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
associated with increased mortality
in pediatric critical illness.1,2
Although many scoring systems
have been developed to assess
organ dysfunction and to quantify
risks of adverse outcomes, there is
no universal agreement on which
scoring system has the highest
predictive power.3–5 This lack of
consensus may in part result from
differences in the criteria and/or
methodologies used to define organ
dysfunction. In the case of
hematologic dysfunction, most
scoring systems include cytopenias
that have not been tested in a
manner to validate specific
thresholds or to consider different
etiologies of cytopenia.4,6–8
Additionally, unlike other organ
systems in which organ function is
assessed using established
functional markers, similar markers
to assess the function of circulating
hematologic cells have not been well
studied. Each of these limitations
affects the quality of data available
to define hematologic dysfunction.
Lastly, hematologic dysfunction has
historically been defined by
combinations of cytopenias and/or
the presence of abnormal results on
plasma-based coagulation assays.
However, except for platelet count,
hemostatic homeostasis is distinct
from bone marrow function, and it
was decided that the Pediatric
Organ Dysfunction Information
Update Mandate (PODIUM) initiative
would consider hematologic
function and coagulation function as
2 separate entities.
To address the lack of consensus for
current definitions of hematologic
dysfunction, we describe here the
results of a structured literature
search to create evidence-informed,
consensus-based definitions for
hematologic dysfunction in critically
ill children as part of the PODIUM
consensus conference series.
S2
METHODS
The PODIUM collaborative sought
to develop evidence-based criteria
for organ dysfunction in critically ill
children. The present article
reports the systematic literature
review on elements of hematologic
dysfunction performed as part of
PODIUM, proposes evidence-based
criteria for hematologic dysfunction
in critically ill children, and
provides a critical evaluation of the
available literature. The PODIUM
Executive Summary details
Population, Interventions,
Comparators, and Outcomes
questions; search strategies; study
inclusion and exclusion criteria; and
methodologies for risk of bias
assessment, data abstraction and
synthesis, and establishing
consensus.9 Search terms specific to
hematologic dysfunction included
anemia, hemoglobin, hematocrit,
leukopenia, thrombocytopenia,
terms addressing red blood cell
(RBC) indices (mean corpuscular
volume, red blood cell distribution
width [RDW]), distribution of
neutrophils (neutrophil index, d
neutrophil index), platelet indices
(mean platelet volume, platelet
distribution width), and circulating
platelet mass (“plateletcrit”).
RESULTS
Of 10 681 unique citations published
between 1992 and 2020, 29 studies
were eligible for inclusion (Fig 1).
Data tables (Supplemental Tables 1
and 2) and risk of bias assessment
summaries (Supplemental Fig 1) are
detailed in Supplemental
Information. Criteria for hematologic
dysfunction in critically ill children
informed by the evaluated evidence
are in Table 1. A cytopenia that
meets the following definitions in
any of 1 of the 3 cell-lines (platelets,
leukocytes, or erythrocytes [RBCs])
is considered sufficient for the
diagnosis of hematologic
dysfunction.
Platelet Count
Hematologic dysfunction will be
defined by a platelet count of
<100 000 cells/μL for patients
without underlying hematologic or
oncologic diagnosis, <30 000 cells/
μL for patients with underlying
hematologic or oncologic diagnosis,
or $50% decrease from baseline for
patients with baseline platelet count
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<100 000 cells/μL. For the purposes
of defining hematologic dysfunction,
thrombocytopenia should exist in the
absence of coagulation dysfunction
as defined by PODIUM criteria.
Rationale
Thresholds for platelet count are
based on Choi et al, the only
included study that evaluated
thresholds of platelet count
predictive of clinical outcomes
stratified by hematologic/oncologic
diagnosis.10 Other studies evaluated
scoring systems that include platelet
counts (eg, the heme portion of the
pediatric logistic organ dysfunction
score, the pediatric risk of mortality
score, disseminated intravascular
coagulation scores, the Rotterdam
score to predict mortality in
meningococcal sepsis, and the base
excess platelet count score) or
identified lower platelet count as a
risk factor for mortality.11–22
Leukocyte Count
Hematologic dysfunction will be
defined by a total leukocyte count
<3000 cells/μL.
Rationale
Low total white blood cell count was
independently associated with adverse
outcomes in several studies. A data-
driven threshold was identified in only
1 study, which derived a threshold of
<4000 cells/μL in a small cohort of
children with meningococcemia.23
Other studies evaluated WBC
thresholds as part of existing scoring
systems or did not derive thresholds
predictive of outcomes.4,11,12,24 As
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

available to validate or refute
thresholds used in existing scoring
systems (ie, the pediatric risk of
mortality score).8 A single study
evaluated absolute neutrophil count
(ANC) in oncology patients admitted
to the PICU, and although ANC may be
an important marker of marrow
failure, applicability of ANC thresholds
outside of the oncology population
evaluated platelet neutrophil product
in children with meningococcal
disease.25,26 The platelet neutrophil
product is a promising measure to
assess marrow failure because it
includes derangements in 2 cells lines,
each of which are consistently
associated with adverse outcomes in
critical illness, though data to date are
limited.
DISCUSSION
The basis for each of our
recommendations is largely expert
opinion, as none of our
recommendations were supported by
randomized clinical studies and only 2
assessed a cytopenia as a continuous
variable to allow determination of a
discriminative threshold for marrow
failure.10,23 Consequently, most studies
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
independent predictive value for
hematologic dysfunction. Similarly, the
relative importance of specific
thresholds across different diagnoses
and causes of multiple organ
dysfunction remains unknown. It is also
not known how the timing or duration
of cytopenias may impact associations
with outcomes and whether these
factors should also be included in the
definition of hematologic dysfunction.
Lastly, none of our recommendations
address the etiologies of cytopenias,
although the lower thresholds for
cytopenias in oncology patients
recognize the presence of
chemotherapy-induced myelo-
suppression when defining hematologic
dysfunction in these patients.
Three of the included studies
correlated increased RDW with
adverse outcomes.28–30 RDW may
serve as a marker of RBC destruction,
altered RBC maturation or
metabolism, and/or marrow activity.
Although RDW was considered for the
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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PODIUM: Pediatric Organ
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