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fmed-10-1137134 March 8, 2023 Time: 15:30 # 1
TYPE Systematic Review
PUBLISHED 14 March 2023
DOI 10.3389/fmed.2023.1137134
OPEN ACCESS
EDITED BY
Jun Teruya,
Texas Children’s Hospital, United States
REVIEWED BY
Laura DiChiacchio,
The University of Utah, United States
Lisa A. Hensch,
Baylor College of Medicine, United States
*CORRESPONDENCE
Giles J. Peek
gilespeek@ufl.edu
Eric I. Jeng
eric.jeng@surgery.ufl.edu
SPECIALTY SECTION
This article was submitted to
Hematology,
a section of the journal
Frontiers in Medicine
RECEIVED 04 January 2023
ACCEPTED 27 February 2023
PUBLISHED 14 March 2023
CITATION
Valdes CA, Sharaf OM, Bleiweis MS, Jacobs JP,
Mumtaz M, Sharaf RM, Jeng EI and Peek GJ
(2023) Heparin-based versus bivalirudin-based
anticoagulation in pediatric extracorporeal
membrane oxygenation: A systematic review.
Front. Med. 10:1137134.
doi: 10.3389/fmed.2023.1137134
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© 2023 Valdes, Sharaf, Bleiweis, Jacobs,
Mumtaz, Sharaf, Jeng and Peek. This is an
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does not comply with these terms.
Heparin-based versus
bivalirudin-based anticoagulation
in pediatric extracorporeal
membrane oxygenation: A
systematic review
Carlos A. Valdes, Omar M. Sharaf, Mark S. Bleiweis,
Jeffrey P. Jacobs, Mohammed Mumtaz, Ramy M. Sharaf,
Eric I. Jeng*and Giles J. Peek*
Department of Surgery and Pediatrics, University of Florida, Gainesville, FL, United States
Introduction: Optimal anticoagulation therapy is essential for the prevention of
thrombotic and hemorrhagic complications in pediatric patients supported with
extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated
bivalirudin has the potential to surpass and replace heparin as the anticoagulant
of choice.
Methods: We conducted a systematic review comparing the outcomes of
heparin-based versus bivalirudin-based anticoagulation in pediatric patients
supported on ECMO to identify the preferred anticoagulant to minimize bleeding
events, thrombotic complications, and associated mortality. We referenced
the PubMed, Cochrane Library, and Embase databases. These databases were
searched from inception through October 2022. Our initial search identified
422 studies. All records were screened by two independent reviewers using
the Covidence software for adherence to our inclusion criteria, and seven
retrospective cohort studies were identified as appropriate for inclusion.
Results: In total, 196 pediatric patients were anticoagulated with heparin and
117 were anticoagulated with bivalirudin while on ECMO. Across the included
studies, it was found that for patients treated with bivalirudin, trends were
noted toward lower rates of bleeding, transfusion requirements, and thrombosis
with no difference in mortality. Overall costs associated with bivalirudin therapy
were lower. Time to therapeutic anticoagulation varied between studies though
institutions had different anticoagulation targets.
Conclusion: Bivalirudin may be a safe, cost-effective alternative to heparin in
achieving anticoagulation in pediatric ECMO patients. Prospective multicenter
studies and randomized control trials with standard anticoagulation targets
are needed to accurately compare outcomes associated with heparin versus
bivalirudin in pediatric ECMO patients.
KEYWORDS
anticoagulation, bivalirudin, extracorporeal membrane oxygenation (ECMO), pediatric,
direct thrombin inhibitor
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Introduction
In this review, we will briefly highlight the issues unique to
pediatric versus adult extracorporeal membrane oxygenation
(ECMO) and summarize the mechanism of action of heparin
and bivalirudin before identifying and summarizing the
literature comparing the outcomes of heparin-based versus
bivalirudin-based anticoagulation in pediatric patients (≤18 years)
supported on ECMO.
There are important physiological considerations that
differentiate the management of pediatric ECMO patients from
adult ECMO patients. Specifically, the field of developmental
hemostasis may explain differences in physiological response to
anticoagulant medications used during ECMO support between
pediatric and adult patients. Developmental hemostasis refers
to a concept that was coined by Andrew and colleagues in the
1980s—their group demonstrated age-related changes in the levels
of various coagulation proteins (1,2). While early studies suggested
that neonates reached adult levels of various coagulant proteins
by six months of age, a later study by their group confirmed
differences in coagulant protein levels between pediatric and
adult patients, including lower levels of prothrombin, factor
V, factor VII, factor IX, factor X, factor XI, and factor XII in
pediatric patients (3). Others have supported these findings,
showing lower prothrombin availability and a lower conversion
rate of prothrombin to thrombin in pediatric patients (4). These
age-related differences in hemostasis are additionally reflected
by the differences in pediatric and adult reference ranges for
antithrombin (AT) and activated partial thromboplastin time
(aPTT) lab values, which must be considered when monitoring
anticoagulation. Yet, while it is understood that hematological
age-related differences in coagulation exist, there remains
uncertainty about the extent of these changes and about how these
differences may impact anticoagulant activity in pediatric patients
requiring ECMO support.
Several in vivo and in vitro studies have shown age-dependent
physiological differences in response to anticoagulant medications
secondary to these age-related changes in hemostasis (5,6).
Heparin has historically been used for anticoagulation in ECMO
patients, yet age-related differences account for differences in its
therapeutic effect in pediatric versus adult patients. The mechanism
of action of heparin is largely driven by its interaction with AT.
AT, a naturally occurring anticoagulant protein, counteracts the
coagulation cascade to maintain hemostasis and limit thrombosis.
AT acts primarily by inhibiting thrombin and factor Xa (7).
Heparin functions primarily by binding to AT and increases its
activity to minimize coagulation (7), yet this complex only inhibits
free thrombin (8). Though less significant, heparin administration
also increases endothelial production of tissue factor pathway
inhibitor (TFPI) and heparin itself increases the activity of this
anticoagulant protein by facilitating its binding to and inhibition
of factor Xa (9,10). Differences in the levels of these procoagulant
and anticoagulant proteins between pediatric and adult patients
incompletely explain the age-dependent differences in heparin’s
therapeutic effect. While pediatric patients have lower thrombin
levels, which would suggest that less inhibition is needed to achieve
a similar therapeutic effect, these patients often require increased
doses of heparin compared to adults. This is partially explained
by the lower serum levels of AT observed in pediatric patients
(11); however, these differences limit the predictability of heparin’s
therapeutic effect. Additionally, patients can become resistant to
its anticoagulative effects due to the diminishing amount of AT
that heparin binds to and uses for its continued function (12),
which is especially pronounced in children given their lower
levels of AT. In addition to these limitations, heparin-induced
thrombocytopenia (HIT) is a complication that can also occur
when platelets are activated in response to heparin, paradoxically
causing thrombosis (13).
As many as 3.6% of ECMO patients develop HIT, which is
associated with a mortality rate of up to 60% in these patients
(14). The prevalence of HIT is reduced in pediatric patients
(15), though it is still associated with significant complications.
There are two mechanisms by which HIT has been described to
occur—type 1 and type 2. In both, heparin administration activates
platelets via different mechanisms and with different consequences.
Specifically, in type 1 HIT, which is the more frequent mechanism
but with less significant consequences (16,17), heparin directly
induces platelet aggregation but is not associated with increased
risk of thrombosis (18). Thus, it is also known as non-immune
heparin-associated thrombocytopenia. Type I HIT is less severe
with mild thrombocytopenia occurring within two days of heparin
initiation—this is self-limited and resolves without cessation of
heparin (17). Whereas in type 2 HIT, an immune response occurs
against platelet factor-4 (PF4)/heparin complexes which form
naturally as endogenous PF4 binds and neutralizes heparin (19).
Immunoglobulin G (IgG) binding to these PF4/heparin complexes
forms an immunocomplex which binds to and activates platelets,
causing thrombosis. Type II HIT is more severe with significant
thrombocytopenia five to ten days after heparin initiation and
requires immediate cessation of heparin (20). Given the clinical
impact of this complication, this is an important limitation of
heparin that must be considered when choosing anticoagulation in
pediatric ECMO patients.
Due to the limitations of heparin, direct thrombin inhibitors
such as bivalirudin are increasingly being used for anticoagulation
in pediatric patients (21). Bivalirudin’s mechanism of action
involves direct inhibition of thrombin activity, without the need
for AT, making it a more predictable option for consistent
anticoagulation—especially in pediatric patients who have varying
levels of AT and thrombin. Additionally, its therapeutic effect is
similar between adult and pediatric patients, though the effect
of a loading dose is variable and incompletely understood (22).
Another advantage over heparin includes bivalirudin’s ability to
bind to and inhibit both free and clot-bound thrombin. For
these reasons, bivalirudin is an attractive alternative to heparin in
pediatric patients requiring ECMO though it has limitations as
well. Elimination of bivalirudin is achieved via proteolytic cleavage
by thrombin and renal excretion (23); however, in contrast to
heparin, bivalirudin has no specific reversal agent although the
half-life of bivalirudin is significantly shorter than that of heparin.
Despite the benefits of bivalirudin compared to heparin, its use is
presently limited due to the lack of prospective randomized studies
supporting its use.
In addition to the development of the hemostatic system as
they grow, babies and children requiring ECMO can vary greatly
in size. Patients under the age of 18 years and from around 2 kg
to in excess of 150 kg may all be in need of ECMO. Clearly,
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FIGURE 1
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.
these patients will need to have their ECMO cannulas and circuits
tailored to their size and specific oxygen consumption, which also
reduces with age (24). ECMO circuits may vary from 1/4” tubing
with a roller pump, through 1/2” tubing with a centrifugal pump
to adult integrated pump-oxygenator devices with 3/8” tubing
stepped down to 1/4” with a bridge to maintain adequate flow
in the oversized oxygenator (25,26). Oxygenators are also sized
according to the expected blood flow from 800 cm2up to around
7,000 cm2. The heterogeneity inherent in caring for these patients
increases both the difficulty of ensuring adequate anticoagulation
and evaluating the published evidence.
Methods
In accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA), we conducted a
systematic review of the literature comparing outcomes of heparin-
based anticoagulation versus bivalirudin-based anticoagulation in
pediatric patients (≤18 years) supported on ECMO. Databases
referenced include PubMed, Cochrane Library, and Embase. These
databases were searched from inception through 29 October 2022.
The search terms were as follows: (bivalirudin OR bivalitroban
OR angiomax OR angiox OR hirulog) AND (heparin OR
unfractionated heparin OR UFH) AND (extracorporeal membrane
oxygenation OR extracorporeal OR membrane oxygenation OR
ECMO OR extracorporeal cardiopulmonary resuscitation OR
ECPR). All records were imported into the Covidence systematic
review software for screening. Two reviewers (CAV and OMS)
independently screened titles and abstracts, and then screened full
texts that adhered to the inclusion criteria.
Full-text articles that were available in English and that offered
direct comparisons of primary heparin-based anticoagulation
versus primary bivalirudin-based anticoagulation in pediatric
patients (≤18 years) supported with ECMO were included.
Specifically, inclusion criteria were as follows: (1) pediatric patients
≤18 years old, (2) comparison of management with heparin-based
anticoagulation versus bivalirudin-based anticoagulation, and (3)
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TABLE 1 Overview of studies and variables recorded.
References Study type Sample size Referenced variables
Bival UFH Baseline
characteristicsaECMO detailsbTime to therapeutic
anticoagulation
Transfusion
requirements and
bleedingc
Thrombotic
complications
Mortality Costs
Ranucci et al. (27)dRetrospective cohort 5 5 Yes Yes No No Yes Yes Yes
Hamzah et al. (28) Retrospective cohort 16 16 Yes Yes Yes Yes Yes Yes Yes
Schill et al. (32) Retrospective cohort 14e34eYes Yes No Yes Yes Yes No
Machado et al. (29) Retrospective cohort 18 14 Yes Yes Yes Yes Yes Yes No
Kaushik et al. (31) Retrospective cohort 8 27 Yes Yes Yes Yes No Yes No
Seelhammer et al. (30) Retrospective cohort 24 65 Yes Yes No Yes Yes Yes No
Rabinowitz et al. (33) Retrospective cohort 32 35 Yes Yes No No No Yes No
Bival, bivalirudin; ECMO, extracorporeal membrane oxygenation; UFH, unfractionated heparin.
aBaseline characteristics include patient age, sex, and weight. Studies may not have included all of these baseline characteristics.
bECMO details include ECMO duration, type of support, indication for support, and cannulation strategy. Studies may not have included all of these ECMO details variables.
cTransfusions and bleeding includes comparisons of blood product utilization and of bleeding events. Studies may not have included all of these variables.
dStudy provides data broken down by the anticoagulant used but only provides statistical comparisons including adult and pediatric patients together. Data in this table and throughout this review summarize the pediatric data without including statistical comparisons.
eRepresents number of ECMO runs, rather than number of patients. This study had a total of 56 ECMO runs in 54 pediatric patients. There was a third group of patients who were switched from UFH to bivalirudin (n= 8 ECMO runs), not included here.
patients supported on ECMO. We excluded non-human studies
and case reports/series.
Results
Search outcome
Our initial search query from the referenced databases returned
516 studies. After removal of duplicates, 422 records underwent
title and abstract screening by two independent reviewers (CAV
and OMS) using the Covidence software. Conflicts were discussed
and resolved after mutual agreement. Title and abstract screening
identified 36 records for full-text review. After full-text review,
seven studies were selected for inclusion (Figure 1). The
references for each of these seven records were also independently
reviewed, and no additional articles were eligible for inclusion.
All seven articles were retrospective cohort studies. Relevant
variables that were consistently reported across articles were
chosen, and data were extracted. These studies are summarized
in Table 1. Variables of interest were stratified as follows: (1)
Baseline characteristics (age, sex, and weight), (2) ECMO details
(ECMO duration, type of support, indication for support, and
cannulation strategy), (3) Time to therapeutic anticoagulation, (4)
Transfusion requirements and bleeding events, (5) Thrombotic
complications, (6) Mortality, and (7) Anticoagulation and ECMO
costs.
Baseline characteristics
All seven studies included in this review discussed baseline
characteristics, including age, sex, and weight (Table 2) (27–33).
Age was reported in six studies (28–33), sex was reported in
five studies (28–31,33), and weight was reported in six studies
(27–29,31–33). There were no significant differences in age, sex,
or weight between pediatric ECMO patients anticoagulated with
heparin versus bivalirudin across all studies reporting these metrics.
Patients were young with most studies reporting mean or median
age of less than 18 months. Sex was well distributed across studies
with a relatively equal distribution of male and female patients.
Lastly, patients were small with most studies reporting a mean or
median weight of less than 15 kg.
ECMO details
Details regarding ECMO support, including ECMO type,
indication, cannulation strategy, and/or duration, were reported
in all seven studies (Table 3) (27–33). All studies reported ECMO
type with no differences in ECMO type across all studies—most
patients were supported with veno-arterial (V-A) or veno-venous
(V-V) ECMO, and few patients were supported with V-A-V
or V-V-A ECMO. Five studies reported indications for ECMO
and found no differences in indications for support between
heparin and bivalirudin cohorts (27,30–33). The most common
ECMO indications reported included post-cardiotomy, respiratory
failure, and extracorporeal cardiopulmonary resuscitation. Out of
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TABLE 2 Baseline patient characteristics.
Study Sample size Heparin Bivalirudin p-Value
Agea,b
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
<1 year: 42 (65) <1 year: 11 (46) 0.21
1–4 years: 12 (18) 1–4 years: 8 (33)
5–17 years: 11 (17) 5–17 years: 5 (21)
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
59 (0–212) 31 (0–99) 0.41
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
39.8 ±76.1 36.0 ±58.8 0.36
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
4.0 (0.5, 92.0) 0.6 (0.0, 80.0) N/A
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
16.3 (4.8, 143.7) 5.5 (3.7, 79.6) 0.23c
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
13.46 (4.54, 118.48) 4.08 (2.34, 16.63) 0.21
Sex (female)
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
30 (46) 11 (46) 0.98
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
8 (50) 10 (62.5) 0.47
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
5 (36) 11 (61) 0.15
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
12 (44.4) 5 (62.5) N/A
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
17 (48.6) 13 (40.6) 0.52
Weight (kg)b
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
15.4 (2.7–71) 8.5 (2.8-43) 0.32
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
14.9 ±22.2 19.9 ±35.5 0.73
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
10 (5, 42) 6 (5, 20) 0.26c
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
6.2 (3.9, 26.4) 4.0 (2.6, 16.9) N/A
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
10.65 (5.20, 36.58) 5.64 (4.20, 11.50) 0.15
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
3 (2.7-15) 7 (2.6-45) N/A
aDisplayed in months unless otherwise specified.
bData displayed as mean ±standard deviation, median (interquartile range, i.e., 25th percentile, 75th percentile), or median (range, i.e., minimum–maximum).
cSchill et al. compares three groups: heparin, bivalirudin, and switched. The p-value represents a comparison between all three groups rather than between heparin versus bivalirudin.
four studies reporting cannulation strategy, only two reported
a statistical comparison. The larger of these studies—a single-
institutional analysis of 65 heparin patients and 24 bivalirudin
patients—found a higher rate of central cannulation in the heparin
cohort (82% [n= 53] vs. 58% [n= 14], p= 0.02) (30). Meanwhile,
Machado and colleagues found no difference in the cannulation
strategy used (central versus peripheral) among their cohort of 32
patients (14 heparin, 18 bivalirudin) (29).
Extracorporeal membrane oxygenation duration was reported
in all seven studies. Only one of these studies reported a significant
difference in ECMO duration between the cohorts evaluated (32).
This study was a single-center analysis by Schill et al. (32) that
included a third group of patients in their analysis of ECMO
duration: patients who were switched from heparin to bivalirudin.
Among 34 ECMO runs in heparin patients, 14 ECMO runs in
bivalirudin patients, and 8 ECMO runs in patients who were
switched from heparin to bivalirudin, median (interquartile range)
duration of ECMO support was significantly different between
groups (p= 0.001). Duration of support was 3.3 (2.1, 6.2) days
in the heparin cohort, 11.0 (6.2, 23.1) days in the bivalirudin
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cohort, and 10.3 (8.3, 18.3) days in the cohort of patient who
switched anticoagulant. In this review, the longest reported median
duration of pediatric ECMO support was 7.2 (4.2, 18.6) days
(30) across heparin cohorts and 12.0 (5.5, 23.5) days (31) across
bivalirudin cohorts.
Time to therapeutic anticoagulation
In this review, three of seven studies (Table 4) directly
compared time to reach therapeutic anticoagulation between
pediatric patients receiving heparin or bivalirudin during ECMO
(28,29,31). These studies differed in their findings, but also
had different therapeutic anticoagulation targets. In the study
by Kaushik et al. (31) comparing 8 patients anticoagulated with
bivalirudin and 27 patients anticoagulated with heparin at a
single institution, there was no difference in time to reach
therapeutic anticoagulation (median [IQR]: 14.5 [6.7, 16] vs.
12 [5.75, 26], respectively; p= 0.37). Anticoagulation targets
in their study included an activated clotting time (ACT) of
200–240 s and/or a goal aPTT of 60–90 s for the heparin
group and a target aPTT of 60–90 s for the bivalirudin group.
While Machado and colleagues’ study also found no significant
difference in time to reach therapeutic anticoagulation, the
heparin group trended toward a shorter time and almost reached
significance (mean ±SD: 12.54 ±9.96 vs. 21.06 ±12.53 h,
p= 0.06) (29). This was a similarly sized single-center study
with a well-balanced distribution of patients (18 patients received
bivalirudin; 14 patients received heparin). However, in this study,
the anticoagulation target goals were left to the discretion of
each individual intensivist and surgeon. In contrast to both
studies, the analysis by Hamzah and colleagues (28), which
was also well-balanced and similarly sized (16 patients received
bivalirudin; 16 patients received heparin), found that patients
anticoagulated with bivalirudin had a significantly shorter time to
reach therapeutic anticoagulation (median [range]: 11 [4–56] vs. 29
[5–128] h, p= 0.01). Again, the therapeutic anticoagulation goals
differed, with a bivalirudin aPTT goal of 58–78 s and a heparin
goal of (1) anti-Xa assay measurements of 0.3–0.7 international
units/ml, (2) aPTT of 60–80 s, and/or (3) ACT of 180–200 s.
These findings suggest inter-site variation in anticoagulation goals
and time to reach therapeutic anticoagulation and suggest that
neither anticoagulant is clearly superior in reaching therapeutic
anticoagulation more quickly.
Transfusion requirements and bleeding
events
Transfusion requirements were compared between pediatric
patients receiving heparin or bivalirudin while on ECMO in four
of the seven studies that were reviewed (Table 5). Transfusions
of packed red blood cells (PRBCs), platelets, cryoprecipitate, and
fresh frozen plasma (FFP) were evaluated in all four studies (28–
30,32). AT administered, as a categorical variable or quantified,
was evaluated in two of seven studies (28,29). Most studies
found no significant differences in the quantity of PRBC, platelets,
cryoprecipitate, or FFP transfused between groups though trends
toward higher transfusion requirements were frequently noted
in heparin cohorts. One of four studies in each of these blood
product categories found a difference between groups. One of two
studies reporting AT administration reported quantitative amounts
of AT transfused, but only reported these values for the heparin
group and did not provide statistical comparisons (29). The other
study only reported AT administration as a categorical variable
and found that more patients in the heparin group required AT
(28).
The study reporting a higher percentage of the heparin group
requiring AT while supported on ECMO was the analysis by
Hamzah and colleagues (28), which found that 50% (n= 8) of
the heparin group versus 13% (n= 2) of the bivalirudin group
received AT (p= 0.02). This was also the study that found
differences in the amount of PRBCs and FFPs administered.
They found that patients anticoagulated with heparin required
more PRBC (median [range], ml/kg/day: 17.8 [3.4–75] vs. 7
[0–27], p= 0.003) and more FFP (median [range], ml/kg/day:
8.5 [0–24] vs. 0 [0–15], p= 0.001). However, they reported
no difference in the amount of platelets and cryoprecipitate
administered between groups.
The study by Seelhammer and colleagues (30) compared 65
patients anticoagulated with heparin and 24 patients anticoagulated
with bivalirudin at a single center and categorized transfusions
provided to pediatric ECMO patients within the first 24 h of starting
anticoagulation and transfusions given between 24 h and 7 days
after the start of anticoagulation. When categorized as such, the
authors found no differences in transfusion requirements within
the first 24 h; however, between 24 h and 7 days, the heparin group
required more platelets (median [IQR], units: 6 [2, 13] vs. 3 [1, 6],
p= 0.04). There were no other differences between groups when
categorized this way.
Schill et al. (32) did not directly compare transfusion
requirements between those who were started on heparin or
bivalirudin as the primary anticoagulant; they included a third
group of patients who were switched from heparin to bivalirudin
in their analysis of transfusions. Thus, p-values reported may
not be representative of a direct comparison between those
who were started on heparin or bivalirudin as their primary
anticoagulant; however, non-significant p-values reported for the
three group comparison allow us to conclude no statistical
difference between these two groups, and significant p-values
allow us to conclude that there may be a difference between
these two groups though the difference could instead be in
relation to the third group. The single-center study found
that among 34 ECMO runs of patients anticoagulated with
heparin and 14 ECMO runs of patients anticoagulated with
bivalirudin (and 8 ECMO runs of patients switched from heparin
to bivalirudin), there were no differences in PRBC, FFP, or
platelet transfusions between the study cohorts (32). A statistically
significant difference in cryoprecipitate was reported (p= 0.047),
with the primary bivalirudin group receiving more cryoprecipitate
than the heparin group (median [IQR], ml/kg/day: 0.5 [0.1,
1.1] vs. 0 [0, 0.3]); however, we cannot conclude whether this
difference was between the heparin and bivalirudin groups or
between either of these groups and the group that switched from
heparin to bivalirudin.
Machado et al. (29) stratified transfusion requirements in the
heparin and bivalirudin cohorts by age group (1 year or younger
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TABLE 3 ECMO details.
Study Sample size Heparin Bivalirudin p-Value
ECMO, type
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
VA: 61 (94) VA: 20 (83) 0.12
VV: 4 (6) VV: 4 (17)
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
VA: 16 (100) VA: 13 (81.2) 0.23
VV: 0 (0) VV: 3 (18.8)
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
VA: 12 (86) VA: 18 (100) 0.25
VV: 1 (7) VV: 0 (0)
Hybrid: 1 (7) Hybrid: 0 (0)
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
VA: 23 (68) VA: 9 (64) 1c
VV: 11 (32) VV: 5 (36)
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
VA: 24 (88.9) VA: 6 (75) N/A
VV: 3 (11.1) VV: 1 (12.5)
VAV: 0 (0) VAV: 1 (12.5)
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
VA: 21 (60) VA: 22 (69) 0.56
VV: 13 (37) VV: 8 (25)
VAV: 0 (0) VAV: 1 (3)
VVA: 1 (3) VVA: 1 (3)
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
VA: 5 VA: 5 N/A
ECMO, indications
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
Post cardiotomy: 18 (28) Post cardiotomy: 3 (13) 0.27
Cardiac: 18 (28) Cardiac: 6 (25)
Respiratory: 13 (20) Respiratory: 9 (38)
ECPR: 16 (25) ECPR: 6 (25)
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
Post cardiotomy shock: 9 (26) Post cardiotomy shock: 7 (50) 0.57c
Respiratory failure: 12 (35) Respiratory failure: 5 (36)
Cardiogenic shock, unrepaired
CHD: 5 (15)
Cardiogenic shock, unrepaired
CHD: 0 (0)
Cardiogenic shock, other cause:
8 (24)
Cardiogenic shock, other cause:
2 (14)
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
Respiratory indication: 5 (18.5) Respiratory indication: 6 (75.0) N/A
(Continued)
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TABLE 3 (Continued)
Study Sample size Heparin Bivalirudin p-Value
Cardiac indication: 18 (66.7) Cardiac indication: 1 (12.5)
ECPR: 4 (14.8) ECPR: 1 (12.5)
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
Acute respiratory distress
syndrome/lower respiratory
tract infection: 13 (37)
Acute respiratory distress
syndrome/lower respiratory
tract infection: 12 (38)
N/A
Intrinsic lung disease/asthma: 3
(8)
Intrinsic lung disease/asthma: 2
(6)
Intoxication: 3 (8) Intoxication: 0 (0)
Cardiac arrest: 2 (6) Cardiac arrest: 2 (6)
Post-pericardiotomy: 9 (26) Post-pericardiotomy: 10 (31)
Unrepaired CHD: 3 (8) Unrepaired CHD: 1 (3)
Acquired heart disease: 1 (3) Acquired heart disease: 4 (13)
Transplant rejection: 1 (3) Transplant rejection: 1 (3)
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
Post cardiotomy: 5 (100) Post cardiotomy: 5 (100) N/A
Cannulation strategy: central vs. peripheral
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
Central: 53 (82) Central: 14 (58) 0.02
Peripheral: 12 (18) Peripheral: 10 (42)
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
Central: 3 (19) Central: 4 (25) N/A
Peripheral: 13 (81) Peripheral: 12 (75)
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
Central: 7 (50) Central: 11 (61) 0.53
Peripheral: 7 (50) Peripheral: 7 (39)
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
Central: 5 (100) Central: 5 (100) N/A
Peripheral: 0 (0) Peripheral: 0 (0)
ECMO durationa,b
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
7.2 (4.2, 18.6) days 5.3 (2.7, 13.8) days 0.19
Kaushik et al. (31) Heparin: n= 27
Bivalrudin: n= 8
6.0 (3.0, 9.0) days 12.0 (5.5, 23.5) days 0.144
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
114 (32–419) 98.8 (46–363) 0.95
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
154.8 ±107.7 166.6 ±65.1 0.60
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
3.3 (2.1, 6.2) days 11.0 (6.2, 23.1) days 0.001c
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
152.47 (90.09, 310.17) 227.60 (136.68, 418.65) 0.83
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
90 (16–124) 110 (87–234) N/A
Values are presented as n(%) unlessot herwise specified.
aDisplayed in hours unless otherwise specified.
bData displayed as mean ±standard deviation, median (interquartile range, i.e., 25th percentile, 75th percentile), or median (range, i.e., minimum–maximum).
cSchill et al. compares three groups: heparin, bivalirudin, and switched. The p-value represents a comparison between all three groups rather than between heparin versus bivalirudin.
and older than 1 year) as transfusion thresholds were different in
infants above and below 1 year of age. No differences were observed
in each of the blood products used when stratified by age group.
When reviewing bleeding events, four of the seven studies
evaluated bleeding events between pediatric patients receiving
heparin or bivalirudin during ECMO (Table 6) (28,29,31,32).
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TABLE 4 Time to reach therapeutic anti-coagulation.
Study Sample size Heparin Bivalirudin p-Value
Time to reach therapeutic anti-coagulationa, h
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
29 (5–128) 11 (4–56) 0.01
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
12.54 ±9.96 21.06 ±12.53 0.06
Kaushik et al. (31) Heparin: n= 27
Bivalrudin: n= 8
12 (5.75, 26) 14.5 (6.7, 16) 0.37
aData displayed as mean ±standard deviation, median (interquartile range, i.e., 25th percentile, 75th percentile), or median (range, i.e., minimum–maximum).
Most of these studies found higher rates of bleeding among
heparin cohorts though only one of these studies reached statistical
significance. Hamzah and colleagues defined bleeding events as
central nervous system bleeding or bleeding that required surgical
intervention and found that the heparin cohort had a significantly
higher rate of bleeding with 75% (n= 12) of patients experiencing
at least one bleeding event compared to 18.8% (n= 3) in the
bivalirudin cohort (p= 0.029) (28). The heparin group had 4
(25%) patients with no episodes, 4 (25%) patients with 1 episode, 4
(25%) patients with 2 episodes, 3 (18.8%) patients with 3 episodes,
and 1 (6.2%) patient with 5 episodes. The bivalirudin group had
13 (81.2%) patients with no episodes, 2 (12.5%) patients with 1
episode, and 1 (6.3%) patient with 2 episodes.
The other three studies reporting bleeding events had
different definitions for bleeding events and reported higher,
though not statistically significant, rates of bleeding in heparin
cohorts. Machado et al. (29) defined major bleeding events as
bleeding resulting in reoperation including mediastinal washout,
or intervention on cannulation site or any type of surgical or
specialized intervention, end-organ hemorrhage or dysfunction, or
death resulting from bleeding. Five patients in the heparin group
required nine mediastinal washouts compared to one patient in the
bivalirudin group requiring two mediastinal washouts. One patient
in the bivalirudin group also had epistaxis and arterial cannula
site bleeding. This study did not provide a statistical comparison
of these bleeding events between groups. The study by Schill and
colleagues comparing three groups found no significant difference
in the rate of hemorrhagic stroke between groups with a rate of 12%
(n= 4) in the heparin group and 7% (n= 1) in the bivalirudin
group. Lastly, Kaushik and colleagues defined major bleeding as
the need for mediastinal/cannula site exploration for control of
bleeding, bleeding requiring factor VIIa administration for control,
gastrointestinal, pulmonary, or intracranial hemorrhage, or any
bleeding requiring blood transfusion (31). Though not statistically
significant, the bivalirudin group had a lower incidence of major
bleeding at 12.5% (n= 1) compared to 44.4% (n= 12) in the heparin
group (p= 0.21).
Thrombotic complications
Out of seven studies, four measured the number of thrombotic
complications between pediatric patients receiving heparin or
bivalirudin while on ECMO (Table 7). Most studies trended toward
a higher rate of thrombosis in the heparin cohorts. Out of the
four studies, two did not find a significant difference in thrombotic
complications between the two groups (28,30), and two did not
provide a statistical comparison (27,29). One of the studies that
did not report a statistical comparison had a small sample size
with only five patients in each group; one patient in the bivalirudin
group experienced a thrombotic complication (27). The other study
reported a higher thrombotic complication rate of 29% (n= 4)
among 14 patients anticoagulated with heparin compared to 5.6%
(n= 1) among 18 patients anticoagulated with bivalirudin (29).
Three of the four studies reported the specific complications that
occurred (28–30), and an additional one study reported ischemic
stroke rate but not overall thrombotic complication rate (32).
There were no differences in the specific thrombotic complications
that occurred between groups. The most common thrombotic
complication reported was ischemic stroke, occurring in up to 21%
of patients anticoagulated with heparin (32) and in up to 13% of
patients anticoagulated with bivalirudin (30).
Mortality
Six of the seven studies evaluated hospital mortality, survival
to decannulation, one-month survival, or six-month survival
(Table 8) (27–30,32,33). Out of six studies comparing hospital
mortality, none found a difference between the heparin and
bivalirudin groups. Hospital mortality across all studies ranged
from 31 (28) to 80% (27) in the heparin group and 19 (28) to
80% (27) in the bivalirudin group. The study that found hospital
mortality to be 80% in both groups had a small sample size of
five patients in each group and was the oldest study in this review,
published in 2011 (27). The next highest reported hospital mortality
rates were 57% (n= 37) (30) in the heparin group and 46% (n= 6)
(32) in the bivalirudin group.
Five studies reported survival to ECMO decannulation—one
study found significantly higher survival in bivalirudin patients
(29), one study found lower though not statistically significant
survival in bivalirudin patients (31), two studies found no
difference in survival to decannulation (28,32), and one study did
not provide a statistical comparison (27). In the study reaching
statistical significance, the bivalirudin cohort had 89% (n= 16)
survival to decannulation compared to 57% (n= 8) in the heparin
cohort (p= 0.0396) (29). This conflicts with the findings of Kaushik
and colleagues’ (31) study in which survival to decannulation was
37.5% (n= 3) in the bivalirudin cohort versus 74.1% (n= 20) in the
heparin cohort (p= 0.091). However, this study had a small sample
size in the bivalirudin cohort of only eight patients compared to
27 patients in the heparin group. Omitting heparin or bivalirudin
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TABLE 5 Transfusion requirements.
Study Sample size Heparin Bivalirudin p-Value
PRBC
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
<24 h: 2 (1,3)a<24 h: 2 (1,3)a0.76
24 h–7 days: 5 (2,15)a24 h–7 days: 3 (1,11)a0.15
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
7.1 (3.2, 14.7)b7.34 (5.3, 12.4)b0.32*
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
≤1 year of age: 1.51 ±2.06c≤1 year of age: 0.75 ±0.41c0.3734
>1 year of age: 1.10 ±1.28c>1 year of age: 0.34 ±0.18c0.4750
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
17.8 (3.4–75)d7 (0–27)d0.003
Platelets
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
<24 h: 1 (1,2)a<24 h: 1 (1,2)a0.86
24 h–7 days: 6 (2,13)a24 h–7 days: 3 (1,6)a0.04
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
3.8 (0.0, 11.6)b4.7 (1.4, 11.8)b0.41*
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
≤1 year of age: 1.07 ±0.63c≤1 year of age: 0.94 ±0.54c0.7645
>1 year of age: 0.40 ±0.34c>1 year of age: 0.31 ±0.38c0.4743
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
6 (1.6–34)d5 (0–12)d0.24
Cryoprecipitate
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
<24 h: 1 (1,2)a<24 h: 1 (1,2)a0.89
24 h–7 days: 2 (1,4)a24 h–7 days: 1 (1,2)a0.15
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
0.0 (0.0, 0.3)b0.5 (0.1, 1.1)b0.047*e
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
≤1 year of age: 0.09 ±0.09c≤1 year of age: 0.14 ±0.07c0.1868
>1 year of age: 0c>1 year of age: 0.0 ±0.01c0.7076
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
0 (0–11)d0 (0–5)d0.38
Fresh frozen plasma
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
<24 h: 1 (1,3)a<24 h: 1 (1,3)a0.47
24 h–7 days: 2 (1,4)a24 h–7 days: 3 (2,6)a0.19
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
0.4 (0.0, 9.6)b1.2 (0.4, 4.1)b0.86*
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
≤1 year of age: 0.51 ±0.64c≤1 year of age: 0.20 ±0.21c0.0840
>1 year of age: 0.20 ±0.18c>1 year of age: 0.06 ±0.11c0.3583
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
8.5 (0–24) 0 (0–15) 0.001
Antithrombin (quantified)
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
≤1 year of age: 0.68 ±1.16f≤1 year of age: N/A N/A
>1 year of age: 0f>1 year of age: N/A N/A
Antithrombin administered
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
8 (50)g2 (13)g0.02
PRBC, packed red blood cell.
aBlood products (U), median (25th, 75th percentile).
bBlood products (ml/kg/day), median (IQR).
cBlood products (ml/kg/h), mean (SD).
dBlood products (ml/kg/day), median (minimum–maximum) or n(%).
eOne heparin patient was transferred on ECLS to a burn center on the day of cannulation. This patient was excluded from survival analysis, both to decannulation and to discharge.
fAT units adjusted per hour of ECMO.
gn(%).
*Value may not be representative of direct comparison between groups.
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TABLE 6 Hospital mortality and survival statistics.
Studyt7 Sample size Heparin Bivalirudin p-Value
Hospital mortality
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
37 (57) 10 (42) 0.20
Rabinowitz et al. (33) Heparin: n= 35
Bivalirudin: n= 32
13 (37) 11 (34) 0.82
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
12 (36)a,b6 (46)c0.91*
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
6 (43) 6 (33) 0.5809
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
5 (31) 3 (19) 0.62
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
4 (80) 4 (80) N/A
Survival to decannulation
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
24 (73)a9 (64) 0.91*
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
8 (57) 16 (89) 0.0396
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
20 (74.1) 3 (37.5) 0.091
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
11 (69) 13 (81) 0.62*
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
2 (40) 3 (60) N/A
One-month survival
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
8 (57) 13 (72) 0.3730
Six-month survival
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
8 (57) 12 (67) 0.5809
Values presented as n(%) unlessot herwise specified.
aOne heparin patient was transferred on ECLS to a burn center on the day of cannulation. This patient was excluded from survival analysis, both to decannulation and to discharge.
bOne heparin patient was decannulated, re-cannulated on bivalirudin, and died.
cOne patient remained hospitalized after two ECLS runs on bivalirudin.
*Value may not be representative of direct comparison between groups.
cohorts with less than 10 patients, survival to decannulation ranged
from 57 (29) to 74.1% (31) in heparin cohorts and from 64 (32) to
89% (29) in bivalirudin cohorts.
Machado et al. (29) also compared 1- and 6-month survival
between the heparin and bivalirudin groups and found no
significant differences in either. Survival at 6 months was 57%
(n= 8) in the heparin cohort and 67% (n= 12) in the bivalirudin
cohort (p= 0.5809).
Anticoagulation and ECMO costs
Out of the seven studies included in this review, one study
evaluated total costs of anticoagulation, and another evaluated
daily costs of ECMO (Table 9) (27,28). Both studies found
that pediatric patients supported with ECMO with bivalirudin
used as the primary anticoagulant had lower healthcare costs.
Hamzah et al. (28) evaluated total costs of anticoagulation while
on ECMO, which included administration of anticoagulant and AT,
as well as laboratory costs. They found the total cost of heparin
administration was significantly higher than that of bivalirudin
(median [minimum-maximum], dollars per day: 1,184 [83–7,142]
vs. 493 [283–1,007], p= 0.03). Ranucci et al. (27) examined daily
costs of ECMO care, which included the cost of the anticoagulant
(bivalirudin vs. heparin), allogeneic blood product costs, and
purified AT cost. The bivalirudin cohort also had significantly lower
daily costs than the heparin cohort (mean ±SD, euros: 312 ±56 vs.
760 ±237, p= 0.008).
Discussion
Optimal anticoagulation therapy is necessary for the prevention
of adverse outcomes in pediatric patients while on ECMO.
While heparin has been the anticoagulant of choice in pediatric
patients on ECMO, the use of bivalirudin as an alternative has
recently become an attractive option. Although there are studies
comparing heparin with bivalirudin in pediatric ECMO patients,
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TABLE 7 Thrombotic complications on ECMO.
Study Sample size Heparin Bivalirudin p-Value
Thrombotic complication, n (%)
Rannuci et al. (27) Heparin: n= 5
Bivalirudin: n= 5
0 (0) 1 (20) N/A
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
3 (18.8) 0 (0) 0.1
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
4 (29) 1 (5.6) N/A
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
14 (22) 3 (13) 0.54
Thrombotic complications, specified
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
Ischemic stroke: 2 (12.5) Ischemic stroke: 0 (0) 0.49
Circuit thrombosis: 1 (6.25) Circuit thrombosis: 0 (0)
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
Ischemic stroke: 7 (21) Ischemic stroke: 1 (7) 0.67a
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
LV clot: 2 (14) LV clot: 0 (0) N/A
Ischemic limb: 2 (14) Ischemic limb: 1 (5.6)
Seelhammer et al. (30) Heparin: n= 65
Bivalirudin: n= 24
Ischemic stroke: 11 (17) Ischemic stroke: 3 (13) 0.75
DVT: 6 (9) DVT: 0 (0) 0.19
Values presented as n(%) unlessot herwise specified.
aSchill et al. compares three groups: heparin, bivalirudin, and switched. The p-value represents a comparison between all three groups rather than between heparin versus bivalirudin.
TABLE 8 Bleeding events.
Study Sample size Heparin Bivalirudin p-Value
Bleeding events
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
No episodes: 4 (25) No episodes: 13 (81.2) 0.029
1 episode: 4 (25) 1 episode: 2 (12.5)
2 episodes: 4 (25) 2 episodes: 1 (6.3)
3 episodes: 3 (18.8) 3 episodes: 0 (0)
5 episodes: 1 (6.2) 5 episodes: 0 (0)
Machado et al. (29) Heparin: n= 14
Bivalirudin: n= 18
Chest washout: 5 (36)*Chest washout: 1 (5.6)** N/A
Epistaxis: 0 (0) Epistaxis: 1 (7.1)***
Arterial cannula site: 0 (0) Arterial cannula site: 1 (7.1)***
Schill et al. (32) Heparin: n= 34
Bivalirudin: n= 14
Hemorrhagic stroke: 4 (12) Hemorrhagic stroke: 1 (7) 1a
Kaushik et al. (31) Heparin: n= 27
Bivalirudin: n= 8
Major: 12 (44.4) Major: 1 (12.5) 0.21
Minor: 1 (3.7) Minor: 1 (12.5) 0.41
Values presented as n(%) unlessot herwise specified.
aSchill et al. compares three groups: heparin, bivalirudin, and switched. The p-value represents a comparison between all three groups rather than between heparin versus bivalirudin.
*Nine events in five patients.
**Two events in one patient.
***The same patient had epistaxis and arterial cannula site bleeding.
there continues to be uncertainty regarding the optimal approach
for reducing adverse thrombotic and bleeding events in this patient
population. In our review of literature comparing heparin and
bivalirudin use for ECMO therapy in the pediatric population,
most patients included in these studies were young and small and
were supported for postcardiotomy support, respiratory failure, or
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TABLE 9 Costs associated with ECMO and anticoagulation.
Study Sample size Heparin Bivalirudin p-Value
Total costs of anticoagulation, $ per daya
Hamzah et al. (28) Heparin: n= 16
Bivalirudin: n= 16
1,184 (83–7,142) 493 (283–1,007) 0.03
Daily costs of ECMO, € per daya
Ranucci et al. (27) Heparin: n= 5
Bivalirudin: n= 4
760 ±237 312 ±56 0.008
ECMO, extracorporeal membrane oxygenation.
aData displayed as mean ±standard deviation, median (interquartile range, i.e., 25th percentile, 75th percentile), or median (range, i.e., minimum–maximum).
ECMO, extracorporeal membrane oxygenation.
extracorporeal cardiopulmonary resuscitation. Results were largely
heterogeneous among studies included. All studies reporting
time to reach therapeutic anticoagulation reported conflicting
results, aligning with the different anticoagulation targets between
sites. Transfusion requirements, bleeding events, and thrombotic
complications tended to be higher in pediatric ECMO patients
anticoagulated with heparin though statistical significance was
not consistently achieved. Mortality during and following ECMO
support was mostly similar between heparin and bivalirudin
cohorts. Lastly, anticoagulation with bivalirudin in these patients
was associated with cheaper anticoagulation and ECMO costs.
Bleeding events are a frequent and unfortunate complication
associated with ECMO support in pediatric patients. The
Extracorporeal Life Support Organization (ELSO) reports that up
to 31% of pediatric ECMO cases are complicated by surgical
or cannula site bleeding and 11% of pediatric patients have an
intracranial hemorrhage while on ECMO (34). Previous studies
have evaluated bleeding complications associated with heparin
and bivalirudin. In a cross-sectional survey of 22 Level IV
NICUs involved in a neonatal ECMO focus group across the
Children’s Hospital Neonatal Consortium from May to July 2022,
DiGeronimo and colleagues reported that the 14 centers that
incorporated bivalirudin into patient care were found to have
fewer bleeding events, longer circuit life, and fewer transfusion
of blood products, albeit one site experienced increased circuit
complications with bivalirudin (35). Similarly, in a meta-analysis of
nine retrospective studies with 994 adult and pediatric patients, of
which five studies included pediatric patients, Mei et al. (36) found
significantly lower risks of major bleeding in pediatric patients
on bivalirudin versus heparin (RR: 0.27, 95% CI 0.11–0.0.64,
p= 0.003). In our review, while only the study by Hamzah et al. (28)
reached significance, most studies reported higher rates of bleeding
in heparin patients, corroborating prior literature that bivalirudin
may be a safer alternative associated with fewer bleeding events.
Inherent to ECMO circuits is the risk of thrombosis (37,38). In
2019, ELSO reported that thrombotic complications occurred in up
to 16.7% of neonatal and 12.4% of pediatric patients (39). Existing
literature suggests that thrombotic complications may also be lower
in pediatric ECMO patients on bivalirudin compared with heparin.
Liu et al. (40) conducted a systematic review and meta-analysis of
14 retrospective studies with 1,501 patients. Their study included
mostly adult patients with only five studies reporting outcomes
in pediatric patients. In a subgroup analysis of the 210 pediatric
patients included, the authors found significantly reduced risk of
thrombosis in pediatric ECMO patients on bivalirudin compared
with heparin (OR = 0.38, 95% CI 0.16–0.92, p= 0.031). Though
statistical significance was not achieved in the individual studies
included in our review of 313 pediatric patients, likely partly due
to the lack of statistical analysis in some studies, our study, which
includes a larger sample, largely supports the findings of Liu and
colleagues that bivalirudin may be associated with a lower rate of
thrombotic complications among pediatric ECMO patients.
Mortality in pediatric ECMO patients represents a major
clinical challenge due to complications such as bleeding
and thrombosis associated with ECMO therapy (39). These
complications can account for up to 30–40% of fatalities in
pediatric ECMO cases (34). Although most studies in our review
did not find a difference in hospital mortality between heparin
and bivalirudin groups, existing literature favors fewer events
of in-hospital mortality in the aggregate of pediatric and adult
patients anticoagulated with bivalirudin compared with heparin. In
a systematic review and meta-analysis of ten retrospective studies
with a total of 847 adult and pediatric patients, Ma et al. (12)
found lower in-hospital mortality in ECMO patients on bivalirudin
versus heparin (I2= 0%, p= 0.007, OR = 0.64, 95% CI: 0.46–0.88).
However, their analysis of in-hospital mortality combined results
of pediatric and adult patients and included only four pediatric
studies with a total of 177 pediatric patients. Thus, this analysis
is mostly reflective of in-hospital mortality in adult patients. In
contrast to the study by Ma and colleagues, our review summarizes
a larger number of pediatric ECMO studies and provides a more
granular analysis of mortality in pediatric patients, including
survival to decannulation, in-hospital mortality, 1-month survival,
and 6-month survival. In our review, granular analysis of these
endpoints suggests no difference in hospital mortality, 1-month
survival, or 6-month survival, and conflicting results for survival
to decannulation.
While our study suggests that bivalirudin may be associated
with lower rates of bleeding and thrombosis with no difference
in mortality when compared to heparin in pediatric ECMO
patients, bivalirudin is a more expensive anticoagulant than the
readily accessible heparin (41). As such, hospitals and patients may
not feel inclined to incorporate bivalirudin into treatment plans.
Surprisingly, both studies reporting a cost analysis in our review
(27,28), found significantly lower total costs of anticoagulation
and daily costs of ECMO, respectively, in pediatric patients treated
with bivalirudin compared to heparin (27,28). Current literature
discusses the potential barriers that bivalirudin poses to ECMO
patients due to its high price. In a retrospective cohort study
with 15 pediatric ECMO patients on bivalirudin, Campbell and
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colleagues found bivalirudin medication to be five times the cost
of heparin. Importantly, the authors note that cost of medication
is only one component of patients’ healthcare bills, which also
includes “the number of circuit changes, additional use of AT and
blood products, and laboratory testing” (42). Our review suggests
that bivalirudin may be a more cost-effective option than heparin
when considering the overall costs of anticoagulation. Perhaps
this is due to the observed decreases in bleeding and thrombotic
complications and/or transfusion requirements when patients are
treated with bivalirudin. Alternatively, this may be attributed to
the cost of AT replacement, which contributes significantly to
the cost of using heparin. Variability in AT replacement across
institutions would be expected to impact the difference in cost of
using these two agents; however, both studies evaluating cost in our
review highlight the cost-effectiveness of bivalirudin. Yet, cost alone
should not determine the anticoagulant used and should only be
interpreted within the context of overall outcomes achieved with
each anticoagulant.
Our study has limitations. All studies included in our systematic
review were retrospective in nature, thus introducing the possibility
of selection bias. Patients anticoagulated with bivalirudin may
have had a history of intolerance to heparin or have received
bivalirudin as the primary anticoagulant of choice. A senior
ECMO team member (Peek) cared for patients in both Kaushik
and Machado’s studies. Although most studies included in our
review had comparable baseline characteristics between groups,
children placed on ECMO have many comorbidities and a wide
range of diagnoses, making comparisons challenging. In addition,
there are institutional differences between study sites regarding
cannulation strategies and cannula sizes used, and we were unable
to control for this variability. Institutional differences in indications
for bivalirudin versus heparin also limit the generalizability of our
findings. By including only comparator studies, we aimed to limit
the effect of these limitations.
Conclusion
In our review of pertinent literature comparing heparin and
bivalirudin use for ECMO therapy in the pediatric population, we
found that bivalirudin-based anticoagulation is safe, efficacious,
and cost-effective. While heparin is indicated in many settings
and may be acceptable for certain pediatric patients requiring
ECMO support, bivalirudin may offer decreased risk of bleeding
and thrombotic complications and lower transfusion requirements
with a lower overall cost in this setting. Anticoagulation targets
differ between institutions, and mortality during and following
ECMO support appear to be similar. Prospective multicenter
studies with standard anticoagulation targets are needed to more
accurately compare the characteristics and outcomes associated
with bivalirudin versus heparin in pediatric ECMO patients.
Data availability statement
The original contributions presented in this study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding authors.
Author contributions
GP, EJ, OS, and CV contributed to the conception and design
of the study. CV and OS organized the database. CV, OS, MM, and
RS wrote the first draft of the manuscript. All authors contributed
to manuscript revision, read, and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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