Perioperative Pediatric Erythrocyte Transfusions: Incorporating Hemoglobin Thresholds and Physiologic Parameters in Decision-Making

Clinical Focus Review Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.
, Editor
Perioperative Pediatric Erythrocyte Transfusions:

Incorporating Hemoglobin Thresholds and Physiologic
Parameters in Decision-making
Laura A. Downey, M.D., Susan M. Goobie, M.D., F.R.C.P.C.
E rythrocyte transfusions in pediatric patients during the

perioperative period are indicated for the treatment of
children’s hospitals.19–21 In fact, perioperative erythrocyte
transfusions often result in higher hemoglobin levels than
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severe anemia, bleeding, and/or decreased oxygen-carrying even “liberal” transfusion thresholds.20–22 Therefore, the
capacity resulting in end-organ dysfunction. However, development of universal, specific, evidenced-based periop-
erythrocyte transfusions can place pediatric patients at risk erative hemoglobin management and erythrocyte transfu-
for transfusion-related adverse outcomes,1 including infec- sion guidelines for the anemic and/or bleeding pediatric
tion,2,3 respiratory complications,2,4 increased transplant patient would standardize care, reduce practice variability,
graft failure,2,5,6 alloimmunization,7,8 prolonged hospital and potentially improve safety.
stays,9 multiorgan failure,3,10 and death.1,3 In addition to However, pediatric anesthesiologists may be hesitant
the risks, recent blood shortages and increased costs associ- to adopt restrictive transfusion strategies due to a lack of
ated with allogeneic blood products have resulted in more robust outcome data and few evidenced-based guide-
healthcare entities focusing on minimizing transfusions lines for optimal hemoglobin thresholds pertaining to the
without compromising patient safety as highlighted in a dynamic environment of the operating room. In this review,
recent policy brief by the World Health Organization.11,12 we will summarize the most up-to-date pediatric evidence
In adult surgical patients, the adoption of patient blood addressing the equivalency or benefits of restrictive versus
conservation strategies, including the “tolerance of anemia,” liberal transfusion strategies across various clinical scenarios.
has reduced allogeneic erythrocyte transfusions, hospital After presenting the evidence and, when evidence is lack-
costs, and adverse events.13,14 However, physicians have been ing, expert consensus, we discuss a novel approach incor-
slow to adopt these strategies in pediatric patients despite porating recommended restrictive hemoglobin transfusion
multiple pediatric studies with matched controls showing thresholds with emerging data on physiologic parameters to
that transfusions are associated with increased morbidity define optimal decision-making strategies for perioperative
and mortality.1–6,10 In a landmark trial in pediatric intensive erythrocyte transfusions.
care patients,TRansfusion strategies for patients In Pediatric
Intensive Care Units (TRIPICU), Lacroix et al.15 demon-
strated that a restrictive strategy reduced erythrocyte trans- Pediatric Patients with Massive Hemorrhage or
fusions by 44% with no increase in mortality. After a decade Critical Bleeding
of research, Valentine et al.16 summarized in the Pediatric Perioperative erythrocyte transfusion management in the
Critical Care Transfusion and Anemia Expertise Initiative scenario of massive hemorrhage or critical bleeding involves
(TAXI) the current evidence and published guidelines a dynamic strategy focusing on the individualized child’s
regarding hemoglobin transfusion thresholds for critically resuscitation requirements. Massive hemorrhage is defined
ill children, which support a more restrictive approach to as blood loss and/or transfusion of more than 40 ml/kg
transfusion. without or without hemodynamic instability. However,
Although the recommendations by Valentine et al.,16 as evidence to guide erythrocyte transfusion management in
well as a few well designed randomized trials,15,17,18 sup- the context of massive hemorrhage for pediatric patients is
port lower hemoglobin thresholds for hemodynamically sparse.
stable pediatric patients, multiple registry-based studies For the actively bleeding, hemodynamically unstable
have demonstrated considerable variability in the incidence pediatric patient, expert consensus recommends goal-
and indication for erythrocyte transfusion at tertiary care directed massive hemorrhage guidelines, including
Submitted for publication March 9, 2022. Accepted for publication August 12, 2022.
Laura A. Downey, M.D.: Department of Anesthesiology, Emory University Medical School, Atlanta, Georgia; and Department of Pediatric Cardiac Anesthesiology, Children’s Healthcare
of Atlanta, Atlanta, Georgia.
Susan M. Goobie, M.D., F.R.C.P.C.: Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.
Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved. Anesthesiology 2022; 137:604–19. DOI: 10.1097/ALN.0000000000004357
604 November 2022 ANESTHESIOLOGY, V 137 • NO 5

Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.
Perioperative Hemoglobin Thresholds in Pediatrics
transfusion of erythrocytes, plasma, and platelets in a 1:1:1 Perhaps there is a lesson to be learned from the follow-
ratio (or a 2:1:1 ratio) until the bleeding is no longer life ing example of a unique population requiring multiple
threatening.16 This ratio-driven, balanced resuscitation strat- transfusions throughout their hospitalization. Pediatric burn
egy is extrapolated from adult trauma. While there is no patients undergo frequent skin excision and grafting proce-
clear consensus regarding the benefits of a balanced resus- dures. A single-center study implemented a restrictive trans-
citation strategy in pediatric trauma, recent retrospective fusion strategy (hemoglobin level greater than 7.0 g/dL)
studies demonstrate decreased 24-h mortality using a bal- and compared the outcomes to a historic cohort (hemo-
anced ratio transfusion approach.23,24 Prospective data from globin level greater than 10.0 g/dL). The restrictive group
Spinella et al.25 and the Massive Transfusion in Children had lower mortality rates and less erythrocyte transfusions
(MATIC) investigators report that a balanced ratio trans- with no difference in sepsis rates42 (table 1). While this may
fusion strategy (plasma:erythrocyte ratio greater than 1:2) represent a change in overall burn management, this study
may improve early survival in children with life-threatening suggests that a restrictive transfusion strategy in pediatric

bleeding. In the actively bleeding, hemodynamically stable burn patients may improve outcomes.
pediatric patient, international perioperative goal-directed Restrictive erythrocyte transfusion strategies for man-
massive hemorrhage guidelines and critical bleeding pro- agement of the critically ill child recommended by expert
tocols derived from expert consensus suggest maintain- group consensus guidelines are as follows (table 2)16: (1)
ing hemoglobin level in the range of 7.0 to 8.0 g/dL in consideration of erythrocyte transfusion in the hemody-
children and 9.0 to 10.0 g/dL in neonates.16,25–27 Despite namically stable critically ill pediatric patient based on clin-
expert consensus panel agreement of 95 to 100%,Valentine ical judgement for a hemoglobin level of 5.0 to 7.0 g/dL,
et al.16 acknowledge that many of these international good (2) transfusion is not necessary for pediatric patients with
practice recommendations are based on weak evidence due hemoglobin level greater than 7.0 g/dL, and (3) transfusion
to lack of randomized controlled trials and due to studies is advised against for a hemoglobin greater than 9.0 g/dL.
influenced by survivorship bias. Thus, perioperative physi- These recommendations pertain to the children with the
cians must consider the challenges of dynamic fluctuations following conditions: critical illness, postsurgery or post-
in the physiologic status of the bleeding child while weigh- procedural, respiratory failure, sepsis, non–life-threatening
ing the risks and benefits of blood loss and blood product bleeding, or renal replacement therapy.These recommenda-
transfusion. While individualized goal-directed real time tions exclude children with the following conditions: acute
transfusion management of the bleeding child is the intent, brain injury, oncologic disease, stem cell transplantation,
with the hemodynamic instability of massive hemorrhage, hemolytic anemia, sickle cell anemia, severe acute respira-
resuscitation takes precedent. As a result, the decision to tory distress syndrome, mechanical support, or cardiac dis-
transfuse is often more empirically driven in the case of ease. Such high-risk patients may require higher transfusion
ongoing hemodynamically significant blood loss. targets (hemoglobin levels between 7.0 and 10.0 g/dL),
guided by physiologic parameters and clinical judgement.
According to Valentine et al.16 in these patients, “transfusion
Pediatric Noncardiac Surgical Patients should be based on evidence of inadequate cardiorespira-
Perioperative erythrocyte transfusions in the pediatric tory support or decreased systemic and/or regional oxygen
noncardiac surgical bleeding patient may be indicated for delivery.” Based on the expert consensus recommendations
treatment of severe anemia, hypotension, and/or decreased of Lacroix et al.15 and Valentine et al.,16 the posttransfusion
oxygen-carrying capacity compromising end-organ func- goal should be to relieve the indication for transfusion and
tion. Procedures such as liver transplantation, craniosyn- not necessarily achieve a normal hemoglobin level for age,
ostosis repair, neurosurgery, major orthopedic surgery, and with a reasonable general posttransfusion hemoglobin tar-
thoracic and abdominal surgery are historically associated get between 7.0 and 9.5 g/dL. Finally, it must be stated that
with significant blood loss requiring erythrocyte transfu- these guidelines in hemodynamically stable noncardiac sur-
sions in over 50% of pediatric cases.19 gery are based on low-quality pediatric evidence (grade
While there are many trials in adult patients supporting 1C or 2C) or expert consensus, except for the nonsurgical
restrictive (7 or 8 g/dL) hemoglobin thresholds to be non- critically ill child (grade 1B evidence), and must be fol-
inferior or superior compared with liberal thresholds (9 or lowed up by high-quality trials to determine safe transfu-
10 g/dL) across a wide variety of clinical scenarios, critical sion strategies for specific pediatric surgical populations.53
illness, and surgical procedures,28–33 only a few prospective While these recommendations do not specifically cover the
trials exist in the pediatric population.15,17,18,34 Unfortunately, intraoperative period, they can be used as a good practice
these trials are focused on nonsurgical critically ill children guide for anesthesiologists caring for a stable child under-
and do not specifically consider the perioperative period. going noncardiac surgery.
These trials, together with a few observational reports in Finally, perioperative management of the hemodynam-
critically ill children with nonhemorrhagic shock, are pre- ically stable bleeding child for noncardiac surgery should
sented in table 1. consider the change from baseline hemoglobin level, the
L. A. Downey and S. M. Goobie Anesthesiology 2022; 137:604–19 605

606
Table 1. Overview of Hemoglobin Transfusion Threshold Trials in Pediatric Perioperative Patients
Patients
Subject Authors Trial Type Population (N) Inclusion Criteria Transfusion Threshold Outcome Recommendations
Cardiac patients Willems et al.35 Subanalysis of Acyanotic 125 Age > 28 days to 7.0 vs. 9.5 g/dL No difference in new/ Transfusion trigger 7 g/dL is safe
TRIPICU < 14 yr (protocol could be suspended for sur- progressive multiorgan in hemodynamically stable
(randomized gery and/or hemodynamic instability) dysfunction syndrome cardiac patients
CLINICAL FOCUS REVIEW
control trial)
Cholette et al.36 Single-center Cyanotic 60 Bidirectional Glenn or 9.0 vs. 13.0 g/dL No difference in mean/peak lactate, Hemodynamically patients with
randomized Fontan arteriovenous oxygen, and arte- single ventricle physiology
control trial riocerebral oxygen; erythrocyte safely tolerate hemoglobin
transfusions and donor exposure 9.0 g/dL
lower in the restrictive group
de Gast-Bakker Single-center Acyanotic 103 Age > 6 weeks to 8.0 vs. 10.8 g/dL Hospital length of stay was lower in Hemodynamically stable
et al.37 randomized < 6 yr restrictive group; no difference in patients with cardiac
control trial adverse events between groups disease safely tolerate
hemoglobin > 8.0 g/dL
Cholette et al.38 Single-center Cyanotic/acyanotic 162 Weight < 10 kg 9.0 vs. 12.0 g/dL (cyanotic)/7.0 vs. Transfusion adherence was 100% The authors conclude that
randomized 9.5 g/dL (acyanotic) in acyantoic patients and 79% in both cyanotic and acyanotic
control trial cyanotic patients; infants can tolerate a restric-
Patients in the restrictive group tive transfusion strategy
received less transfusion; no
difference between hemoglobin
level, lactate, and arteriovenous
oxygen
Nonhemorrhagic LaCroix et al.15 Multicenter Patients in pediatric 637 Stable ICU patients, 7.0 vs. 9.5 g/dL No difference in new or progressive Transfusion trigger of 7.0 g/dL
shock (TRIPICU trial) randomized ICU age > 3 days multiorgan dysfunction syn- is safe in stable critically ill
control trial and < 14 yr drome or death between groups; pediatric patients
Anesthesiology 2022; 137:604–19

(noninferiority) restrictive transfusion reduced
erythrocyte transfusions by 44%
de Oliveira et Single-center Patients with 102 Age > 1 yr and < 19 yr ScvO2 < 70% and hemoglobin Intervention group was more likely Goal-directed therapy with
al.39 randomized nonhemorrhagic with severe sepsis < 10 g/dL or “standard treatment” to receive a transfusion within ScvO2 monitoring
control trial shock the first 6 h
Srouji et al.40 Single-center Patients with septic 94 Age < 18 yr with severe Erythrocyte transfusion within first 48 h Early erythrocyte transfusion was Consider alternative to transfu-
prospective shock sepsis of sepsis onset independent predictor of organ sion in pediatric patients with
observational dysfunction; early erythrocyte less sever shock
trial transfusion was associated with
increased risk for patients with
lowest shock severity
Muszynski et Multicenter cohort Patients with severe 401 Severe sepsis; > 44 7.4 g/dL transfusion < 48 h 68% of children received eryth- Erythrocyte transfusions are
al.41 study sepsis weeks gestational 9.5 g/dL transfusion > 48 h rocyte transfusion in first 48 h; associated with increased
age to < 18 yr of age; early erythrocyte transfusion mortality even when
no ECMO associated with 2.9-fold higher controlling for confounders
odds of mortality indicating severity of illness.
(Continued)
L. A. Downey and S. M. Goobie
Table 1. (Continued)

Patients
Burn patients Voigt et al.42 Single-center Patients with severe 1,460 Pediatric burn patients Preprotocol patients, transfusion Restrictive transfusion strategy had Pediatric burn patients have
prospective burns at a single center < 10.0 g/dL (759 patients); lower hemoglobin levels, low improved outcomes using a
cohort study admitted between postprotocol patients, transfusion intraoperative transfusion rates, restrictive transfusion strategy
1997 and 2003 and < 7.0 g/dL (701) lower mortality, and decreased (hemoglobin < 7.0 g/dL)
between 2008 and length of hospitalization; groups
2017 had similar rates of sepsis
Africa anemia Lackritz et al.43 Prospective All children admitted 683 Age < 3 yr of age Transfusion < 5.0 g/dL Transfusion in patients with hemo- Transfusion is recommended
studies observational to a Kenyan hospital globin < 3.9 g/dL decreased in pediatric patients with
study 1989 to 1990 mortality, whereas transfusion hemoglobin < 5.0 g/dL
between 4 and 5.0 g/dL did not with evidence of respiratory
improve mortality distress or hemodynamic
instability
Maitland et Open label Children in Uganda 1,563 Pediatric patients with Patients randomized to immediate Delaying transfusion for clinical Patients with chronic stable
al.44,45 (TRACT randomized and Rwanda with uncomplicated transfusion or no immediate signs reduced overall transfu- anemia (no clinical signs of
trial) control trial uncomplicated anemia (4 to 6 g/dL); transfusion (control; triggered by new sions by 50%; 28-day mortality anemia) tolerate hemoglo-
anemia age > 2 months signs of clinical anemia or was 0.9% in the immediate bin 4.0 to 6.0 g/dL without
and < 12 yr hemoglobin < 4.0 g/dL) transfusion versus 1.7% in increased mortality or serious
control group without increase adverse events
risk of serious adverse events
Connon et al.46 Secondary analysis Children from Uganda 3,894 682 pediatric patients Patients randomized to immediate Factors that increased risk of Patients with uncomplicated

of TRACT trial and Malawi surviv- readmitted of the transfusion or no immediate readmission included: severe severe anemia (4-6g/dL) who
ing anemia 3,894 survivors of the transfusion (control; triggered by new anemia (hemoglobin did not a have a transfusion
TRACT trial signs of clinical anemia or < 3.6 g/dL), younger age, acute during the initial admission
hemoglobin < 4.0 g/dL) for first severe malaria, HIV infection, had the lowest rates of
admission and sickle cell disease readmission
Neonates Kirpalani et al.34 Multicenter Extremely 451 < 1,000 g, gestational Hemoglobin (g/dL; central) threshold The primary outcome was the Restrictive transfusion strategy
(PINT study) prospective ran- low-birth-weight age of < 31 weeks, triggers erythrocyte transfusion combination of either death or did not increase the likelihood
domized trial infants > 48 h since delivery based on age and respiratory support survival with bronchopulmonary of death, cognitive deficit,
dysplasia, severe retinopathy of cerebral palsy, necrotizing
prematurity, or brain injury; fewer enterocolitis, bronchopul-
infants received one or more monary dysplasia, and
transfusions in the low threshold retinopathy of prematurity at
group; rates of the primary 24 months
outcome were 74.0% in the
low-threshold group and 69.7%
in the high-threshold group
(Continued)
607
608
Patients
47
Whyte et al. Post hoc analysis Extremely low-birth- 430 Extremely low-birth- From PINT trial No differences between groups Suggested that a liberal
(PINTOS trial) of PINT trial weight infants weight infants (from High threshold (liberal): necrotizing enterocolitis, apnea, transfusion threshold led to
PINT trial) 1 to 7 days: respiratory support (< 12.2); infections, need for postnatal reductions in both cognitive
no respiratory support (< 10.9) steroids, oxygen requirements, delay and mortality
8 to 14 days: respiratory support (< 10.9); time to extubation, or time to

no respiratory support (< 9.0) discharge
> 15 days: respiratory support (< 9.0);
no respiratory support (< 7.7)
Low threshold (restrictive):
1 to 7 days: respiratory support (< 10.4);
8 to 14 days: respiratory support (< 90);
> 15 days: respiratory support (< 7.7);
Franz et al.18 Multicenter ran- Extremely low-birth- 1,013 Infants with birth Hematocrit threshold (%) sliding scale Neurodevelopmental outcome was Restrictive transfusion strategy is
(ETTNO trial) domized control weight infants weight > 400 g and based on age and state of health assessed in a post hoc analysis as safe as liberal transfusion
trial (< 1,000 g) at 36 < 1,000 g at less Liberal: of PINT; significant difference in in low-birth-weight infants
NICUs in Europe than 73 h after birth; < 7 days: < 41 critical; < 35 noncritical cognitive delay favoring liberal with either critical or noncriti-
gestational age < 30 8 to 21 days: < 37 critical; < 31 threshold group cal health state
weeks noncritical
> 21 days: < 34 critical; < 28 non-
critical
Restrictive:

< 7 days: < 34 critical; < 28 noncritical
8 to 21 days: < 30 critical; < 24
noncritical
> 21 days: < 27 critical, < 21 noncritical
Kirpalani et al.17 Multicenter ran- Extremely low-birth- 1,824 Birth weight < 1,000 g Sliding scale based on age Among infants with birth weights Restrictive transfusion strategy is
(TOP trial) domized control weight infants at 41 and Liberal: of < 1,000 g, no difference in as safe as liberal transfusion
trial NICUs in the NICHD gestational age of < 7 days: hemoglobin 12 g/dL death, cerebral palsy, cognitive in very low-birth-weight
> 22 weeks and < 29 7 to 14 days: 11.5 g/dL delay, or severe hearing/visual infants
weeks > 14 days: 10 g/dL impairment between restrictive
Restrictive: and liberal transfusion strategies
< 7 days: hemoglobin 10 g/dL at 24 months of corrected age;
7 to 14 days: 9.5 g/dL at discharge, no difference in
> 14 days: 8 g/dL serious adverse events; at 24
months, no difference in death or
developmental impairment
ECMO, extracorporeal membrane oxygenation; ETTNO, Effects of Transfusion Thresholds on Neurocognitive Outcomes; HIV, human immunodeficiency virus; ICU, intensive care unit; NICHD, Neonatal Research Network of the Eunice Kennedy Shriver
National Institute of Child Health and Human Development; NICU, neonatal intensive care unit; PINT, Premature Infants in Need of Transfusion; PINTOS, Premature Infants in Need of Transfusion Outcomes; ScvO2, central venous oxygen saturation; TOP,
Transfusion of Prematures; TRACT, Transfusion and Treatment of African Children; TRIPICU, Transfusion strategies for patients In Pediatric Intensive Care Units.
Table 2. Summary of Current International Expert Recommendations for Hemoglobin Transfusion Thresholds in Pediatric Patients
Organization Recommendations for Children Recommendations for Neonates
American Society of Excluded from the focus of these guidelines are neonates, infants, and children weighing Excluded from the focus of these guidelines are neonates, infants, and children weighing

Anesthesiologists Task less than 35 kg. less than 35 kg.
Force on Perioperative
Blood Management48
(currently being updated)
Guidelines from the 2013: We suggest that a critical hemoglobin threshold of 8 g/dL for erythrocyte transfusion may be 2013: Not applicable.
European Society of safe in severe pediatric perioperative bleeding. Hemoglobin concentrations vary with age and 2017: Except for premature babies and cyanotic newborns, hemoglobin targets in bleeding children
Anesthesiology49,50 sex, and erythrocyte transfusion should be tailored accordingly. The required transfusion volume (includes term neonates) are 7 to 9 g/dL.
can be calculated as: body weight (kg) × desired increment in hemoglobin concentration (g/dL).
In massive bleeding, hemoglobin concentrations should be maintained at 8 g/day, while in stable,
critically ill children, 7 g/dL may suffice.
2017: Except for premature babies and cyanotic newborns, hemoglobin targets in bleeding children
are 7 to 9 g/dL
Patient Blood Management Hemoglobin concentration < 70 g/L: Erythrocyte transfusion is often appropriate. However, transfusion Appendix F: In the absence of clear evidence from high-quality trials, there is wide variation in such
Guidelines: Module 6 may not be required in wellcompensated patients or where other specific therapy is available. thresholds in international practice, as demonstrated by a recent survey of 1,018 neonatologists
Neonatal and Pediatrics, Hemoglobin concentration of 70 to 90 g/L: Erythrocyte transfusion may be appropriate. The decision in 22 countries.
National Blood Authority to transfuse patients should be based on the need to relieve clinical signs and symptoms of For infants of extremely low birth weight or < 28 weeks gestation, most neonatologists favored-
Australia51 anemia and the patients response to previous transfusions. hemoglobin thresholds for transfusion of 95 to 120 g/L for infants not receiving mechanical
Hemoglobin concentration > 90 g/L: Erythrocyte transfusion is often unnecessary and may be ventilation and then decreasingthresholds over subsequent weeks. Neonatologistsfavored higher
inappropriate. thresholds for infants receiving increased respiratory support in the form of supplemental oxygen.
New information is expected from large randomized controlled trials that are currently underway.
The threshold for transfusion for premature infants within these ranges may be influenced by the
presence of symptoms and other factors such as:
• Anticipated blood loss (e.g.,hemolysis, phlebotomy, or surgery)

• Quality of nutrition
• Severity of illness
• Site of sampling–hemoglobin measured on blood samples obtained from a large artery or from
veins tendsto be lower than that from free-flowing capillary samples.
In general, the decision to transfuse should be based on laboratory measurement of hemoglobin
rather thanon estimates obtained from blood gas analyzers, except in cases of clinical urgency.
Pediatric Critical Care In children (not demonstrating the following: shock physiology, respiratory failure, acute brain injury, Neonates are excluded.
Transfusion and Anemia congenital heart disease, and hematological or oncological diagnosis and not on ECMO, VAD, or
Expertise Initiative RRT) with hemoglobin < 5.0 g/dL,erythrocyte transfusion was recommended.
(TAXI)16 If hemoglobinwas 5.0 to 7.0 g/dL, consideration of erythrocyte transfusion was recommended.
In the majority of patients with hemoglobin > 9.0 g/dL, erythrocyte transfusion was advised against.
Term infants and critically ill children up to 18 yr old were included.
(Continued)
609
calculated allowable estimated blood loss based on weight,

the physiologic status of the child as determined by indica-
tors of end organ perfusion, and comorbidities. High-quality
CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; NATA, Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis; RRT, Renal Replacement Therapy; VAD, ventricular assist device.
outcomes research regarding restrictive transfusion strate-
gies in pediatric perioperative patients is lacking, and while
the focus on optimal hemoglobin transfusion parameters
should be considered, it is equally important to consider the
physiologic parameters that may influence short- and long-
term patient outcomes (fig. 1). This concept of harnessing
physiologic parameters to guide transfusion decisions will
Patient Blood Management The authors suggest the addition of erythrocytes to maintain a hematocrit > 24% during CPB based No specific neonatal hemoglobin thresholds are recommended.
be explored in more detail in the latter part of this clinical

focus review.

Pediatric Cardiac Surgical Patients
Recommendations for Neonates
Pediatric patients undergoing cardiac surgery have addi-

tional factors increasing the likelihood of receiving allo-
geneic blood transfusions including complex surgeries,
chronic cyanosis, hypothermia, and the effects of cardio-
Society for the Advancement Transfusion guidelines for all blood components should be weight and age appropriate, based on both Neonates are excluded.
pulmonary bypass (CPB). An analysis of the Society for

Thoracic Surgery (Chicago, Illinois) database showed that
all registry centers administered erythrocytes to 100% of
patients less than 12 months of age undergoing cardiac sur-
gery with CPB.20 While transfusion rates decreased in older
patients, variability across institutions increased (toddlers,
should use restrictive transfusion thresholds for allogeneic erythrocyte transfusion when supported
on the estimation of the degree of hemodilution related to CPB prime and cardioplegia (grade 2C).
78.6% [54.6 to 91.7%]; children, 50.0% [25.5 to 63.7%];

laboratory andphysiologic clinical criteria, not based on a hemoglobin concentration alone, and
The authors recommend a postoperative hemoglobin threshold or transfusion in stable, acyanotic
cardiac children with clinical signs suggestive of symptomatic anemia as of 90 g/L (grade 1C).
The authors recommend a postoperative hemoglobin threshold for transfusion in stable, cyanotic
cardiac children with hemoglobin 70 or 80 g/L in the presence of clinical signs suggestive of
adolescents, 25.8% [12.5 to 40%]).20 Despite multiple stud-

ies associating bleeding and erythrocyte transfusions with
worse postoperative outcomes,4,9,10,54 the factors influencing
transfusion thresholds in this population (age, cardiac phys-
iology, cyanosis or intracardiac mixing, surgical complexity,
and CPB effects) have made determining an optimal hemo-
globin transfusion threshold elusive. With the increased
focus on the risk–benefit profile of erythrocyte transfusions,
it is worth revisiting the literature regarding the hemoglo-
bin transfusion threshold trials in pediatric cardiac surgical
patients (table 1).
by published evidence and expert consensus.
Due to the high rate of bleeding and transfusion in car-

diac surgery, the majority of pediatric perioperative transfu-
Recommendations for Children
sion trials supporting restrictive transfusion practices are in

symptomatic anemia (grade 1B).
cardiac surgical patients. Many pediatric cardiac centers tar-

get hemoglobin level on-CPB of greater than 8 g/dL based
on two randomized trials (and post hoc analyses) in infants
undergoing biventricular repair with low-flow hypother-
mic CPB, which demonstrated improved outcomes and
neurocognitive development.55–58 However, a single pedi-
atric center caring for Jehovah’s Witness patients has pro-
vided some insight into the feasibility and safety of lower
on-CPB hemoglobin triggers. Utilizing blood conservation
for Neonates and Children
of Blood Management27
techniques developed for their pediatric Jehovah’s Witness

Surgery: 2019 NATA
Undergoing Cardiac
patients, Naguib et al.59 demonstrated that a target on-CPB

goal of a hemoglobin level of greater than 7.0 g/dL allowed
Organization
Guidelines52
for bloodless surgery in 36% of children weighing between

6 and 18 kg and in 81% of those weighing more than
18 kg. While no major adverse events were reported, neu-
rocognitive and developmental testing was not performed,
610 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie


Fig. 1. Hypothetical physiologic strategies to guide erythrocyte transfusion decisions in pediatric patients perioperatively.
making it difficult to determine the long-term impact of institutions to perform complex neonatal surgeries without
this practice. A recent randomized trial in adult cardiac the need for erythrocyte or platelet transfusion in 30 to 50%
patients found that moderate hemodilution to a hematocrit of neonates.62–65 In summary, despite the absence of pro-
of 21 to 25% on CPB was associated with increased risk of spective trials, minimizing CPB prime volumes can reduce
postoperative neurocognitive dysfunction and stroke com- the need for blood product transfusions in pediatric patients
pared to mild hemodilution (hematocrit greater than 25%), undergoing cardiac surgery.52
despite no differences in cerebral oximetry, hemodynamics, Three randomized trials have demonstrated that imple-
and pre- and post-CPB hematocrits.60 While adult cardiac menting a postoperative restrictive transfusion strategy
centers may tolerate on-CPB hemoglobin levels as low as resulted in fewer transfusions and lower hemoglobin lev-
7.0 g/dL, with monitoring for evidence of tissue hypoxia els but no difference in lactate levels or arteriovenous oxy-
through serial lactate levels, cerebral oximetry, and mixed gen nor adverse clinical outcomes in children undergoing
venous oxygen saturation,61 it is hard to extrapolate this biventricular or palliative procedures35–38 (table 1).These tri-
data to pediatric patients due to differences in cyanotic and als demonstrated that hemodynamically stable children who
acyanotic heart disease, cerebral autoregulation, and preex- underwent biventricular repair tolerate hemoglobin levels
isting cardiovascular and neurologic disease burden. Expert greater than 7.0 g/dL without impaired clinical outcome,
consensus recommends an on-CPB hemoglobin target of while children who underwent palliative procedures toler-
8 g/dL or higher for acyanotic pediatric patients under- ate hemoglobin levels greater than 9.0 g/dL.35–38 These trials
going biventricular repair; however, there is currently not focused on postoperative intensive care unit (ICU) trans-
enough outcome data to make recommendations regarding fusion practices, not intraoperative transfusion thresholds.
on-CBP targets in cyanotic patients. Therefore, although individualized goal-directed transfu-
Relatively large CPB priming volumes result in hemo- sion is the aim, prospective studies focusing on intraop-
dilution of erythrocytes, platelets, and coagulation factors, erative transfusion thresholds for complex cardiac surgical
thus increasing the need for blood product transfusions. As patients are lacking. A recent retrospective study demon-
clinicians consider ways to reduce transfusions, one method strated that each 5% increase in ICU arrival hematocrit
that has been shown to decrease CPB-related hemodilution greater than 38% for acyanotic and 42% for cyanotic chil-
and thus erythrocyte transfusions is to miniaturize CPB dren was associated with a significant increase in the odds of
circuits. Allowing for a 50% reduction in the CPB prime perioperative mortality and major complications.22 While
volumes, these miniaturized circuits have permitted several this retrospective study can only demonstrate an association

of worse outcomes with higher intraoperative hemoglo- accepted definition of the “normal” hemoglobin level for
bin level, it highlights the need for prospective studies with neonates, as they have unique physiologic and developmen-
well defined perioperative transfusion guidelines reserving tal differences mandating a wide range of recommended
transfusions for patients with clinical evidence of poor oxy- hemoglobin thresholds (tables 1 and 2). Furthermore, the
gen delivery and avoiding overtransfusion in clinically stable definition of liberal versus restrictive transfusion threshold
patients. varies widely across different weights, ages, and critical ill-
Although a number of prospective studies demonstrate nesses ranging from liberal (hemoglobin level of 7.5 to 12.0
no benefit of higher hemoglobin thresholds35–38 and a larger g/dL) to restrictive (hemoglobin level of 6.5 to 10.0 g/
number of retrospective studies associate erythrocyte trans- dL) as detailed in tables 1 and 2. Due to the limited ability
fusions with worse outcomes,4,10,66 clinicians remain skepti- to tolerate physiologic stress, historical recommendations
cal in adopting restrictive transfusion strategies for pediatric have favored more liberal transfusion strategies. Erythrocyte
cardiac surgical patients due to a lack of robust outcome transfusions are independently associated with intraventric-

data and the unique physiology requiring physicians to ular hemorrhage,69,70 necrotizing enterocolitis69-72, broncho-
optimize oxygen delivery in patients with chronic hypox- pulmonary dysplasia,73 retinopathy of prematurity,73–75 and
emia and dynamic intracardiac shunts. A goal-directed death.76 In fact, due to the lack of transfusion-related out-
erythrocyte transfusion strategy targeting specific physio- come data at the time, neonates were not included in the
logic parameters may be a more appropriate approach to guidelines of Valentine et al.16
transfusion than a specific hemoglobin target.66 However, Although the trial of Lacroix et al.15 suggests that restric-
without high-quality outcome data on physiologic trans- tive transfusion strategies appear to be safe in the neona-
fusion thresholds, expert consensus recommends a restric- tal population, there has been a lack of consensus on the
tive approach to transfusion in cardiac children. Current optimal hemoglobin levels for term and preterm neonates
expert consensus recommends a postoperative hemoglobin until recently. Previously, in the Premature Infants in Need
transfusion threshold in stable, acyanotic cardiac patients of Transfusion Outcomes (PINTOS) trial, Kirpalani et al.34
with hemoglobin levels greater than 7.0 or 8.0 g/dL in the reported no difference in death, cerebral palsy, cognitive delay,
presence of signs of symptomatic anemia (grade IB evi- or severe hearing/visual impairment between restrictive and
dence).52,67 For stable, cyanotic cardiac children without liberal transfusion strategies at 18 to 21 months in extremely
signs of symptomatic anemia, the recommended postopera- low-birth-weight neonates. However, a post hoc analysis of
tive transfusion threshold is a hemoglobin level greater than this study suggested that higher hemoglobin levels may be
9.0 g/dL (grade 1C).52,67 associated with better cognitive outcomes.47 Consequently,
multicenter randomized clinical trials by Kirpalani et
al.17 in the Transfusion of Prematures (TOP) study and
Term and Preterm Neonates Franz et al.18 in the Effects of Transfusion Thresholds on
While there is a paucity of data on perioperative neonatal Neurocognitive Outcomes of Extremely Low-Birth-
blood transfusions, neonates (age 0 to 30 days old) are one Weight Infants (ETTNO) study were conducted comparing
of the most frequently transfused groups, with up to 42 to restrictive versus liberal transfusion thresholds in extremely
90% of premature and low-birth-weight neonates receiving low-birth-weight preterm infants on the risk of death or
at least one blood transfusion during their hospitalization.18 neurocognitive outcomes at 2 yr. Transfusion thresholds
Although most of the perioperative transfusion literature were determined by postconceptual age and state of health.
in neonates comes from the pediatric cardiac literature, a Both trials found that a restrictive transfusion strategy did
recent single-center study reported that 6% (25 of 420) of not increase the risk of death, cerebral palsy, cognitive defi-
neonates undergoing index general surgery cases received cit, necrotizing entercolitis, bronchopulmonary dysplasia, or
perioperative transfusions. Risk factors for perioperative retinopathy of prematurity.17,18 While previous guidelines
transfusion included surgery type, history of prematurity, recommended higher hemoglobin thresholds for extremely
prior transfusion, or structural heart disease.68 High-quality low-birth-weight neonates, both studies demonstrated no
outcomes data regarding transfusion triggers for neonates in difference in mortality or neurodevelopmental impairment
the perioperative period are evolving. Herein is highlighted at hospital discharge or at 22- to 26-month follow-up uti-
recent literature and expert consensus guidelines on trans- lizing a restrictive transfusion strategy. As such, these stud-
fusion thresholds in neonates, premature, and extremely ies recommend employing a restrictive transfusion strategy
low-birth-weight infants in an attempt provide guidance using a hemoglobin transfusion threshold ranging from
for perioperative transfusion decisions. 7.0 to 11.0 g/dL, based on postconceptual age, age-specific
Neonates can be divided into two categories based on hemoglobin reference ranges, level of respiratory support,
gestational age: term or preterm (preterm defined as ges- ongoing or anticipated red cell loss due to critical illness, and
tational age less than 37 weeks); and/or based on weight: nutritional status (table 2).
low birth weight (between 2,500 and 1,000 g) or extremely In a recent review of evidence-based guidelines for neonatal
low birth weight (less than 1,000 g). There is no universally transfusions, Zerra et al.77 point out that the trials of Kirpalani

et al.17 and Franz et al.18 function to compare liberal versus the need for transfusion in individual patients with different
restrictive transfusion strategies based on laboratory thresholds degrees of physiologic adaptation to anemia.” This statement
alone (hemoglobin or hematocrit). Zerra et al.77 highlight the is reminiscent of an oft-repeated statement in pediatric medi-
need to identify more all-inclusive markers of physiologically cine: One size does not fit all. Despite the increasing support for
relevant outcomes such as tissue oxygen delivery and long- restrictive transfusion strategies in pediatric patients, inter-
term effects of transfusions on neurodevelopment, immunity, national expert consensus guidelines on erythrocyte trans-
and inflammation, especially in neonates with varying levels fusions agree decisions to transfuse should not be dictated
of illness, age, and gestational age.While these data are difficult by hemoglobin concentration alone but should also consider
to extrapolate to the intraoperative period, especially for neo- the child’s underlying physiologic condition and anemia-
nates with ongoing bleeding, the current literature suggests related signs and symptoms (table 2). Unfortunately, cur-
that term and preterm, low-birth-weight and extremely low- rently lacking is a decision-making algorithm that identifies
birth-weight neonates appear to tolerate restrictive transfusion specific individuals for whom permissive anemia is unsafe

strategies without increased risk of neurocognitive deficits or, conversely, individuals that meet transfusion triggers for
(tables 1 and 2) in a hemodynamically stable patient without whom transfusion is actually unnecessary. However, emerg-
evidence of end-organ tissue hypoxia. ing literature suggests that combining patient hemodynamics
and serial measurements of biochemical markers indicative of
Moving Away from a Hemoglobin Number: sufficient perfusion (e.g., lactate, base deficit, pH) with novel
Incorporating Physiological Parameters to Guide technologies, such as cerebral and somatic dynamic near
Transfusion Management Decisions infrared spectroscopy, may allow us to better quantify and
monitor oxygen consumption and delivery and the decision
The etiology of a low hemoglobin level in pediatric patients to transfuse or to withhold transfusion.81–86
may stem from chronic anemia (nutritional deficiencies, dis- Recently, critics of the above neonatal transfusion trials,
ease state, and side effects of treatment) or acute blood loss point out that erythrocyte transfusion strategies based on
from ongoing bleeding. Although the etiology of anemia hemoglobin thresholds alone may not be an accurate predic-
is often not delineated, multiple studies have demonstrated tor of physiologic relevant outcomes such as tissue oxygen
that preoperative anemia is associated with increased blood delivery, especially in a neonate with varying levels of illness,
transfusions78 and overall mortality.1,79 While an in-depth age, and gestational age. Several studies, including two recent
discussion of anemia as a risk factor for perioperative mor- prospective trials, in extremely low-birth-weight preterm
bidity and mortality is beyond the scope of this review, these neonates demonstrated that cerebral and somatic oximetry
studies found that anemic children tend to be younger, may reflect tissue hypoxia better than the hemoglobin level
required emergency surgery, and had a higher incidence of alone.81–83 In addition to increases in cerebral and somatic
major comorbidities. Unfortunately, it is unclear whether oxygenation and decreases in fractional oxygen extraction
the adverse outcomes from perioperative anemia are related after blood transfusions, two recent studies found that oxy-
to the etiology of anemia, the subsequent transfusions to gen extraction preferentially increases in the brain over the
treat the anemia, or both. Recent studies from Africa sug- gut in more anemic and immature infants.82,83 Another recent
gest that children with chronic anemia but without evi- study compared the effect of erythrocyte transfusions on pul-
dence of respiratory distress, hemodynamic instability, or monary vascular resistance by echocardiography and cere-
altered consciousness may safely tolerate a hemoglobin level bral and splanchnic oxygen saturations in neonates with or
between 4.0 and 6.0 g/dL (table 1).44–46 These data suggest without a patent ductus arteriosus.84 The authors report a
that a child’s ability to tolerate certain hemoglobin levels decrease in pulmonary vascular resistance (change in right
may differ depending on the cause and chronicity of the ventricular pressure) and cerebral oxygen extraction after
anemia, thus highlighting the importance of patient fac- erythrocyte transfusion in all patients, but neonates with pat-
tors on anemia tolerance and the need for individualized ent ductus arteriosus had significantly lower splanchnic oxy-
goal-directed guidelines for transfusions. gen saturation and higher fractional oxygen extraction, even
In fact, patient blood management experts have called for after an erythrocyte transfusion.84 This study highlights the
goal-directed individualized guidelines for hemoglobin man- complexity of the relationship between tissue oxygenation/
agement including or withholding erythrocyte transfusion extraction and transfusion decisions in patients with cardiac
rather than focusing on a single hemoglobin threshold num- shunts. While the premature extremely low-birth-weight
ber. A 2021 Cochrane Review on transfusion thresholds for population has received significant attention due to large
guiding erythrocyte transfusions80 identified that the major research networks, studies examining physiologic parame-
limitation of most transfusion strategy trials is that these tri- ters for transfusion triggers in other pediatric populations are
als “compare only two separate thresholds for hemoglobin scarce. A single study in 92 pediatric scoliosis patients found
concentration, which may not identify the actual optimal associations between a 15% drop in cerebral oximetry with
threshold for transfusion in a particular patient. Hemoglobin lower hematocrits and lower blood pressure.85 Although the
concentration may not be the most informative marker of authors demonstrate that lower hematocrits are associated

with decreased cerebral oximetry, it is not clear whether on an assessment of the patient’s underlying comorbidities
a 15% drop in cerebral oximetry is clinically significant. and anemia symptoms.
Furthermore, this study does not differentiate the indepen- The authors propose there is no ideal, one size fits
dent association of hypotension or anemia on decreases in all, hemoglobin threshold for the pediatric patient in the
cerebral oximetry. Highlighted is the need for future research perioperative period. Instead, future research should focus
to identify novel methods to monitor tissue oxygen delivery, on patient-centered outcomes that incorporate patient
as hemoglobin number alone may not be an accurate predic- factors, surgical and medical complexity, and physiologic
tor of physiologic relevant outcomes in perioperative pedi- parameters to develop tools to guide the management of
atric patients with different illness severities, comorbidities, anemic and/or bleeding pediatric patients. Knowledge that
ages, or surgical procedures. the child is physiologically optimized would go a long way
Furthermore, although erythrocyte transfusion increases in promoting restrictive goal-directed transfusion decisions
hemoglobin levels with a corresponding increase in blood in the perioperative setting. In conclusion, anesthesiologists

oxygen content, a child’s tolerance of anemia is based more on caring for pediatric surgical patients should turn our collec-
tissue oxygen delivery, end organ perfusion, oxygen extraction, tive focus to the individualized patient and the physiologic
and compensatory physiology than a single hemoglobin num- status of the neonate, infant, child, or adolescent in deciding
ber. In a recent study of adult blunt-trauma patients, Özakın et the optimal hemoglobin threshold, while avoiding erythro-
al.86 correlated multiple physiologic and laboratory parameters cyte transfusions whenever possible.
in patients who required erythrocyte transfusions with those
who did not. Harnessing this data, the authors developed a Research Support
score using lactate, base deficit, and systolic blood pressure to
Support was provided solely from institutional and/or
predict a need for blood transfusion.While this study does not
departmental sources.
specifically compare outcomes based on hemoglobin levels, it
does emphasize the complexity of the decision to transfuse, as
well as the need for developing more comprehensive tools uti-
Competing Interests
lizing multiple physiologic and laboratory parameters to guide The authors declare no competing interests.
transfusions in perioperative pediatric patients.
Therefore, prospective research harnessing restrictive Correspondence
hemoglobin strategies together with end organ monitor- Address correspondence to Dr. Goobie: Boston Children’s
ing, physiologic markers of tissue hypoxia, and long-term Hospital, 300 Longwood Avenue, Boston, MA 02115.
patient outcomes is needed to further guide goal-directed [email protected]. Anesthesiology’s
care of the anemic and/or bleeding child. We propose such articles are made freely accessible to all readers on www.
a model in figure 1, which shows hypothetical physiologic anesthesiology.org, for personal use only, 6 months from the
strategies to guide erythrocyte transfusion decisions in cover date of the issue.
pediatric patients perioperatively.
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Perioperative Pediatric Erythrocyte Transfusions: Incorporating Hemoglobin Thresholds and Physiologic Parameters in Decision-Making

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Clinical Focus Review Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.

Perioperative Pediatric Erythrocyte Transfusions:

E rythrocyte transfusions in pediatric patients during the

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604 November 2022 ANESTHESIOLOGY, V 137 • NO 5

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L. A. Downey and S. M. Goobie Anesthesiology 2022; 137:604–19 605

Anesthesiology 2022; 137:604–19

L. A. Downey and S. M. Goobie

Anesthesiology 2022; 137:604–19

8 to 14 days: respiratory support (< 10.9); time to extubation, or time to

Anesthesiology 2022; 137:604–19

Organization Recommendations for Children Recommendations for Neonates

L. A. Downey and S. M. Goobie

Anesthesiology 2022; 137:604–19

calculated allowable estimated blood loss based on weight,

be explored in more detail in the latter part of this clinical

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Pediatric patients undergoing cardiac surgery have addi-

pulmonary bypass (CPB). An analysis of the Society for

78.6% [54.6 to 91.7%]; children, 50.0% [25.5 to 63.7%];

The authors recommend a postoperative hemoglobin threshold or transfusion in stable, acyanotic

adolescents, 25.8% [12.5 to 40%]).20 Despite multiple stud-

Due to the high rate of bleeding and transfusion in car-

sion trials supporting restrictive transfusion practices are in

cardiac surgical patients. Many pediatric cardiac centers tar-

techniques developed for their pediatric Jehovah’s Witness

patients, Naguib et al.59 demonstrated that a target on-CPB

for bloodless surgery in 36% of children weighing between

610 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie

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612 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie

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614 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie

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616 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie

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618 Anesthesiology 2022; 137:604–19 L. A. Downey and S. M. Goobie

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L. A. Downey and S. M. Goobie Anesthesiology 2022; 137:604–19 619

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