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42 Perioperative Management ofPolycythemia
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407
visual disturbances, atypical chest pain, and paresthesia; cardiovascular risk assessment; and assessment of spleen and
liver size by physical examination. In addition to routine
laboratory tests like a complete blood cell count with differential, peripheral blood smear, and chemistries with liver and
renal function and electrolytes, tests for JAK2 V617F mutation and, if negative, for mutations of CALR exon 9 and
MPL exon 10 should be done; testing for acquired von
Willebrand disease in patients with clinical evidence of
bleeding or platelet counts >1 million/mL also needs to be
done. Some patients may need bone marrow biopsy. PV is a
panmyelopathy. When it presents with erythrocytosis, leukocytosis, and thrombocytosis with or without splenomegaly,
the diagnosis of PV is conrmed, regardless of the clonal
marker. However, if it can present as isolated erythrocytosis,
leukocytosis, or thrombocytosis, with splenomegaly and/or
myelobrosis, or any combination of these, JAK2 driver
mutation expression eliminates the possibility of secondary
or spurious erythrocytosis.
Perioperative Management
In general, treatment of PV has two goals: alleviating symptoms and prolonging survival by prevention of thrombosis,
intractable splenomegaly, and leukemic transformation.
Specically, for perioperative care, the goal is simple, prevention and management of thromboembolic complications
by phlebotomy therapy to reduce blood hyperviscosity and
control of thrombocytosis [21]. A Dutch study showed that
major clinical variations exist in treatment strategies for
PV.Phlebotomy shortens the time to achieve hematocrit control, while hydroxyurea seems to better control platelet and
leukocyte levels. The thrombotic vascular event rate remains
clinically signicant [22].
Phlebotomy
Thrombosis, without any doubt, is the most immediate threat
to patient with PV. Phlebotomy is the cornerstone of management for these patients. Phlebotomy reduces the RBC
mass and expanding the plasma volume [23]. Phlebotomy
can be accomplished by daily or every-other-day procedures,
or all at once by erythrocytapheresis [24]. Phlebotomy usually neither causes myelobrosis nor stimulates hematopoiesis because PV hematopoiesis is autonomous [25].
Cytoreductive Therapy
PV patients at high risk of thrombosis is indicated to have
cytoreductive therapy, typically with hydroxyurea, which is
adopted by the PV Study Group. Hydroxyurea is a nonalkylating agent used to treat patients with PV [21, 26].
Hydroxyurea can decrease the production of
deoxyribonucleotides via inhibition of the enzyme
ribonucleotide reductase by scavenging tyrosyl free radicals
as they are involved in the reduction of nucleoside
diphosphates. It suppresses the bone marrow production of
blood cells [25]. Hydroxyurea does impair DNA synthesis;
it may cause therapy-related acute myeloid leukemia
because they facilitate clonal expansion of hematopoietic
stem cell bearing harmful mutations [27].
Prevention andTreatment ofThrombocytosis
Aspirin: Aspirin plays an important role in management of
patient with PV [28]. A randomized, controlled study has
demonstrated the efcacy of low-dose aspirin therapy in preventing thrombotic complications in PV patients [29].
Other Symptomatic Management
Aquagenic pruritus: Ruxolitinib, psoralen and ultraviolet
A, PegFIN, and hydroxyurea are all therapeutic options
depending on its severity. Thrombocytosis-induced von
Willebrand syndrome usually does not cause spontaneous
bleeding; for minor surgery or dental procedures,
tranexamic acid or e-aminocaproic acid should be adequate
treatment. For major surgery in patient with thrombocytosisinduced von Willebrand syndrome, platelet count reduction
therapy to achieve normal ristocetin cofactor activity is
necessary [21, 28]. Interferon: PegFIN is a good therapeutic option for the control of thrombocytosis for migraine
relief or TIA [21].
For venous thromboembolism, anticoagulation should be
immediately commenced. Low molecular weight heparin is
still the rst choice in the acute setting, followed by vitamin
K antagonists as per guidelines [30]. Direct oral anticoagulants are also increasingly used in the non-myeloproliferative
neoplasm population for prophylaxis and venous thromboembolism therapy [30].
Prognosis
Patients with PV require long-term management to prolong
survival and improve quality of life. Nearly all patients
should initially receive treatment with aspirin [29] and phlebotomy to achieve a target hematocrit <45% [28]; management should evolve with the natural course of the disease [8,
28]. Management decisions should be modied or updated
by new conditions and new evidence (Fig. 42.1) based on
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Fig. 42.1 Management of patient
with polycythemia vera (Modied
from [30])
J. Zhao et al.
both objective measures and subjective measures. Some
patients will benet from the addition or modication of
therapeutic approaches [28, 31]. Early diagnosis and
evidence- based patient management will improve long-term
clinical outcomes and better quality of life.
Anesthetic Considerations
Patients with PV should have a thorough preoperative evaluation and risk stratication and control of hematocrit level
to <45%. Intraoperatively hemodilution may be considered
to avoid blood hyperviscosity by infusion of crystalloid uids. Postoperative care should emphasize close monitoring
of hematocrit level and occurrence of potential
complications.
Summary
Perioperative patients more likely have anemic problem than
polycythemia. Polycythemia means more total red blood cell
mass than a normal human body needs. Polycythemia can be
primary, secondary, and mixed types. PV is the most common type of primary polycythemias. PV is a neoplasm with
overproduction of both morphologically and functionally
normal blood cells. Polycythemia leads to high blood viscosity which predisposes patients to thrombotic/embolic complications as stroke, heart attack, and peripheral vascular
events. Patients with PV may suffer from hemorrhagic complication as well. Patients with PV are usually treated with
phlebotomy to Hct level<45% and aspirin, which will sufce for low cardiovascular risk patients. High-risk patients
will often warrant cytoreductive therapy with hydroxyurea.
Sometimes interferon or Ruxolitinib will be needed. The
anesthesia team should emphasize thorough preoperative
evaluation and Hct control to <45%, and appropriate hemodilution intraoperatively, close monitoring of Hct level, and
clinical indications of postoperative complications.
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Blood Management
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inthePremature Neonate
RobertJungerwirth, HaoWu, andHannahJ.Hsieh
43
Introduction
Advances in neonatology over the past two decades have
resulted in increased survival of preterm neonates. This has
resulted in an increased number of procedures, anesthetics,
and transfusions in this patient population [1]. Neonates (and
particularly premature neonates) pose many unique
perioperative challenges for the anesthesiologist (smaller
size, increased airway complications, apneic and bradycardia
episodes, developing cardiac and respiratory physiology,
metabolic derangements due to immature renal and hepatic
systems, and comorbidities of prematurity such as intracranial
hemorrhage, necrotizing enterocolitis, sepsis). Anemia and
thrombocytopenia are very common in neonates, especially
preterm neonates [2–5]. Preterm infants are likely overtransfused in general as a population [6, 7]. Although rigorous regulations and screening of donor blood have decreased
the incidence of infectious transmission, preterm infants are
a vulnerable population and are at higher risk for complications given their comorbidities.
There is much debate regarding the effectiveness of transfusion and optimal transfusion thresholds, and there is no
consensus among NICUs [8, 9] or pediatric anesthesiologists
[10, 11]. Many of our current guidelines directing management are based on expert opinion. The research and evidence
to guide transfusion practice in neonates is ongoing; research
has come out attempting to dene red blood cell transfusion
triggers and thresholds in neonates and infants, and there are
ongoing studies looking at platelet and plasma transfusions
[12].
R. Jungerwirth · H. J. Hsieh (*)
NYU Langone Health, Department of Anesthesiology,
Perioperative Care, and Pain Medicine, New York, NY, USA
e-mail: Hannah.hsieh@nyulangone.org
H. Wu
NYU Medical Center, Department of Anesthesiology,
New York, NY, USA
Causes andRisk Factors forAnemia
After birth, both term and preterm infants experience a progressive decline in hemoglobin (Hgb). For healthy term
infants, Hgb concentrations range from 14.6 to 22.5g/dL at
birth and decline to a nadir of 10–12g/dL by 8–10weeks of
age. This is often termed the “physiologic anemia of infancy”
and is well tolerated in healthy term infants without need for
treatment. Levels of Hgb gradually increase over time and
reach adult levels by 2years of age [13].
In contrast, preterm infants experience a more precipitous
decline in Hgb concentration to a nadir of 7–8 g/dL at
4–6weeks of age termed “anemia of prematurity” [14]. This
is often accompanied by clinical signs of anemia such as pallor, poor weight gain, decreased activity, tachycardia, and
tachypnea [15]. This anemia of prematurity occurs due to a
combination of physiologic and nonphysiologic factors.
Several of these physiologic processes are related to birth
and the transition to extrauterine life, including shorter neonatal RBC survival time compared to adults, shift of the oxygen dissociation curve due to the change from
high-oxygen-afnity hemoglobin F to low-oxygen-afnity
hemoglobin A, and lower plasma concentrations of erythropoietin in response to anemia [13, 14].
Nonphysiologic factors that contribute to this anemia of
prematurity include iatrogenic blood loss from phlebotomy,
sepsis, inadequate nutrition, acute blood loss or hemorrhage,
hemolytic disease of the newborn, and cardiorespiratory disease [13, 15, 16].
Surgery is a major cause of acute blood loss and anemia
requiring transfusion in neonates. In an examination of all
RBC transfusions over a period of 2 years at The Royal
Children’s Hospital in Melbourne, Australia, neonates were
signicantly more likely to receive an RBC transfusion than
older children. Neonates were also more likely to undergo
major surgery such as laparotomy and thoracic surgery, with
laparotomy associated with a higher incidence of RBC transfusion in neonates than in older children [17].
© Springer Nature Switzerland AG 2021
C. S. Scher et al. (eds.), Essentials of Blood Product Management in Anesthesia Practice,
https://doi.org/10.1007/978-3-030-59295-0_43
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Anemia has been shown to be signicantly associated
with mortality and increased incidence of red blood cell
transfusion in premature neonates [18]. In a study by Goobie
etal., preoperative anemia was an independent risk factor
for postoperative mortality in neonates, with a preoperative
Hct <40% as the optimal cutoff point to predict overall
mortality [19].
Even though RBC transfusion can be a life-saving measure, especially in the setting of acute perioperative blood
loss, transfusion of RBC has also been suggested to be associated with increased mortality in preterm infants [20–22].
There has been a concerted effort to nd ways to prevent
anemia and the need for unnecessary transfusion and their
associated possible side effects.
Use ofHemoglobin andHematocrit toGuide
RBC Transfusion
In adults, guidelines for transfusion traditionally rely on
maintaining a certain Hgb and Hct that we believe can adequately maintain oxygen delivery to tissues. However, in
preterm neonates it is unclear what parameters best indicate
an imbalance in oxygen delivery and demand and subsequently need for transfusion. Several countries have published national transfusion guidelines for neonates; however
there are wide variability among them and no general consensus (Table43.1).
Liberal Versus Restrictive RBC Transfusion
Guidelines
As there is no consensus on what the threshold should be for
transfusion in premature neonates, there have been several
studies comparing restrictive and liberal Hgb thresholds to
identify an optimal transfusion threshold. Adopting a restrictive transfusion threshold would not only signicantly
decrease the number of transfusions and exposure to blood
products but will also result in nancial savings. After
implementing a program to improve guideline compliance,
one center saw a nancial savings of $780,074 over
12months [
27].
A randomized control trial by Bell etal. found that premature infants in the restrictive transfusion group had signicantly higher rates of severe adverse brain events (dened as
grade 4 intraparenchymal brain hemorrhage or periventricular leukomalacia, or both) and increased episodes and frequency of apnea compared to those in the liberal transfusion
group. They postulated that those in the restrictive transfusion
group likely had lower systemic oxygen transport to the brain,
possibly leading to increased brain injury and apneic events.
This decreased arterial oxygen content likely leads to
increased cerebral blood and severe brain hemorrhage. It is
unclear whether these short-term ndings will result in longterm issues with brain development and function [28].
In comparison, there have been several studies that
showed no signicant difference in outcomes between
patients transfused under liberal or restrictive guidelines [
6,
7, 29, 30]. One study reported that after adopting a more
restrictive transfusion strategy in ELBW infants, their transfusion rate decreased by 71% without a change in their primary outcomes of overall survival rate or acute complications.
Of note, all of their study participants received concomitant
weekly recombinant human erythropoietin treatment [7].
An observational study by Valieva etal. found that liberal transfusion had no signicant effect on several clinical
indices for anemia such as weight, heart rate, or apneic episodes. They did, however, see an increase in oxygen supplementation and use of diuretics after transfusion and
found an association between transfusion and the
development of necrotizing enterocolitis. Given these
results, the center subsequently adopted a more restrictive
transfusion strategy [29].
In the Premature Infants in Need of Transfusion (PINT)
study, researchers found no difference in their primary outcome of death or major morbidity (dened as BPD, ROP, or
ultrasound ndings of brain injury) in premature ELBW
Table 43.1 Comparison of most recent international guidelines for RBC transfusion in neonates
American Red Cross [23] British Committee for Standards
No
Postnatal
age
0–7days Hct <20–30% Hct <30–45% Hgb <10g/dL Hgb
8–14days Hct <20–30% Hct <30–45% Hgb <7.5–8.5g/dLHgb
≥14days
a
Respiratory support is dened as moderate to severe cardiopulmonary disease with need for supplemental oxygen, continuous positive airway
pressure, or mechanical ventilation
respiratory
support
Hct <20–30% Hct <30–45% Hgb <7.5–8.5g/dLHgb
With
respiratory
a
support
in Hematology [24]
No respiratory
support
With
respiratory
support
<10–12g/dL
<9.5–10g/dL
<8.5–10g/dL
Australian National Blood
Authority [25]
With
No respiratory
support
Hgb 10–12g/dLHgb 11–13g/dLHgb 10g/dL
Hgb 8.5–11g/dLHgb
Hgb 7–10g/dLHgb 8.5–11g/dLHgb 7.5g/dL
respiratory
support
10–12.5g/dL
Canadian Blood Services [26]
No
respiratory
support
Hct 30%
Hgb 8.5g/dL
Hct 25%
Hct 23%
With
respiratory
support
Hgb 11.5g/
dL Hct 35%
Hgb 10g/dL
Hct 30%
Hgb 8.5g/dL
Hct 25%
43 Blood Management inthePremature Neonate
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infants randomized to restrictive versus liberal transfusion
thresholds [6]. The same patients were subsequently followed up at 18 and 21months of age, and researchers found
no signicant difference between groups in combined death
or severe adverse neurodevelopmental impairment (cerebral
palsy, cognitive delay, visual or hearing impairment) [31].
As of the date of publication, there are two ongoing trials
looking at the neurocognitive development of premature
infants who were transfused according to liberal or restrictive guidelines. The Effects of Transfusion Thresholds on
Neurocognitive Outcome of Extremely Low Birth-Weight
Infants (ETTNO) study included 920 ELBW neonates randomized into restrictive vs liberal blood transfusion groups.
They followed the long-term development of these patients
and will report on the incidence of death or major neurodevelopmental impairment at 24months of age (ClinicalTrials.
gov, NCT 01393496) [32]. The Transfusion of Prematures
(TOP) trial included more than 1800 preterm ELBW neonates randomized to either a liberal or restrictive transfusion
algorithm. Their primary outcome is death of neurodisability
at 22–26months of age. They will also follow up with these
patients at 5–6years of age to assess their neurological and
functional outcomes (ClinicalTrials.gov, NCT 01702805).
The results of these two upcoming studies are highly anticipated and will no doubt contribute to this eld.
Other Transfusion Markers
In neonates, typical indications for transfusion include maintenance of specic Hgb or Hct level, replacement of phlebotomy losses, or clinical symptoms such as apnea,
tachycardia, tachypnea, or growth failure [9]. More recent
research has suggested that Hgb and Hct are not adequate
measures of tissue oxygenation and need for transfusion
[33–35]. In addition, evidence has shown that our conventional clinical and laboratory indices (such as hypotension,
tachycardia, hematocrit, and metabolic acidosis) are poor
predictors of measured blood volume and hypovolemia in
sick preterm infants [36]. One study by Keyes etal. showed
that transfusion in premature infants did not result in a predictable change in several traditional clinical indicators for
transfusion (heart rate, respiratory rate, or incidence of apnea
or bradycardias). There was also no correlation between
these clinical variables and Hct [37]. More research needs to
be done to nd superior indicators of perfusion and oxygenation to possibly use as transfusion markers.
blood volume [
a reduction in total blood volume leads to redistribution of
blood ow to essential organs such as the brain and heart.
This results in hypoperfusion and hypoxia of low ow tissues in the early stages of anemia [39]. Additionally, very
low RCV values have been associated with high mortality
rate in high-risk newborns [40].
In healthy patients, Hct correlates with total body
RCV.But in sick infants, there is a poor correlation between
Hct and RCV [41], because plasma volume tends to fall and
uctuate due to impaired capillary integrity and subsequent
extravasation of plasma components. In these patients, blood
volume cannot be accurately predicted from Hgb or Hct concentration [36]. Some infants can maintain a relatively normal Hgb level while in fact they have a low RCV [42].
However, RCV is difcult to measure and likely has limited
clinical utility in estimating total blood volume and need for
transfusion [33].
38]. Blood volume is important in anemia, as
Reticulocyte Count
Reticulocytes are immature red blood cells and a marker for
the bone marrow response to anemia. In conjunction with
Hgb and Hct, the reticulocyte count may be useful in determining whether a transfusion is indicated. Some guidelines
have cited an absolute reticulocyte count of <100,000 cells/
μL or reticulocyte count <5% along with Hgb and Hct as an
indication for RBC transfusion [9, 43]. However, evidence
for reticulocyte count as a reliable transfusion trigger is still
lacking [44].
Serum Lactate
Lactate is an end product of anaerobic metabolism and can
be an indication for hypoxia and hypoperfusion. It has been
looked at as a possible biochemical trigger for transfusion in
preterm neonates. Studies have shown that lactate signicantly decreases after RBC transfusion. However, there has
been no correlation between pretransfusion lactate and Hgb,
Hct, or other clinical variables for anemia (heart rate, respiratory rate, number of apneas or bradycardias, or weight
gain) [45–47]. Many clinical conditions such as sepsis,
asphyxia, and congenital cardiac lesions and use of inotropes
may also lead to increased serum lactate levels. While lactate
is a marker for anemia, it is too nonspecic to serve as a
transfusion trigger in preterm neonates [16, 44].
Red Cell Volume andBlood Volume
Red cell volume (RCV), the total amount of red cells in the
circulation expressed as mL/kg body weight, has been purported to be superior to hematocrit as a surrogate for total
Near-Infrared Spectroscopy
Near-infrared spectroscopy (NIRS) is a noninvasive and continuous monitoring tool that measures regional tissue oxygen
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R. Jungerwirth et al.
saturation (rSO2) by determining the ratio of oxygenated Hgb
to total Hgb. NIRS has been advocated as an important clinical tool in conjunction with Hgb and Hct to determine an
imbalance between oxygen delivery and demand and possible
need for transfusion. Since 75–85% of the total cerebral blood
volume is venous, NIRS measurement of cerebral regional
tissue oxygen saturation (CrSO2) is therefore a surrogate for
the cerebral venous saturation. Using pulse oximetry saturation (SaO2) as the measure for cerebral arterial saturation, the
cerebral fractional tissue oxygen extraction (FTOE) can then
be calculated. FTOE reects the ratio of cerebral oxygen supply and demand and may serve as an indication of cerebral
hypoxia and ischemia [48, 49].
Much of the research utilizing NIRS in neonates has
looked specically at cerebral saturation and perfusion, as it
is thought that many of the neurological injuries in this
patient population are due to imbalances in cerebral perfusion [50]. There is evidence showing that CrSO2 increases
after RBC transfusion, consistent with the belief that CrSO2
is a marker for tissue oxygenation. This has not only been
shown in adults after intraoperative RBC transfusion [51] but
also in children and neonates [34, 35, 48, 52, 53]. While
CrSO2 measurements in neonates were found to be reliable,
several studies determined that NIRS is unreliable to measure absolute concentrations of oxygenated and deoxygenated Hgb [49, 54]. In fact, many studies have since shown a
poor correlation between pre- and post-transfusion Hgb and
CrSO2 [33–35, 48, 55], suggesting that Hgb is a poor marker
for tissue oxygenation [34, 55].
A study by Wardle et al. found only a weak correlation
between FTOE and Hgb, further supporting the idea that
Hgb concentration is a relatively poor indicator of adequate
tissue oxygenation. Interestingly they found a signicant
correlation btw RCV and FTOE.They also conrmed that
preterm infants with symptomatic anemia had higher FTOE
(increased tissue extraction of oxygen), while those with
asymptomatic anemia had FTOE similar to controls [33].
Van Hoften et al. observed that FTOE decreased immediately after RBC transfusion along with a signicant increase
in CrSO2 [48].
NIRS has not only been utilized to measure cerebral saturation and perfusion in neonates, but also to measure the
regional saturation of other peripheral tissues [34, 35, 53].
Bailey etal. saw a signicant increase in regional splanchnic
tissue oxygen saturation (SrSO2) after transfusion [34], and
a study by Dani etal. showed that RBC transfusions resulted
in increase in cerebral, splanchnic, and renal oxygenation in
preterm infants with symptomatic anemia of prematurity. Of
note, this study also observed an associated decrease in
FTOE after transfusion [53].
A study conducted by Seidel etal. found that infants with
very low initial NIRS values had the highest number of oxygen desaturations and after transfusion had the most reduc-
tion in the number of desaturations. This suggests that infants
with low CrSO2 values (<55%), especially those with frequent desaturations, may benet the most from RBC transfusions [35].
Bailey etal. looked at the usefulness of a metric called
splanchnic-cerebral oxygenation ratio (SCOR) as a marker
for need for transfusion in preterm infants. In the infants that
clinically improved after transfusion, their pretransfusion
SCOR was signicantly lower than those who did not have a
clinical improvement after transfusion. These patients also
had a signicant increase in SCOR during the transfusion.
The authors hypothesized that symptomatic neonates had
low SCOR because they maintained cerebral blood ow and
oxygenation by shunting blood away from their splanchnic
circulation. This evidence suggests that SCOR may be useful
as a transfusion trigger in this patient population [55].
All of these ndings suggest that NIRS may be a reliable
marker for an imbalance between tissue oxygen delivery and
demand and useful as a marker for the need for RBC
transfusion.
Selection ofRBC Products
Leukoreduced
Leukoreduction of RBCSrSO2 is the process of removing
donor leukocytes from RBC units to decrease the risk of
transfusion reactions such as febrile nonhemolytic transfusion reactions, allergic reactions, and alloimmunization [56].
Leukoreduction also lters out pre-inammatory cytokines
that have accumulated during the storage period such as
tumor necrosis factor (TNF-alpha), interleukin-1 (IL-1), and
interleukin-8 (IL-8). Leukoreduction may also decrease
transmission of infectious agents commonly transmitted via
leukocytes such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human T-cell lymphocytic virus (HTLV)-I
[57]. Leukoreduction of RBC however is not as effective at
preventing transfusion-related graft-versus-host disease
(GVHD).
Given their immature immune systems, donor leukocytes
from red blood cell transfusions may depress the immune
response, generate alloantibodies, and result in microvascular injury through the generation of free radicals in susceptible tissue beds such as the lungs and retina. After the
institution of a nationwide Canadian universal pre-storage
leukoreduction program in 1999, a study looking at premature infants showed that there were no signicant reductions
in NICU mortality or bacteremia. However, there was a
reduction in clinical outcomes such as bronchopulmonary
dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage. They also saw an average decrease of 11days of NICU stay [58].
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Irradiated
Exposing blood products to ionizing radiation damages
nuclear DNA in order to inactivate donor T cells, thereby
signicantly decreasing the risk of transfusion-related
GVHD in at-risk patients (including low birth weight neonates, neonates who have undergone intrauterine transfusions, newborns undergoing exchange transfusion, and those
with congenital immunodeciencies). For at-risk patients, all
blood components with viable T cells should be irradiated,
including RBCs, platelets, granulocytes, and fresh plasma.
Cryoprecipitate is unlikely to contain viable T cells, and
there is controversy whether irradiation of frozen plasma is
necessary given the destructive effect of the freezing- thawing
process on donor T cells. In comparison to leukoreduction,
blood product irradiation does not produce a CMV-safe
product.
Irradiation of RBC however can damage the cell membrane, reducing its shelf life to 28days. This damage is also
thought to cause increased concentrations of potassium in
irradiated units. Reducing the time between irradiation and
transfusion can minimize the potassium leak, and RBC
washing is indicated prior to large-volume transfusions to
reduce the risk of hyperkalemia. Platelet properties and storage, contrastingly, do not appear to be affected by
irradiation.
Age ofBlood
Refrigerated RBCs can be stored up to 42days in the United
States, with average shelf life between 2 and 3weeks. There
have been several studies investigating the effect of age of
RBC on outcomes, without signicant differences. The Age
of Red Blood Cells in Premature Infants (ARIPI) trial was a
double-blind, randomized controlled trial where 377 very
low birth weight neonates were assigned to receive transfusions of RBCs stored less than 7days (mean 5.1days, SD
2.0days) or standard blood bank practice (mean 14.6days,
SD 8.3days). They found no signicant difference in mortality or major neonatal morbidities (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis,
intraventricular hemorrhage) [59]. These results may not be
generalizable, however, given that transfusion thresholds
were not standardized across patients, and average storage
duration of refrigerated RBCs is around 18days in the United
States [12].
The Tissue Oxygenation by Transfusion in Severe Anemia
with Lactic Acidosis (TOTAL) trial randomized 290 children
aged 5months to 5years in Uganda with lactic acidosis from
severe anemia (mostly secondary to malaria) to leukoreduced
RBC transfusion of units stored 1–10days (median 8days) or
25–35days (median 32days). There were no signicant dif-
ferences in the groups in terms of clinical assessment, cerebral oxygen saturation, electrolyte abnormalities, adverse
events, survival, or 30-day recovery [60]. There is also an
ongoing study investigating outcomes after transfusion of
RBC less than 7 days versus standard blood bank practice
(oldest in inventory) called the Age of Blood in Children in
Pediatric Intensive Care Units (ABC PICU) study [61].
Complications andRisks ofTransfusion
Neonates pose some unique challenges with respect to anesthesia and blood products. Infants and neonates are disproportionately more likely to have adverse events from RBC
transfusions – Stainsby et al. estimated the incidence of
adverse events for infants less than 12 months to be
37:100,000, compared to 18:100,000in children 1–18years
and 13:100,000in adults [62]. Given the high probability of
transfusion among preterm infants, there is a risk of exposure
to multiple donors. Implementation of transfusion guidelines
and transfusion reduction methods can reduce both the risk
of blood transfusion and number of donors to whom infants
are exposed. Some have suggested multipack collection or
directed donation to minimize exposure to multiple donors.
Premature infants may be more susceptible to hyperkalemia (especially after transfusion of older or irradiated blood),
hypocalcemia, hypoglycemia (possibly due to a reduction in
glucose infusion during transfusion), and hypothermia with
large-volume blood transfusions. Transfusion-related graftversus- host disease occurs more often in sick neonates, so
the use of directed donor products from close relatives and
irradiated products is important [63]. Furthermore, an analysis of UK adverse outcomes of blood transfusion in children
found a signicant number of cases with errors at different
stages in the transfusion chainincluding patients receiving a
blood component that did not meet the required specication, and even was intended for a different patient [62].
Transfusion-Related Lung Injury
Although transfusion is relatively safe, neonates (particularly preterm neonates) are at increased risk for transfusion
related lung injury (TRALI) [12, 62, 64, 65]. TRALI can be
a difcult diagnosis, especially in neonates because they are
often already critically ill. It is challenging to exclude a previous history of acute lung injury, as many are already intubated with abnormal chest radiographs. These patients are
also very vulnerable to uid overload, but it can be quite difcult to determine uid status in these patients. They also
have relatively immature immunosuppression and immature
neutrophil physiology. This also contributes to the possible
underreporting of TRALI in neonates and infants [65].
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Infection
Blood transfusion carries the risk of transmitting bacteria,
viruses, and other pathogens, the most common one being
CMV.It is estimated that the prevalence of CMV is 30–70%
in blood donors in the United States. As such, seronegative
neonates should be transfused CMV-seronegative or leukoreduced units. Glanternik etal. also report three neonatal cases
of transfusion-transmitted babesiosis, for which there is no
FDA-approved test in donated blood nor is testing mandated.
Susceptibility to babesiosis was correlated with lower birth
weight and lower gestational age [66].
Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a chronic lung disease resulting from disrupted alveolar growth. It is the most
common sequelae of preterm birth, characterized by supplemental oxygen requirement and severity assessment at
36weeks, corrected gestational age. Many factors contribute
to BPD, including oxidative and inammatory injury to the
immature lungs. RBC transfusion may increase oxidative
stress, and neonates who developed BPD have been shown to
have received more RBC transfusions than those who did not
[67]. Valieva etal. however found that the incidence of BPD
was signicantly associated with number of transfusions at
day of life 28, but not at 36weeks corrected gestational age
[29]. Similarly, Chen etal. did not nd a signicant difference
in respiratory outcomes among 36 very low birth weight
preterm babies randomized to liberal versus restrictive PRBC
transfusion criteria. They did however nd that development
of chronic lung disease was associated with total transfused
volume over 30mL over 30days in very low birth weight
infants [30].
conducted a prospective multicenter observational cohort
study among 598 VLBW infants, adjusting for birth weight,
center, breastfeeding, illness severity, and duration of initial
antibiotic treatment. They found that severe anemia (within
the week of developing NEC) was associated with increased
risk of NEC (adjusted cause-specic HR 5.99, 95% CI 2–18).
They however found no difference in the rate of NEC among
patients who were transfused versus not transfused within a
week of developing NEC (adjusted cause-specic HR 0.44,
95% CI 0.17–1.12) [
increases the risk of NEC, or rather that transfusion is a surrogate marker for severe anemia-related NEC.It has also
been suggested that blood transfusion can blunt the prandial
increase in mesenteric perfusion, and there is some evidence
that withholding feeds during blood transfusion may reduce
the risk of NEC [76].
75]. It is unclear that blood transfusion
Severe Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) is a signicant cause of
brain injury among premature infants, often due to germinal
matrix fragility and changes in cerebral blood ow. A retrospective case-control study looking at VLBW with initial
head US showing no hemorrhage found that those with subsequent grade 3 or 4 IVH were signicantly more likely to
have received a blood transfusion [77]. The same group
looked at neonates with grade 1 IVH who subsequently
extended to grade 3 or 4 hemorrhage and found that blood
transfusion was associated with IVH extension. It is unclear
however whether the extension of IVH is in part due to blood
transfusion or rather the reason for transfusion itself [78]. In
a multicenter prospective study of VLBW infants, Bednarek
etal. (1998) suggest a higher risk of grade 3–4 IVH among
patients in NICUs with liberal transfusion guidelines, though
not clinically signicant [8].
Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is characterized by intestinal
inammation and ischemic necrosis. Incidence of NEC ranges
from 2 to 15% among preterm infants and mortality rate of
15–30%, inversely related to gestational age and birth weight.
Its pathogenesis is likely multifactorial, related to genetic
predisposition, immaturity of neonatal GI tract vascular
autoregulatory responses, anemia, changes in intestinal
microbial colonization, intestinal and immunologic immaturity,
and a highly immunoreactive intestinal mucosa [68].
There have been some studies reporting an association
between RBC transfusion and increased risk of NEC [69,
70]. However, more recent studies have found no association
between transfusion and NEC [71–73], and some have found
transfusion to be protective against NEC [74]. Patel etal.
Retinopathy ofPrematurity
Several studies have suggested that there is a correlation
between both the number and volume of blood transfusions
and retinopathy of prematurity (ROP); however, the
pathophysiology is unclear. It is thought that transfusing premature infants with adult hemoglobin that has a greater afnity to ofoad oxygen causes increased oxygen delivery to the
immature retina. Furthermore, increased free iron and free
radical generation could contribute to retinal injury. Given
their susceptibility to ROP risk factors as early as birth to
4weeks of life, it is important to use methods to avoid unnecessary transfusions among preterm infants [79].
Several studies have found a correlation between blood
transfusion and ROP. A prospective observational study of
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45 preterm low birth weight infants found that transfusion
volume during the rst week (OR 1.16, 95% CI 1.03–1.3)
and during the rst 2months of life (OR 2.93, 95% CI 1.52–
5.62) were associated with the development of ROP. Inder
etal. also found that among 56 VLBW infants, transfusion
volume to 28days was associated with risk of developing
ROP (adjusted OR 2.03, CI 1.13–4.49). And among a cohort
of 98 extremely low birth weight infants, the number of
transfusions within 30days was correlated with the development of ROP (OR 1.27, 95% CI 1.04–1.55) [22, 80, 81].
More recently, Lundgren etal. have conducted a prospective study of 78 and retrospective cohort of 227 extremely
preterm infants, both of which found that anemia during the
rst week of life was an independent risk factor for ROP.In
the cohort of 227 infants, both the duration of anemia and
blood transfusion were associated with ROP warranting
treatment; in the multivariate models however, only the
number of anemic days during the rst week of life was
included in the best-t model (as well as sepsis during the
rst 4 weeks of life and days of ventilation from birth to
35weeks) [82, 83].
Alternatives toTransfusion
Prevention of anemia can signicantly impact the number of
blood transfusions among preterm infants, reducing its associated morbidity and mortality. A retrospective analysis of
four western US NICUs with the same RBC transfusion
guidelines found that despite no difference in compliance to
their guidelines, blood transfusion rates varied widely
between the units. The lower-transfusing NICUs had lower
rates of NEC and IVH, as well as cost savings of $6970 per
1000 NICU days. Moreover, the units with lower rates of
transfusion had written anemia-prevention guidelines which
included measures like umbilical milking at VLBW delivery,
use of cord blood for admission studies, and darbepoetin
dosing for selected neonates [84].
Blood Conservation
Blood conservation methods can reduce the contribution of
phlebotomy to neonatal anemia, especially among low birth
weight infants. Such methods include microtechnique laboratory procedures, noninvasive monitoring, and the use of
fetal blood from the placenta for baseline laboratory tests.
Grouping lab draws can help reduce the amount of blood
overdraw, and any blood waste can be re-administered.
Among 63 patients admitted to the PICU for greater than
48hours, patients less than 10kg had the greatest amount of
phlebotomy-induced blood loss per kilogram, due to their
small size and proportion of blood loss to body weight. They
were also subjected to a greater number of blood draws with
a longer length of stay and greater amount of blood loss per
kilogram per PICU stay. Furthermore, blood drawn for single test had signicantly more blood overdraw than for multiple tests [
Use of an in-line, ex vivo bedside monitor in the rst
2weeks of life of critically ill ELBW infants with UAC had
signicantly less laboratory blood loss (22%) and received
signicantly less RBC transfusion volumes (33%). The monitor drew 1.5mL blood samples; analyzed them for blood
gas, electrolytes, and hematocrit levels; and then reinfused
all except 25 microL of blood. The study was terminated
prematurely when one center’s NICU changed its method of
lab testing, however, and there were no differences in
mortality, morbidity, and neurodevelopmental outcomes at
18–24months [86]. Mahieu etal. also showed that the introduction of a point-of-care-testing analyzer (for bedside blood
gases, hemoglobin, electrolytes, and bilirubin) signicantly
decreased transfusions among VLBW infants from 50% to
38.9%, with overall cost reduction of 8.51% per neonate
87].
[
85].
Delayed Umbilical Cord Clamping andCord
Stripping
Delayed umbilical cord clamping (DCC) may provide a
newborn more time for the transition from fetal to neonatal
life, especially among premature infants. It also allows for
placental transfusion which increases neonatal blood volume, ameliorates the hemodynamic changes associated with
the transition, and may reduce the risk of IVH, blood transfusion, respiratory distress or support, and death.
A randomized controlled trial in which very preterm
infants either had their cord clamped immediately or delayed
showed that delayed cord clamping was signicantly associated with decreased incidence of IVH and sepsis, with no
difference in incidence of BPD and NEC [88]. Another study
found that delayed cord clamping was associated with
decreased hypothermia, neonatal respiratory interventions
(surfactant therapy or intubation in the delivery room, in the
rst 24hours of life, or during the NICU stay), and blood
transfusions [89]. Strauss etal. however showed that although
a 1-minute delay in cord clamping resulted in higher hematocrit and RBC volume and mass, there was no difference in
number of blood transfusions [90].
In a retrospective cohort study of 4680 premature neonates, those who received DCC had reduced odds of severe
neurologic injury (adjusted OR 0.80, 95% CI 0.64–0.99) and
mortality (adjusted OR 0.74, 95% CI 0.59–0.93); there were
no signicant differences in the odds of BPD, ROP stage >3,
NEC stage >2, late-onset sepsis, or receipt of >2 blood transfusions [91]. A case-control study of 45 infants monitored
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