NeoReviews September2007

Historical Perspectives: Perinatal Profiles: Geoffrey S.
Dawes: A Neonatologist's
Appreciation
Roderic H. Phibbs
NeoReviews 2007;8;e365-e367
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historical perspectives
Perinatal Profiles:
Geoffrey S. Dawes:
A Neonatologist’s Appreciation
Roderic H. Phibbs, MD* investigators concentrated particu-
larly on the preparations for and
Introduction mechanisms of adaptation to extra-
When neonatology was emerging as uterine life. A central focus of the
a clinical discipline in the late 1950s research was the adaptive mechan-
and early 1960s, it had the advantage isms in the circulatory and respiratory
The Underpinnings of of a strong foundation of basic re- systems, including placental func-
Neonatal/Perinatal Medicine search in fetal and neonatal physiol- tion, establishment of lung function,
ogy. In particular, the new clinical and changes in the pulmonary and
enterprise (it was not yet a subspe- systemic circulations. Although
Author Disclosure cialty) focused on cardiorespiratory most of the work examined cardio-
pathophysiology. This foundation respiratory physiology and its neuro-
Dr Phibbs did not disclose any
came from a few distinguished re- humoral regulation, researchers also
financial relationships relevant to search laboratories studying fetal and studied fetal growth and metabo-
this article. neonatal physiology and the pro- lism, and their studies included the
cesses of the transition from fetal to responses to stresses such as hypoxia
neonatal life. The preeminent labora- and hemorrhage. One of the hall-
tory in the field was the Nuffield In- marks of the research of this highly
stitute for Medical Research at Ox- productive group was the elegance of
ford, directed by Geoffrey S. Dawes. their experimental designs.
Geoffrey Dawes became the di-
rector of the Institute in 1948. He Responses to Stress
received his medical degree in 1943, The clinical implications of this work
and in the following 5 years, he were self-evident. What happened
gained recognition as a prominent when the adaptive mechanisms for
investigator in pharmacology and extrauterine life failed? What were
physiology. The very short interval the responses to stresses such as as-
between receiving his degree and be- phyxia? Beginning in 1958, Dawes
ing named director of an important and his associates had an ideal oppor-
research institute indicates how tunity to expand this line of research.
quickly the academic leadership rec- The United States National Insti-
ognized his exceptional qualities. As tutes of Health were supporting
the new director, Dawes set the pri- studies on the mechanisms of brain
mary focus of research for the Nuf- injury in the fetus and newborn be-
field Institute as developmental phys- ing performed in a primate labora-
iology. In this role, the Nuffield tory in Puerto Rico, and various
became the successor to the path of groups of investigators were invited
research started by Sir Joseph to participate in the different aspects
Barcroft at Cambridge early in the of the research. Dawes and the Nuf-
twentieth century. Dawes and his co- field team were among those invited
to collaborate and made several ex-
tended visits over the next few years
*Department of Pediatrics and Cardiovascular to conduct research with other inves-
Research Institute, University of California, San
Francisco, Calif. tigators, particularly Stanley James
and Karlis Adamsons. They made ex-
NeoReviews Vol.8 No.9 September 2007 e365

Fetal Physiology
During the formative era of “mod-
ern” neonatology, ie, neonatal care
based on cardiopulmonary patho-
physiology in the mid to late 1950s
and early 1960s, many conferences
dealt with the general topic of how to
deploy a system of physiology-based
care for newborns. Dawes was highly
sought after for such conferences as
much for his insightful, probing
commentary on the work of others as
for presentation of his own research.
A good example of these times was
the Ross Conference “Adaptations
to Extrauterine Life,” held in Van-
couver in November 1958. The
Session Chairs were Dawes and
McCance from Cambridge, and
Harvard’s Clement Smith, the au-
thor of the text Physiology of the New-
born Infant, which was required
reading for budding neonatologists.
Mildred Stahlman, L. Stanley James,
Thomas Oliver, Sidney Segal, and Jim
Sutherland were among the attendees
who were emerging as some of the
early leaders in neonatology. In this
program, Dawes’ presentation was ef-
fects of anoxia on newborn animals.
The proceedings of the conference re-
flect the interests and intellectual en-
ergy of the formative years of neona-
tology. The program ended with a
Figure. The paradigm of the progression of cardiorespiratory changes during asphyxia.
roundtable discussion on clinical ap-
Reprinted with permission from Dawes GS. Fetal and Neonatal Physiology. Chicago, Ill:
plications in which McCance com-
Yearbook Medical Publishers, Inc; 1968.
mented on “euthermia versus hypo-
thermia” and Smith commented on
“the effects of placental transfusion,”
tensive observations of the sequences ample, see Figures 1.6 and 1.7 on
both subjects of research publications
of responses to progressive asphyxia. page 1–7 of the Fourth Edition the
in 2006 and 2007.
The resulting studies brought forth American Academy of Pediatrics
In 1967, Julius Comroe, the di-
the paradigm of the progression of Textbook of Neonatal Resuscitation). rector of at the Cardiovascular Re-
cardiorespiratory changes during as- They also started to study the research Institute at the University of
phyxia. The Figure from Dawes’ sponses to various components of re- California, San Francisco (UCSF),
book that illustrates this paradigm suscitation. For example, they dem- invited Geoffrey Dawes to take a sab-
has been reproduced both in its orig- onstrated that when heart failure is batical at the Institute to write the
inal form and with minor modifica- due to acute asphyxia, correction of book on fetal physiology. Dawes ac-
tions in many clinical textbooks, usu- acidosis by an infusion of alkali cepted and came to San Francisco for
ally as the starting point for a quickly restores normal myocardial the latter half of 1967. Comroe pro-
discussion of fetal asphyxia. (For ex- contractility. vided Dawes with editorial staff, a
e366 NeoReviews Vol.8 No.9 September 2007

medical illustrator, and an editorial tended and participated actively in whom stayed on for many years and
advisory committee of physiologists the weekly perinatal/neonatal clini- others of whom were there for sev-
who met with him weekly to critique cal conferences. The proximity of the eral years, then moved to other aca-
his most recent chapter. Dawes clinical units facilitated the Insti- demic positions, usually in physiol-
clearly wanted the text to appeal to tute’s close collaboration with obste- ogy. The second group was the
clinicians as well as physiologists, tricians and pediatricians. research fellows in training. Some of
meeting frequently with Bill Tooley, When Dawes began using the these were predoctorate, but in later
the head of neonatology at UCSF, to chronic in utero fetal lamb prepara- years, many were postdoctorate pedi-
discuss his strategy for upcoming tion, he noticed that fetal lambs atricians and obstetricians. The at-
chapters and regularly attending the made intermittent respiratory move- traction of the Nuffield for physicians
weekly neonatal/perinatal clinical ments that occurred during rapid eye headed for careers in academic neo-
conferences, where he was an impos- movement sleep. Moving to the hu- natology and perinatology were ob-
ing presence. man, his obstetrically trained re- vious, so talented young clinicians
The product of the sabbatical was search fellows could detect fetal flocked to the Institute. They later
the superbly written and beautifully breathing movements by ultrasonog- filled many university faculty posi-
illustrated Fetal and Neonatal Physi- raphy that also were intermittent. tions in neonatology and perinatol-
ology, published by Year Book Medi- These observations spawned a burst ogy, particularly in the United King-
cal Publishers, Inc, in 1968. Al- of clinical research in many centers as dom, Canada, the United States,
though not a clinical text in the strict perinatologists studied the effects of Australia, and New Zealand. The
sense, most of the book is highly various maternal states on fetal third group of investigators was the
relevant to the practice of clinical breathing. In time, fetal breathing established academicians, usually in
neonatology. It quickly became re- movements became part of the bio- perinatology, neonatology, or physi-
quired reading for serious students of physical profile of fetal well-being. ology, who spent a sabbatical leave
neonatology. It remains highly rele- As Dawes became familiar with (generally 6 months to 1 year) work-
vant today and is so well written and the clinical methods of assessing fetal ing in the Institute before returning
illustrated that it probably still well-being, he was unhappy with the to their home medical schools. The
should be required reading for neo- way fetal heart rate tracings were investigators who passed through the
natologists in training. used to detect a fetus in distress be- Nuffield became a sort of informal
The original home for the Nuf- cause the system depended on expert network that continued to commu-
field Institute for Medical Research recognition of particular patterns. nicate and often collaborate in re-
was in an abandoned astronomical He accumulated a very large database search.
observatory in central Oxford. The of digitized human fetal heart rate Many of Geoffery Dawes’ long list
building was designed by Christo- tracings and, with his strong back- of awards are related to neonatology
pher Wren, the great 17th century ground in mathematics, launched on and perinatology. Some of these in-
architect who designed many of the a large-scale analysis. Ultimately, he clude Fellow, Royal Collage of Ob-
important buildings built after the developed a program that would al- stetricians and Gynaecologists, the
great fire of London. However, this low automated detection of fetal dis- American Academy of Pediatrics, and
fine building of historic interest was tress. An instrument company pro- American Collage of Obstetricians
not well suited for experimental duced a microprocessor that used his and Gynecologicts; the Apgar Award
physiology. When a new hospital of method to detect troublesome pat- from the American Academy of Pedi-
Obstetrics and Neonatal Pediatrics terns of the fetal heart rate. atrics; and the James Spence Award
was built at Headington on the out- from the British Pediatric Associa-
skirts of Oxford, the Nuffield Insti- Developing Leaders tion.
tute moved into a large new facility Another major contribution of Geoffrey Dawes stepped down as
immediately adjacent the clinical Dawes was the development of lead- the director of the Nuffield Institute
buildings, which was symbolic of ers in academic neonatology and in 1985 and died in 1996. A more
Dawes’ close ties to clinical perina- perinatology. There were three types complete appreciation of him by Sir
tology and neonatology. There was of researchers at the Nuffield. The Graham Liggins appeared in Bio-
continuous exchange between the first were what might be considered graphical Memoirs of Fellows of the
buildings, and Dawes regularly at- the permanent scientists, some of Royal Society 1998.

Historical Perspectives: Perinatal Profiles: Geoffrey S. Dawes: A Neonatologist's
Appreciation
Roderic H. Phibbs
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Developmental Defects in Neutrophils from Preterm Infants
Sharat Chandra, Hillary Haines, Colin Michie and Akhil Maheshwari

Article hematology
Developmental Defects in
Neutrophils from Preterm
Infants
Sharat Chandra, MD,
Objectives After completing this article, readers should be able to:
MRCPCH,* Hillary Haines,
MD,† Colin Michie, 1. Define key neutrophil functions and involved mechanisms.
‡
FRCPCH, Akhil 2. Identify developmental defects in preterm neutrophils.
Maheshwari, MD†§ 3. Describe the effect on neutrophils of clinical interventions, such as the use of
recombinant myeloid growth factors and drugs commonly used in the neonatal
intensive care unit.
Author Disclosure
Drs Chandra, Haines,
Michie, and
Abstract
Neutrophil development starts in the early second trimester in the human fetus and
Maheshwari did not
continues through the rest of the gestation. Preterm birth can interrupt the matura-
disclose any financial tion of fetal neutrophils and place the preterm neonate at risk of life-threatening
relationships relevant infections. Various developmental defects have been identified in preterm neutrophils,
to this article. such as in the ability of circulating neutrophils to cross the endothelial barrier and
abnormalities in chemotaxis, respiratory burst, and degranulation. The availability of
recombinant human myeloid growth factors has renewed interest in understanding
the mechanisms and natural history of such defects. In this article, we review various
aspects of the developmental immaturity of preterm neutrophils.
Introduction
Neutrophils are the first-line defenders against bacterial and fungal pathogens. In the
human fetus, neutrophil development starts at a relatively late stage (10 to 14 weeks’
gestation), when hematopoietic progenitor cells in the bone marrow begin to differentiate
into neutrophil precursors. (1)(2) Functional maturation of neutrophils continues
through the rest of the gestation, and interruptions in this process due to preterm birth can
place the preterm neonate at risk of life-threatening infections.
Neutrophil Kinetics
Bone marrow neutrophils are broadly classified into early precursors that have a capacity for
four to five cell divisions and the later, postmitotic stages that are in the process of
differentiation (Fig. 1). Studies in adults show that the neutrophil proliferating pool (NPP)
contains about 2⫻109 cells/kg body weight, and the neutrophil storage pool (NSP)
contains about 6⫻109 cells/kg body weight. (1) The NPP and NSP together contain
nearly 90% of all neutrophils in the body. The remaining 10% (0.6⫻109 cells/kg body
weight) are distributed equally free in circulation or emarginated to the vascular endothe-
lium in microcirculatory channels. During acute inflammation, neutrophils are released
initially from the NSP, and once these stores are exhausted, progressively immature cells
are mobilized (the “left” shift of sepsis). Circulating neutrophils persist in the bloodstream
for 6 to 8 hours and subsequently for a few hours to several days in tissues.
Developmental Defects
In the mid-gestation fetus and preterm infant, the NSP is very small and can be exhausted
readily during sepsis. (1) The NPP also is smaller, about one-tenth the size (per kilogram
*Department of Pediatrics, University of South Alabama, Mobile, Ala.

†
Department of Pediatrics, University of Alabama at Birmingham, Ala.
‡
Department of Paediatrics, Ealing Hospital, NHS Trust, London, United Kingdom.
§
Department of Cell Biology, University of Alabama at Birmingham, Ala.

hematology neutrophil defects
that have a glutamate-leucine-

arginine (ELR) tripeptide sequence
(such as interleukin-8 [IL-8/
CXCL8]) have neutrophil-specific
chemotactic activity. (12)
In inflamed areas, transient in-
terruptions in the flow of marginat-
ing neutrophils cause them to roll
on the vascular endothelial surface.
This process is mediated through a
process of repetitive binding and
release of the selectin ligands (L-
selectin on neutrophils, E- and
P-selectin on endothelium) from
their sialomucin receptors called
Figure 1. Neutrophils differentiate in the bone marrow through a series of well-defined
addressins. The term “selectin” is
stages, which can be grouped broadly into the neutrophil proliferating pool (NPP) and the
derived from a key lectin domain
neutrophil storage pool (NSP). In the preterm infant, the size of the NSP is very small and
can be depleted easily during sepsis. that interacts selectively with
oligosaccharide receptors bearing
sialylated carbohydrate moieties.
L-selectin is expressed constitu-
of body weight) seen in adults. (3) In extremely preterm tively on neutrophils and is shed after cellular activation.
neonates, the total neutrophil mass (estimated indirectly (13) In contrast, E- and P-selectin appear on endothelial
by measuring plasma concentrations of soluble CD16, cells during inflammation and represent the “reserve”
which is shed from the neutrophil surface) is about one capacity for neutrophil recruitment that is deployed dur-
fifth of that seen in adults. (4) ing a microbial insult. (14)
Rolling neutrophils slow down and attach to endo-
thelium through the binding of beta2-integrins to vari-
Effect of Common Clinical Interventions
ous receptors on endothelial cells. (15) These beta2- or
Recombinant granulocyte colony-stimulating factor (G-
leukocyte integrins are heterodimeric molecules that
CSF), granulocyte macrophage colony-stimulating fac-
mediate cell-cell and cell-matrix interactions. Neutro-
tor (GM-CSF), and corticosteroids can release neutro-
phils display three integrins that have an identical 95-
phils from the NSP. (5)(6)(7) Epinephrine can release
kDa beta2-chain (CD18): leukocyte function-associated
emarginated neutrophils rapidly into circulation for
antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18), Mac-1
about 30 to 45 minutes. (8) A mild demarginating
(alphaMbeta2, CD11b/CD18), and p150,95 (alphaX
response also has been reported in preterm infants after
beta2, CD11c/CD18). These integrins bind to endothe-
red cell transfusions. (9)
lial receptors such as the intercellular adhesion
molecule-1 (ICAM-1) and ICAM-2. LFA-1 binds to
Recruitment of Circulating Neutrophils to both ICAM-1 and ICAM-2; Mac-1 and p150,95 bind
Sites of Inflammation exclusively to ICAM-1. ICAM-3 is expressed on hema-
Circulating neutrophils leave the intravascular compart- topoietic cells and does not participate in leukocyte-
ment to enter the tissues in three major steps: margin- endothelial interactions. Integrin activation requires
ation and rolling on vascular endothelium, attachment to chemokines such as IL-8 (produced by activated endo-
the endothelial cells, and transendothelial migration thelium), which increase the number and avidity of
(Fig. 2). (10)(11) Leukocyte traffic is directed preferen- beta2-integrins and cause rearrangement of the cyto-
tially to inflamed areas through regional changes in skeleton. (16) ICAM-2 is expressed constitutively on
vascular flow and along concentration gradients of endothelial cells and may act as the initial ligand for
humoral chemoattractants such as chemokines, bacterial neutrophil integrins. ICAM-1, like E-selectin, is upregu-
products (such as formyl-met-leu-phe [f-MLP]), com- lated during inflammation. (17)
plement fragments (C5a), and leukotrienes (LTB4). Transendothelial migration (TEM) of activated neu-
Among chemokines, members of the CXC subfamily trophils involves the platelet-endothelial cell adhesion

preterm and term neonates. Mac-1

expression is about 10% of adult
levels at 27 weeks’ gestation, in-
creases to 45% at 36 weeks’ gesta-
tion, is 57% at term, and reaches
adult values in early childhood.
(23) Although most studies are in
agreement on lower Mac-1 expres-
sion on neonatal neutrophils, there
is one report of normal Mac-1 in
neonates, and the authors cau-
tioned that neutrophil isolation
techniques can influence Mac-1 ex-
Figure 2. Schematic representation of recruitment of circulating neutrophils to inflamed pression. (24)
tissues. Neutrophils adhere transiently to inflamed endothelium to roll on its surface, slow TEM of neutrophils is affected
down and attach to the endothelium, become activated, and migrate through the by their deformability. Although
endothelium into the tissues. initial studies reported conflicting
data, deformability of mature rest-
molecule (PECAM1, CD31), the integrin-associated ing neutrophils appears to be similar in healthy preterm
protein (IAP, CD47), and a number of other junctional neonates, term neonates, and adults. (25) However, the
molecules. (18) TEM is a rapidly occurring process that release of immature neutrophils from the NSP during
is completed in less than 2 minutes after leukocyte- sepsis is associated with an overall reduction in neutro-
endothelial contact is established and may occur either phil deformability. (26)
through transcellular diapedesis or via active migration of
neutrophils through “pores” at tricellular endothelial Effect of Common Clinical Interventions
junctions. G-CSF increases the expression of beta2-integrins, but
lowers L-selectin expression on neonatal neutrophils
Developmental Defects (both term and preterm). (27) In contrast, early dexa-
Compared with neutrophils from adults, neutrophils methasone administration decreases beta2-integrin ex-
from both term and preterm neonates adhere poorly to pression on neutrophils. (28)
the endothelium. Neonatal neutrophils have lower selec-
tin and beta2-integrin expression. L-selectin expression is Chemotaxis
lower at birth than in adults and decreases further during Once outside the blood vessel, neutrophils migrate along
the first 24 to 72 hours after birth. (19) Neonatal concentration gradients of various chemoattractants
“stress,” as in perinatal asphyxia, may reduce further such as IL-8 (and other ELR⫹ CXC chemokines),
L-selectin expression on neutrophils. (20) In addition, f-MLP, and C5a. (12) These chemotactic stimuli bind to
neonatal neutrophils have defective shedding of high-affinity G-protein-coupled receptors on the leuko-
L-selectin. (19) The combination of lower expression cyte surface, and minute spatial gradients in chemoat-
and impaired shedding of L-selectin reduces the fre- tractant concentrations can cause the receptors to be
quency of neutrophil rolling events, which are a rate- distributed asymmetrically toward the migrating neutro-
limiting step in tissue recruitment of neutrophils. Char- phil pseudopodium. Cellular movement involves a num-
acteristics of preterm vascular endothelium, such as lower ber of intracellular signaling pathways and cytoskeletal
P-selectin expression, contribute further to defects in proteins. A chemoattractant hierarchy has been reported
neutrophil recruitment. (21) wherein bacterial products are preferred over host che-
Neonatal neutrophils have lower expression of Mac- mokines. (29)
1(CD18/CD11b), one of the beta2-integrins, which
correlates with lower neutrophil-endothelial adherence Developmental Defects
and transmigration. (22) Neutrophils from both pre- Neutrophils from both term and preterm neonates have
term and term infants are unable to upregulate Mac-1 an impaired chemotactic response. Neutrophils from
expression following stimulation by bacterial products. newborns migrate at about half the speed traveled by
The absolute Mac-1 content per neutrophil is lower in adult cells. (30)(31) Although neutrophils from term

infants achieve normal chemotactic function by 2 weeks fuses with a lysosome for killing of internalized microor-
after birth, such postnatal neutrophil maturation begins ganisms and terminal degradation of the cargo. (44)
2 to 3 weeks after birth in immature preterm infants and Phagocytosis is more efficient when the target is op-
proceeds very slowly. (32) Neutrophils from preterm sonized by specific immunoglobulin G (IgG) or comple-
infants born at 34 to 36 weeks’ gestation achieve normal ment factors. IgG promotes phagocytosis by neutralizing
chemotaxis by 40 to 42 weeks postconceptional age bacterial inhibitors of phagocytosis such as the capsular
(PCA). In more immature preterm infants (⬍34 wk), polysaccharide and by activating the classic pathway of
neutrophil chemotaxis improves with time but remains complement that provides the opsonic C3 fragments.
impaired compared with adults, even at 42 weeks PCA. Opsonins also convert the relatively hydrophilic micro-
(33) The presence of various clinical confounders makes bial surface to be more hydrophobic and, therefore, more
it difficult to separate the effects of clinical stress from the readily ingested. Neutrophils express receptors for IgG
effects of prematurity on neutrophil function. Gram- (Fcgamma receptors I-III, or CD16, CD32, CD64),
negative sepsis may depress neutrophil chemotaxis; su- C3b (CR1), and iC3b (CR3). In some instances, micro-
perficial infections are associated with enhanced chemo- organisms may be ingested without opsonization
taxis. (34)(35) through lectin-carbohydrate (lectins on bacterial fim-
Neonatal neutrophils bind various chemoattractants briae interact with neutrophil glycoproteins), protein-
normally. However, chemoattractant-induced mem- protein (proteins such as filamentous hemagglutinin that
brane depolarization, calcium transport, and sugar up- express the arg-glyasp or RGD amino acid sequence bind
take are relatively less efficient. Neonatal neutrophils to integrins), and hydrophobic-protein (bacterial glyco-
show an incremental chemotactic response to increasing lipids and neutrophil integrins) interactions. (44)(45)
chemokine concentrations, but these responses remain The interaction of IgG or complement receptors on
lower than in adult neutrophils. (36) The chemotactic the neutrophil surface with the opsonized particle trigger
defect in neonatal neutrophils may be multifactorial, cytoskeletal rearrangements to enclose the opsonized
affected by factors such as a larger, poorly motile neutro- particle within a phagosome. Phagocytosis is most effi-
phil subpopulation; impaired calcium mobilization; and cient when organisms are coated with both IgG and C3,
aberrations in intracellular signaling pathways such as which allows cooperative interaction of cognate recep-
nuclear factor-kappa-B activation. (37)(38) Lower tors for both the opsonins. As mentioned previously,
Mac-1 expression also can impede chemotaxis due to neutrophils express integrin receptors for matrix proteins
impaired neutrophil interaction with the extracellular with the RGD tripeptide motif (such as fibronectin,
matrix. (37)(39) laminin, and collagen) and ingest C3-coated particles
more efficiently when adherent to surfaces coated with
Effect of Common Clinical Interventions these RGD-bearing proteins. (44)(46)(47)
In preterm infants, intrapartum exposure to magnesium
sulfate reduces both neutrophil chemotaxis and random Developmental Defects
motility. (40) Theophylline concentrations in the high Neutrophils from preterm neonates have a developmen-
therapeutic range (84 mcmol/L or 15 mcg/mL) cause tal defect in phagocytosis that corrects by late third
dose-dependent reductions in neutrophil chemotaxis. trimester or term gestation (to become comparable to
Cells from preterm infants are particularly sensitive to adult neutrophils). (31) Preterm neutrophils ingest par-
this effect. In contrast, theophylline concentrations in ticles more slowly and ingest fewer bacteria (such as
the low therapeutic range (28 mcmol/L or 5 mcg/mL) Escherichia coli). The lack of opsonic activity is an impor-
increase neutrophil activity. (41) Indomethacin also has tant consideration because preterm infants often have
an adverse effect on neutrophil chemotaxis, which is lower concentrations of specific antibodies. Adult neu-
more pronounced in preterm infants. (42) Both G-CSF trophils lose their phagocytic efficiency if suspended in
and GM-CSF increase neutrophil chemotactic respon- serum of preterm infants. (48) Similarly, neutrophils of
siveness to other chemoattractants. (43) preterm neonates significantly increase their phagocytic
function following exposure to adult serum or therapeu-
Phagocytosis tic Ig preparations. (48)(49)(50)
Phagocytosis is a specific form of endocytosis directed at Compared with term neonates and adults, preterm
engulfing solid particles into an internal phagosome. neutrophils have a lower expression of CD16 (Fc-
This internalized phagosome “matures” through inter- gamma-RIII) and CD32 (Fc-gamma-RII), the two most
actions with the endosomal compartment and eventually abundant neutrophil IgG receptors. In “stressed” pre-

term neonates who have severe respiratory distress syn- mechanisms, such as low pH (as low as 6.0), defensins,
drome or sepsis, CD16 expression may be even lower. bactericidal/permeability-increasing protein (BPI), lac-
(51) Whereas CD16 expression normally increases to toferrin, lysozyme, and a variety of cationic proteins.
adult levels over the first 3 weeks after birth, CD32 Defensins are broad-spectrum antimicrobial peptides
deficiency does not correct with time. CD32 is the that have activity against gram-positive and gram-
high-affinity receptor for IgG2 (important against encap- negative bacteria, fungi, and enveloped viruses. (60) BPI
sulated bacteria), and CD32 deficiency may represent an binds lipopolysaccharide (LPS) and blocks its effects, can
important immune defect in preterm neonates. (52) damage the outer membrane of gram-negative bacteria,
Unlike CD16 and CD32, CD64 expression on neonatal and has some opsonic activity. (61) Lactoferrin, an iron
neutrophils (both preterm and term) may be higher than chelator, is bacteriostatic as it deprives bacteria of the
on neutrophils from adults. (53). CD64 is not affected iron required for growth. Lactoferrin also is involved in
by neonatal “stress,” as in respiratory distress and or neutrophil degranulation, oxygen radical production,
prolonged rupture of membranes, and emerging data and granulocytopoiesis. Lysozyme hydrolyzes a glyco-
suggest that CD64 might be a useful early marker for side bond in the bacterial cell wall peptidoglycan. Pri-
bacterial infections. (54) mary granules also contain other cationic antibacterial
proteins such as azurocidin, indolicin, and cathelicidins.
Effect of Common Clinical Interventions (44)(62)
G-CSF and GM-CSF both activate neutrophil phagocy-
tosis. The benefits of intravenous immunoglobulin
(IVIG) as a source of opsonic activity remain uncertain. Developmental Defects
(48)(50)(55) A major limitation may be in the formula- Although preterm neutrophils have a higher oxygen
tion of current IVIG preparations, which may not have consumption and normal/elevated release of superoxide
adequate concentrations of antibodies against neonatal and H2O2, the overall respiratory burst is depressed. This
pathogens. (56) deficiency is more marked in preterm infants who have a
high severity of sickness. (31)(63)(64) Neutrophil oxi-
Killing dative burst remains impaired in preterm infants despite
The phagolysosome provides an enclosed space in which opsonization with IgG and complement. (65)
an ingested microbe is exposed to high concentrations of Perinatal events can influence the respiratory burst in
toxic substances, while limiting the exposure of the neonatal neutrophils. Labor and vaginal delivery activate
phagocyte and other cells to these potentially injurious the generation of free oxygen radicals in neonatal neu-
agents. (44) The major killing mechanism in neutrophils trophils. In contrast, perinatal distress can suppress the
involves the generation of highly reactive free oxygen neutrophil respiratory burst. Cytokines such as interfer-
radicals in a “respiratory burst.” An NADPH-dependent ons and tumor necrosis factor (TNF)-alpha as well as LPS
respiratory burst oxidase localized on the cell membrane can prime neutrophils for an accelerated respiratory burst
(and, therefore, the phagosome membrane) reduces mo- in vitro, but prolonged exposure to these agents (during
lecular oxygen (O2) to superoxide anion (O䡠2⫺). (57) sepsis) can dampen their effect. Reduced respiratory
Subsequent generation of hydrogen peroxide (H2O2) burst activity in preterm infants correlates with impaired
and the hydroxyl radical (OH䡠) (formed in the presence intracellular killing of Staphylococcus aureus or E coli.
of iron) also contributes to the microbicidal capacity of Whereas bacterial killing by neutrophils from term neo-
neutrophils. (58) nates consistently has been found to be normal, killing of
Such oxygen-dependent bactericidal mechanisms can staphylococci was impaired in preterm neonates whose
be divided broadly into myeloperoxidase (MPO)- birthweights were less than 2,000 g. (66)
independent (such as H2O2) and MPO-dependent The postnatal maturation of the respiratory burst
(MPO catalyzes reactions between H2O2 and halides to response varies according to gestational age. During the
form highly reactive products). (59) H2O2 is a weak first postnatal week, infants born at 24 to 28 weeks’
bactericidal agent per se, but the MPO-H2O2-halide gestation have a lower respiratory burst than those born
system increases its efficacy by nearly 50-fold. The bac- at 29 to 35 weeks’ gestation. The differences between
tericidal effects of free oxygen radicals are due to oxidiz- preterm infants born at different gestational ages disap-
ing effects on various components of the bacterial cell pear in about 2 months, but overall, neutrophils from
wall. (58) preterm infants continue to have a weaker oxidative burst
Neutrophils also have elaborate nonoxidative killing than neutrophils from adults. The postnatal maturation

such as cathepsins, proteinase-3, and

elastase; and antimicrobial proteins
such as defensins and the BPI. These
granules release their contents into
the phagolysosomes and are involved
in intracellular killing. The specific
granules contain antibacterial agents
such as lactoferrin and lysozyme, re-
ceptors for complement compo-
nents, and bacterial products such as
f-MLP. Specific granules fuse with
the cell membrane to release their
contents by exocytosis and bring
functionally important membrane
proteins such as integrins, cytochrome-
b558, and receptors for chemotactic
agents and opsonins to the cell sur-
face. Specific granules play an impor-
tant role in extracellular killing. (74)
Figure 3. Neutrophils have two major types of intracellular granules: azurophilic (or Developmental Defects
primary) and specific (or secondary).
Neutrophils from term neonates
have granule contents and degran-
of the respiratory burst may not be seen at all in sick ulation responses similar to those from adults. (75)
preterm infants receiving intensive care. (67) However, neutrophils from preterm infants have a lower
Preterm neutrophils respond poorly to LPS due to capacity to release BPI, elastase, and lactoferrin than
lower expression of the LPS receptor (CD14) and the neutrophils from adults and term infants. (31)(76)
adhesion molecule CD11b and secretion of neutrophil
elastase. (68) In addition, CD14-independent upregula- Effect of Common Clinical Interventions
tion of CD11b in response to TNF-alpha and bacterial Whereas G-CSF activates mature neutrophils without
products such as f-MLP is impaired. Such hyporespon- degranulation of primary granules, (77) GM-CSF in-
siveness to LPS may predispose the preterm neonate duces degranulation and exocytosis of granule contents.
further to gram-negative sepsis. (78) Anti-inflammatory agents such as corticosteroids
and indomethacin inhibit the degranulation of secondary
Effect of Common Clinical Interventions granules. (79)
In “stressed” preterm infants receiving intensive care,
recombinant GM-CSF can boost the neutrophil respira-
tory burst to levels seen in term neonates. (69) Similarly,
Cytokine Production
Emerging data show that neutrophils can synthesize
G-CSF can enhance the neutrophil respiratory burst
cytokines in response to a variety of inflammatory stimuli.
response in septic preterm infants. (70)(71) In adults,
The expression profiles of neutrophil-derived cytokines
hypertonic saline may enhance host response to bacterial
are similar with those of monocytes and macrophages,
challenge by augmenting superoxide formation in neu-
including TNF-alpha, IL-1-beta, both CC and CXC
trophils. (72) Intracellular killing also may be augmented
chemokines (eg, IL-8, interferon-inducible protein 10,
by fluoroquinolones such as ciprofloxacin, which have a
and macrophage inflammatory protein-1-alpha), and an-
potent intraphagosomal bactericidal activity against both
giogenic factors such as vascular endothelial growth fac-
gram-positive and gram-negative bacteria. (73)
tor. There is no information on cytokine production by
Degranulation neonatal neutrophils.
Neutrophils contain two major types of granules (Fig. 3)
(62): “azurophilic” granules (stain positive with the azure Resolution of the Inflammatory Response
A dye) and “specific” granules (do not stain with azure A). Neutrophils also assist in the clearance of apoptotic neu-
Azurophilic granules contain MPO; proteolytic enzymes trophils or other cellular debris at sites of inflammation.

Thus, neutrophils may contribute to resolution of in- 17. Kellersch B, Kolanus W. Membrane-proximal signaling events in
flammation, acting as a back-up system in situations beta-2 integrin activation. Results Probl Cell Differ. 2006;43:245–257
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NeoReviews Quiz
1. Circulating neutrophils leave the intravascular compartment to enter the tissues in three major steps:
margination and rolling on vascular endothelium, attachment to endothelial cells, and transendothelial
migration. Several molecules play key roles in each of these processes. Of the following, the molecule most
involved in transendothelial migration is:
A. Endothelial intercellular adhesion molecule-1.
B. Leukocyte function-associated antigen-1.
C. L-selectin ligand on neutrophils.
D. Platelet-endothelial cell adhesion molecule.
E. P-selectin ligand on endothelium.
2. Chemotaxis represents migration of neutrophils outside of blood vessels along concentration gradients of
various chemoattractants. Several common clinical interventions can influence the neutrophil chemotactic
response in neonates. Of the following, the intervention most likely to increase neutrophil chemotaxis in
neonates is:
A. Dexamethasone treatment for chronic lung disease.
B. Granulocyte colony-stimulating factor administration for leukopenia.
C. Indomethacin treatment for patent ductus arteriosus.
D. Intrapartum exposure to magnesium sulfate.
E. Theophylline administration in high therapeutic range.
3. Phagocytosis represents engulfment of microorganisms or other target particles by neutrophils into an

internal phagosome. The internalized phagosome fuses with a lysosome, which causes terminal degradation
of the internalized target. Phagocytosis is most efficient when the target is opsonized by specific
immunoglobulin G or complement factors. Of the following, the opsonin that is expressed in higher
concentrations in neonatal neutrophils relative to adult neutrophils is:
A. CD 11b.
B. CD 16.
C. CD 18.
D. CD 32.
E. CD 64.
4. Neutrophils contain two major types of granules: “azurophilic” granules that stain positive with azure A dye
and “specific” granules that do not stain positive with azure A dye. These granules play an important role
in intracellular killing of microorganisms by neutrophils. Of the following, the constituent of the “specific”
neutrophil granules most critical for host defense is:
A. Antibacterial lactoferrin.
B. Antimicrobial defensin.
C. Bactericidal permeability-increasing protein.
D. Myeloperoxidase.
E. Proteolytic cathepsin.

Developmental Defects in Neutrophils from Preterm Infants
Sharat Chandra, Hillary Haines, Colin Michie and Akhil Maheshwari

s;8/9/e368

Transfusions in the Preterm Infant
Robin K. Ohls

Article hematology
Transfusions in the Preterm

Infant
Robin K. Ohls, MD*
1. Characterize physiologic oxygen delivery in neonates.

Author Disclosure 2. Review findings of studies of high and low transfusion thresholds in neonates.
Dr Ohls did not 3. Describe strategies to decrease red cell transfusions in neonates.
disclose any financial
relationships relevant
to this article.
Abstract
Preterm infants in the neonatal intensive care unit receive a greater number of red cell
transfusions than any other hospitalized patient group. During the first weeks after
birth, when blood draws are frequent and phlebotomy losses are high, approximately
50% of extremely low birthweight (ELBW) infants receive their first transfusion. (1)
By the end of hospitalization, approximately 85% of ELBW infants have received at
least one transfusion. (2)(3)(4) Although the numbers of transfusions administered to
preterm infants remains significant, they have decreased over the last 20 years,
primarily due to the institution of restrictive transfusion guidelines in conjunction
with the study of erythropoietin administration to preterm infants. (5)(6) This article
reviews the need for administering red cell transfusions, summarizes studies evaluating
the efficacy of restrictive transfusion guidelines, and provides strategies to decrease red
cell transfusions in neonates, including instituting neonatal transfusion guidelines.
Administering Red Cell Transfusions: Oxygen Delivery and Consumption

The primary purpose of a red cell transfusion is to provide an immediate increase in oxygen
delivery to the tissues. (7) Oxygen delivery (DO2) can be quantified as the product of
cardiac output (CO) and arterial oxygen content (CaO2):
CO (dL/min)⫻CaO2 (mL/dL)⫽DO2 (mL/min)
Arterial oxygen content is determined by the hemoglobin concentration, the arterial

oxygen saturation (%), the oxygen-carrying capacity of hemoglobin (Hgb) (mL/g ⫻ g/dL
Hgb), and the solubility of oxygen in the blood (in mL/dL):
CaO2⫽(SaO2⫻1.34⫻[Hgb])⫹(0.0031⫻PaO2)
Improving cardiac output, oxygen saturation, or hemoglobin concentration increases the

amount of oxygen supplied to tissues. If both oxygen saturation and cardiac output are
maximized, the only way to deliver more oxygen to tissues is to increase the hemoglobin
concentration. Such an increase is achieved by increasing the red cell mass, either through
a red cell transfusion or the administration of red cell growth factors.
The ratio of oxygen consumption to oxygen delivery is known as the oxygen extraction
ratio and generally ranges from 0.15 to 0.33, which means that the body consumes 15% to
33% of the oxygen delivered. As the oxygen extraction ratio reaches or exceeds 0.40, organ
and cellular function can begin to decline. (8) In young, healthy, conscious adults, the
critical threshold below which oxygen consumption equals oxygen delivery occurs at less
than 7.3 mL/kg per minute of oxygen. (9)(10) Any further decrease in oxygen delivery
results in a decrease in oxygen consumption and tissue hypoxia.
Neonates have a leftward-shifted oxygen-hemoglobin dissociation curve due to fetal
*Professor of Pediatrics, Director, Neonatal-Perinatal Fellowship Program, Children’s Hospital of New Mexico, Pediatrics/Division
of Neonatology, University of New Mexico, Albuquerque, NM.

hematology transfusions
hemoglobin and decreased concentrations of 2,3- groups (18.7% restrictive versus 23.3% liberal), although
diphosphoglycerate. In addition, preterm infants experi- mortality rates were significantly lower in the restrictive
ence increased demands of accelerated growth. Despite group among patients who were less acutely ill (8.7%
these added burdens, neonates have a great ability to versus 16.1%) and patients younger than 55 years of age.
compensate for a gradual decrease in hemoglobin and The mortality rate during hospitalization was lower in
may be able to deliver an adequate amount of oxygen to the restrictive group (22.2% versus 28.1%, P⫽0.05). The
tissues. (11)(12)(13) For example, newborns whose he- authors concluded that a restrictive strategy of red cell
moglobin concentrations are less than 4 g/dL (40 g/L) transfusion was at least as effective as a liberal transfusion
because of chronic severe fetomaternal hemorrhage can strategy and possibly superior. Subsequent studies have
appear adequately compensated for this value of hemo- noted similar findings (20)(21) and resulted in the de-
globin, as indicated by a normal heart rate, normal per- velopment of more conservative transfusion guidelines
fusion, and no acidosis. (14) for adult intensive care unit (ICU) patients.
Anemia occurs when the red cell mass is not adequate
to meet the oxygen demands of the tissues, and the Pediatric Studies
current treatment for anemia is a red cell transfusion. Few studies have been performed in the pediatric popu-
Studies evaluating administration of artificial oxygen car- lation. Pediatric intensivists have relied on adult ICU
riers are ongoing, but have not yet included neonates. study results, and caregivers have been cautious about
(15) Presently, the only method to increase hemoglobin implementing more restrictive transfusion guidelines. In
acutely and significantly is by red cell transfusion. The one retrospective analysis, children admitted to pediatric
difficulty comes in distinguishing a neonate who has intensive care units (PICUs) who had hemoglobin values
anemia and requires immediate treatment from a neo- of 9 g/dL (90 g/L) or less were evaluated. (22) Of 240
nate who has a low hematocrit. Although the risk of children enrolled, 131 were transfused and 109 were not.
transmission of known infectious agents such as hepatitis Transfusions were associated with increased days of oxy-
B and C virus and human immunodeficiency virus (HIV) gen use, mechanical ventilation, vasopressor infusion,
is relatively low in the blood supplied to United States PICU stay, and hospital stay. The authors concluded that
hospitals, the risk of infectious agents newly identified in red cell transfusions were associated with increased use of
transfused blood such as Trypanosoma cruzi, West Nile resources in critically ill children.
virus, Plasmodium sp, and parvovirus B19, remains to be A prospective study to determine the incidence of red
determined. (16)(17)(18) The decision to transfuse, cell transfusions in critically ill children was performed in
therefore, should be taken with deliberation, and care- Canadian centers. (23) Among 985 children, at least one
givers should be consistent in obtaining consent prior to transfusion was given in 139 cases (14%). The most
a transfusion and documenting benefit in the neonate common reasons for transfusions were: hemoglobin
following a transfusion. value less than 9.5 g/dL (95 g/L), cardiac disease,
increased illness severity, and multiple organ dysfunc-
Studies Evaluating the Efficacy of tion.
Transfusion Guidelines A multicenter study recently performed in Canadian
Increasingly restrictive transfusion guidelines have been PICUs evaluated the efficacy of restrictive versus liberal
evaluated over the past 2 decades. The ability of critically transfusion guidelines in critically ill pediatric patients.
ill patients to adapt to lower hemoglobin values recently (24) Investigators enrolled 637 stable, critically ill chil-
has been investigated, and studies in adults, children, and dren who had hemoglobin concentrations less than
neonates have sought to determine the safety and efficacy 9.5 g/dL (95 g/L) within 7 days of PICU admission.
of transfusion guidelines. Patients enrolled in the restrictive transfusion group
(320 patients) were transfused if their hemoglobin de-
Adult Studies creased below 7 g/dL (70 g/L), and those enrolled in
The results of studies evaluating transfusion guidelines in the liberal strategy group (317 patients) were transfused
critically ill adults have changed transfusion practices if their hemoglobin decreased below 9.5 g/dL (95 g/L).
significantly over the last decade. (19)(20)(21) The most Hemoglobin concentrations were maintained more than
noteworthy of these, known as the Transfusion Require- 2 g/dL (20 g/L) lower in the restrictive strategy group,
ments in Critical Care (TRICC) trial, randomized 838 and those patients received 44% fewer transfusions. Only
critically ill adults to a restrictive or liberal transfusion 7 patients (2%) in the liberal strategy group were not
strategy. (19) The 30-day mortality was similar between transfused compared with 174 patients (54%) in the

restrictive strategy group. Multiorgan system failure oc-

curred in a similar percentage of patients (12%) in both Red Cell Transfusion
Table 1.
groups, and mortality was identical. The authors con-
cluded that a transfusion threshold of 7 g/dL (70 g/L)
Guidelines From the United
can be used in stable pediatric intensive care patients States Recombinant Human
without increasing adverse outcomes. Erythropoietin Trial (26)
Despite these studies, the optimal hemoglobin con-
centrations and transfusion thresholds remain to be de- Do not transfuse for blood out alone
termined in pediatric intensive care patients, especially
those who have cyanotic heart disease. A marked variabil- Do not transfuse for low hematocrit (Hct) alone
ity still exists among pediatric intensivists in terms of
Transfuse at Hct <35% (0.35) for infants who are:
both hemoglobin thresholds for transfusions and the
● Receiving >35% oxygen
volume of transfusions ordered. (25) Similar to other
● Receiving continuous positive airway pressure or
types of patients and age ranges tested, further study is mechanical ventilation with mean airway pressure of
required in pediatric patients to determine a definitive 6 to 8 cm H2O
marker for transfusion need.
Transfuse at Hct <30% (0.30) for infants who are:
● Receiving any supplemental oxygen
Neonatal Studies
● Receiving continuous positive airway pressure or
Twenty to thirty years ago, standard transfusion practices mechanical ventilation with mean airway pressure
in the neonatal intensive care unit (NICU) involved <6 cm H2O
maintaining the hematocrits of infants at or above 40%, ● Having significant episodes of apnea and bradycardia
and the volume of blood removed through phlebotomy (>9 episodes in 12 h or 2 episodes in 24 h requiring
was replaced when losses reached 10 mL/kg. Transfu- bagging while receiving therapeutic doses of
methylxanthines)
sion practices began to change in many units in the ● Experiencing heart rates >180 beats/min or
United States following the publication of a randomized respiratory rates >80 breaths/min for 24 h
trial of recombinant human erythropoietin (Epo) ther- ● Experiencing weight gain <10 g/d over at least
apy in preterm infants who had anemia of prematurity. 4 days while receiving 100 kcal/kg per day
● Undergoing surgery
(26) The study investigators created guidelines for the
restrictive use of red cell transfusions for preterm infants Transfuse at Hct <20% (0.20) for infants who are:
that still are used in many NICUs today (Table 1). ● Asymptomatic, with absolute reticulocyte count
As a result of this and other studies, the number of <100ⴛ103/mcL (100ⴛ109/L)
transfusions given to neonates in the United States,
especially extremely low-birthweight (ELBW) infants,
decreased from an average of 10 per hospitalization to 4 develop neonatal transfusion guidelines. Other coun-
per hospitalization. (5) Decreases in transfusions admin- tries, such as Canada, published guidelines in the 1990s.
istered to preterm infants also occurred in many coun- In 2002, in response to a significant upswing in the
tries throughout Europe. (6) The average number of number of patients infected with HIV and hepatitis C via
transfusions given to similarly sized infants decreased to blood transfusions, (27) the Canadian Paediatric Society
three per infant during an entire hospitalization. The revised their transfusion guidelines to an even greater
lower number of transfusions administered to European restrictive level (summarized in Table 2). (28)
ELBW infants likely was due to decreased phlebotomy Three randomized studies evaluated the impact of
losses. In multicenter studies employing restrictive trans- restrictive transfusion guidelines in preterm infants. The
fusion guidelines and recording phlebotomy losses, pre- first, performed by Bifano and colleagues and published
term infants in the United States averaged 80 mL/kg in in abstract form, (29)(30) evaluated ELBW infants
phlebotomy losses compared with 40 mL/kg for infants weighing 650 to 1,000 g who were randomized from
in Europe and South America. (2)(3)(4) Because of their 1 to 36 weeks postmenstrual age (PMA) to a “high”
incredibly small blood volumes, there always will be a hematocrit strategy (hematocrit maintained at ⬎32%
direct correlation between blood removed for phlebot- [0.32]) or a “low” hematocrit strategy (hematocrit
omy and blood transfused in critically ill ELBW infants. maintained at ⱕ30% [0.30]). Hematocrits were main-
(26) tained in the designated range with transfusions and Epo
The American Academy of Pediatrics has begun to in the high group, and with transfusions alone in the low

were randomized to a liberal or restrictive transfusion

Canadian Paediatric
Table 2. strategy. Infants received transfusions only when their
hematocrit dropped below the assigned value, and trans-
Society Recommendations for fusion thresholds decreased with improving clinical sta-
Red Cell Transfusions (28) tus. The primary outcome was a difference in the number
of transfusions. Secondary outcomes included morbidi-
Red cell transfusions should be considered in neonates ties associated with prematurity and hospital days.
in the following specific clinical situations:
There were no differences in baseline characteristics
● Hypovolemic shock associated with acute blood loss between the two groups, and average birthweight for all
● Hematocrit between 30% and 35% (0.30 and 0.35)
or hemoglobin between 10 and 12 g/dL (100 and infants enrolled was just less than 1,000 g. Infants ran-
120 g/L) in extreme illness for which red cell domized to the restrictive strategy received fewer trans-
transfusion may improve oxygen delivery to vital fusions (an average of two fewer transfusions per pa-
organs tient), but had more episodes of apnea. In addition,
● Hematocrit between 20% and 30% (0.20 and 0.30) infants treated with the restrictive strategy had a greater
or hemoglobin between 6 and 10 g/dL (60 and
100 g/L), and the infant is severely ill and/or incidence of intraparenchymal brain hemorrhage or
receiving mechanical ventilation with compromised periventricular leukomalacia. Because of this finding, the
oxygen delivery authors concluded that, although both transfusion pro-
● Hematocrit falling below 20% (0.20) or hemoglobin grams were well tolerated, the findings of more frequent
falling below 6 g/dL (60 g/L), with absolute major adverse head ultrasonographic events in the re-
reticulocyte count of 100 to 150ⴛ103/mcL (100 to
150ⴛ109/L) or less, suggesting low plasma strictive transfusion group suggested that such a practice
concentration of erythropoietin, with the presence of might be harmful to preterm infants. These findings were
the following clinical signs: poor weight gain, heart discussed in a series of letters to the editor following
rate >180 beats/min, respiratory distress and publication of the original study. (32)(33)(34) All of the
increased oxygen needs, and lethargy discussions centered on the conclusions reached by the
investigators and the need for further studies to confirm
those conclusions.
group. Statistically significant differences in hematocrit Kirpalani and colleagues (35) recently published the
were achieved by week 2 of the study and were main- PINT (preterm infant in need of transfusion) study. They
tained through 36 weeks PMA (Figure). sought to determine whether ELBW infants transfused at
There were no differences in baseline characteristics lower hemoglobin thresholds versus higher thresholds
between the two groups, and the average birthweight of have different rates of survival or morbidity at discharge.
all infants enrolled in the study was less than 900 g. At This large, multicenter, randomized clinical trial was
36 weeks PMA, there was no difference between the 22 designed to examine the impact of transfusion strategy
infants evaluated in the low hematocrit group and the 21 on the incidence of a composite outcome of death,
infants evaluated in the high hematocrit group for weight retinopathy of prematurity, bronchopulmonary dyspla-
gain during hospitalization, the number of days spent on sia, or abnormal brain ultrasonography findings in
a ventilator, or the total number of hospital days. At 1 ELBW infants. A total of 451 infants were randomized to
year of age, both weight gain and head growth were one of two transfusion strategies defined by the hemo-
similar for the two groups. In addition, there were no globin thresholds for red cell transfusion. The thresholds
differences in neurodevelopmental impairments between varied with age and level of respiratory support required.
the two groups, including a subgroup of infants whose No baseline differences existed between the 223 in-
hematocrits were 22% (0.22) or lower for more than fants randomized to the low transfusion threshold and
3 weeks. The investigators concluded that treatments the 228 infants randomized to the high transfusion
aimed at maintaining hematocrit levels above 32% (0.32) threshold. The average birthweight of study participants
did not demonstrate benefit in ELBW infants and in- was 770 g. A significant difference in hematocrit values
curred additional cost. Restrictive transfusion policies between groups was achieved by the first week of study.
were not associated with adverse outcomes (Table 3). The composite primary outcome was similar for both
Bell and colleagues (31) recently published a random- groups: 74% in the low group compared with 70% in the
ized study on liberal versus restrictive guidelines for red high group (P⫽0.25). The incidence of brain injury
cell transfusion in preterm infants. A total of 100 preterm determined by ultrasonography was 12.6% in the low
infants weighing 500 to 1,300 g at birth at a single center group and 16% in the high group (P⫽0.53). The authors

isovolemic hemodilution (the pro-

cess of removing whole blood and
replacing it with an isotonic solu-
tion, usually normal saline) on neu-
rocognitive functioning in healthy
adults. They determined that the
P300 latency period reflected
changes in oxygen. Near-infrared
spectroscopy also has been evalu-
ated as a tool to identify need for
transfusions in preterm infants,
(43) but lack of reproducibility in
preterm infants remains a signifi-
cant factor preventing general use
of this technique. (44) These stud-
ies emphasize the difficulty in deter-
mining which infants should re-
ceive red cell transfusions, and what
signs, symptoms, and laboratory
measurements should be used to
determine that need.
Figure. Differences in percent hematocrit (Hct) between infants randomized to the high Strategies to Decrease Red
hematocrit strategy (solid line) and infants randomized to the low hematocrit strategy Cell Transfusions in
(dashed line) were achieved by week 2 of the study (*P<0.05), and maintained through Neonates
36 weeks postmenstrual age (PMA). Indications for Red Cell
Transfusions
concluded that maintaining a higher hemoglobin con- The indications for red cell transfusions in neonates rely
centration in ELBW infants resulted in more infants more on the rate of fall in hemoglobin, rather than a
receiving transfusions but conferred little evidence of specific hemoglobin trigger. Neonates who have signifi-
benefit. The infants in the PINT study were of lower cant acute blood loss require immediate volume resusci-
gestational age and birthweight than the infants enrolled tation, but may not require a red cell transfusion. Term
in the Bell study, yet there was no difference between the newborns may tolerate perinatal blood losses up to one
two groups in any morbidities. Because the Bell study third or more of their total blood volume. A neonate
was published prior to the PINT study, controversy arose likely would benefit from a red cell transfusion if acidosis
regarding the benefits and risks of restrictive transfusion persists after volume resuscitation and adequate recircu-
guidelines. Table 3 summarizes the neurologic findings lation of the expanded blood volume or if hemorrhage is
reported in the three randomized studies. ongoing. Infants whose hemoglobin values are 10 g/dL
A difficulty in interpreting results of transfusion stud- (100 g/L) or greater following volume expansion may
ies in neonates is that such studies measured what infants have adequate oxygen delivery to tissues and simply may
received, rather than what they actually needed. Neo- require iron supplementation to replace iron stores lost
natal, pediatric, and adult transfusion practices would due to the hemorrhage.
benefit greatly from studies that generate transfusion The volume of red cells to transfuse in a neonate who
guidelines based on need by identifying a useful transfu- has known acute hemorrhage can be determined using
sion marker. Such research remains to be accomplished, the following formula: (45) volume of red cells to
but a few investigators have attempted to define param- transfuse⫽desired rise in hematocrit⫻1.6⫻weight (kg).
eters, either through direct or indirect oxygen delivery, Thus, a 2.0-kg infant who has an acute drop in hemato-
(8) resolution of signs of anemia, (36)(37)(38) or crit at birth to 20% (0.20) would need 80 mL packed red
changes in cardiovascular parameters measured by echo- cells to achieve a desired hematocrit of 45% (0.45).
cardiography. (39)(40)(41) Work performed by Weis- Caution should be exercised prior to the acute trans-
kopf and colleagues (42) evaluated the effects of acute fusion of an infant who has a significantly low hematocrit

Summary of Neurologic Findings for High

Table 3.
infant who has a significantly low
hematocrit (⬍20% [0.20]) in
and Low Hematocrit Strategies whom an immediate increase in ox-
ygen delivery to tissues is necessary
Study Low Hematocrit High Hematocrit
Strategy Strategy because a significant increase in
Bifano et al (29)(30) (nⴝ50) (nⴝ22) (nⴝ21) blood volume may result in the de-
Intraventricular hemorrhage (n) 0 1 velopment of congestive heart fail-
Any neurodevelopmental insult or 12 (55%) 10 (48%) ure.
growth deficiency (n, %)
Bell et al (31) (nⴝ100) (nⴝ28) (nⴝ24)
Intraventricular hemorrhage (n, %) 5 (10%) 8 (16%) Postnatal Changes in
Periventricular leukomalacia (n, %) 4 (14%) 0 Hematocrit
Kirpalani et al (35) (nⴝ451) (nⴝ175) (nⴝ188) All neonates undergo a natural ad-
“Ultrasonographic brain injury” 22 (12.6%) 30 (16%) aptation to the extrauterine envi-
(n, %) ronment that allows them to com-
pensate for a gradual drop in
hematocrit. Soon after birth, in-
at birth; it is vitally important to determine whether the creased oxygenation results in systemic oxygen delivery
infant experienced an acute or chronic fall in hematocrit. that far exceeds the tissues’ demand for oxygen. Lacking
Infants who experience twin-to-twin transfusion syn- hypoxic stimuli, Epo concentrations fall and erythro-
drome or chronic fetomaternal hemorrhage may be com- poiesis declines. Hemoglobin concentrations decrease
pensated at birth, despite a hematocrit below 30% (0.30). over the first 2 to 3 postnatal months as the infant gains
An exchange transfusion should be considered for an weight, remain stable over the next several weeks as
erythropoiesis increases, then rise
in the fourth to sixth postnatal
month in response to an even
Guidelines to Reduce Neonatal
Table 4.
greater Epo stimulus. (46) Term
Transfusions infants tolerate such changes in he-
moglobin and hematocrit without
● Review delayed cord clamping with the obstetric team and document the plan
consequence, and this period of
in the mother’s chart. The infant should be held below the placenta while the
cord is intact for 30 to 45 sec. decreasing hemoglobin concentra-
● Monitor and record phlebotomy losses daily. tions is termed “physiologic.” Pre-
● Use inline blood sampling or use microsampling devices to decrease the volume term infants experience a decrease
need for each laboratory test in hemoglobin to lower values than
● Remove umbilical lines and arterial lines as soon as possible
that seen in term infants, and the
● Order laboratory tests judiciously (avoid ordering tests every “x” hours) and
reconsider the need for “standard” or “routine” tests, such as weekly complete decrease is proportional to the de-
blood counts, daily blood gas measurements, or daily chemistry panels gree of prematurity. Hemoglobin
● Determine transfusion guidelines by identifying the lowest hemoglobin or concentrations between 7 and
hematocrit value that will be tolerated for clinical scenarios and days of age, 8 g/dL (70 and 80 g/L) occur
such as: 1) infant is receiving 100% oxygen, significant ventilator support, and
commonly in preterm infants who
blood pressure support and has a metabolic acidosis; 2) infant is receiving
minimal ventilator support or continuous positive airway pressure; 3) infant is have not had significant phlebot-
receiving enteral feedings and requiring oxygen; 4) infant is receiving full omy losses.
feedings, growing well, and receiving no oxygen support. Consider these Epo concentrations in preterm
scenarios if the infant is less than 2 weeks of age, 2 to 4 weeks of age, or infants who have anemia still are
greater than 4 weeks of age
significantly lower than those
● Initiate erythropoietin treatment during the first day after birth by
administering a subcutaneous injection of 400 U/kg or by adding 200 U/kg into found in adults, given the degree
a protein-containing intravenous solution (such as a 5% dextrose solution with of the anemia. (47)(48) This nor-
2% amino acids) to run over 4 to 24 hours mocytic, normochromic anemia,
● Administer parenteral iron, 3 mg/kg once a week or 0.5 mg/kg per day (iron termed the “anemia of prematu-
dextran added to parenteral nutrition or administered intravenously over 4 to
rity,” commonly affects infants
6 hours), until the infant tolerates adequate volume feedings, then administer
oral iron at 4 to 6 mg/kg per day born at 32 weeks’ or less gestation
and is the most common anemia

Table 5. An Example of Transfusion Guidelines

● A central hematocrit should be obtained on admission, and no further hematocrits obtained unless specifically ordered.
● Transfusions generally should be considered only if acute blood loss of >10% associated with symptoms of decreased
oxygen delivery occurs or if significant hemorrhage of >20% total blood volume occurs.
● In term and preterm infants, a transfusion should be considered if an immediate need for increased oxygen delivery to
tissues is suspected clinically.
● Transfuse 20 mL/kg packed red cells unless the hematocrit is >29% (0.29). A volume of 20 mL/kg also could be used if
significant phlebotomy losses are anticipated in smaller infants whose hematocrits are >29% (0.29). The volume may be
administered in two 10-mL/kg aliquots.
● For infants receiving erythropoietin, considerations of the above guidelines should be made regarding the rate of
decrease in hemoglobin or hematocrit, the infant’s reticulocyte count, the postnatal day of age, the need for
supplemental oxygen, and the overall stability of the infant.
● Central measurements of hemoglobin or hematocrit are preferred; alternatively, heel stick measurements may be
obtained after warming the heel adequately. An infant meeting the following criteria should not be transfused
automatically, but a transfusion should or can be considered for the following:
1) A transfusion should be considered if acute blood loss of >10% associated with symptoms of decreased oxygen
delivery occurs or if significant hemorrhage of >20% total blood volume occurs.
2) For infants requiring moderate or significant mechanical ventilation, defined as mean arterial pressure (MAP) >8 cm
H2O and FiO2 >0.40 on a conventional ventilator or MAP >14 and FiO2 >0.40 on high-frequency ventilator,
transfusions can be considered if the hematocrit is <30% (0.30) (hemoglobin <10 g/dL [100 g/L]).
3) For infants requiring minimal mechanical ventilation, defined as MAP <8 cm H2O and/or FiO2 <0.40 on a
conventional ventilator or MAP <14 and/or FiO2 <0.40 on high-frequency ventilator, transfusions can be considered
if the hematocrit is <25% (0.25) (hemoglobin <8 g/dL [8 g/L]).
4) For infants receiving supplemental oxygen who do not require mechanical ventilation, transfusions can be considered
if the hematocrit is <20% (0.20) (hemoglobin <7 g/dL [70 g/L]), and one or more of the following is present:
● >24 h of tachycardia (heart rate >180 beats/min) or tachypnea (respiratory rate >60 breaths/min)
● A doubling of the oxygen requirement from the previous 48 h
● Lactate >2.5 mEq/L (2.5 mmol/L) or an acute metabolic acidosis (pH <7.20)
● Weight gain <10 g/kg per day over the previous 4 days while receiving >120 kcal/kg per day
● If the infant will undergo major surgery within 72 h
5) For infants who have no symptoms, transfusions can be considered if the hematocrit is <18% (0.18) (hemoglobin
<6 g/dL [60 g/L]) associated with an absolute reticulocyte count of <100ⴛ103/mcL (100ⴛ109/L) (<2%)
seen in the neonatal period. The anemia of prematurity is increase the hemoglobin concentration appreciably dur-
not specifically responsive to the addition of iron, folate, ing that time, the infant should continue to be observed
or vitamin E, although these substrates (as well as vitamin for signs consistent with anemia.
B12) are administered to infants receiving recombinant
Epo to maximize erythropoiesis. (4)(49) Some infants Cord Blood
may be asymptomatic from their low hematocrit; others Cord blood collection has been studied as a form of
demonstrate signs of anemia that are alleviated by trans- “autologous” donation, although most labor and deliv-
fusion. In preterm infants, determining when to trans- ery services and corresponding blood banks are not pre-
fuse is not straightforward. (50) pared for collection and storage of neonatal cord blood.
When considering a transfusion in a preterm infant An alternative to cord blood collection that reduces
who has a low hematocrit that is not due to acute erythrocyte transfusions is delayed clamping of the um-
hemorrhage, the clinician should determine initially if bilical cord. It is possible to promote placental transfer of
the infant needs an immediate increase in oxygen to blood to preterm infants by delaying the clamping of the
tissues. If the answer is yes, treatment consists of a umbilical cord for 30 seconds. Transfer of 10 to
transfusion of packed red cells. If there is no evidence 15 mL/kg body weight can be expected using this
that an immediate increase in oxygen delivery is neces- method. (51) Mercer and colleagues (52) performed a
sary, treatment with red cell growth factors and appro- randomized trial of delayed cord clamping among infants
priate substrates might be considered. Because the pro- whose birthweights were less than 1,500 g and found
cess of stimulating erythropoiesis requires at least 1 week lower rates of intraventricular hemorrhage and late-onset
to affect the reticulocyte count significantly and may not sepsis in the infants who underwent delayed cord clamp-

ing. In other studies, a delay in cord clamping of 30 sec- months’ corrected age in extremely low birth weight infants treated
onds resulted in improved iron status, (53) fewer trans- with early erythropoietin and iron. Pediatrics. 2004;114:1287
fusions, (54) and an association with improved 5. Widness JA, Seward VJ, Kromer IJ, et al. Changing patterns of
red blood cell transfusion in very low birth weight infants. J Pediatr.
neurodevelopmental outcomes. (52) 1996;129:680
6. Maier RF, Sonntag J, Walka MM, et al. Changing practices of
red blood cell transfusions in infants with birth weights less than
Guidelines to Decrease Transfusions in 1000 g. J Pediatr. 2000;136:220
Neonates 7. Ohls RK. Why, when and how should we provide red cell
Most (85% to 90%) ELBW infants receive transfusions. transfusions to neonates? In: Ohls RK, Yoder M, eds. Questions and
However, 10% to 15% never receive a transfusion. This Controversies in Neonatology Series: Hematology, Immunology, and
Infectious Diseases. Philadelphia, Pa: Elsevier Health Science, in
percentage can be increased through the use of such
press.
measures as delayed cord clamping, immediate red cell 8. Alverson DC. The physiologic impact of anemia in the neonate.
growth factor and iron therapy, judicious laboratory Clin Perinatol. 1995;22:609
testing using microsampling, and a restrictive transfusion 9. Lieberman JA, Weiskopf RB, Kelley SD, et al. Critical oxygen
policy. Table 4 offers suggested guidelines to optimize an delivery in conscious humans is less than 7.3 mL O2 ⫻ kg(⫺1) ⫻
min(⫺1). Anesthesiology. 2000;92:407– 413
infant’s chances of remaining transfusion-free. Most im-
10. Madjdpour C, Spahn DR, Weiskopf RB. Anemia and periop-
portantly, such measures can be identified and a plan erative red blood cell transfusion: a matter of tolerance. Crit Care
created prenatally with the family. In addition, neonatol- Med. 2006;34:S102
ogists can establish a relationship with the family and 11. Oski FA, Delivoria-Papadopoulos M. The red cell, 2,3-
discuss their NICU transfusion thresholds. An example diphosphoglycerate, and tissue oxygen release. J Pediatr. 1970;6:
941–956
of transfusion guidelines currently used by several
12. Delivoria-Papadopoulos M. Postnatal changes in oxygen trans-
NICUs participating in a study comparing Epo with port of term, preterm and sick infants: the role of red cell 2,3
darbepoetin (a long-acting red cell growth factor) ad- diphosphoglycerate in adult hemoglobin. Pediatr Res. 1971;5:235
ministered to preterm infants is provided in Table 5. 13. Wimberley PD. Fetal hemoglobin, 2,3-diphosphoglycerate
and oxygen transport in the newborn premature infant. Scand
J Clin Lab Invest Suppl. 1982;161:1
Summary 14. Willis C, Forman CS Jr. Chronic massive fetomaternal hemor-
Previously, limited knowledge of the pathophysiology of rhage: a case report. Obstet Gynecol. 1988;71:459
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a selected review. Transfus Apher Sci. 2006;34:25
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benefit ratios. (1) Over the last 2 decades, researchers West Nile virus through blood transfusion in the United States in
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miology. N Engl J Med. 2003;349:1205
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18. Alter HJ, Stamer SL, Dodd RY. Emerging infectious diseases
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409
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31. Bell EF, Strauss RG, Widness JA. Randomized trial of liberal transfusion volume in the critically ill. Arch Dis Child. 2005;90:724
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infants. Pediatrics. 2005;115:1685 levels during infancy: associations with erythropoiesis. J Pediatr.
32. Boedy RF, Mathew OP. Letter to editor: randomized trial of 1996;128:791
liberal versus restrictive guidelines for red blood cell transfusion in 47. Brown MS, Garcia JF, Phibbs RH, et al. Decreased response of
preterm infants. Pediatrics. 2005;116:1048 plasma immunoreactive erythropoietin to “available oxygen” in
33. Murray N, Roberts I, Stanworth S. Letter to editor: red blood anemia of prematurity. J Pediatr. 1984;105:793
cell transfusion in neonates. Pediatrics. 2005;116:1609 48. Stockman JA, Graeber JE, Clark DA, et al. Anemia of prema-
34. Swamy RS, Embleton ND. Letter to editor: red blood cell turity: determinants of the erythropoietin response. J Pediatr.
transfusions in preterm infants: is there a difference between restric- 1984;105:786
tive and liberal criteria? Pediatrics. 2005;115:257 49. Haiden N, Schwindt J, Cardona F, et al. Effects of a combined
35. Kirpalani H, Whyte RK, Andersen C. The Premature Infants in therapy of erythropoietin, iron, folate, and vitamin B12 on the
Need of Transfusion (PINT) study: a randomized, controlled trial transfusion requirements of extremely low birth weight infants.
of a restrictive (low) versus liberal (high) transfusion threshold for Pediatrics. 2006;118:2004
extremely low birth weight infants. J Pediatr. 2006;149:301 50. Keyes WG, Donohue PK, Spivak JL, et al. Assessing the need
36. Wardle SP, Garr R, Yoxall CW, Weindling AM. A pilot ran- for transfusion of premature infants and the role of hematocrit,
domised controlled trial of peripheral fractional oxygen extraction clinical signs, and erythropoietin level. Pediatrics. 1989;84:412
to guide blood transfusions in preterm infants. Arch Dis Child Fetal 51. Aladangady N, McHugh S, Aitchison TC, et al. Infant’s blood
Neonatal Ed. 2002;86:F22 volume in a controlled trial of placental transfusion at preterm
37. Bifano EM, Smith F, Borer J. Relationship between determi- delivery. Pediatrics. 2006;117:93
nants of oxygen delivery and respiratory abnormalities in preterm 52. Mercer JS, Vohr BR, McGrath MM, et al. Delayed cord
infants with anemia. J Pediatr. 1992;120:292 clamping in very preterm infants reduces the incidence of intraven-
38. Izraeli S, Ben-Sira L, Harell D, et al. Lactic acid as a predictor tricular hemorrhage and late-onset sepsis: a randomized, controlled
for erythrocyte transfusion in healthy preterm infants with anemia trial. Pediatrics. 2006;117:1235
of prematurity. J Pediatr. 1993;122:629 53. Chaparro CM, Neufeld LM, T Alavez G. Effect of timing of
39. Bard H, Fouron JC, Chessex P, Widness JA. Myocardial, umbilical cord clamping on iron status in Mexican infants: a ran-
erythropoietic, and metabolic adaptations to anemia of prematurity domized controlled trial. Lancet. 2006;367:1997
in infants with bronchopulmonary dysplasia. J Pediatr. 1998;132: 54. Philip A. Delayed cord clamping in preterm infants. Pediatrics.
630 2006;117:1434

NeoReviews Quiz
5. Preterm infants, especially extremely low-birthweight (ELBW) infants, in the neonatal intensive care unit
receive a greater number of red cell transfusions than any other hospitalized patient group. Of the
following, the best estimate for the percentage of ELBW infants that receive at least one red cell
transfusion by the end of hospitalization is:
A. 40%.
B. 55%.
C. 70%.
D. 85%.
E. 100%.
6. The primary purpose of a red cell transfusion is to provide an immediate increase in oxygen delivery to the
tissues. Oxygen delivery, expressed in milliliters of oxygen per kilogram of bodyweight per minute, can be
calculated from cardiac output and arterial oxygen content. The latter can be calculated from hemoglobin
concentration, arterial oxygen saturation, and partial pressure of arterial oxygen. Of the following, the
critical threshold for oxygen delivery in healthy adults below which tissue hypoxia is likely to ensue is:
A. 5.0 mL/kg per minute.
B. 7.3 mL/kg per minute.
C. 10.0 mL/kg per minute.
D. 12.3 mL/kg per minute.
E. 15.0 mL/kg per minute.
7. A 2-day old preterm neonate, whose birthweight is 1,950 g, has a sudden onset of pallor. Physical
examination reveals marked abdominal distention, enlarged liver, and features of respiratory and cardiac
failure. Abdominal ultrasonography reveals multiple hemangiomas in the liver and hemoperitoneum. The
infant’s hematocrit is 16% (0.16). A red cell transfusion is ordered with the goal of achieving a desired
hematocrit of 40% (0.40). Of the following, the volume of red cells needed for transfusion in this infant is
closest to:
A. 25 mL.
B. 50 mL.
C. 75 mL.
D. 100 mL.
E. 125 mL.
8. A 10-week-old preterm infant, whose birthweight was 840 g, is breathing spontaneously in room air, has
two to four episodes of apnea and bradycardia per day that resolve with stimulation, is receiving full
enteral feedings by orogastric gavage, and is gaining weight at a rate of 15.6 g/kg per day. The infant’s
absolute reticulocyte count is 48ⴛ103/mcL (48ⴛ109/L). You follow guidelines for restrictive use of red cell
transfusions as proposed in the United States Multicenter Epo Study, of one of the earlier randomized trials
of erythropoietin treatment in preterm infants. Of the following, the hematocrit threshold for red cell
transfusion in this infant is closest to:
A. 20% (0.20).
B. 25% (0.25).
C. 30% (0.30).
D. 35% (0.35).
E. 40% (0.40)

Transfusions in the Preterm Infant
Robin K. Ohls

s;8/9/e377

Article respiratory disorders
Magnesium and Perinatal

Asphyxia
Cléa R. Leone, MD, PhD,*
Naila O.E. Barbosa, MD*
1. Describe magnesium metabolism in the newborn.
2. Analyze the role of magnesium in the events that follow an hypoxic-ischemic insult in
Author Disclosure the newborn.
Drs Leone and 3. Evaluate the evidence of a potential protective effect of magnesium in newborns after
Barbosa did not a hypoxic-ischemic event.
disclose any financial
relationships relevant
to this article.
Abstract
The pathophysiology of perinatal hypoxic-ischemic insults has been investigated
exhaustively to identify the components that must be blocked to reduce neurologic
injury in the newborn. Among potential therapeutic strategies for neuroprotection,
administration of magnesium has been the object of experimental studies and,
recently, clinical trials. This interest is related to the compound’s potential effect of
blocking glutamate-controlled N-methyl-D-aspartate (NMDA) receptors and the
voltage-dependent calcium channels, preventing the influx of extracellular calcium
into the neurons, as well as its action as a membrane stabilizer. To date, results have
been variable and are not sufficient to recommend this therapy in newborns who have
perinatal asphyxia.
Introduction
Magnesium is an important intracellular cation that acts as a cofactor in the cellular
bioenergetic process. A possible neuroprotective effect of magnesium has been suggested
in hypoxic-ischemic episodes through an antagonistic action at the N-methyl-D-aspartate
(NMDA) receptor. (1)
Perinatal asphyxia is an important cause of long-term disability. At the cellular level, a
hypoxic-ischemic insult initiates a sequence of biochemical events that leads to an accu-
mulation of intracellular calcium. Evidence suggests that stimulation of excitatory amino
acid receptors plays a role in the pathogenesis of perinatal hypoxic-ischemic brain injury.
Therefore, competitive and noncompetitive NMDA antagonists could be useful as neuro-
protective agents. (2)
Some animal models have demonstrated that administration of magnesium sulfate has
neuroprotective effects against hypoxia-ischemia, but such an effect has not been proved in
humans. The primary problems with human studies are the variable doses of magnesium
sulfate analyzed, the potential for deleterious effects, and the attempts to provide treat-
ment in time to prevent irreversible damage. (3)
Magnesium Metabolism
Magnesium is essential for a number of cellular functions, including DNA transcription,
mitochondrial oxidative phosphorylation, hormone receptor binding, gating of calcium
channels, transmembrane ion flux, regulation of adenylate cyclase, muscle contraction,
neuronal activity, control of vasomotor tone, cardiac excitability, and neuronal transmitter
release. (3)(4)
Despite its importance, magnesium homeostasis is poorly understood and has received
less attention than other electrolytes. The apparent lack of correlation between serum and
*Department of Pediatrics, School of Medicine, University of São Paulo, Brazil.

respiratory disorders perinatal asphyxia
tissue magnesium concentrations and the subsequent cium, and water. Another explanation might be the
difficulty in their interpretation contribute to this lack of presence of an active transport of magnesium along the
interest in routine serum magnesium measurements. proximal tubule that decreases with age. (14)(15)
In humans, less than 1% of total body magnesium is Understanding of the hormonal control of magne-
found in the extracellular fluid compartment. It is distrib- sium is incomplete, probably because a specific endocrine
uted primarily between bone (65%) and the intracellular control similar to the one that exists for calcium has not
components of muscle and soft tissues (34%). Serum yet been identified. Parathyroid hormone (PTH) admin-
magnesium is present in three states: ionized (62%), istration can result in elevated serum magnesium concen-
protein-bound (33%) (primarily to albumin), and in trations through increased magnesium reabsorption in
complexes with anions (5%). (3)(5) Serum magnesium the kidney, release from bone, and absorption in the
concentrations are maintained within a narrow range and small intestine. Otherwise, chronic hypermagnesemia
are remarkably stable. The homeostatic mechanisms re- may impair PTH secretion through a feedback system
sponsible for maintaining such limits seem to be the due to magnesium’s effect as a cofactor of the enzyme
balance between absorption from the gastrointestinal adenylate cyclase in parathyroid tissue (8)(13)
tract and excretion by the kidney. (6)(7) Vitamin D has been shown to enhance intestinal
Gastrointestinal tract absorption appears to depend magnesium absorption, but the effects of calcitonin on
on the amount of magnesium in the diet. Approximately the mineral are not known. Steroid hormones, aldoste-
40% of the total magnesium consumed is absorbed, rone, and insulin may decrease magnesium excretion in
mostly from the small intestine. The absorption is pri- the kidney. (8)(16)
marily by a passive paracellular mechanism that is depen- Magnesium is transported actively through the pla-
dent on solvent drag. (8) centa, so cord blood magnesium concentrations are
The recommended daily intake of magnesium for higher than maternal values. The third trimester of ges-
children and adults is 4 to 5 mg/kg. (9) The major tation is the period of great incorporation, correspond-
dietary sources of magnesium include nuts, unprocessed ing to about 2 to 3 mg/kg per day. (17)
cereals, and vegetables. (10) The magnesium concentra- In the neonatal period, some conditions may lead to
tion in human milk has been determined to be between imbalances of magnesium homeostasis, including intra-
25 and 45 mg/L; infant formulas contain about 50 to uterine growth restriction (IUGR). Term newborns who
96 mg/L. (11) experienced IUGR (birthweight less than the 10th per-
The kidney is the major organ involved in magnesium centile for gestational age and a birthweight ratio less
regulation, although the major regulator of reabsorption than 0.85) had higher concentrations of ionized magne-
is the plasma magnesium concentration. (12) The fil- sium during the first postnatal week compared with term
tered magnesium load in excess of the amount filtered newborns who did not have IUGR in a Brazilian study.
under normal circumstances usually is excreted. Under (18) These results may indicate a nutritional adaptation
conditions of magnesium deprivation, however, there is a of the fetus to the lower availability of magnesium during
complete reabsorption. (4) gestation in the presence of IUGR.
Approximately 75% of the total plasma magnesium is
filtered through the glomerular membrane. In the adult, Perinatal Asphyxia
about 50% to 60% of the filtered magnesium is reab- Perinatal hypoxic-ischemic insults and their consequent
sorbed in the thick ascending loop of Henle and 15% in biochemical events may lead to varying degrees of neu-
the proximal tubule. Only 3% to 5% of the filtered ronal injury, including irreversible injury. (19)
magnesium is excreted in the urine under normal condi-
tions. (8) Many drugs, such as amphotericin B, digoxin, Energy Metabolism
gentamicin, and loop diuretics, may increase renal elim- Hypoxia-ischemia results in a switch to anaerobic metab-
ination of magnesium by inhibiting reabsorption in the olism, with insufficient adenosine 5⬘-triphosphate (ATP)
kidneys. (13) production, accumulation of lactic acid, and inability to
Magnesium homeostasis may differ in the neonate maintain cellular functions. A reduction in ATP synthesis
compared with the adult. Magnesium reabsorption oc- caused by oxygen limitation disrupts ionic equilibrium
curs predominantly in the proximal tubule rather than across membranes. Potassium quickly accumulates in the
the loop of Henle in neonates, possibly due to immatu- extracellular space, while sodium and water enter the cell,
rity of the paracellular pathway and the consequent pas- with the subsequent development of cellular swelling.
sage of significant amounts of magnesium, sodium, cal- (20)(21)(22)

Calcium Homeostasis (20) (23) This is particularly important in the fetal brain
Calcium ions accumulate in the cytosol as a consequence because of the larger proportion of NMDA receptors in
of the increased cellular influx into neuronal cells caused neurons than in the adult brain, reinforcing the contri-
by the loss of the membrane potential, leading to the bution of glutamate-mediated neurotoxicity in this pe-
opening of voltage-dependent calcium channels. In ad- riod. (24)
dition, during hypoxia, the stimulation of NMDA recep-
tors of the agonist-operated calcium channel by gluta- Oxygen Free Radical Production
mate increases calcium influx into neuronal cells. An intense production of oxygen free radicals during the
Calcium also is released from mitochondria that are hypoxic-ischemic process increases the destructive capac-
stimulated by the increase in intracellular sodium and ity of cellular antioxidants and scavengers. Such free
free fatty acids and from the endoplasmic reticulum radicals disrupt the cellular membrane, contributing to
because of the depletion of ATP. Moreover, calcium cell death.
efflux across the plasma membrane is decreased by energy
failure. (20)(21)(22) Magnesium and Perinatal Asphyxia
The excessive increase in intracellular calcium inter- A possible neuroprotective action has been attributed to
feres with many enzymatic reactions, such as activation of magnesium in hypoxic-ischemic insults, based on a
phospholipases. Such reactions lead to membrane phos- variety of effects that this cation could have in the patho-
pholipid hydrolysis, with the consequent disruption of physiologic mechanisms present before and after cere-
cellular and organelle membranes, increase in their per- bral ischemia. Magnesium may serve as an NMDA recep-
meability, and further unfavorable modification in the tor antagonist, membrane stabilizer, vasodilator, and
ionic distribution. Other consequences include alter- anticonvulsive. Magnesium can block the glutamate-
ation of the arachidonic acid cycle, with effects on pros- controlled NMDA receptor and the voltage-dependent
taglandin synthesis, gene expression, and protein synthe- calcium channels, preventing the influx of extracellular
sis as well as increased production of free radicals. calcium into neurons. (21)(25) Magnesium also prevents
(20)(21) persistent membrane depolarization that results from
failure of the Na-K-ATP-dependent pump. (23) A hypo-
Excitatory Neurotransmitter Release tensive effect has been proposed by the properties of
Amino acid glutamate is one of the most important magnesium as a calcium antagonist. (21) Magnesium
excitatory neurotransmitters in the brain. The presence also has anticonvulsive properties that may contribute to
of an NMDA receptor site in the developing brain that diminished extension of brain damage. Cerebral isch-
involves regions of agonist (glutamate) and antagonist emia, through the release of excitatory amino acids, is
(magnesium) activities may indicate a possible route for associated with the presence of epileptiform activity,
protection. (20)(21)(22) which can disrupt the balance between blood flow and
During hypoxia-ischemia, glutamate is released from cell metabolism, thereby increasing the area of lesion in
the intracellular compartment linked to the entrance of the brain. (21)
calcium into cells and their subsequent depolarization. In Unfortunately, the results of experimental studies ex-
addition, the sodium-dependent uptake of glutamate by amining such magnesium effects have been variable. (26)
the presynaptic membranes decreases, which maintains (27) A deficiency of magnesium enhanced the suscepti-
an increased extracellular concentration of glutamate and bility of hamster hearts to free radical damage, which
a sustained stimulation of its receptors. (20)(21) could be applicable to neurons. (28) In the neonatal rat
Two mechanisms of glutamate-induced neuronal model, smaller brain lesions were seen after a single dose
damage have been proposed. One is rapid cell death, of magnesium sulfate 15 minutes after an NMDA insult,
which occurs within minutes after induction of the insult (29) and the association of magnesium sulfate and free
and involves an intense influx of sodium, chloride, and radical inhibitors reduced the neuronal lesion after a
water, resulting in cell swelling and lysis. The second, hypoxic-ischemic insult in rats. (30) In newborn piglets,
more delayed, mechanism occurs 24 hours after the however, magnesium sulfate failed to prevent delayed
insult and is dependent on the influx of calcium through cerebral energy failure after transient hypoxia-ischemia.
NMDA-stimulated calcium channels. The result is an (27) Moreover, administration of this therapy during a
increase in cytosolic calcium concentration that sustains process of asphyxia did not compromise fetus near-term
the process by further activating glutamate release and lambs, but also did not reduce cerebral injury. (31)
the other damaging mechanisms already mentioned. In humans, the results are more controversial, al-

Figure 1. Ionic magnesium concentrations in term newborns who did and did not have perinatal asphyxia during the first postnatal
week. The values in the third and seventh postnatal days were higher in the group that had perinatal asphyxia (*P<0.05). Reprinted
with permission from Barbosa NOE, Leone Cr. Rev Paul Pediatr. 2006. (38)
though there are some positive findings. Magnesium encephalopathy (HIE). (37) Such decreased magnesium
sulfate frequently is administered to pregnant women for concentrations could be an indicator of more intense
treatment of pre-eclampsia. Some studies have shown a neurologic injury. Other authors have suggested an ad-
reduction in the incidence of cerebral palsy in newborns verse outcome associated with higher concentrations of
after maternal administration of magnesium sulfate, al- ionic magnesium at birth. (24) In another study of
though others have not shown this effect. (32)(33) Clin- newborns who had HIE, the mean red cell magnesium
ical observations suggest a similar potential protective content was significantly lower than in healthy newborns.
effect in preterm newborns exposed to antenatal magne- (28) This fact is particularly important because stores
sium sulfate, in whom the incidence of cerebral palsy was of magnesium in red cells usually remain constant
reduced at 3 years of age. (34) However, a logistic throughout gestation.
regression analysis examining the risk of cerebral palsy in Few studies have examined ionic magnesium in peri-
a cohort of newborns who weighed less than 2,000 g and natal asphyxia; total magnesium concentration generally
whose mothers had received magnesium sulfate showed has been the reference. We have observed higher concen-
no significant effects. (35) trations of ionized magnesium in umbilical cord blood of
Randomized, controlled studies performed in Austra- term newborns who had perinatal asphyxia 3 and 7 days
lia that included preterm newborns born at less than after birth in relation to term newborns without perinatal
30 weeks of gestation, who were evaluated at 2 years of asphyxia (Fig. 1). (38) However, total magnesium con-
age, suggested a smaller frequency of death and cerebral centrations did not differ (Fig. 2). These results were
palsy after the use of antenatal magnesium, although the attributed to a renal effect of mild asphyxia, evidenced by
effects were not significant. (36) the higher lactate and creatinine values observed in the
The duration and severity of a hypoxic-ischemic insult newborns who had asphyxia.
seems to influence the concentration of magnesium in In another study of asphyxiated near-term newborns,
cord blood. For example, magnesium values were lower two different doses of magnesium sulfate were admin-
in umbilical cord blood of infants after severe distress and istered within 12 hours of birth. (39) Infants who re-
those who had moderate or severe hypoxic-ischemic ceived 400 mg/kg had a reduction in mean arterial

Figure 2. Total magnesium concentrations in term newborns who did and did not have perinatal asphyxia during the first postnatal
week. There were no differences between the groups. Reprinted with permission from Barbosa NOE, Leone CR. Rev Paul Pediatr.
2006. (38)
blood pressure of about 13% after 1 hour of infusion; was associated with an increase in the need for mechan-
those who received 250 mg/kg did not develop hypo- ical ventilation and oxygen use. Although no protective
tension, although they did experience respiratory depres- effect was shown in this study, earlier use of magnesium
sion. In contrast, Gathwala and associates (25) docu- after birth might have been more effective if the dose was
mented no effect on heart rate, respiratory rate, oxygen controlled to avoid undesirable effects on the cardiovas-
saturation, and mean arterial pressure in term newborns cular system.
following treatment with magnesium sulfate at doses of In Japan, a nonrandomized clinical trial was con-
250 mg/kg 30 minutes after birth and 125 mg/kg at ducted among 30 term newborns who had moderate
24 and 48 hours after birth. and severe HIE in four hospitals. (19) The infants
The mean serum concentrations of magnesium mea- received 250 mg/kg of magnesium sulfate over 1 hour
sured after different therapeutic schedules have been
within 6 hours of birth, with two additional doses
recognized as regulators of adverse effects, primarily
administered at 12 and 24 hours. Dopamine was
cardiovascular. A range of 1.25 to 2.04 mEq/L
infused concomitantly. Neither hypotension nor
(1.25 to 2.04 mmol/L) is expected to be neuropro-
changes in heart rate were observed, although hypo-
tective, although symptoms of hypermagnesemia have
tonia occurred and the infants were maintained on
been reported at serum concentration above 2 mEq/L
(2 mmol/L), which is very close to the therapeutic concen- mechanical ventilation. There were four neonatal
tration. deaths, and at follow-up at 18 months of age, 22
A recent randomized, controlled study in term new- infants (73%) had normal development and 6 infants
borns who had different grades of HIE documented no had cerebral palsy.
effect of 250 mg/kg of magnesium sulfate administered The calcium-channel and neuromuscular blocking as-
at about 12 hours after birth on the concentrations of pects of magnesium suggest that it may have other effects
glutamine and aspartate in the cerebrospinal fluid at that require control after its administration. Hemody-
72 hours after birth. (23) Nevertheless, magnesium use namic instabilities, such as hypotension, bradycardia,

delayed intraventricular conduction, and even complete 14. Lelivre-Pegorier M, Merlet-Benichou C, Roinel N, de
atrial-ventricular block and apnea, have been described. Rouffignac C. Developmental pattern of water and electrolyte
transport in rat superficial nephrons. Am J Physiol. 1983;245:
F15F-21
Conclusion 15. Quamme GA. Renal magnesium handling: new insights in
Among potential reasons for the conflicting clinical re- understanding old problems. Kidney Int. 1997;52:1180 –1195
sults obtained to date are that: 1) the concentration of 16. Vetter T, Lohse MJ. Magnesium and the parathyroid. Curr
magnesium needed to act on NMDA receptors has not Opin Nephrol Hypertens. 2002;11:403– 410
17. Venkataraman PS, Tsang RC. Calcium, magnesium and phos-
been reached in some studies, 2) other events may cause phorus in the nutrition of the newborn. J Am Coll Nutr. 1995;14:
neuronal injury, 3) the optimal time to administer mag- 439 – 447
nesium sulfate after an hypoxic-ischemic insult is not yet 18. Barbosa NOE, Okay TS, Leone CR. Magnesium and intra-
known, 4) the effective dose of magnesium sulfate has uterine growth restriction. J Am Coll Nutr. 2005;24:10 –15
not been determined, and 5) another aspect of damage 19. Ichiba H, Yokoi T, Tamai H, Ueda T, Kim TJ. Neurodevel-
opmental outcome of infants with birth asphyxia treated with
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age. Brain Res Rev. 1999;30:107–134
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NeoReviews Quiz
9. Magnesium, one of the principal cations in the body, plays an important role as a cofactor in many
enzymatic reactions and is essential for a number of cellular functions. Of the following, the most
accurate statement regarding magnesium metabolism in the newborn is that:
A. Cord blood magnesium concentration is higher than maternal magnesium concentration, reflecting
active placental transport of magnesium.
B. Gastrointestinal absorption of magnesium amounts to 80% of magnesium ingested in the diet.
C. Magnesium in the serum is present largely in its protein-bound state, primarily bound to albumin.
D. Magnesium reabsorption in the kidney occurs predominantly in the thick ascending limb of the loop of
Henle.
E. The highest distribution of body magnesium is in the intracellular components of muscle and soft
tissues.
10. Perinatal hypoxic-ischemic insults and associated biochemical events result in varying degrees of neuronal
injury in the fetus/neonate. Of the following, the most important contributor to hypoxia-ischemia-
induced neuronal injury in the fetus is:
A. Calcium efflux from neuronal cells.
B. Excitatory neurotransmitter glutamate-mediated toxicity.
C. Lactic acid accumulation from anaerobic metabolism.
D. Oxygen free radical-mediated injury during reperfusion.
E. Phospholipase-induced hydrolysis of neuronal cell membranes.
11. Magnesium produces several biochemical effects that may be neuroprotective, which accounts for the
interest in this cation as a potential therapeutic strategy for reduction of brain injury following a
hypoxic-ischemic insult in the newborn. Of the following, the most likely important mechanism for
magnesium-induced neuroprotection is:
A. Anticonvulsive effect.
B. Cerebral vasodilatation.
C. Neuronal cell membrane stabilization.
D. N-methyl-D-aspartate receptor blockage.
E. Oxygen free radical scavenging.

Index of Suspicion in the Nursery
Katharine Kevill and Richard Auten

index of suspicion in the nursery
Case Presentation rate of 60 to 90 breaths/min, with

A 2.6-kg infant was born at increased work of breathing, gradu-
38 weeks’ gestation to a 16-year-old ally requiring increases in supple-
G1P0 woman. The prenatal history mental oxygen to achieve an SpO2 in
included maternal Chlamydia infec- the mid-90s. Chest computed to-
tion. The baby was delivered via mography (CT) scan performed at
emergent cesarian section because of 2 weeks of age showed attenuation of
nonreassuring fetal heart tones. His the pulmonary vasculature and hy-
Apgar scores were 7 and 9 at 1 and perinflation of the lungs. Although
The reader is encouraged to write 5 minutes, respectively. He exhibited motion artifact limited the evalua-
possible diagnoses for each case tachypnea and hypoxia at birth, with tion, the chest CT showed no focal
before turning to the discussion. a respiratory rate of 80 to 100 lung opacities and no other anatomic
We invite readers to contribute breaths/min, grunting, chest retrac- defects. Repeated echocardiography
case presentations and discussions. tions, and coarse breath sounds. revealed a small patent foramen ovale
Please inquire first by contacting Other than a mild systolic ejection (left-to-right shunt) and normal ven-
Dr. Philip at aphilip@stanford.edu. murmur, the remainder of the phys- tricular size and function. Multiple
ical examination findings were nor- therapies are tried without obvious
mal. The baby’s A-a gradient (a mea- improvement, including inhaled al-
sure of the difference in the partial buterol, systemic dexamethasone,
pressure of oxygen in the alveolar and systemic sildenafil. An aggressive
spaces and the arterial blood) was diuretic regimen and supplemental
elevated, initially 473 mm Hg on oxygen achieves stable SpO2 and
100% FiO2. Chest radiographs work of breathing.
showed no signs of acute air space An extensive evaluation is per-
disease for the first several postnatal formed to determine the cause of the
weeks. patient’s persistent respiratory dis-
Over the next several months, the tress. A single test reveals the diagno-
infant continues to have a respiratory sis.

Figure 1. Noncontrast-enhanced, thin-section (high-

resolution) multidetector CT scan demonstrates abnormalities
at several levels in an intubated child (examination performed
with inspiratory hold). A. Axial image just below the level of
the carina demonstrates scattered increased density of the
lung parenchyma (mosaicism) abutting (arrowheads) a more
normal area of aeration (A); note also scattered bandlike
opacities (arrows). B. Axial image at the level of the mid-heart
shows the increased lung density noted previously and several
scattered cystic lucencies (arrows); posteromedial opacities are
due to atelectasis often seen with intubation. C. Axial image at
the lung base demonstrates increased lung density, scattered
nodular opacities, posteromedial atelectasis, and irregular sep-
tal thickening (arrows).
Case Discussion immunoglobulin measurement, and examination of a lung biopsy demon-

Serial chest CT scans performed at lymphocyte enumeration studies strated findings consistent with pul-
2 and 3 months of age revealed find- were normal. Multiple blood, urine, monary alveolar proteinosis, includ-
ings consistent with interstitial lung and sputum studies failed to identify ing coarsely granular, strongly
disease (ILD), including worsening any viral or bacterial infection. periodic acid-Schiff stain-positive al-
ground-glass opacities and septal A bronchoscopy performed at veolar exudate; mild thickening of
thickening (Fig. 1). Chronic aspira- 5 weeks of age revealed laryngomala- the alveolar septae; and interstitial
tion was ruled out as a cause when cia, but the magnitude was insuffi- inflammation (Fig. 2). Genotyping
swallow and milk scintigraphy stud- cient to explain a primary cause for revealed no pathologic mutations in
ies revealed no evidence of aspira- the respiratory distress. At 2 months the surfactant protein B or C (SP B
tion, and the upper gastrointestinal of age, cardiac catheterization was and SP C) genes, but did identify
tract showed no evidence of a tra- performed to evaluate the possibility three mutations in the ABCA3 gene.
cheoesophageal fistula. A negative of pulmonary artery hypertension. The third member of the ATP-
sweat test ruled out cystic fibrosis as a The pulmonary vascular resistance binding cassette (ABC) transporter
cause for the baby’s chronic respira- was elevated to 4 Woods units on family is believed to play a major role
tory distress. Immunodeficiency was room air, but normalized to 2 Woods in surfactant synthesis. Although the
considered as a cause for the worsen- units with administration of 40% ox- genetic studies on the patient’s blood
ing ILD, but results of a complete ygen. could not confirm whether these mu-
blood count and differential count, At 3 months of age, microscopic tations were on the same or opposite

dren and fatal lung disease in infants.

Abnormal lamellar body formation
was observed in infants who had
ABCA3 deficiency whose lung biop-
sies were evaluated by electron mi-
croscopy.
To date, there is no specific treat-
ment for infants who have ABCA3
deficiency; lung transplant is the only
definitive therapy offered. The pa-
tient described in this case deterio-
rated, despite aggressive diuretic
therapy and intermittent high-dose
steroids. He received a bilateral lung
transplant at age 8 months.
Figure 2. Histologic appearance of a lung biopsy obtained at 3 months of age.
Staining was with hematoxylin-eosin, 20x magnification. Alveoli are filled by a Lessons for the Clinician
granular, eosinophilic exudate, with moderate reactive change within thickened ILD is a potential cause for persistent
alveolar septa. respiratory distress in term infants
who have elevated A-a gradients and
diffuse radiographic findings. A sys-
chromosomes, it was determined Defective surfactant protein pro-
tematic approach to the differential
that, in view of the clinical course and cessing underlies many cases of pul-
diagnosis can be helpful, including
other supportive laboratory findings, monary alveolar proteinosis (PAP), a
assessment of the severity of the lung
the patient had congenital alveolar rare syndrome that has an estimated
disease and identification of primary
proteinosis due to ABCA3 gene mu- worldwide prevalence of 3.7 per
disorders that can predispose to ILD,
tations. 1 million. It is characterized patho-
such as immunodeficiency and aspi-
logically by intra-alveolar filling with
ration. A lung biopsy often is neces-
Pathogenesis/Incidence/ surfactant lipoprotein and physiolog-
sary for definitive diagnosis, with
Natural History ically by disturbances of pulmonary
proper attention to lung fixation to
Pediatric interstitial lung disease gas exchange. Fluid returned on
allow for electron microscopy. How-
(PILD) describes a heterogenous bronchoalveolar lavage appears milky
ever, ILD due to several types of
group of rare disorders characterized and stains positively for periodic
surfactant dysfunction now is detect-
by diffuse pulmonary infiltrates that acid-Schiff in alveolar macrophages.
able through molecular genetic test-
result in tachypnea, crackles, and hy- PAP occurs in three clinically recog-
ing. (Katharine Kevill, MD, Richard
poxemia. The discovery of genetic nized forms: congenital (2% of total
Auten, MD, Department of Pediat-
defects in surfactant function has re- cases), secondary (5% to 10% of cases),
rics, Duke University, Durham, NC)
vealed causes for some cases of PILD and idiopathic. Some authors consider
that otherwise would have been clas- genetic defects in surfactant produc-
sified as idiopathic. SP B deficiency tion to be forms of congenital PAP. ACKNOWLEDGMENTS. We thank
initially was described in 1993 as a Hereditary ABCA3 deficiency is Donald Frush, MD, Department of
fatal cause for respiratory distress in a an autosomal recessive disorder Pediatric Radiology at Duke, for the
term infant, and SP C deficiency was caused by mutations in the gene en- radiographic images.
identified initially in 2001 in an in- coding member A3 of the ABC fam-
fant whose family history was signifi- ily of proteins. The ABC transporters
cant for three generations of ILD. are a large family of transmembrane Suggested Reading
Most recently, ABCA3 deficiency proteins that transport substrates Fan L, Langston C. Interstitial lung disease.
was recognized as a congenital error across biologic membranes. Since its In: Chernick V, Boat TF, Wilmot RW,
Bush A, eds. Kendig’s Disorders of the Re-
in surfactant metabolism in a group original description, ABCA3 defi- spiratory Tract in Children. 7th ed. Phila-
of infants who had severe neonatal ciency has been associated with both delphia, Pa: Elsevier; 2006:666 – 675
surfactant deficiency. interstitial lung disease in older chil- Nogee LM. Genetic mechanisms of surfac-

tant deficiency. Biol Neonate. 2004;85: children. Paediatr Respir Rev. 2004;5: 7th ed. Philadelphia, Pa: Elsevier; 2006:
314 –318 316 –322 747–761
Presneill JJ, Nakata K, Inoue Y, Seymour JF. Berclaz P, Trapnell B. Rare childhood lung Prestridge A, Wooldridge J, Deutsch G, et
Pulmonary alveolar proteinosis. Clin disorders. In: Chernick V, Boat TF, Wil- al. Persistent tachypnea and hypoxia in a
Chest Med. 2004;25:593– 613 mot RW, Bush A, eds. Kendig’s Disor- 3-month-old term infant. J Pediatr.
De Blic J. Pulmonary alveolar proteinosis in ders of the Respiratory Tract in Children. 2006;149:702–706

Index of Suspicion in the Nursery
Katharine Kevill and Richard Auten

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Historical Perspectives: Perinatal Profiles: Geoffrey S.

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*Department of Pediatrics, University of South Alabama, Mobile, Ala.

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that have a glutamate-leucine-

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preterm and term neonates. Mac-1

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such as cathepsins, proteinase-3, and

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3. Phagocytosis represents engulfment of microorganisms or other target particles by neutrophils into an

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Transfusions in the Preterm

1. Characterize physiologic oxygen delivery in neonates.

Administering Red Cell Transfusions: Oxygen Delivery and Consumption

CO (dL/min)⫻CaO2 (mL/dL)⫽DO2 (mL/min)

Arterial oxygen content is determined by the hemoglobin concentration, the arterial

Improving cardiac output, oxygen saturation, or hemoglobin concentration increases the

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restrictive strategy group. Multiorgan system failure oc-

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were randomized to a liberal or restrictive transfusion

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isovolemic hemodilution (the pro-

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Summary of Neurologic Findings for High

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Table 5. An Example of Transfusion Guidelines

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Magnesium and Perinatal

*Department of Pediatrics, School of Medicine, University of São Paulo, Brazil.

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Case Presentation rate of 60 to 90 breaths/min, with

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Figure 1. Noncontrast-enhanced, thin-section (high-

Case Discussion immunoglobulin measurement, and examination of a lung biopsy demon-