anemia guideline

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BEST PRACTICE GUIDELINE ARTICLE

Management of anemia in the newborn

Naomi L.C. Luban

Departments of Pediatrics and Pathology, The George Washington University School of Medicine, United States

Laboratory Medicine and Pathology, Transfusion Medicine/The Edward J. Miller Blood Donor Center,

Children's National Medical Center, Washington, DC, United States

Abstract

Red blood cell (RBC) transfusions are administered to neonates and premature infants using

poorly defined indications that may result in unintentional adverse consequences. Blood

products are often manipulated to limit potential adverse events, and meet the unique needs of

neonates with specific diagnoses. Selection of RBCs for small volume (520 mL/kg) transfusions

and for massive transfusion, defined as extracorporeal bypass and exchange transfusions, are of

particular concern to neonatologists. Mechanisms and therapeutic treatments to avoid

transfusion are another area of significant investigation. RBCs collected in anticoagulant-

additive solutions and administered in small aliquots to neonates over the shelf life of the

product can decrease donor exposure and has supplanted the use of fresh RBCs where each

transfusion resulted in a donor exposure. The safety of this practice has been documented andprocedures established to aid transfusion services in ensuring that these products are available.

Less well established are the indications for transfusion in this population; hemoglobin or

hematocrit alone are insufficient indications unless clinical criteria (e.g. oxygen desaturation,

apnea and bradycardia, poor weight gain) also augment the justification to transfuse.

Comorbidities increase oxygen consumption demands in these infants and include bronchopul-

monary dysplasia, rapid growth and cardiac dysfunction. Noninvasive methods or assays have

been developed to measure tissue oxygenation; however, a true measure of peripheral oxygen

offloading is needed to improve transfusion practice and determine the value of recombinant

products that stimulate erythropoiesis. The development of such noninvasive methods is

especially important since randomized, controlled clinical trials to support specific practices are

often lacking, due at least in part, to the difficulty of performing such studies in tiny infants.

2008 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS

Neonate;

Premature;

Blood transfusion

Contents

1. Red blood cells for small volume transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4942. Iatrogenic anemia of infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4953. Criteria and guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

Department of Laboratory Medicine, Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC 20010, United States.Tel.: +1 202 884 5292; fax: +1 202 884 2007.

E-mail address: [email protected].

0378-3782/$ - see front matter 2008 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.earlhumdev.2008.06.007

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

w w w . e l s e v i e r . c o m / l o c a t e / e a r l h u m d e v

Early Human Development (2008) 84, 493498
mailto:[email protected]://dx.doi.org/10.1016/j.earlhumdev.2008.06.007http://dx.doi.org/10.1016/j.earlhumdev.2008.06.007mailto:[email protected]


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4. Measurements to define the need to transfuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4955. In-line devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4966. Autologous transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496

6.1. Cord clamping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4967. Cord blood collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497Research directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

1. Red blood cells for small volume transfusion

Most premature infants of 2427 weeks gestation requiretransfusions of red blood cells (RBCs) during their neonatalcourse [1]. Most of these transfusions will be administeredin the first postnatal month [2]. Restrictive guidelines havebeen developed which have decreased donor exposure andtransfusion number, but several factors continue to con-tribute to the need to transfuse. These include iatrogenic

anemia, oxidative hemolysis secondary to sepsis, and rapidgrowth with concomitant protein and iron deficiency. Theselection of the transfusion product continues to becontroversial. Issues include 1) intraerythrocyte, 2,3DPGand subsequent oxygen offloading capacity which decreaseduring storage; 2) potassium content which increases duringstorage; 3) solute load from the anticoagulant solutionswhich might result in osmotic diuresis with subsequentalteration of cerebral microcirculation and result inintracranial (periventricular) hemorrhage; 4) transfusion-associated viral diseases and graft-versus-host-diseaseresulting from passive transfer of viral-infected whiteblood cells (monocytes) and engraftable lymphocytes,

respectively.Several clinical articles and reviews have addressed thetransfusion of RBCs packaged in small volumes in differentanticoagulant-additive solutions (herein called a-RBCs) toreduce donor exposure [312]. The solutions have in commonthe use of mannitol, glucose, sodium chloride, phosphateand other additives (Table 1). To ensure that the hematocritis more comparable to a standard packed RBCs, and toincrease the red cell mass of the product, a-RBCs can beconcentrated by either centrifugation [13] or inverted

gravity sedimentation [14]. We evaluated the potentialtoxicities arising from the use of three then commonanticoagulant solutions in the settings of massive or largevolume transfusion (i.e., exchange transfusion, cardiopul-monary bypass pump prime, extracorporeal membraneoxygenation) and small volume transfusions [15]. Weestimated that concentrations of the solutes might reachdangerous or toxic levels in the setting of massive transfu-sion while the quantity of additives in small volume

transfusions are unlikely to result in either acute orcumulative toxicity over time; solutes could be furtherreduced by hard packing a-RBCs to a hematocrit of 80%. Ourtheoretical calculations have been supported by more thannine infant studies (Table 2). While each study differs inthe age of the product used, volume per kilogram (kg)transfused, type of anti-coagulant-additive solution, clinicaland laboratory parameters measured, none demonstratedadverse metabolic consequences that might be expectedfrom the solute loads.

In a two arm randomized study of infants weighing 0.6 to1.3 kg, 31 infants received CPDA-1 RBCs stored up to 7 days,while 30 received either AS-1 (19) or AS-3 RBCs (11) stored upto 42 days. Approximately half of the AS-1 and AS-3 units

were greater than 15 days of age at transfusion. Changes inpH, glucose, lactate, calcium, sodium and potassium wereminimal. In an expanded open safety study, 33 infantsweighing 0.6 to 1.25 kg received 120 transfusions of AS-3RBCs, of which 42 were older than 21 days at time oftransfusion [4]. No clinical adverse consequences or sig-nificant differences in chemical analyses were observed.Mangel et al. [10] reported on their experiences with AS-3units stored for up to 35 days in 56 infants who received 263transfusions. Donor exposures were minimal (mean of 1.7)despite 4.7 transfusion episodes per infant. This study did notevaluate pre- and post-blood chemistries (other thanhematocrit) and the indications for transfusion were not

detailed. Of note are the volume of RBCs in mL/kg transfused(7 mL/kg), which is much lower than U.S. and UK practiceand the lower hematocrit (5560%), which likely increasedthe donor exposure number when compared to U.S. and UKpractice. Van Stratten et al. [16] performed a study ofdifferent design utilizing a bag system with SAG-M. Bloodunits were split using a sterile docking device into 4 equalvolumes in small bags integrally attached to the main bag.These units were arbitrarily held for 21 days. Ninety-sixpreterm infants were classified as high or low risk based onthe expected need for transfusion. Mean donor exposurewas 1.1 with 3.22.1 transfusion/infant in the high and 1.1with 0.4 transfusions/infant in the low risk groups, withlimited wastage. This study was not designed to evaluate

Table 1 Formulation of anticoagulant-additive solutions in

blood collection sets

Constituent CPDA-1 AS-1 AS-3 AS-5

Volume (mL) 63 100 100 100

Hematocrit (%) 7080 5560 5560 5560

Sodium chloride (mg) None 900 410 877

Dextrose (mg) 2000 2200 1100 900

Adenine (mg) 17.3 27 30 30

Mannitol (mg) None 750 None 525

Trisodium citrate (mg) 1660 None 588 None

Citric acid (mg) 206 None 42 None

Sodium phosphate

(monobasic) (mg)

140 None 276 None

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safety or efficacy. In all published studies to date (Table 3),exposure of one to two donors is common with variabletransfusion number and volume, despite the use of singleunit assignment.

2. Iatrogenic anemia of infancy

Despite limiting donor exposures and transfusion episodes,premature infants still require transfusions of RBCs foriatrogenic loss [17] and for cardiorespiratory instability. Afew studies [1720] have addressed blood sampling as acause of iatrogenic anemia. Iatrogenic blood loss in 99extremely premature infants was studied in relationship toseverity of disease and gestational age. Sampling in mL/kgbody weight exhibited a wide range (0.9 to 39 mL in the firstweek of life) and was correlated directly with volumetransfused (mean 33.3 mL/kg) over a 4 week period [20].Since some NICUs now use indwelling catheters more oftenthan heel picks to obtain blood for testing and point of caretesting (POCT) has dramatically decreased iatrogenic bloodloss, the relevance of this study should be questioned. In a

retrospective chart review, the effect of introduction ofPOCTon RBC transfusion frequency in the first 2 weeks of lifewas reviewed. There were 46 infants less than 1000 g prePOCTwho received 5.7+ 3.7 transfusions and 78.4 + 51.6 mL/kg transfusion volume versus 3.1 + 2.07 and 44.4 + 32.9 mL/kgin 34 infants in post POCT period [21]. These studies highlightthe need to analyze the necessity of every blood draw,support the use of noninvasive monitoring methods anddevelop measures of true tissue oxygenation as a guide to theneed for transfusion.

3. Criteria and guidelines

Transfusion practices can be guided by the use of guidelineswhich shouldbe evidence-based, weigh benefits andrisks andensure that improved patient outcome is the primary endpoint. Optimally, well powered, randomized clinical trials,blinded and/or placebo controlled, would inform practice. In

fact, such rigor is rare outside of large network trials. Thereare, however, at least two sets of transfusion guidelines thathave been established based on consensus. These includethose prepared by members of the Pediatric HemotherapyCommittee of the American Association of Blood Banks [22]and by the UK's National Blood Service [23]. These guidelinesare often abstracted from clinical trials whose focus wereneither reduction in transfusion nor morbidity and mortality(and so may not accurately reflect clinical practice in arapidly changing area of neonatal medicine). Liberal versusrestrictive transfusion strategies have been tested in severaladult studies, in a few pediatric ICU and two recent NICUstudies. In an effort to guide transfusion practices, Bell et al.[24] conducted a randomized single institution study compar-

ing two sets of guidelines utilizing a threshold hematocritbelow which a RBC transfusion was administered. Theirhypothesis was that infants on the restrictive arm wouldrequire fewer transfusions with no more adverse outcomesthan the liberally transfused infants. Among the 100 infantswith birth weights of 500 to 1300 g in the study, the liberalgroup received more RBC transfusions (5.2 + 4.5) than therestrictive (3.3 + 2.9) with no difference in donor exposure(2.8 + 2.5 versus 2.2 + 2.0). The restrictive group had morebrain hemorrhage, periventricular leukomalacia and apnea,ascribed to lower arterial oxygen and compensatory increasein cerebral blood flow. However, these findings were notrepeated in the PINTstudy [25], a randomized trial of similar

design of over 200 infants highlighting the need for furtherlarge, multi-institution randomized clinical trials in this area.

4. Measurements to define the need to transfuse

The observation that infants may be asymptomatic with lowhemoglobin concentrations while others are symptomaticwith similar or higher hemoglobin concentrations supportsthe concept that hemoglobin alone is an inadequate measureof the need to transfuse. The ability to reliably and non-

Table 3 Small-volume RBC transfusions given as stored RBCs to limit donor exposure without causing apparent adverse effects

Reference Solution Storage Dose Hct (%) Transfusions Donors

Liu CPDA-1 35 days 15 mL/kg 75 5.6 2.1

Lee CPDA-1 35 days 13 mL/kg 6875 6.0 2.0

Wood NR 35 days 15 mL/kg NR 5.6 4.9

Strauss AS-1 42 days 15 mL/kg 85 3.5 1.2

Strauss AS-3 42 days 15 mL/kg 85 3.6 1.3

van Straaten SAG-M 35 days 15 mL/kg NR 3.2 1.1 high risk

SAG-M 35 days 15 mL/kg NR 0.4 1.1 low risk

Mangel AS-3 21 days 7 mL/kg 5560 4.7 1.7

da Cunha CPDA-1 28 days 15 mL/kg NR 4.4 1.6

Jain AS-1 42 days 15 mL/kg 60 6.7 1.8

NR = not recorded.

Table 2 Quantity (total mg/kg) of additives infused during a

transfusion of 15 mL per kg of AS-1 or AS-3 RBCs at Hct of 60%

Additive AS-1 AS-3 Toxic dose

Sodium chloride 42 7.5 137 mg/kg/day

Dextrose 129 23 240 mg/kg/hr

Adenine 0.6 0.6 15 mg/kg/dose

Citrate 9.8 12.6 180 mg/kg/hr

Phosphate 2.0 5.6 N60 mg/kg/day

Mannitol 33 0 360 mg/kg/day

From Luban et al. [15], 11

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invasively measure tissue hypoxia could provide improvedmethods to evaluate different interventions and confirm theclinical significance of measured hemoglobin. Compensatoryresponses to decreased tissue oxygen concentration includeincreases in heart rate, cardiac output and cerebral bloodflow. Fractional oxygen extraction (FOE) increases tomaintain oxygen consumption. There is a progressive shiftto anaerobic respiration which results in an increase in lacticacid. Several authors [26,27] have shown post-transfusiondecrease in lactic acid and hypothesize that this reflectsimproved oxygen delivery. However, there are the technicaland biological variables that affect the FOE measurement,which include fasting, cold, increased activity, hemolysis andvenous occlusion, especially when the specimen is obtainedfrom a peripheral vein. In a study by Fey and Losa [28] thatattempted to control these variables, capillary whole bloodlactic acid was analyzed pre- and 48 h post-transfusion in 18premature infants. Lactic acid measurements did notcorrelate with either respiratory rate or bradycardiacepisodes when regression analysis was performed [28]. Thehigh coefficient of variation of 19.8% of repeated measures

of lactic acid likely contributed to the poor correlation. Somehave suggested that elevated lactic acid results from thecatecholamine surge associated with sepsis or injury. In thiscircumstance, post-transfusion lactate might fall as a resultof decrease in catecholamine response rather than fromimprovement in anaerobic metabolism.

Utilizing a different approach, Wardle et al. presentsupport for the use of near infrared spectroscopy (NIRS)measurement of FOE [29,30]. In a pilot study, 37 infants wererandomized to one of two groups: the decision to transfusewas based on peripheral FOE or based on the hemoglobinconcentration. The NIRS group was determined by an FOE ofgreater than 0.47 while the conventional group wastransfused based on clinical need. Of the 56 transfusions

given to the NIRS group, 33 (59%) were given because ofclinical concerns. The investigators concluded that eithertheir FOE criteria were insensitive or clinical indicationscomplicated the study design. In another pilot study using atechnique similar to NIRS, absolute concentrations of tissuehemoglobin, including oxygen bound and oxygen freehemoglobin was measured in 10 very low birth weight infantsusing diffuse optical spectroscopy (DOS) [31]. This metho-dology measured tissue oxygen concentrations non-inva-sively in muscle pre- and post-transfusion. Increases in tissueoxygenation were noted post-transfusion and correlatedwith mean hemoglobin increases for all 10 infants.

Mock et al. [32] correlated hematocrit to RBC volume in

26 premature infants of birth weight less than 1300 g, studiedon 43 occasions using a non-radioactive biotinylated RBClabeling flow cytometric method. Their goal was to developan accurate RBC volume measurement and establish therelationship between circulating red cell volume andhematocrit to assess whether previously reported poorcorrelations between hematocrit and RBC volume was dueto artifact or unique preterm physiology. They hypothesizedthat if RBC volume and hematocrit correlated, thenhematocrit could be used as a definitive test for transfusionneed. Despite good correlation between the two assays(r= 0.907), 95% confidence limits for predicting the circula-tory RBC volume ranges were so broad as to make the RBCvolume measurement of questionable clinical significance

and usefulness. Other measurements like paired pre- andpost-transfusion measurements of oxygen consumption(VO2), mixed venous oxygen saturation (M VO2) an dhemoglobin-oxygen dissociation curve alone or in combina-tion would theoretically demonstrate post-transfusionimprovement in oxygen delivery. Any method must beavailable real time or its usefulness will be limited.

5. In-line devices

If methods are insufficient to guide transfusions, combiningmethods to decrease iatrogenic loss and improve erythropoi-esis might prove to be advantageousto theinfant. Since bloodgas analyses are a primary source of iatrogenic loss, in-linedevices that permit continuous pH, pO2, and pCO2 measure-ments should theoretically decrease venous blood loss. Using229 paired samples, an in-line intra-umbilical artery deviceversus specimens collected by phlebotomy were compared in16 neonates monitored over 37 days. Blood volume loss andhemolysis were assessed as well as bias, precision andcorrelation of the in-line devices readout compared toreference methods. A dramatic difference in blood volumeloss was observed: 247 L in those infants with in-linemonitors versus 250 L for reference methods of commonlyperformed laboratory tests. The devices were not withoutproblems which included large flush volumes, softwareissues, cost and practicality [33]. Using an in-line, ex vivobedside monitor that withdraws blood through an umbilicalartery catheter andreturns it to thepatient,Madanet al. [21]noted 25% less cumulative phlebotomy loss in the first twoweeks of life in the monitored (n =46) versus control group(n =47). Based on previous studies, there was an anticipated35% decrease in phlebotomy losses, which was only achievedin week one of the two-week analysis [21]. Because the

analyte panel was limited, additional phlebotomy was stillrequired.In future studies, technical issues andcost will needto be addressed as well as impact on mortality and morbidity,for which this study was underpowered. Time and technologywill ultimately yield improvements with such devices.

6. Autologous transfusion

6.1. Cord clamping

True autologous transfusion in an infant can occur by delayingcord clamping or by collecting, storing, and re-infusing cordblood as a blood product. In a randomized study, 39 infants ofb

33 weeks gestation were randomized to a 20 s (n = 20) or 45 s(n =19) delay in cord clamping with oxytoxin administrationafter delivery of the first shoulder in mothers delivering byCaesarian section. By day 42 of life, 16 of 20 infants in theimmediate and 9 of 19 in the delayed clamp group hadbeen transfused. This resulted in 2.4 transfusions in theimmediate versus 1.2 transfusions in the delayed group(pb0.05) despite equivalent iatrogenic blood loss [34]. Thissupports the early work of Kinmond who demonstrated lesshypovolemia and fewer days of both oxygen dependency andtransfusion need in premature infants delivered vaginally [35],but refutes the work of others whoshowedno advantage of lateclamping to the infant. McDonnell and Henderson-Smart [36]measuring circulating red cell volume using biotinylated RBCs

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could provide the physiological basis of delay of cord clamping.In another study, infants born following delayed clamp hadgreater circulatory red cell volumes (42.1 mL/kg) as comparedto immediate (36.8 mL/kg). Clinical benefit was not measuredin this study [37]. Most recently, blood volume measurementsusing either a dilution of fetal hemoglobin or biotin-labeledautologous red blood cell method were performed in 46preterm infants, 24 to 32 weeks gestation, randomized toeither an early or delayed clamping. This study confirmed thatinfants born with delayed clamp time had a greater bloodvolume (74.4 mL/kg) than early clamp group (62.7 mL/kg) forbothvaginal andcesarean deliveries. Of interestno differenceswere noted for hematocrit measured at 4 h [38].

The potential advantages and disadvantages of clampinghave been debated and are different for term versus preterminfants. In countries with limited access to safe blood fortransfusion, the value of late cord clamping might be ofsignificant value. A meta-analysis of early versus late cordclamping including 7 studies of 297 preterm infants, defined asless than 37 weeks gestationhas been publishedrecently. In thisanalysis, Rabe demonstrated that delayed cord clamping (30 to

120 s) was associated with fewer transfusions for anemia (RR2.01) or lower blood pressure (RR2.58)and less intraventricularhemorrhage (RR 1.74) [39]. This meta-analysis supports theneed to implement changes in clinical obstetrical practice.

7. Cord blood collection

Collection of autologous cord blood for storage and re-infusion has been studied infrequently. In one study, therewere 44 collections into a closed blood collection systemwith CPD from infants with a mean gestational age of 324 weeks while the placenta was still in utero. A mean offorty-four3.4 mL of cord blood was collected which, at a

transfusion volume of 10

15 mL/kg, could provide one or 2transfusions. Bacterial contamination rate was high (15.8%)[40]. While autologous collections can be transfused withoutadverse consequences [41], smaller collection volumes withpoor product quality in infants weighing less than 1000 g raiseissues as to whether this process, while feasible, isworthwhile. In another study of infants with congenitalanomalies diagnosed prenatally, 26 infants had bloodcollected and transfused during the first 3 days post delivery.No bacterial contamination was noted. The unusual successin collection and transfusion was ascribed to patientselection, meticulous preparation, and the short storagetime [42]. This level of success has been repeated in a recentstudy of 52 newborns where autologous blood was held for up

to 23 days; 40% of infants between 1000 and 2500 g weresupported using only autologous blood in this study [43].

Key guidelines

Utilize transfusion guidelines based on published recom-mendations, updated regularly based on randomizedclinical trials.

Assign one or two infants to a single RBC unit for smallvolume transfusions to limit donor exposure withoutconcern for age/anticoagulant.

r-EPO should be limited to selected premature infantsuntil studies better inform its use [4452].

Encourage delayed cord clamping to increase newbornred cell mass/volume.

Research directions

Perform well powered studies of restrictive vs. liberaltransfusion criteria.

Develop real time noninvasive measures of tissue oxygendelivery.

Develop in-line and reflectometric devices to diminishiatrogenic blood loss.

Establish systems to select, screen and collect blood froma single donor that can be processed and packaged tofurther limit donor exposure.

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