk factor for
poor outcome in critically ill children, although specific threshold values associated with
increased mortality are poorly defined by the current literature.

a
Department of Pediatrics, Critical Care Medicine, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio; bDepartment of Pediatrics, Critical Care Medicine,
University of Rochester, Rochester, New York; cDepartment of Pediatrics, Critical Care Medicine & Hematology, University of Minnesota, Minneapolis, Minnesota; dDepartment of Pediatrics, Critical
Care Medicine, CHU Sainte Justine, University of Montreal, Montreal, QC, Canada; eDepartment of Pediatrics, Critical Care Medicine & Center for Blood Oxygen Transport and Hemostasis,
University of Maryland, Baltimore, Maryland; and fDepartment of Pediatrics, Hematology/Oncology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York

The guidelines/recommendations in this article are not American Academy of Pediatrics policy, and publication herein does not imply endorsement.

Drs Muszynski and Parker contributed to study design, reviewed all included studies, drafted and revised organ dysfunction criteria, drafted the initial manuscript, and reviewed and
revised the manuscript; Drs Cholette, Steiner, Tucci, and Doctor contributed to study design, reviewed all included studies, drafted and revised organ dysfunction criteria, and
reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

PEDIATRICS Volume 149, number s1, January 2022:e2021052888K SUPPLEMENT ARTICLE

Organ dysfunction is consistently METHODS Platelet Count
associated with increased mortality The PODIUM collaborative sought Hematologic dysfunction will be
in pediatric critical illness.1,2 to develop evidence-based criteria defined by a platelet count of
Although many scoring systems for organ dysfunction in critically ill <100 000 cells/μL for patients
have been developed to assess children. The present article without underlying hematologic or
organ dysfunction and to quantify reports the systematic literature oncologic diagnosis, <30 000 cells/
risks of adverse outcomes, there is review on elements of hematologic μL for patients with underlying
no universal agreement on which dysfunction performed as part of hematologic or oncologic diagnosis,
scoring system has the highest PODIUM, proposes evidence-based or $50% decrease from baseline for
predictive power.3–5 This lack of criteria for hematologic dysfunction patients with baseline platelet count

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consensus may in part result from in critically ill children, and <100 000 cells/μL. For the purposes
differences in the criteria and/or provides a critical evaluation of the of defining hematologic dysfunction,
methodologies used to define organ available literature. The PODIUM thrombocytopenia should exist in the
dysfunction. In the case of Executive Summary details absence of coagulation dysfunction
hematologic dysfunction, most Population, Interventions, as defined by PODIUM criteria.
scoring systems include cytopenias Comparators, and Outcomes
that have not been tested in a questions; search strategies; study Rationale
manner to validate specific inclusion and exclusion criteria; and
Thresholds for platelet count are
thresholds or to consider different methodologies for risk of bias
based on Choi et al, the only
etiologies of cytopenia.4,6–8 assessment, data abstraction and
included study that evaluated
Additionally, unlike other organ synthesis, and establishing
thresholds of platelet count
consensus.9 Search terms specific to
systems in which organ function is predictive of clinical outcomes
hematologic dysfunction included
assessed using established stratified by hematologic/oncologic
anemia, hemoglobin, hematocrit,
functional markers, similar markers diagnosis.10 Other studies evaluated
leukopenia, thrombocytopenia,
to assess the function of circulating scoring systems that include platelet
terms addressing red blood cell
hematologic cells have not been well counts (eg, the heme portion of the
(RBC) indices (mean corpuscular
studied. Each of these limitations pediatric logistic organ dysfunction
volume, red blood cell distribution
affects the quality of data available score, the pediatric risk of mortality
width [RDW]), distribution of
to define hematologic dysfunction. neutrophils (neutrophil index, d score, disseminated intravascular
Lastly, hematologic dysfunction has neutrophil index), platelet indices coagulation scores, the Rotterdam
historically been defined by (mean platelet volume, platelet score to predict mortality in
combinations of cytopenias and/or distribution width), and circulating meningococcal sepsis, and the base
the presence of abnormal results on platelet mass (“plateletcrit”). excess platelet count score) or
plasma-based coagulation assays. identified lower platelet count as a
However, except for platelet count, risk factor for mortality.11–22
hemostatic homeostasis is distinct RESULTS
from bone marrow function, and it Of 10 681 unique citations published Leukocyte Count
was decided that the Pediatric between 1992 and 2020, 29 studies Hematologic dysfunction will be
Organ Dysfunction Information were eligible for inclusion (Fig 1). defined by a total leukocyte count
Update Mandate (PODIUM) initiative Data tables (Supplemental Tables 1 <3000 cells/μL.
would consider hematologic and 2) and risk of bias assessment
function and coagulation function as summaries (Supplemental Fig 1) are Rationale
2 separate entities. detailed in Supplemental Low total white blood cell count was
Information. Criteria for hematologic independently associated with adverse
To address the lack of consensus for dysfunction in critically ill children outcomes in several studies. A data-
current definitions of hematologic informed by the evaluated evidence driven threshold was identified in only
dysfunction, we describe here the are in Table 1. A cytopenia that 1 study, which derived a threshold of
meets the following definitions in
results of a structured literature <4000 cells/μL in a small cohort of
any of 1 of the 3 cell-lines (platelets,
search to create evidence-informed, children with meningococcemia.23
leukocytes, or erythrocytes [RBCs])
consensus-based definitions for Other studies evaluated WBC
is considered sufficient for the
hematologic dysfunction in critically thresholds as part of existing scoring
diagnosis of hematologic
ill children as part of the PODIUM systems or did not derive thresholds
dysfunction.
consensus conference series. predictive of outcomes.4,11,12,24 As

S2 MUSZYNSKI et al
 Hemoglobin concentration
Severe hematologic dysfunction will be
defined by a hemoglobin concentration
<5 g/dL. Mild hematologic dysfunction
will be defined by a hemoglobin
concentration of between 5 and 7 g/dL.

Rationale
Hemoglobin <5 g/dL was associated
with higher risk of mortality in

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Kenyan children.27 There are a
paucity of data describing
relationships between anemia and
outcomes in the general PICU
population, and thresholds of
anemia associated with outcomes
are unknown. Although these data
do not exist, the addition of anemia
to the definition of hematologic
dysfunction was felt to be
FIGURE 1 important, and consensus-based
Study flow diagram according to the Preferred Reporting Items for Systematic Review and thresholds are provided.
Meta-Analysis Protocols recommendations.

such, no high-quality data are remains unclear.24 Two studies

DISCUSSION
available to validate or refute evaluated platelet neutrophil product The basis for each of our
thresholds used in existing scoring in children with meningococcal recommendations is largely expert
systems (ie, the pediatric risk of disease.25,26 The platelet neutrophil opinion, as none of our
mortality score).8 A single study product is a promising measure to recommendations were supported by
evaluated absolute neutrophil count assess marrow failure because it randomized clinical studies and only 2
(ANC) in oncology patients admitted includes derangements in 2 cells lines, assessed a cytopenia as a continuous
to the PICU, and although ANC may be each of which are consistently variable to allow determination of a
an important marker of marrow associated with adverse outcomes in discriminative threshold for marrow
failure, applicability of ANC thresholds critical illness, though data to date are failure.10,23 Consequently, most studies
outside of the oncology population limited. were not able to determine specific

TABLE 1 PODIUM: Criteria for Hematologic Dysfunction in Pediatric Critical Illness

Organ system Criterion for organ dysfunction Suggested thresholds Conditions Severity
Hematology Platelet counta <100 000 cells/mL Patients without underlying Not graded
hematologic or oncologic
diagnoses
<30 000 cells/mL Patients with underlying
hematologic or oncologic
diagnoses
$50% decrease from baselineb Patients with baseline
thrombocytopenia
regardless of etiology (ie,
baseline platelet count
<100 000 cells/mm3)
Hematology Leukocyte count <3000 cells/mL None Not graded
Hematology Hemoglobin 5 <7 g/dL None Nonsevere
Hemoglobin <5 g/dL None Severe
a
For the purposes of defining hematologic failure, thrombocytopenia should exist in the absence of coagulation dysfunction (ie, presence of at least 2 of the 4 PODIUM coagulation
dysfunction criteria).
b
For patients with underlying hematologic or oncologic disease and baseline thrombocytopenia, both <30 000 cells/μL and 50% decrease from baseline criteria must be met.

PEDIATRICS Volume 149, number s1, January 2022 S3

thresholds for each cell type with definition of hematologic dysfunction, is a risk factor for poor outcome (ie,
independent predictive value for it was noted that elevated RDW is not risk of mortality), although the
hematologic dysfunction. Similarly, the specific to critical illness, and explicit threshold values for any
relative importance of specific mechanisms underlying these specific cytopenia (eg, platelets,
thresholds across different diagnoses associations are unclear. Notably, leukocytes, RBCs) associated with
and causes of multiple organ RDW may also represent appropriate increased mortality is poorly
dysfunction remains unknown. It is also marrow response to anemia. Future defined by the current literature.
not known how the timing or duration studies are needed to determine why Additionally, current definitions that
of cytopenias may impact associations RDW is associated with adverse rely on cell number do not
with outcomes and whether these outcomes and how to measure these incorporate cellular function or the

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factors should also be included in the mechanisms in critically ill patients. etiology of the cytopenias that may
definition of hematologic dysfunction. inform diagnostic and/or
Lastly, none of our recommendations Lastly, in addition to cytopenias, therapeutic options.
address the etiologies of cytopenias, critically ill patients may also
although the lower thresholds for experience hematologic cell
cytopenias in oncology patients dysfunction. Incorporation of ABBREVIATION
recognize the presence of cellular functional analyses would ANC: absolute neutrophil count
chemotherapy-induced myelo- align how we define hematologic PODIUM: Pediatric Organ
suppression when defining hematologic dysfunction with how we assess Dysfunction
dysfunction in these patients. other organ systems. Development Information Update
and validation of feasible assays to Mandate
Three of the included studies
measure specific functions of RBCs, RBC: red blood cell
correlated increased RDW with
platelets, and leukocytes are needed. RDW: red blood cell distribution
adverse outcomes.28–30 RDW may
serve as a marker of RBC destruction, width
altered RBC maturation or CONCLUSIONS
metabolism, and/or marrow activity. Hematologic dysfunction in critically
Although RDW was considered for the ill children, as defined by cytopenia,

DOI: https://doi.org/10.1542/peds.2021-052888K
Accepted for publication Sep 24, 2021
Address correspondence to Jennifer A. Muszynski, MD, MPH, Department of Pediatrics, Critical Care Medicine, Nationwide Children’s Hospital, The Ohio State University College of Medicine,
700 Children’s Dr, Columbus, Ohio 43205. E-mail: jennifer.muszynski@nationwidechildrens.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2022 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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