Neonatal transfusions

June 21, 2018 | Author: Naomi Luban | Category: Documents


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Vox Sanguinis (2009) 96, 62–85

INTERNATIONAL FORUM

© 2008 The Author(s) Journal compilation © 2008 International Society of Blood Transfusion DOI: 10.1111/j.1423-0410.2008.01105.x

Neonatal transfusions INTERNATIONAL © XXX International 2008 The Authors ForumFORUM Blackwell Oxford, Vox VOX 1423-0410 0042-9007 Sanguinis UK Publishing Ltd

H. V. New, S. J. Stanworth, C. P. Engelfriet, H. W. Reesink, Z. K. McQuilten, H. F. Savoia, E. M. Wood, S. Olyntho, F. Trigo, S. Wendel, Y. Lin, H. Hume, J. Petäjä, T. Krusius, S. Villa, S. Ghirardello, J. von Lindern, A. Brand, J. E. Hendrickson, C. D. Josephson, R. G. Strauss, N. L. C. Luban & W. Paul

Transfusions in the neonatal period require specific precautions, such as to prevent graft-versus-host disease and to limit donor exposure as much as possible. Of interest are also the current triggers for red blood cell (RBC) and platelet transfusions, and the occurrence of adverse reactions. It, therefore, seemed of interest to report and describe practice and policies with regard to neonatal transfusions at a number of different countries, regions or institutions. We obtained 10 contributions to this International Forum. The answers to the questions contain a lot of interesting information that cannot be included in this Editorial. The reader is therefore strongly advised to read the individual answers in order to fully appreciate this forum. We hope these responses will stimulate debate and comment, and provide impetus for progress in this field. Readers are therefore invited to send comments to C. P. Engelfriet, which will be published in Vox Sanguinis later. Question 1: Components a. Do you specify any additional safety measures (e.g. donor selection, microbiological screening, and other donation testing) for blood components for neonates? In three of the countries/centres from which information was obtained, no additional safety measures are taken for neonatal blood components. Two countries, Italy and the UK [except for fresh-frozen plasma (FFP)], use only repeat

donors, that is, at least three donations (Italy) or one donation (UK) in the last 2 years. Leucoreduction of RBC and platelet concentrates (PC) is now general practice in many countries and helps to prevent the transmission of cytomegalovirus (CMV). However, in Australian, US and Italian responses, leucoreduction appears to be a special feature for neonates/ children. In addition, in some countries/centres, CMVnegative donors are selected, but usually only for specific indications, such as for neonates who received intrauterine transfusions (IUT), for those < 1200 g and/or those who are immunocompromised. In the Netherlands, only parvovirus B19 safe blood is used for neonates. RBC concentrates less than 5 days old are used for all neonates in Italy, whereas in several other countries, these are reserved for large volume neonatal transfusions. In Washington DC, USA, lead testing is required (< 3 mcg/dl), and in Iowa, USA, only ABO-identical donors are used for platelets and plasma. RBC units for neonatal transfusion are described as sickle negative in Brazil and some parts of the UK, and for large volume transfusions by two of the US centres. b. What are your irradiation guidelines for neonatal transfusion? How much does practice vary nationally in your country, if at all? Not all countries have official guidelines for the indications for irradiated cell concentrates and there is significant variation in practice (the replies are summarized in Table 1

Table 1 Indications given for irradiating cell concentrates Australia Brazil Canada Finland Italy The Netherlands UK USA, Atlanta USA, Washington DC USA, Iowa

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Intrauterine transfusions (IUT), HLA matched or from relatives (mandatory), exchange transfusion (recommended; mandatory if previous IUT), top-ups post-IUT; suspected or confirmed T-cell immunodeficiency IUT (mandatory), ≤ 30 days old, birth weight < 1200 g, immunodeficiency IUT; exchange transfusion; neonatal extracorporeal membrane oxygenation; birth weight < 1250 g (four-fifths of centres routinely use for all neonates); congenital immunodeficiency; from a relative First week of life if birth weight < 1500 g or born ≤ 27 + 6 weeks IUT; exchange transfusion if previous IUT or critically ill, ≤ 30 weeks gestation, birth weight ≤ 1500 g immunodeficiency, from first or second degree relative < 32 weeks gestation, birth weight < 1500 g; after prior IUT; immunodeficiency After prior IUT, congenital T-cell deficiency, recommended for exchange transfusion (mandatory in Northern Ireland; Wales only if low birth weight, recommended elsewhere) All infants < 6 months < 1250 g All infants first year of life receive irradiated cell concentrates

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and also indicate much additional local variation). Irradiation of cell concentrates is mandatory or recommended for IUTs in all countries/centres and for exchange transfusions in some. Only Iowa, Atlanta and Brazil responded that all concentrates are routinely irradiated for transfusions to all their neonates for a certain period after birth: 1 year in Iowa, 6 months in Atlanta and 30 days in Brazil; others have more selective indications. However, it was stated by Strauss that in the USA most university/academic medical centres provide irradiated cellular components for a predetermined period of time to neonates/infants, ranging from the first 4 months of life until a few years of age. Other indications are for infants born before 30–32 weeks of gestation and infants with a birth weight ≈ 1200–1500 g, and it is not clear how long the irradiated blood is given in these cases apart from in Finland where it is during the first week if the birth weight is < 1500 g. All concentrates from relations as well as those for immunocompromised neonates. c. Do you recommend or routinely provide any pathogeninactivated types of blood components (e.g. plasma) for groups of neonates? Do any of your hospitals obtain alternative pathogen-inactivated components directly from commercial sources? Pathogen-inactivated cell concentrates are, at present, not used, but as pointed out by Lindern, Brand and Strauss, products prepared from pooled plasma require a pathogeninactivation step in their preparation, for example, intravenous immunoglobulin (IVIG). In Finland, solvent/detergent (SD)-treated FFP is used for infants and in the UK FFP for neonates is imported from the USA (volunteer donors) to reduce the risk of variant Creutzfeldt–Jakob disease (vCJD). It is treated with methylene blue. Methylene blue-treated cryoprecipitate is used for infants in Scotland and Northern Ireland. In the USA, pathogen-inactivated blood components such as platelets and plasma treated with nucleic acid crosslinking systems are transfused only in institutionally approved investigational settings. d. Is it established practice in your country to reserve small volumes from a single RBC donation (‘paedipacks’ or splits) for transfusion to one recipient as a means to reduce donor exposure? How many splits do you produce from one donation? Do you have any data on the implementation of paedipacks by your hospitals? In all countries/centres, small volumes of RBCs from one donation are reserved for one, sometimes two (Atlanta, Iowa and the Netherlands), neonate(s) in order to reduce donor exposure. The number of split units from one donation varies from three to eight (higher in Washington) or is determined by the birth weight, for example, 10 ml/kg in Brazil. No national data on the use of such split units are available, but the Finns feel that this is effectively implemented whereas in Italy there is multicentre audit data showing that

a significant number of neonatal units do not routinely use split units. e. What are the national recommendations in your country for the use of blood components in additive solutions, for example, when large-volume neonatal RBC transfusions are prescribed for exchange transfusion, cardiac surgery and extracorporeal membrane oxygenation (ECMO)? Is the additive solution removed and replaced with FFP (or another fluid) before transfusion? There are no specific national recommendations for the use of blood components in additive solutions, except in Italy, the UK and the Netherlands. However, it appears to be common practice to remove the additive solution when RBCs are to be used for exchange transfusions, cardiac surgery and ECMO apart from in the UK. The additive solutions are usually replaced by plasma/FFP or saline, although in Washington citrate–phosphate–dextrose–adenine 1 (CPDA-1) units are mostly used for these indications. Both Italy and Iowa prefer to reconstitute RBCs for exchange with plasma from the same donation where possible. In the UK, Northern Ireland is the only region where additive solutions are removed and replaced with plasma for exchange transfusion units. In the UK, the use of CPD units is discouraged (except for exchange transfusion), because they contain more plasma than units in additives, increasing the theoretical risk of vCJD. f. What haematocrit (Hct) do you recommend for neonatal exchange transfusions? Is whole blood supplied for this or any other indication for neonates? Do you use hyperconcentrated RBCs for neonatal top-up transfusions? The Hct of RBC concentrates provided for exchange transfusions is often very precise, but varies between 0·4–0·45, 0·4–0·5/0·6, 0·5–0·55 and 0·5–0·7 in different countries. No specific Hct is recommended in Canada or Finland. In Australia, individual packs are labelled with the Hct as a service to the clinicians, and in Washington the Hct is individualized to the patient’s requirements. Whole blood is used only rarely. Instead, packed RBCs with plasma/FFP or CPD/ CPDA-1 are used for exchanges. Packed RBCs with a high Hct are used for small volume transfusions in some centres in Canada (0·7–0·8) and in two of the centres in the USA (0·6 in one and 0·8–0·85 in the other). g. Do you allow directed donation for neonates? If so, what are your guidelines/restrictions? In most countries, directed donations are allowed, but only for special indications, such as maternal antibodies against a high-frequency RBC alloantigen, or against a human platelet antigen (HPA) when no compatible allogeneic platelets are available. In two of the US centres, directed donations are allowed although not encouraged, but no special indications are mentioned. In Iowa, the only accepted indication for directed donation is to reduce donor exposure for infants anticipated to require so many transfusions that they

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would be exposed to more than one allogeneic donor. In Finland, directed donations are not provided. Question 2: Demographics Do you have any information on component usage figures for neonates, for example, transfusions to neonates per 1000 admissions to neonatal intensive care unit (NICU)? If not, can you estimate this from other sources of information? There is little accurate data on usage rates specific to neonates, including transfusion rates to neonates per 1000 admissions. Some data concerning the use of blood components were obtained from all countries/centres except Brazil and Australia. The main conclusion from these data is that birth weight is a very important factor in the decision to transfuse blood components to neonates. See, for example, the data provided by Strauss: of neonates with a birth weight < 1000 g, about 90% were given RBC transfusions. Data for FFP and platelet transfusions are also sparse. In the UK, an estimated 122 of 3498 neonatal unit admissions received platelet transfusions (33/1000). Question 3: Transfusion triggers a. Do you have national or regional guidelines or recommendations for neonatal RBC/FFP/platelet transfusion triggers in your country? What are they (in brief)? There are national guidelines or recommendations for neonatal transfusions in all countries, except Australia and the USA (and only for platelets and FFP in Brazil). Recommendations incorporate information from haemoglobin (Hb) concentration, gestational age, postnatal age and respiratory support. Guidelines for FFP or platelets appear to be less well-developed than for RBCs. The trigger for platelet transfusions also depends on the clinical condition and whether there is neonatal alloimmune thrombocytopaenia or active bleeding. It varies from < 20 × 109/l to < 100 × 109/l. b. Do you have data from multicentred audits that support the RBC transfusion triggers currently being used? Good data from multicentre audits to support the adopted transfusion triggers are lacking. From a regional audit in Iowa, it appeared that compliance with the guidelines was 70% for RBCs, 69% for platelets, 65% for plasma and 94% for cryoprecipitate. At the hospital and clinics of Iowa University, compliance was 90–95%. Question 4: Haemovigilance a. Do you have a national or regional guideline for administration of blood that is specific for neonates? National or regional guidelines for administration of blood components specifically to neonates do not generally exist. In the UK, there is a national guideline document specific to

transfusion in neonates and children that includes information on administration. b. Do you have a transfusion adverse event-reporting system that captures data associated with neonatal (or paediatric) transfusions separately from adults? Is this reported separately through national haemovigilance? Although there are haemovigilance programmes in all countries/regions, no specific data on neonatal related adverse advents after transfusions are available. In Brazil and Canada, the information can be deduced from the birth dates mentioned in the reports. In most countries, the currently existing haemovigilance systems do not have separate categories in reports for neonates. In the UK, the Serious Hazards of Transfusion (SHOT) scheme recently reviewed results of 10 years. The data suggest that there was an adverse event after RBC transfusions in 37 : 100 000 RBC units issued for infants < 12 months old, whereas in adults such events occurred in 13 : 100 000 RBC units. c. Have any specific measures been taken to reduce errors in patient identification for neonates? Have you considered a national numbering scheme for transfusion? Despite the results from the SHOT report suggesting a higher incidence of adverse events related to infants under 12 months of age, and a general acknowledgement of potential higher risks for neonates, none of the replies indicated specific measures to address issues of patient identification or to reduce transfusion errors for neonates. In Finland, all neonates as citizens have a unique individual social security number that is also used for the identification of patients in hospitals. In Italy, there are plans to link up the blood transfusion services region wide through a common IT software system. There are plans for a national numbering system for including children and neonates in UK. Question 5. Alternatives to transfusion a. What, if any, are the recommended situations in which erythropoietin (EPO) is used to prevent transfusion for premature infants? Erythropoietin is hardly used at present to prevent RBC transfusion to neonates. It is not certain whether this treatment is effective and there is a greater risk of retinopathy in premature infants treated with EPO. An accepted indication is given for infants whose parents are Jehovah Witnesses and in Iowa it is given to infants with severe haemolytic anaemia with reticulocytopenia due to anti-D or anti-Kell. b. Do you recommend the use of IVIG to reduce exchange transfusion for haemolytic disease of the newborn? To what degree is IVIG used for this indication? Except in Brazil where the efficacy of IVIG therapy is considered to be doubtful, this therapy is used in all countries/ centres. The main indication is a rise of the bilirubin level in spite of intensive phototherapy. In Finland, no exchange transfusions were carried out over the last 12 months due to

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IVIG therapy in contrast to the usual 10–20 exchange transfusions per year. However, the infants later needed top-up RBC transfusion that renders the reduction of donor exposure by IVIG therapy doubtful. In the Netherlands, a clinical trial is being conducted to compare the effect of highdose IVIG and placebo on the number of exchange and top-up transfusions. H. V. New Department of Paediatrics Imperial College Healthcare NHS Trust St Mary’s Hospital Praed Street London, W2 1NY UK E-mail: [email protected] S. J. Stanworth National Blood Service John Radcliffe Hospital Osler Road Headington Oxford, OX3 9BQ UK E-mail: [email protected]

C. P. Engelfriet Sanquin Research and Sanquin Diagnostic Services P.O. Box 9190 NL-1006 AD Amsterdam the Netherlands E-mail: [email protected] H. W. Reesink Sanquin Consulting Services Amsterdam the Netherlands E-mail: [email protected] and Department of Gastroenterology and Hepatology Academic Medical Center Amsterdam the Netherlands E-mail: [email protected]

Z. K. McQuilten, H. F. Savoia & E. M. Wood

Question 1 In Australia, blood and its components for transfusion are collected from volunteer non-remunerated low-risk donors who have completed a confidential interview and donor declaration, and satisfied a health assessment. All allogeneic donations are tested by the Australian Red Cross Blood

Service (ARCBS) for human immunodeficiency virus 1/2 (HIV 1/2) antibody and RNA, hepatitis B surface antigen, hepatitis C antibody and RNA, human T-lymphotropic virus I/II (HTLV I/II) antibody and syphilis. In addition, universal pre-release bacterial testing of platelets is now in place. All paediatric RBC and platelet units are provided by ARCBS as pre-storage leucodepleted (national specification < 1 × 106 white blood cells per unit). It is recommended that CMV seronegative donors’ RBCs and platelets are used in premature or immunocompromised neonates and neonates who received IUT. Components whose plasma contains a clinically significant RBC alloantibody are considered unsuitable for use for neonatal transfusion. Question 2 The Australian and New Zealand Society for Blood Transfusion, in conjunction with ARCBS and the New Zealand Blood Service, have published guidelines for the clinical indications for γ-irradiated blood components [1]. These are currently being updated. Irradiation is recommended for all neonates receiving exchange transfusion (provided this does not unduly delay transfusion) and is absolutely indicated if there has been a previous IUT or if the donation comes from a relative. For top-up RBC transfusions and platelet transfusions, irradiation is indicated if there has been a previous IUT or the donation comes from a relative. In addition, irradiation is recommended for all infants with a suspected or diagnosed T cell immune-deficiency state. These are the minimum requirements for irradiation and are followed Australia-wide. Individual institutions have additional local guidelines including, in many instances, broader criteria for irradiation. For example, some institutions have a universal irradiation policy for all RBCs and platelets for neonates to avoid inadvertent administration of a nonirradiated unit when clinically indicated. National guidelines recommend that ‘where the patient is at particular risk from hyperkalaemia, it is recommended that red cells be transfused within 24 hours of irradiation’ and that ‘in considering the clinical significance of [the potential for hyperkalaemia in the recipient], both the speed and volume of the transfusion, as well as the age of the blood, must be taken into account’ [1]. Therefore, ‘blood less than 5 days of age should be used for intrauterine and exchange transfusion, and must be transfused within 24 hours of irradiation’ [1,2]. Question 3 Pathogen-inactivated blood components such as RBCs, platelets or plasma are at present not used in Australia. Question 4 In Australia, paediatric size RBC, platelet and FFP units are provided. RBC units collected from a single donor are divided

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into four smaller packs and are intended for use by a single neonate to minimize donor exposure. Single-donor collected apheresis platelets are likewise divided into four packs of equal volume and intended for use by a single neonate. Information on paediatric product specifications is available from ARCBS at http://www.transfusion.com.au. There is no published national information on the implementation of paediatric sized RBC, platelet or FFP units. Question 5 There are no national recommendations for the use of blood components in additive solutions when large volume transfusions are prescribed. Practice varies between institutions and clinicians. Some institutions will remove the additive solution, but this is variable. Question 6 Paediatric RBC units prepared by ARCBS have a specified Hct of 0·5 to 0·7. Units intended for exchange transfusion are provided with the Hct measured on the individual pack, as a service to the treating clinician. There is some regional variation in the use of whole blood for neonatal transfusion. Whole blood is used in very limited amounts for paediatric cardiac surgery in some centres, but is no longer used for neonatal exchange transfusion. Question 7 Australian Red Cross Blood Service can provide directed donations where there is a defined medical indication (e.g. provision of compatible RBCs, platelets and/or leucocytes when an anonymous allogeneic donor is unable to provide the necessary transfusion products), and in some circumstances if it is the parent’s preference. All directed donors must meet the usual donor selection criteria. Exceptions may be made under medical supervision, for example, in cases of neonatal alloimmune thrombocytopaenia where a maternal donation may be one suitable component, but this is a rare event as HPA-matched platelets from volunteers are usually provided. Directed donations are subject to the same safety precautions as any other donation. All directed donations from family members are irradiated prior to transfusion. Question 8 There are no national data available on blood component usage for neonates in Australia. Questions 9 and 10 There are no national or regional guidelines for neonatal transfusion triggers. Paediatric guidelines are expected to be developed in the near future as part of a national update of transfusion practice documents. Individual institutions currently have their own guidelines that often include transfusion triggers for various components. These will usually

combine a trigger level (e.g. Hb or Hct for RBCs) with clinical criteria. In addition, the British Committee for Standards in Haematology transfusion guidelines for neonates [2] are widely referenced and used in Australia. To our knowledge, there are no Australian multicentre audit data published in this area. Question 11 There is no national or regional administration guideline specifically written for transfusion of neonates, although some information is included in the Australian and New Zealand Society for Blood Transfusion/Royal College of Nursing of Australia guidelines [3] (currently in revision), and some practical advice (e.g. on the use of syringe drivers for neonates and small children) is available in another widely used document [4]. Individual institutions may have policies for neonates including, for example, minimum criteria for patient identification, use of neonatal giving sets and monitoring of neonates during transfusion. Question 12 Within Australia, there are several different incident-reporting systems presently in use regionally and not all are specifically transfusion focused. Adverse events associated with neonatal transfusions are not generally captured separately. A national haemovigilance programme is in development. Question 13 No specific measures have been taken nationally to address patient identification for neonates, with individual institutions each having their own protocols in place. There is no current plan for a national numbering scheme for transfusion. Question 14 No national Australian guidelines or recommendations exist on the use of EPO in premature infants. Question 15 In line with national guidelines [5], and in consultation with experts in fetomaternal and transfusion medicine, IVIG is used occasionally in Australia for prevention and management of severe haemolytic disease of the newborn. According to the national ARCBS IVIG database, 11 patients received IVIG for haemolytic disease of the newborn in 2007: two women who received multiple treatments antenatally and nine babies who each received one or two doses only.

References 1 Australian and New Zealand Society of Blood Transfusion Inc, Australian Red Cross Blood Service, New Zealand Blood Service: Guidelines for Gamma Irradiation of Blood Components; Revised 2003; available at: http://www.anzsbt.org.au/publications/ documents/ANZSBTguide_May03.pdf

© 2008 The Author(s) Journal compilation © 2008 International Society of Blood Transfusion, Vox Sanguinis (2009) 96, 62–85

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2 British Committee for Standards in Haematology Transfusion Task Force: Transfusion guidelines for neonates and older children. Br J Haematol 2004; 124:433 – 453 3 Australian and New Zealand Society of Blood Transfusion Inc, Royal College of Nursing of Australia: Guidelines for the Administration of Blood Components, October 2004; available at: http:// www.anzsbt.org.au/publications 4 Department of Health/Government of South Australia, Australian Red Cross Blood Service: Flippin’ Blood, 2006, 1st edn, August 2006; a BloodSafe flip chart to help make transfusion straitforward; available at http://www.health.sa.gov.au/bloodsafe/Portals/0/ flippn’bloodchartSept06.pdf 5 National Blood Authority: Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia, 2007 December; available at: http://www.nba.gov.au/ivig/Criteria/7.html Z. K. McQuilten Australian Red Cross Blood Service/The Royal Melbourne Hospital PO Box 354 South Melbourne Victoria 3205 Australia H. F. Savoia Consultant Haematologist Royal Children’s Hospital Flemington Road Parkville Victoria 3052 Australia E. M. Wood Transfusion Medicine Specialist Australian Red Cross Blood Service P.O. Box 354 South Melbourne Victoria 3205 Australia E-mail: [email protected]

S. Olyntho, F. Trigo & S. Wendel

Question 1 We routinely perform serological (HIV, HTLV, hepatitis B and C virus, syphilis and Chagas disease) and microbiological testing for each blood bag collected, independent of who will receive the blood component. Donor selection criteria are universal, and therefore no distinction is made for neonates [1]. Question 2 Irradiated blood components are used for neonates up to 28 days of life [1]; leucodepleted components are used up to 6 months of life [1]. If the CMV status is unknown, CMV-negative (or leucodepleted within 48 h of collection) components are used for neonates up to 4 months. Haemoglobin S containing blood components are not utilized in any patient.

Exchange transfusion is performed with blood collected for not longer than 5 days. Irradiated blood is used for IUT and neonates ≤ 30 days. Older neonates will receive irradiated blood if an immunodeficiency status is diagnosed. Irradiation in neonatal transfusion practice is mandatory only for IUT according to the Brazilian blood regulation; it is recommended for very low birth weight neonates (< 1200 g). Therefore, this practice is variable for each blood service in our country. No national statistics are available of this practice [1]. Question 3 There is no pathogen-reduction technology accepted and validated by the Brazilian Health Ministry at the moment. We believe that the application of this technology should be widespread for all transfusions independent of the recipient’s age, provided its efficacy and safety is confirmed in the literature. Question 4 We process a RBC unit into several splits of 10 ml/kg weight of the neonatal recipient routinely, independent of the final number of splits. We have no information regarding the use of paedipacks. Question 5 There are no specific national recommendations for that. In our service, we remove the additive solution and add normal saline to the component for some specific conditions: prematurity, repeated transfusions (> three episodes), ECMO, cardiac surgery, exchange transfusion, massive transfusion, and renal and hepatic failures. Question 6 For neonatal exchange transfusion, we recommend a final Hct of 40–45%. We do not supply whole blood to any patient, but rather use the addition of FFP to a packed RBC unit to achieve such an Hct. Apart from exchange transfusion, this product is also supplied for ECMO and massive transfusions. We do not use hyperconcentrated RBCs in our service. Question 7 We only allow for directed donations in case of rare phenotypes or platelet refractoriness [1]. Question 8 We do not have such data from national audits. Question 9 Brazilian national guidelines for FFP use [2] concern all indications for adults and children; specific guidelines for neonatal transfusion of FFP only include two indications:

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(i) purpura fulminans of the newborn; and (ii) protein C or S deficiency. Similarly, Brazilian national guidelines for platelet use [3] concern all indications for adults and children; specific guidelines for neonatal transfusion include: • prophylatic transfusion trigger of 30 000/mm3 for all newborn; • prophylatic transfusion trigger of 50 000/mm3 for all febrile newborn; and • prophylatic transfusion trigger of 30 000/mm3 for neonatal alloimmune thrombocytopaenia, using HPA-1a-negative platelets or platelets derived from the mother. There is no national guideline for RBC transfusion. We have written guidelines for transfusion practice in our hospital based on literature data, including the neonatal period, at www.hospitalsiriolibanes.org.br/medicos_profissionais_saude/ manuais_guias/guia_conduta_hemoterapicas.asp. Question 10 Unfortunately, we do not know of any multicentred audits in Brazil to support transfusion guidelines. Question 11 There are no specific national guidelines in Brazil, except for those cited in Question 9. Please refer to our hospital’s transfusion guidelines at www.hospitalsiriolibanes.org.br/medicos_profissionais_saude/ manuais_guias/guia_conduta_hemoterapicas.asp. Question 12 The Brazilian Haemovigilance System captures data from 50 voluntary hospitals, which represent the Brazilian diversity of health care (The Sentinel Project). Final reports derived from data collected do not discriminate adults from kids, even though the birth date is informed by the ‘sentinel hospitals’. Question 13 There is no national legislation to reduce such errors. Nine Brazilian Blood Services utilize the ISBT 128 identification number, which we believe is the proper way of identifying the sample and the units. Identification bandurists are also utilized in our service for all patients, independent of age. Question 14 We are currently reviewing the use of EPO in the neonatal period, especially for anaemia of prematurity. Question 15 The use of IVIG for haemolytic disease of newborn is controversial, almost always associated with exchange transfusion in the literature [4–7]. We do not routinely use this therapeutics in such cases.

References 1 Brazilian Federal Act 153/2004; available at http://e-legis. anvisa.gov.br/leisref/public/showAct.php?id=11662&word= 2 Brazilian Federal Act 10/2004; available at http://e-legis. anvisa.gov.br/leisref/public/showAct.php?id=9572&word= 3 Brazilian Federal Blood Act 129/2004; available at http:// e-legis.anvisa.gov.br/leisref/public/showAct.php?id=11175&word= 4 Mochizuki K, Ohto H, Hirai S, Ujiie N, Amanuma F, Kikuta A, Miura S, Yasuda H, Ishijima A, Suzuki H: Hemolytic disease of the newborn due to anti-Di: a case study and review of the literature. Transfusion 2006; 46:454 –60 5 Mundy CA: Intravenous immunoglobulin in the management of hemolytic disease of the newborn. Neonatal Netw 2005; 24:17– 24. Review 6 Lakatos L: Bloodless treatment of infants with haemolytic disease. Arch Dis Child 2004; 89:1076 7 Gottstein R, Cooke RW: Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88:F6–10. Review S. Olyntho & F. Trigo Attending Physician Sírio Libanês Hospital Blood Bank São Paulo Brazil

S. Wendel Medical Director Sírio Libanês Hospital Blood Bank São Paulo Brazil E-mail: [email protected]

Y. Lin & H. Hume

We are answering on behalf of the Canadian Blood Services, the sole blood provider for all Canadian provinces and territories with the exception of Québec. As we are a supplier, we conducted a survey of five major neonatal centres across Canada accounting for over 6000 neonates admitted to NICU annually, to enhance our contribution to this international forum. In Canada, the term ‘neonate’ when used in the field of transfusion medicine refers to an infant less than 4 months of age. Question 1 No additional safety measures are specified for blood components for neonates with respect to donor selection, microbiological screening or other donation testing. However, all cellular blood components supplied by Canadian Blood Services have been leucoreduced since January 1999. Although we have continued CMV screening in the era of universal pre-storage leucoreduction, recommendations from the Canadian Consensus Conference on prevention of post-transfusion CMV did not recommend providing CMV seronegative products in addition to leucoreduction for neonates [1]. In practice, four

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of the five neonatal centres do routinely provide CMV seronegative leucoreduced products to neonates admitted to the NICU; one institution restricts use to neonates undergoing stem cell transplantation or in the setting of a CMV seronegative donor for solid organ transplantation. Question 2 We do not have national irradiation guidelines for neonatal transfusion. However, Canadian Blood Services has published recommendations for neonatal transfusion practice in the Canadian Blood Services’ Clinical Guide to Transfusion [2]. Recommended indications for γ-irradiation of cellular blood components include IUT, neonatal exchange transfusion, neonatal ECMO, low birth weight infants (< 1250 g), granulocyte transfusion, patients with congenital immunodeficiency syndromes, haematopoietic or solid organ transplant recipients, patients with Hodgkin’s disease, other patients undergoing chemotherapy or radiotherapy, transfusions of donations from a biologic relative and of HLA-matched blood components. In practice, four of the five neonatal centres surveyed routinely use γ-irradiated cellular products for neonates with the remaining centre using γ-irradiated cellular products in selected indications similar to those stated above. Question 3 At the present time, no pathogen-inactivated blood components are supplied by the Canadian Blood Services to hospitals for neonates (or any other patients) and hospitals do not obtain alternative pathogen-inactivated components directly from commercial sources. Question 4 Splits from a dedicated RBC donor unit are routinely used in our hospitals to reduce donor exposure. Splits are produced using methods such as paedipacks attached to the original donation, transfer packs via a sterile docking device and syringes. Generally, three to four splits are produced though as many as eight splits may be derived from one donation. There are no data on implementation of paedipacks in hospitals, but these have been widely used for many years in Canada. Question 5 We do not have national recommendations for the use of additive solutions in large volume transfusions. The Clinical Guide to Transfusion suggests that for massive transfusions (including cardiopulmonary bypass, exchange transfusion and ECMO), neonates should receive blood products collected into CPDA-1 or that have had additive solution removed and the RBCs resuspended in an appropriate medium such as saline [2]. However, with the Canadian Blood Services’ transition to the buffy-coat method, blood collected into CPDA-1 will no longer be available. All surveyed hospitals routinely removed additive solution for large volume trans-

fusion. For exchange transfusion, all hospitals used FFP as replacement fluid. For cardiopulmonary bypass and ECMO, there was variation in replacement with the use of no replacement fluid, saline, albumin, FFP or frozen plasma. Question 6 No specific Hct for reconstituted blood is recommended for neonatal exchange transfusion in the Clinical Guide to Transfusion [2]. Whole blood is not supplied for neonatal exchange transfusion or any other indication in neonates (or any other patients). Two of the five surveyed hospitals used hyperconcentrated RBCs with an Hct target of 0·70–0·80 l/l for neonatal small volume transfusion; the other three centres did not. Question 7 Directed donations at Canadian Blood Services are permitted from parent to child only. Only RBCs are routinely prepared from directed donations unless a specific request is made for plasma or platelets. However, with the introduction of the use of plasma components from predominantly male donors (as a transfusion-related acute lung injury risk-reduction measure), plasma from maternal directed donations is no longer used and platelets from maternal directed donations would only be used if there was a specific medical indication. The use of directed donations for neonatal transfusions in Canada is quite variable across the country; for example, in 2007, one Canadian Blood Services centre collected over 60 directed donations for neonates compared to only one such collection at another centre of similar size. Question 8 The survey of five major neonatal centres across Canada encompassed over 6000 neonatal admissions to NICU per year. Four centres reported neonatal transfusion rates of 9–23%. The range of neonatal transfusion rates for each of the components were: RBCs 7–23%, platelets 2·8–7·7% and plasma 1·4–4·6%. Question 9 The following recommendations were adapted from other published guidelines [3,4] and are provided by the Canadian Blood Services’ Clinical Guide to Transfusion [2]. For neonatal RBC transfusions, the recommendations are [2,3]: • Hb < 70 g/l with low reticulocyte count and symptoms of anaemia; • Hb < 100 g/l in an infant with one of the following: on < 35% O2; on continuous positive airway pressure (CPAP) and/or mechanical ventilation with mean airway pressure < 6 cm H2O; with significant apnoea or bradycardia; with significant tachycardia or tachypnea; with low weight gain; • Hb < 120 g/l in an infant with one of the following: on > 35% O2, on CPAP/intermittent mandatory ventilation with mean airway pressure ≥ 6–8 cm H2O; and

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• Hb < 150 g/l in an infant on ECMO or with congenital cyanotic heart disease. For neonatal platelet transfusion, the recommendations are [2,4]: • platelet transfusion thresholds for bleeding prophylaxis: stable term neonates with platelet counts < 20 × 109/l; stable premature neonates with platelet counts < 30 × 109/l; sick premature neonates with platelet counts < 50 × 109/l; preparation for invasive procedures or minor surgery with platelet counts < 50 × 109/l; and for major surgery, < 100 × 109/l; and • platelet transfusion thresholds for clinically significant bleeding: neonates with platelet counts < 50 × 109/l; neonates with conditions that enhance the risk of bleeding (e.g. disseminated intravascular coagulation or other significant coagulopathy) and platelet counts < 100 × 109/l; neonates with documented significant platelet functional disorders irrespective of circulating platelet count. For neonatal plasma transfusion, recommendations are similar to those in adults with the primary indication being the correction of bleeding due to multiple acquired coagulation factor deficiencies. In practice, three of five surveyed hospitals had their own specific guidelines for neonatal RBC, platelet and plasma transfusions. Although generally in keeping with the above recommendations, any discrepancies in transfusion thresholds were more liberal in the hospital guidelines. Question 10 No data are available from multicentred audits on neonatal RBC transfusion triggers being used. Question 11 We do not have a national guideline for administration of blood specific for neonates. Question 12 We have a national haemovigilance system, the Transfusion Transmitted Injury Surveillance System [5], that captures serious adverse transfusion reactions. Although neonatal and paediatric reactions are not reported separately, these reactions can be easily extracted as the age of the recipient is reported. Question 13 No specific national measures have been implemented to reduce errors in patient identification for neonates, nor has a national numbering scheme been considered. Question 14 In our survey, four of the five hospitals used EPO for premature neonates only in the situation of a Jehovah’s Witness recipient. The remaining hospital reported never using EPO.

Question 15 We do recommend the use of IVIG to reduce exchange transfusion for haemolytic disease of the newborn with established jaundice [6]. In the survey, all five hospitals recommended IVIG in this setting; IVIG was routinely used at four hospitals and inconsistently used at the remaining one.

Acknowledgements We acknowledge the important contributions of the five Canadian neonatal centres who participated in the survey for this forum: BC Children’s Hospital, Vancouver; Capital Health Transfusion Services, Edmonton; The Hospital for Sick Children, Toronto; Children’s Hospital of Eastern Ontario, Ottawa; and IWK Health Centre, Halifax.

References 1 Laupacis A, Brown J, Costello B, Delage G, Freedman J, Hume H, King S, Kleinman S, Mazzulli T, Wells G: Prevention of posttransfusion CMV in the era of universal WBC reduction: a consensus statement. Transfusion 2001; 41:560–569 2 Webert K, Hume H: Neonatal and pediatric transfusion practice; in: Clarke G, Blajchman M (eds): Clinical Guide to Transfusion, 4th edn. Toronto Canada, Canadian Blood Services, 2007:124–139; available at: http://209.217.107.132/Web/tmws.nsf/resources/ CBC_CGT/$file/CBS-CGT-BM.pdf 3 Roseff SD, Luban NLC, Manno CS: Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 2002; 42:1398 –1413 4 Blanchette VS, Rand M, Carcao MD, Hume H: Platelet transfusion therapy in infants and children; in: Kickler T, Herman JH (eds). Current Issues in Platelet Transfusion Therapy and Platelet Alloimmunity. Bethesda, MD, AABB Press, 1999 5 Public Health Agency of Canada: Transfusion Transmitted Injury Surveillance System; available at: http://www.phac-aspc.gc.ca/ hcai-iamss/tti-it/index.html 6 Anderson D, Ali K, Blanchette V, Brouwers M, Couban S, Radmoor P, Huebsch L, Hume H, McLeod A, Meyer R, Moltzan C, Nahirniak S, Nantel S, Pineo G, Rock G: Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev 2007; 21(2 Suppl 1):S9–56

Y. Lin Transfusion Medicine Resident University of Toronto 1 King’s College Circle Ontario Canada M5S 1A8 and Canadian Blood Services 1800 Alta Vista Drive Ottawa Ontario Canada K1G 4J5

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H. Hume Executive Medical Director Transfusion Medicine Canadian Blood Services 1800 Alta Vista Drive Ottawa, Ontario Canada K1G 4J5 E-mail: [email protected]

J. Petäjä & T. Krusius

In Finland, neonates are transfused with paediatric RBCs (leucodepleted RBCs in saline–adenine–glucose–mannitol (SAGM) solution and divided in doses of 100 ml), reconstituted blood, volume-reduced platelets suspended in PAS solution and SD virus-inactivated FFP. Reconstituted blood is prepared from less than 5 days old leucodepleted RBCs by replacing SAGM with SD virus-inactivated FFP. Reconstituted blood should be transfused in 24 h after production. As fresh as possible paediatric RBCs (maximum age 14 days) are selected for γ-irradiation. Irradiated RBCs can be transfused up to 48 h from irradiation. Unless indicated otherwise, the answers below describe the practice at Helsinki University Central Hospital providing NICU services for one-third of all newborns in Finland. Finland does not have national guidelines for neonatal transfusions, and evidently based on national low birth weight and extremely low birth weight infant registry data, the transfusion triggers vary substantially between the five university hospital districts. Question 1 In Finland, there are no additional donor selection or testing requirements for blood components intended for neonatal transfusions. All blood components are pre-storage leucodepleted. Donor anti-CMV testing is not performed. All donations are screened for hepatitis B and C virus and HIV by nucleic acid amplification technique using single samples. Question 2 Cellular blood components are irradiated for IUT and for infants in the first week of life when the birth weight is below 1500 g or the infant is born before 28 weeks of gestation. Other indications for irradiation including exchange transfusion depend on case and institute specific judgement. Question 3 Only SD-treated FFP is available in Finland and neonates are also transfused with SD-treated FFP. RBC or PCs are not pathogen inactivated. Question 4 One leucodepleted RBC component is divided into three 100-ml paediatric bags, which are provided to one patient. It is a nationwide and effectively implemented practice to transfuse

all three paedipacks to one neonate, if it is needed to reduce donor exposure. Saving blood may override the donor exposure aspect, that is, the reservation of all three subunits for one individual patient may be broken and a subunit may be transfused to a second patient. Question 5 Major surgery and exchange transfusions of neonates are performed with reconstituted blood that is produced by replacing SAGM solution by SD-treated FFP. Question 6 For neonatal exchange transfusion, no patient-specific Hct target is being used. The Hct of reconstituted blood is 0·40–0·50. Question 7 Directed donations are not provided. Question 8 Concerning the year 2007 at Helsinki Central University Hospital, we had 541 admissions to the NICU and 637 units of RBCs, 551 units of FFP and 90 PCs were consumed. Usage of blood components in neonates in Finland 2007 are as follows (the results are given per 1 000 000 inhabitants): • reconstituted blood (or irradiated) 114 • paediatric RBCs, three paedipacks of 100 ml (or irradiated) 271 • volume-reduced platelets (or irradiated) 114 Question 9 Red blood cell triggers have been defined and implemented. They are based on the Hb level, postnatal age and respiratory support. They take into consideration whether the sample is arterial or capillary (capillary Hb is about 15 % higher than arterial). The following triggers are for arterial samples: • Hb < 123 g/l for age 1–7 days, respirator or CPAP; • Hb < 109 g/l for age 1–7 days but no respirator or CPAP; • Hb < 110 g/l for age 8–14 days, respirator or CPAP; • Hb < 91 g/l for age 8–14 days but no respirator or CPAP; • Hb < 91 g/l for age at least 15 days and on respirator or CPAP; and • Hb < 78 g/l for age at least 15 days but no respirator or CPAP. Platelet triggers are: • platelet count < 20 × 109/l for all neonates; • platelet count < 50 × 109/l for neonates undergoing intensive care; • platelet count < 50 × 109/l for neonates who have bleeding (including intraventricular haemorrhages) or who are undergoing an invasive procedure. For FFP, no strictly defined criteria for transfusion; loose guidelines based on prothrombin time and comorbidities. Sepsis, necrotizing enterocolitis and subclinical (laboratory signs of ) diffuse intravascular coagulopathy result in liberal

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use of FFP. Neonates are actively analysed for platelet count, prothrombin time, D-dimer and antithrombin for the laboratory diagnostics of neonatal coagulopathy. Active effort is currently being taken to better define indications for FFP use and, hopefully, to reduce plasma transfusions. Question 10 No data are available from multicentred audits on neonatal RBC transfusion triggers being used. Question 11 In Finland, there are no national guidelines for transfusions of neonates. Hospitals may have their own guidelines. Question 12 Reports on adverse reactions and events are collected in one national haemovigilance system. There is no separate system for neonates. During the last 3 years, annually one report on adverse reaction or event in neonates has been submitted. Question 13 Every Finnish citizen, also neonates, has an individual social security number that is used also in the hospital for identification of the patient. The name and social security number (also bar coded) is printed on the wrist band of each patient. Question 14 Erythropoietin use is not encouraged. The prerequisite is that enteral feeding has been established allowing enteral iron supplementation; intravenous iron is not being used. We have only used EPO in selected cases of religious contraindications for blood products. Question 15 Intravenous immunoglobulin was chosen to be the first line therapy for postnatal care for haemolytic disease of the newborn more than 1 year ago. During the past 12 months, not a single exchange transfusion has been carried out because of immune haemolysis, which contrasts with the previously typical 10 to 20 exchange transfusions in Helsinki annually. However, several late (few weeks to 2 months after discharge) RBC transfusions have been given to these infants, which typically was not the case previously when we favoured exchange transfusions. Consequently, the impact of IVIG to reduce donor exposure remains to be demonstrated. J. Petäjä Head of Neonatology Section Department of Pediatrics Jorvi Hospital Helsinki University Central Hospital Espoo Finland E-mail:[email protected]

T. Krusius Medical Director Finnish Red Cross Blood Service Kivihaantie 7 Helsinki Finland E-mail:[email protected]

S. Villa & S. Ghirardello

Question 1 Blood components for neonates are selected among repeat donors (defined by current Italian law as donors who donated blood at last three times in the last 2 years). In addition, we select RBCs less than 5 days old, and in order to reduce the risk of transmission of CMV infections, all cellular blood components are leucodepleted before storage. Red blood cells are usually split in 4–5 aliquots. In agreement with our NICU, the same donation may be assigned to different neonates, as freshness of blood is regarded as having higher priority than the reduction of donor exposure. Question 2 Our guidelines for irradiation, in line with recent national recommendations [1], are as follows: • irradiation dose – 30 Gy; • clinical indications – RBC and PCs for transfusion in neonates weighing ≤ 1500 g at birth and/or with gestational age ≤ 30 weeks or in neonates who have congenital or acquired immunodeficiency, for IUTs, for exchange transfusions in critical neonates or in patients who underwent IUT. In addition, as for adults, we irradiate blood donated by first and second degree relatives, or HLA-compatible donors. Our procedure requires that irradiation should be performed no more than 24 h before transfusion. However, in most cases, irradiation is performed 1–2 h before release of the unit. Data derived from the only multicenter audit [2] performed in 111 NICUs in Italy during 2001–2004 (before publication of national guidelines) showed that 32·7% of the NICUs always irradiate RBCs, while 28·2% irradiate only in selected conditions, including congenital or acquired immunodeficiency, severe prematurity and donations from relatives, and 39·1% never irradiate blood units. Question 3 No. Question 4 Additional data from the above multicenter audit showed that 25% of the NICUs do not aliquot single RBC units to reduce donor exposure, while this is done occasionally by 22% of the NICUs. In most cases, 4–5 aliquots are prepared from each unit.

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Question 5 For large-volume RBCs transfusion, the national guidelines, jointly published by the Italian Blood Transfusion Society and the Italian Society of Neonatology [1], recommend the use of reconstituted whole blood cell. The RBCs used must be fresh (within 5 days of collection), they must have had any additives or conservants removed before reconstitution, and they must be leucodepleted. As far as plasma is concerned, when it is possible to use blood of the same blood group, it is preferable to use the plasma from the same unit of blood from which the RBCs were obtained; otherwise, group AB plasma from another donor is used. The final product must have Hct between 0·40 and 0·60 for total exchange transfusion and 0·80 for partial exchange transfusion, be irradiated (when indicated) and transfused within 24 h of production (if produced in an open circuit) or, in any case, within 48 h of irradiation.

Platelet transfusion is recommended when the platelet count falls below 30 000/μl in all cases; in newborns with birth weight less than 1000 g in the first week of life or with third–fourth degree of severe intraventricular haemorrhage, in critically ill patients and in those undergoing invasive procedures, a platelet count higher than 50 000/μl should be maintained. In patients with active bleeding, platelet transfusion is recommended when the platelet count falls below 100 000/μl. Fresh-frozen plasma is recommended in disseminate intravascular coagulation associated to active bleeding, laboratory evidence of severe coagulopathy associated to augmented risk of bleeding and congenital coagulation factors deficiency when specific commercial factors are not available.

Question 6 See Question 5. In addition, we do not supply whole blood for this or other indication for neonates. For top-up transfusion, we use routine RBCs with an Hct between 0·60 and 0·65 [1].

Question 12 No.

Question 7 We do not recommend directed donation, although it may become necessary in particular cases of alloimmunization. As stated above, we irradiate all units collected from directed donations. Question 8 The national audit showed low mean RBCs transfusion requirements among newborns with birth weight between 1000 and 1500 g and with birth weight less than 1000 g: they were 0·8 (standard deviation 0·7) and 2·4 (standard deviation 1·2) units, respectively. This audit showed that four factors influence the number of RBC units transfused in the neonatal period, in order of importance: RBC Hct, volume of blood samples collected in the first 2 weeks, infectious episodes and duration of oxygen requirement. Questions 9 and 10 Recommendations on neonatal transfusion practice that were recently published by the Italian Society of Neonatology [1] and were based on experts’ opinions and data from international literature [3] stated the following: RBCs transfusion triggers vary according to mechanical ventilation, O2 supplementation, Hct and clinical conditions. RBCs transfusion is recommended in mechanically ventilated babies or with 0·4 fraction inspired oxygen requirement to maintain Hct higher than 40%. Spontaneous air-breathing newborns should be transfused with Hct lower than 25–35%, depending on age (less than 15 days old, between 15 and 28, and more than 28).

Question 11 No.

Question 13 In our unit, the whole process of hospitalization is managed through NeoCare® (Informatica e Tecnologia s.r.l., Bari, Italy), a software that allows patient management from admission to discharge. Information concerning ventilator parameters and clinical data is automatically registered and integrated with parameters manually entered by staff. Therapies are prescribed by medical staff and administered after automatic recognition of the patient’s ID barcode, generated by the NeoCare system. Connection to the database used by blood transfusion services region-wide (EmoNet, Insiel S.p.A., Trieste, Italy) is in progress. Questions 14 and 15 Erythropoietin utilization is very heterogeneous [4]. Some NICUs do not prescribe EPO in the neonatal period; our internal protocol provides for 18 doses (250 UI/Kg three times a week for 6 weeks) of subcutaneous EPO for asymptomatic newborns after the first 2 weeks of life, together with iron and folate when necessary, if never transfused and with a Hb concentration and Hct slightly above the 3rd percentile for age; below this level a transfusion is always given. We utilize IVIG (0·5–1 g/dl in 2 h infusion) in patients with haemolytic disease when serum bilirubin level rises despite intensive phototherapy or when total serum bilirubin level is within 2–3 mg/dl of that requiring exchange transfusion, in line with recent international guidelines [5].

References 1 Società Italiana di Medicina Trasfusionale e Immunoematologia (SIMTI) e Società Italiana di Neonatologia (SIN): Recommendations on transfusion therapy in Neonatology. Blood Transfus 2006; 4:158–180

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2 Radicioni M, Mezzetti D, Lungarotti MS: La pratica trasfusionale in età neonatale: indagine multicentrica fra i centri di Terapia Intensiva (TIN) e Patologia Neonatale italiani (2001–2004). I Congresso Nazionale del Gruppo di Ematologia Neonatale. Amalfi, December 2004. 3 British Committee for Standards in Haematology: Transfusion guidelines for neonates and older children. Br J Haematol 2004; 124:433–453 4 Obladen M, Diepold K, Maier RF; and the European Multicenter rhEPO Study Group: Venous and arterial hematologic profiles of very low birth weight infants. Pediatrics 2000; 106:707–711 5 American Academy of Pediatrics: Management of hyperbilirubinemia in the newborn infant more than 35 or more weeks of gestation. Pediatrics 2004; 114: 297–313 S. Villa Centro Trasfusionale e di Immunoematologia Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena Via Francesco Sforza, 35 Milan Italy E-mail: [email protected] S. Ghirardello NICU and Institute of Pediatrics and Neonatology University of Milan Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena Via Commenda, 2 Milan Italy E-mail: [email protected]

J. von Lindern & A. Brand

In the Netherlands, neonatal care is concentrated in 10 NICUs and fetal transfusion therapy is concentrated in one national centre. The yearly birth rate is almost 200 000; approximately 3000 infants are born after a gestational age < 32 weeks. In the Netherlands, all RBCs and PC transfusions are prestorage leucoreduced by filtration. Additional CMV testing of donors is not applied, except for IUTs. Mandatory screening includes genome amplification tests for hepatitis C and B virus and HIV 1/2/0 and antibody assays for lues, hepatitis B virus and HTLV 1/2. In 2004, a Dutch consensus report appeared describing the indications and product advices for different patient populations [1]. Questions 1–7 For all blood products, RBCs, PCs and plasma (FFP) intended for transfusions to neonates, general safety measurements in addition to standard mandatory requirements are: • blood groups compatible with the child and maternal antibodies;

• RBC compatibility testing with maternal serum; • avoidance of passive transfer of alloantibodies against RBC and leucocytes; • preferential avoidance of parvovirus B19 transmission; • long erythrocyte and platelet survival; • prevention of transfusion-associated graft-versus-host disease; • devoid of substances possibly toxic for the neonate; • adequate temperature avoiding cold exposure; and • limitation of donor exposure. For all products, donors are selected with repeat neutralizing immunoglobulin G (IgG) antibodies against parvovirus B19. In cases RBC transfusion volumes exceed 80 ml/kg (e.g. exchange transfusions, ECMO or surgery), a storage interval of less than 5 days after withdrawal, providing higher 2,3-bisphosphoglycerate levels, is advised. The supernatant (avoiding high potassium) is removed and replaced by FFP of blood group AB (fulfilling criteria mentioned below) to an Hct of 0·45 l/l. For top-up transfusions, donor exposure must be weighted against better RBC survival. RBCs from a single donor (four paedipacks) stored up to 35 days are recommended. Although paedipacks are routinely ordered for neonates, we have no data whether the intention (reservation for one or two infants) is really executed in our country and information on the number of donors neonates are exposed to is lacking. For top-up transfusions, we currently use the same Hct of 0·58 + 0·05 l/l as for all RBC products. As transfusion volumes for preterm infants range from 10–20 ml/kg, corresponding with 2–4 units for an adult patient, a higher Hct of 0·80 l/l may be desirable to reduce the volume. Unfortunately, the relation between transfusion dose and cardiovascular stress of RBC transfusions in neonates has hardly been investigated [2]. For infants born after less than 32 weeks of gestational age and/or weighing less than 1500 g at birth, the national consensus guideline recommends irradiating cellular components with 25 Gy; after irradiation RBC transfusion must be accomplished within 24 h. For PC and FFP products, we use selected donors without a previous history of pregnancy and/or transfusions, with a low (< 1/32) titre of anti-A and/or -B and without irregular RBC antibodies, including anti-Wra, to achieve a lower likelihood of causing transfusion-related acute lung injury. For neonates suspected for neonatal alloimmune thrombocytopaenia, there is always at least one HPA-1aneg/5bneg PC in stock in one of the four Dutch Blood Banks available for mutual exchange. Our national blood supply only delivers quarantine FFP. For neonates AB plasma, fulfilling aforementioned safety criteria, is divided into smaller volumes (75 ml) as paedipacks. Only pathogen-inactivated products from pooled plasma are currently commercially available, but are not recommended for incidental transfusions to newborns. Pathogen-inactivated single donor products will be advantageous for neonates, because, depending on the season, donor viraemia with

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respiratory and gastrointestinal viruses is likely to occur and may harm very preterm infants. However, because RBC transfusions are the dominant type of blood products needed by preterm infants, the availability of pathogen-inactivated FFP would be a moderate gain. If pooled blood products are indicated, for example, IVIG, these require a pathogeninactivation step. Directed donations are only allowed for medical indications, for example, maternal products, if the mother has IgG antibodies against a public RBC antigen or against a platelet (non-HPA-1a and/or 5b) antigen and if an indication for granulocyte transfusions could arise. Question 8 Yearly ca. 3000 infants are born after a gestational age of less than 32 weeks. In 2006, we evaluated transfusion practice in two of the 10 NICUs, using the same national guideline of Hb triggers for neonates. Approximately 50% of preterm infants received RBC transfusions. More than 90% of the infants born after a gestational period of less than 28 weeks and less than 20% of infants born after 30 weeks were transfused. Infants born between 28–30 weeks of gestation were transfused in 40 to 60%. Questions 9–10 National consensus recommendations for transfusion of RBC and PC are available [1]. These take days after birth, ventilatory support and supplemental oxygen need into account. In brief, < 24 h after birth the Hb trigger is 8 mmol/l in case of arrhythmia and respiratory insufficiency. In the first month after birth, beyond the first 24 h, a trigger of 6 mmol/l (Hct 29 l/l) is recommended for stable infants and after more than 4 weeks in uncomplicated conditions 4·5 mmol/l. In case of high-oxygen consumption above 40% or assisted ventilation, the Hb trigger is 8 mmol/l. For stable infants with cardiopulmonary abnormalities and oxygen use, a trigger of 7 mmol/l is advised. The recommended prophylactic platelet transfusions trigger is 20 × 10E9/l the first month of life. In case of (suspicion of ) neonatal alloimmune thrombocytopaenia the trigger is 50 × 10E9/l because of the high risk of intracranial haemorrhage. In sick infants with a birth weight < 1500 g the trigger is also 50 × 10E9/l. For interventions, including exchange transfusions and surgery, prophylactic triggers range from 50– 100 × 10E9/l depending on the extent and localization of the intervention. In case of bleeding, the aim is to increase the platelet level above 50 × 10E9/l. For FFP transfusions, no specific indications for neonates are available and general indications are used. FFP is mainly used in case of exchange transfusions or surgery or severe diffuse intravascular coagulopathy and for rare inherited coagulation factor deficiency for which no recombinant or purified products are available.

Unfortunately, an audit of neonatal centres whether these transfusion triggers are appropriate has never been conducted. Questions 11–13 The NICUs use local transfusion protocols that are not publicly exchanged. Neither are there specific national instructions for reporting adverse events in neonates. The Dutch Transfusion Reactions in Patients registration agency relies, similar to the UK SHOT, on voluntary reporting and does not mention diagnosis or age in the periodical reports. Specific measures to reduce errors in neonatal transfusion are not available and a national numbering system has not been considered (yet). Questions 14–15 In our centre rHuEPO is not used, supported by Cochrane Reviews and the reported higher occurrence of retinopathy of prematurity associated with EPO [3]. As alternative for allogeneic transfusions, we evaluated the use of autologous cord blood RBCs. We could prepare autologous RBC products for only 27% of preterm infants who required transfusions at high costs [4]. Delayed cord clamping may be a better alternative [5]. However, in particular very low birth weight children with a low Apgar score, having the highest probability to be transfused, often need immediate clamping because of medical care. With respect to reduce postnatal haemolysis indicating exchange transfusions in alloimmune haemolytic anaemia by high dose immunoglobulin, we are currently performing a clinical trial to compare the effect of high dose IVIG with placebo on the number of exchange transfusions and top-up transfusions.

References 1 Dutch Consensus on Blood Transfusion (CBO) 2004. Het Zuiden: The Netherlands 2 Wong H, Connelly R, Day A, Flavin MP: A comparison of high and standard blood transfusion volumes in premature infants. Acta Paediatr 2005; 94:624– 625 3 Aher SM, Ohlsson A: Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; 3:CD004865 4 Khodabux CM, von Lindern JS, van Hilten JA, Scherjon S, Walther FJ, Brand A: A clinical study on the feasibility of autologous cord blood transfusion for aemia of prematurity. Transfusion 2008; 48:1634 –1643 5 Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W: Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial. Pediatrics 2006; 117:1235– 1242 J. von Lindern Department of Neonatology Leiden University Medical Centre (LUMC) Leiden the Netherlands

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A. Brand Sanquin Div South West and Transfusion Medicine LUMC Plesmanlaan 1a 2333 BZ the Netherlands E-mail: [email protected]

H. V. New & S. J. Stanworth

Question 1 Components for use in neonates are prepared from previously tested donors who have given at least one donation in the previous 2 years negative for the mandatory microbiological tests. The exception to this is FFP for neonates, as this is sourced from US male donors and methylene-blue treated (see Question 2 below), and it is not possible to maintain these supplies of FFP from second-time donors. RBCs and PCs are negative for CMV antibodies although leucodepleted components may be used if CMV antibody-negative components are not available (except in Northern Ireland). Components are screened for clinically significant blood group antibodies including high-titre anti-A and anti-B. RBC units for exchange transfusion are sickle negative in some parts of the UK and this, together with K-negativity, is extended to all neonatal RBCs in some regions. Platelets are collected from apheresis donations to reduce donor exposure.

Question 4 It is considered good practice to dedicate splits from a single donation of RBCs for neonates who are likely to be repeatedly transfused. The donation may be split into 4, 5, 6 or 8 aliquots, with regional variation. Hospitals vary as to their preference for number of splits and the way in which they allocate splits to neonates in order to reduce in donor exposure. There are no national data in the implementation of ‘paedipacks’ by hospitals. Some audits have suggested variable rates of successful uptake for these units, but others have confirmed significant regional reductions in donor exposure by ‘paedipack’ use.

Question 2 Irradiation is largely undertaken by the blood services and there should be little variation in practice throughout the country. For neonatal transfusion, national guidelines [1,2] specify that irradiation is essential for all RBCs and platelets where the neonate has had a prior IUT, or there is proven or suspected congenital T-cell immunodeficiency (not including HIV). For RBCs for exchange transfusion without prior IUT, there is variation between parts of the UK, from being mandatory in Northern Ireland to being for low birth weight babies only in Wales. In the rest of the UK, it is recommended for this indication.

Question 5 Red blood cells for neonatal cardiac surgery in the UK are either suspended in additive solution (SAGM) or in CPD anticoagulant (with adenine in Wales at present, but this will cease in future). Traditionally, there has been variation in choice of component by the paediatric cardiac centres although there is regional variation: in Scotland and Northern Ireland all blood for neonatal large volume transfusions apart from exchange transfusion is in SAGM. There is more plasma in the CPD as compared to the SAGM component (approximately 115 ml vs. 6 ml), and therefore, in view of the current UK concerns over transfusion transmission of vCJD, it is recommended that UK paediatric cardiac centres using CPD should switch to SAGM. This is also appropriate for other large-volume transfusions such as neonatal resuscitation or non-cardiac surgery. RBCs for neonatal exchange transfusion continue to be supplied in CPD (again currently with adenine in Wales), not SAGM, as it is not clear as to how far the evidence from cardiac surgery can be extrapolated to this situation. Additive solutions and plasma are not removed or replaced except in Northern Ireland. Here, for non-group O neonates, RBC units for exchange transfusion (group O) are resuspended in AB plasma or plasma of the baby’s blood group due to concerns over possible risks of haemolysis from the residual group O plasma in these units. The exception to this is a group A baby of a group A mother: in this situation group A RBCs in CPD are used.

Question 3 The UK blood services import all FFP for neonates (and children under 16 years) from US volunteer donors in order to reduce the risk of transfusion transmission of vCJD. Because of differing baseline level of infection risk in the USA than the UK, the imported single-donor FFP units are treated with methylene blue. Methylene blue cryoprecipitate from US donors is provided for neonates and children in Scotland and Northern Ireland, and in the near future this will also be extended to England. A small proportion of hospitals independently purchase SD-treated FFP from commercial sources for use in neonates.

Question 6 The general recommendations are for an Hct of 0·5–0·6. In England, RBCs for exchange are now being supplied with a narrower range Hct of 0·5–0·55 to help neonatologists exchange transfuse neonates to the appropriate Hct. This follows controversy as to whether whole blood (Hct 0·30–0·45) or packed cells are the optimal product, and some neonatologists are concerned about raising the baby’s Hct too rapidly by concentrates of higher Hct. Whole blood is not routinely supplied for neonatal transfusions, and it is not as consistent a product as RBC concentrates. We do not use hyperconcentrated RBCs for neonates.

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Question 7 Directed donations are discouraged, in view of uncertain benefits and potential disadvantages. A position statement by the National Blood Service (NBS), limits the possible indications (for both adults and children) that include: provision of maternal platelets in the unlikely situation that platelets from a suitable unrelated donor cannot be provided in neonatal alloimmune thrombocytopenia; provision of matched platelets for refractory patients where there is no other alternative; and provision of RBCs of very rare phenotype for a patient with antibodies. Question 8 We do not have any good data on component usage figures for neonates. Earlier studies of blood usage from the Northeast England and London and the South East focused on blood usage by component and in the surveys neonatal transfusion was not separated from paediatric transfusion. A populationbased epidemiological survey of transfused patients in 2004 indicated that 1·7% of RBCs were transfused to infants less than 12 months, most of which would be to neonates [3]. The NBS has now completed a national study of transfusion recipients (the EaSTR study – Epidemiology and Survival of Transfusion Recipients). RBC recipients (9142) were selected from blood bank records at 29 representative hospitals over a 12-month period (2001–2002). Of RBC recipients, 1·8% were aged less than 28 days at transfusion and this group received 90% of neonatal splits issued to study hospitals (AW Wells, personal communication). We have also recently undertaken a large prospective survey of thrombocytopaenia and platelet transfusions in neonates, and found that 122 out of the total of 3498 neonatal admissions received platelet transfusions, corresponding to a rate of 33/1000 admissions (SJ Stanworth, personal communication). Question 9 A national guideline for neonatal and paediatric transfusion [1] can be found at www.bcshguidelines.co.uk (see also the UK Blood Services Handbook of Transfusion Medicine [4]). These recommendations provide guidance on Hb thresholds for transfusion depending on the clinical situation, distinguishing between mechanical ventilation, oxygen dependency and late anaemia in stable neonates, with threshold Hb levels for transfusion defined as 12, 8–11, and 7 g/dl, respectively. Triggers for platelet transfusion are 20–30 × 109/l for well babies, and 50 × 109/l for those with risk factors including clinical instability and birth weight < 1000 g with age < 1 week. FFP may be given for neonates with a significant coagulopathy and risk of bleeding or imminent invasive procedure. There is awareness of the recent randomized control trials on neonatal RBC transfusion thresholds, although it is currently uncertain as to how the study results will impact on practice given the differences between them.

Question 10 There are no multicentred audits in the UK although many neonatal units have undertaken single centre audits. These single centre audits document evidence for a steady reduction in RBC transfusions, most of which remain top-up transfusions, and that some neonates continue to receive only single transfusions. Question 11 A national transfusion guideline exists for administration of blood to both neonates and older children [1], and further details are given in the UK Handbook of Transfusion Medicine [4]. Question 12 The Serious Hazards of Transfusion scheme is a UK-wide independent professionally led haemovigilance system that recently reviewed and published its paediatric results for 10 years after its inception [3]. During this time, it has analysed 3239 reports of transfusion safety events for all patient ages. The data indicated that 321 reports (10%) were related to transfusion of children under 18 years, and 147/3239 (4·5%) were related to infants less than 12 months of age. By using population-based epidemiological data on numbers of RBC transfusions, an incidence of adverse outcomes of 37 : 100 000 RBC units issued for infants less than 12 months is suggested, compared to 13 : 100 000 for adults – a disproportionately higher incidence of transfusion adverse events in infants compared to adults. Common problems include failure to meet special requirements, errors in the laboratory, wrong selection of group O FFP and platelets, and miscalculated prescriptions. There is an ongoing initiative to try and use the data from national haemovigilance as it relates to paediatric and neonatal practice in a better way, alongside improved definitions for some of the adverse events as related to neonates. Question 13 Few specific measures have been taken at a national level to reduce errors in patient identification for neonates, although this is a recurring theme at transfusion meetings. SHOT has produced some educational documentation specific to children and there have been some dedicated national paediatric transfusion educational days. There are plans for a national numbering system including for children and neonates. Question 14 The national guideline recommends against routine use of EPO in this group. Two indications may be: (i) preventing anaemia in infants who have received IUTs for alloantibodymediated anaemia; and (ii) a non-emergency situation where RBC transfusions are against the parent’s wishes and are not felt to be absolutely essential to save the life of the baby (e.g. preterm babies of Jehovah’s witnesses).

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Question 15 Recent guidance from the UK Department of Health states that IVIG may be used in selected cases of haemolytic disease of the newborn. In response to a recent questionnaire sent to tertiary level neonatal units, 25/38 had used IVIG to try to prevent exchange transfusion, suggesting that it may be a significant part of UK neonatal practice (G Ng, personal communication).

Acknowledgements We are grateful to colleagues within the UK blood services for their comments on this response, in particular, Sandra Gray, Joan Jones, Sheila MacLennan, Kieran Morris and Angus Wells. H. V. New Department of Paediatrics Imperial College Healthcare NHS Trust Praed Street London, W2 1NY UK E-mail: [email protected] S. J. Stanworth National Blood Service Haematology Level 2 John Radcliffe Hospital Osler Road Headington Oxford, OX3 9BQ UK E-mail: [email protected]

References 1 British Committee for Standards in Haematology: Transfusion guidelines for neonates and older children. Br J Haematol 2004; 124:433–453 2 British Committee for Standards in Haematology: Guidelines on gamma irradiation of blood components for the prevention of transfusion-associated graft-versus-host disease. Transfus Med 1996; 6:261–271 3 Stainsby D, Jones H, Wells AW, Gibson B, Cohen H; SHOT Steering Group: Adverse outcomes of blood transfusion in children: analysis of UK reports to the serious hazards of transfusion scheme 1996–2005. Br J Haematol 2008; 141:73–79 4 McClelland DBL (ed): Handbook of Transfusion Medicine, 4th edn. London, The Stationary Office, 2007; available at www. transfusionguidelines.org.uk/docs/pdfs/htm_edition-4_all-pages.pdf

J. E. Hendrickson & C. D. Josephson

Question 1 Yes, for neonates of 0–28 days of life, we transfuse leucoreduced ( CMV safe), irradiated cellular blood products. For neonates

weighing less than 1200 g, we transfuse CMV seronegative, irradiated cellular blood products. The platelets transfused at our institution (including to neonates) are apheresis-derived and cultured (via BacT/ALERT) to determine bacterial contamination prior to transfusion. Question 2 There are no national guidelines for irradiation in the USA. At our institution, all infants < 6 months old receive irradiated cellular blood products (primarily to prevent transfusionassociated graft-versus-host disease in infants with potentially undiagnosed immunodeficiencies). However, this practice varies between centres in the USA. We recently performed a survey of platelet transfusion practices among more than 1000 US neonatologists and found that 62% provide irradiated platelets for all neonates, 19% provide irradiated products only for neonates with specific indications, and 8% provide irradiated products only for very low birth weight neonates [1]. Question 3 No, we currently do not provide pathogen-inactivated/pathogenreduced blood products at our institution. SD-treated plasma is no longer available in the USA. All platelets transfused at our institution are apheresis-derived, and undergo culture to determine the presence of bacterial contamination. Question 4 Yes, we attempt to reduce donor exposure in our neonates. We assign 1 standard RBC unit to two neonates, and provide as many transfusions as possible from this single unit to minimize donor exposure. Sterile docking of the RBC units allows aliquots to be made (typically into a syringe for a neonate). The dedicated unit is utilized for 14 days (after collection) for cardiac neonates, and for up to 21 days for non-cardiac neonates. Typically, each unit provides 4–6 aliquots for transfusion, but this varies depending on the quantity requested per aliquot. This policy has been in place for years and we have no specific data on implementation. Question 5 There are no national recommendations with regards to additive solutions and neonates, although AABB has started the process to formulate guidelines. Given the large cardiac and ECMO populations at our institution, CPDA-1 units are utilized for neonates (to safely provide blood for potentially large volume transfusions). Leucoreduced, irradiated, haemoglobin S-negative units ≤ 5 days old are utilized for exchange transfusions and ECMO; leucoreduced, irradiated, haemoglobin S-negative units < 14 days old are utilized for cardiac patients. If the neonate is listed for heart transplant, washed ABO-compatible RBCs are provided (thus decreasing passive transfer of anti-A and anti-B and allowing for the possibility of ABO-incompatible

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heart transplantation). For neonatal exchange transfusions, the additive solution is replaced with FFP. For ECMO, 25% albumin, tris-hydroxymethyl aminomethane, bicarbonate, calcium gluconate and heparin are added to the CPDA-1 units.

survey of US and Canadian neonatologists [1]. At our institution, FFP is primarily used to correct coagulation disorders (prolonged prothrombin time and partial thromboplastin time), but there are no firm guidelines.

Question 6 Neonatal exchange transfusions are performed with CDPA-1 units as above, reconstituted to an Hct of 50% with FFP. Whole blood is not utilized at our institution. Hyperconcentrated RBCs are not typically utilized for top-off transfusions.

Question 10 The transfusion triggers utilized are extrapolated from existing literature; no multicentre audit data are available to our knowledge.

Question 7 Directed donations are allowed for neonates, with RBCs preferably collected in CPDA-1. If the RBCs are collected in AS-1, then washing is performed for large-volume transfusion (> 20 cc/kg). All directed donor units are irradiated. In cases of neonatal alloimmune thrombocytopaenia, washed, irradiated, maternal apheresis platelets (or offending antigen negative, irradiated products from apheresis donors) are utilized; paternal donations are not accepted. Question 8 Our institution has two campuses: one campus has a level III NICU and the other has a NICU composed solely of surgical patients. In the level III NICU (whose average census is 30 neonates), approximately 45 splits of FFP, 36 apheresis platelet splits, and 98 RBC splits are transfused monthly. Given 685 admissions to this NICU in 2007, approximately 778 splits of FFP, 631 apheresis platelet splits, and 1717 RBC splits were transfused per 1000 admits. These numbers exclude blood products supplied to neonates in the cardiac ICU or in the operating rooms. In the surgical NICU located on our other campus (whose average census is also 30 neonates), approximately 9 splits of FFP, 21 apheresis platelet splits and 64 RBC splits are transfused monthly. Given 444 admissions to this surgical NICU in 2007, approximately 240 splits of FFP, 570 apheresis splits and 1730 RBC splits were transfused per 1000 admits. Question 9 Conflicting data exist regarding optimal transfusion triggers in neonates [2–4]. In the USA, there are no national guidelines at present. At out institution, we have in place detailed guidelines for neonatal RBC transfusion. These guidelines take into account oxygenation status, ventilatory settings, circulatory/cardiac status, and other comorbidities. The transfusion trigger for healthy neonates is Hct < 20–22%, and the trigger for critically ill neonates is Hct 35–40%, with moderately ill neonates being transfused at an Hct of 28– 35%. A platelet transfusion trigger of 40 000 platelets/mm3 is typically used for neonates; again, this varies depending on the clinical situation and gestational age. Significant variability in platelet transfusion triggers was seen in our recent

Question 11 There are no national guidelines for administration of blood to neonates. Thus, institutional guidelines are utilized. Question 12 All transfusion reactions are reported to the paediatric blood bank, reviewed by the blood bank directors and discussed at Transfusion Committee Meetings at each hospital. Transfusionrelated deaths mandate national reporting to the Food and Drug Administration. The blood supplier and the Food and Drug Administration are notified in the case of septic transfusion reactions when the unit gram stain and/or culture is positive, as well as about potential transfusion-related acute lung injury cases. The Joint Commission for Accreditation of Healthcare Organization is notified for mistransfusions involving ABO-incompatibility and patient misidentification, which they define as a sentinel event. Question 13 A number of policies are in place to minimize transfusion errors in neonates. First, a nurse checks the patient’s chart to ensure a blood product was ordered and signs off on a blood product pick up slip. A runner then transports the pick up slip to the blood bank window. A check is performed at the blood bank window, with the patient’s name, medical record number, donor unit number and expiration date of the donor unit verified. Following transport to the NICU, two nurses at the bedside confirm the patient’s name and medical record number (on armband) and ensure that these match the name and medical record number on the donor unit. BloodLOC™, a mechanical barrier system that utilizes a three-letter code present only on the unique patient’s arm band, is being implemented at out institution for non-emergent RBC transfusion [5]. Question 14 Erythropoeitin is rarely used at our institution to decrease transfusions in premature infants, given the cost as well as the potential associated risk of retinopathy of prematurity. Question 15 With respect to haemolytic disease of the newborn, if the total serum bilirubin level is rising despite intensive phototherapy

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or is within 2 to 3 mg/dl of the recommended exchange level, IVIG is typically given in accordance with the American Academy of Pediatrics guidelines [6] (at 0·5–1 g/kg). The decision to exchange transfuse the neonate depends on the age of the neonate, the total bilirubin level, the rate of rise of the bilirubin, the Hb level and other clinical determinants. J. E. Hendrickson & C. D. Josephson Department of Pathology Children’s Healthcare of Atlanta 1405 Clifton Road, NE Atlanta GA 30322 USA E-mails: [email protected]; [email protected]

References 1 Josephson DC, Su LL, Christiansen RD, Hillyer CD, Castillego MI, Emory MR, Lin Y, Hume H, Easley K, Poterjoy B, Sola-Visner, M: Platelet transfusion practice among neonatologists in the U.S. and Canada: results of a survey. Pediatrics 2009; in press 2 Lacroix J, Hebert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, Joffe A, Biarent D, Meert K, Peters MJ for TRIPICU Investigators, Canadian Critical Care Trials Group, Pediatric Acute Lung Injury Sepsis Investigators Network: Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609–1619 3 Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, Peliowski A, Rios A, LaCorte M, Connelly R, Barrington K, Roberts RS: The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr 2006; 149:301– 307 4 Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, Gress GA, Johnson KJ, Kromer IJ, Zimmerman MB: Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics 2005; 115:1685–1691 5 Josephson CD LL, Carrie S, Polstra B, Castillejo M, Hillyer CD: Use of a mechanical barrier system for prevention of ABO-incompatible blood transfusions: logistics and efficacy in a pediatric environment. Transfusion 2007; 47(Suppl):113A 6 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation: clinical practice guideline. Pediatrics 2004; 114:297–316

R. G. Strauss

Question 1 Blood components transfused to neonates are collected, processed and issued according to AABB and Food and Drug Administration requirements mandated for patients of all ages, plus the following special safety measures for neonates/ infants.

First, all cellular blood components (RBCs and platelets) are pre-storage leucoreduced, primarily to reduce the risk of transfusion-transmitted CMV infections (reviewed in [1]). As an additional measure for possibly further reducing the risk of CMV, we do not select blood components from CMV seronegative donors for further leucoreduction for two reasons: (i) the superiority of this ‘double safety measure’ has never been demonstrated, may delay availability of needed transfusions while searching for blood components from seronegative donors that are additionally leucoreduced, and adds unjustified costs; and (ii) the selection of blood components from CMV seropositive donors for leucoreduction, actually, may be safer than CMV seronegative donors because of the presence of high concentrations of CMV viral particles in plasma during primary injection of seroconverting donors (i.e. window phase infections with large numbers of virus in plasma while still seronegative) – CMV virons that cannot be removed effectively by leucoreduction [2]. Second, ABO identical donors are ‘always’ used (i.e. except in extreme emergencies when group O platelets might be the only unit available) for platelet and plasma transfusions to avoid passive anti-A and/or anti-B. Question 2 As reviewed in [1], all cellular blood components are γ-irradiated for all infants during the first year of life. γ-irradiation is not required for blood components frozen without a cryoprotectant (e.g. plasma and cryoprecipitate). Clearly, irradiated cellular components are required for IUTs, exchange transfusions, infants with congenital and acquired disorders of severe cellular immunodeficiency, and transfusions of cellular components donated by blood relative donors. Although it is controversial whether all preterm neonates should be transfused with irradiated cellular blood components, simply because they are premature, most university/academic medical centres in the USA provide irradiated cellular components for a predetermined period of time to neonates/infants – ranging from the first 4 months of life (to correspond to pre-transfusioncompatibility testing standards) until a few years of age (e.g. until 1 year of age at the University of Iowa Hospitals and Clinics). This practice of ‘blanket’ irradiation for all neonates/infants/children until a predetermined age is intended to prevent transfusing unirradiated cellular blood components, inadvertently, to patients with congenital immunodeficiency diseases, in whom the diagnosis has been overlooked, because they are too young to exhibit classical diagnostic criteria. Question 3 Pathogen-inactivated products that are commercially available (i.e. approved for sale by Food and Drug Administration) are transfused to neonates (e.g. plasma derivatives such as clotting factor concentrates and immunoglobulins) – although,

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they often are prescribed for indications not FDA approved. Pathogen-inactivated blood components that are not FDA approved for sale (e.g. platelets and plasma treated with nuclei acid cross-linking systems) are transfused only in institutionally approved investigational settings for which parental informed consent is obtained. Question 4 As reviewed in references [1,3], for about 15 years, we have selected RBCs stored for up to 42 days in additive solutions (e.g. AS-1, AS-3 and AS-5) for small-volume transfusions (i.e. 15 ml/kg of infant weight when transfused). As rationale, several controlled clinical trials have established the efficacy, safety and cost-effectiveness of this practice in infants – including comparisons of pre-transfusion and post-transfusion laboratory test results, clinical end-points and post-transfusion circulating kinetics of biotinylated RBCs. Similar practices are widely established in the USA, although some physicians still insist on transfusing RBCs stored (often for no more than 1 week) in CPDA solutions – despite the fact that the superiority of CPDA over additive solutions for smallvolume transfusions has never been shown by controlled clinical trials. The number of ‘splits’ or aliquots removed from a dedicated RBC unit, obviously, varies with the size of the infant being transfused, the dose of RBCs prescribed for each transfusion and the total number of transfusions needed by the infant during the permitted storage time for the RBC unit. In our experience [1,3], by assigning one-half of a fresh RBC unit to each neonate/infant at the time of the infant’s first transfusion, 80% of infants receive all small-volume transfusions from 1 unit, and the remaining 20% from 2 units. Obviously, infants needing additional RBC transfusions for surgery, exchange transfusions or ECMO will be exposed to more donors. Question 5 I am not aware of ‘national’ recommendations in the USA for use of RBCs stored in additive solutions for large-volume transfusions. However, because the safety of large doses of additives in infants is unknown – particularly, if recirculated multiple times through the infant’s body as during extracorporeal procedures – it is common practice to remove the additive solution by washing the RBCs or by centrifugation to concentrate the RBCs followed by removal of the supernatant, when entire units of RBCs are to be transfused. It is unnecessary to add fluids to the washed/centrifuged RBCs when they are being combined with other fluids in an extracorporeal circuit. However, it is customary to resuspend RBCs in plasma (i.e. to prepare a unit of reconstituted whole blood) before performing an exchange transfusion. Ideally, the unit of plasma should be from the same donation processed to prepare the RBC unit.

Question 6 For exchange transfusions, we use compatible RBCs from the freshest unit available that is negative for sickle Hb and has been leucoreduced, γ-irradiated, washed and resuspended in compatible plasma (if possible, plasma from the same donation from which the unit of RBCs was prepared) to an Hct of 40–45% and volume of 370 to 400 ml. Similar units of RBCs are prepared for IUTs, except that the final Hct is adjusted to 70%. For small-volume (i.e. top-up) transfusions (15 ml/kg infant weight when transfused), we centrifuge/pack RBCs to an Hct of ≈ 80 to 85% to ensure a consistent dose of RBCs for all transfusions [1,3]. This results in a predictable increase in Hct values (i.e. a mean of 12 Hct percentage points) and, although not required for safety, centrifugation does remove some of the additive solution. Question 7 With one exception, we do not allow directed donations, because the safety of ‘standard blood centre’ donors has been reported by several investigators to be superior to donors chosen by the family, when based on infectious disease test results. In addition, parents of the neonate may pose particular risks. First, maternal plasma often contains antibodies to leucocyte antigens inherited by the neonate from the father (i.e. risk of transfusion-related lung injury mediated by antibodies in blood components from the mother transfused to an infant with leucocytes expressing antigens able to react with passively acquired maternal antibody). This may be especially problematic in infants who already have underlying pulmonary problems. Second, paternal RBCs and leucocytes may express antigens that, when transfused to the infant, may react with maternal antibodies that have been transported across the placenta to the neonate – antibodies for which pre-transfusion compatibility testing is not always performed (e.g. antibodies directed against leucocyte antigens and/or rare ‘private’ RBC antigens). As the one exception, directed donors are accepted when multiple RBC transfusions are anticipated (e.g. surgery) and when one donor can supply all RBC units that might be needed. In this setting, the possible risks of directed donors are offset by reducing the expected exposure to multiple allogeneic donors to only one directed donor. The methods (e.g. donating multiple units in a short period of time), feasibility and success of this ‘single/limited donor program’ have been reported [4]. Question 8 Data from the University of Iowa Hospitals and Clinics are as follows (unpublished data from Dr John Widness). From 2000 through 2006, a total of 12 336 neonates/infants were studied. Of infants with birth weight < 1000 g, 88% were transfused with one or more blood components. Of infants with birth weight < 1000 g, RBCs were transfused to 87% of infants

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(6·3 transfusions per transfused infant); platelets to 35% of infants (4·0 transfusions per transfused infant); plasma to 19% of infants (2·0 transfusions per transfused infant); cryoprecipitate to 12% of infants (1·2 transfusions per transfused infant). In contrast, only 9% of infants with birth weight between 1500 and 2500 g were transfused with any blood component, and only 3% of infants with birth weight > 2500 g were transfused, emphasizing the fact that need for transfusions is greatly influenced by birth weight. Granulocyte/neutrophil transfusions are no longer transfused for neonatal sepsis at our centre. Data from a multicenter ‘regional’ reports are somewhat similar to ours, if one takes into account the broad range of infant birth weights [5]. Of 1759 neonates/infants studied, 17% received RBCs (median number of transfusions per infant = 3), 4% received platelets (median number of transfusions per infant = 3), 6% received plasma (median number of transfusions per infant = 1) and 2% received cryoprecipitate (median number of transfusions per infant = 1). Question 9 I am not aware of official national or regional guidelines for neonatal blood component transfusions in the USA. However, many physicians consider the guidelines published in [3] for RBC and platelets to be reasonable practices. RBCs are transfused to maintain the Hct > 40 to 45% for severe cardiopulmonary diseases, > 30–35% for moderate cardiopulmonary disease, > 30–35% for major surgery or critical illnesses such as sepsis, > 20–25% for stable anaemia complicated by unexplained breathing disorders, tachycardia or poor growth. Although clinical trials have been performed to test whether lower pre-transfusion Hcts can be safely accepted, current data are controversial and do not establish the efficacy and safety of lower (i.e. restrictive) pre-transfusion Hcts over standard (i.e. liberal) transfusion guidelines (reviewed in [5]). Platelets are transfused to maintain the platelet count > 50 000 to 100 000/μl for significant bleeding, > 50 000/μl for invasive procedures such as surgery, > 20 000/μl prophylactically for clinically stable infants, and > 50 000/μl prophylactically for clinically unstable infants. Although occasional physicians transfuse to maintain the blood platelet count > 150 000/μl in high-risk situations, there are no data to support this practice of keeping the platelet count within the normal range [3]. Question 10 I know of no multicenter audit data that document how closely RBC transfusion guidelines are followed nationally in the USA. However, in an audit of regional practices, compliance to guidelines for neonatal/infant transfusions were 70% for RBCs, 69% of platelets, 65% for plasma and 94% for cryoprecipitate [5]. Notably, compliance was much worse if more than four transfusions were given. Results of transfu-

sion practices at the University of Iowa Hospitals and Clinics, generally, show adherence to local guidelines for ≈ 90 to 95% of transfusions ordered by the paediatric service. Question 11 I am not aware of a national/regional guideline in the USA for the transfusion of blood components specifically to neonates. However, many/most institutions have local guidelines. Question 12 I am not aware of any transfusion adverse event reporting system in the USA (i.e. national haemovigilance) that captures data for neonatal/paediatric transfusions. Question 13 The same systems that are in place to reduce errors of patient identification for patients of all ages at our hospital are applied to neonates. Because of their small body size, location in specialized beds/warmers and, often, extensive, instrumentation, special care is taken to adhere to all existing rules/ systems for collection of pre-transfusion-compatibility blood samples, testing in the blood bank, issuing of blood components and transfusion into the correct infant. I have not been involved in considerations for a national transfusion numbering scheme. Question 14 As reviewed in [6], rHuEPO is not used widely in the USA as a ‘routine’ standard of care for the treatment of the anaemia of prematurity. Although rHuEPO, when given in adequate dosage and with sufficient iron, will stimulate erythropoiesis in preterm infants, it has not been consistently successful in reducing RBC transfusions to a clinically significant degree. Thus, because transfusion reduction benefits are questionable, physicians have been unwilling to accept the possible risks [5] – regardless of how small they might be – except for special patients [e.g. small preterm neonates born of Jehovah’s Witness parents and neonates with anaemia and reticulocytopenia due to severe haemolytic anaemia of the fetus/ newborn due to anti-Rh(D)or anti-Kell]. Question 15 Although there is no written policy for the routine administration of IVIG at our centre, use of IVIG has been reported as therapy for haemolytic disease of the fetus/newborn for quite sometime and, recently, has had increasing popularity. Accordingly, our neonatologists usually prescribe one dose of IVIG, as 1·0 g/kg infant weight infused intravenously over 4 h, for infants with haemolytic disease due to anti-D. It is also given to some infants with haemolysis due to other antibodies directed against RBC antigens. However, this last practice varies among neonatologists and is always coupled with intensive phototherapy.

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Acknowledgement Supported in part by NIH Program Project Grant P01-HL46925 and Clinical Research Center Grant RR00059.

References 1 Strauss RG: Data-driven blood banking practices for neonatal RBC transfusions. Transfusion 2000; 40:1528–1540 2 Zieman M, Krueger S, Maier AB, Unmack A, Georg S, Henning H: High prevalence of cytomegalovirus DNA in plasma samples of blood donors in connection with seroconversion. Transfusion 2007; 47:1972–1983 3 Strauss RG: How I transfuse red blood cells and platelets to infants with the anemia and thrombocytopenia of prematurity. Transfusion 2008; 48:209–217 4 Strauss RG, Wieland MR, Randels MJ, Koerner TAW: Feasibility and success of a single-donor red cell program for pediatric elective surgery patients. Transfusion 1992; 32:747–749 5 Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA, Miner C, Wiedmeier SE, Burnett J, Eggert LD, Christensen RD: Adherence to NICU transfusion guidelines: data from a multihospital healthcare system. Journal of Perinatology 2008; 28:492–497 6 Strauss RG: Controversies in the management of the anemia of prematurity using single-donor red blood cell transfusions and/or recombinant human erythropoietin. Transfus Med Rev 2006; 20:34–44 R. G. Strauss Professor of Pathology & Pediatrics University of Iowa College of Medicine 200 Hawkins Drive C250 GH Iowa City IA 52242-1009 USA E-mail: [email protected]

N. L. C. Luban & W. Paul

Question 1 We perform lead testing on all donors and do not utilize blood units with blood leads of greater than 3 mcg/dl for neonatal recipients.

Number of patients transfused (%) Baseline 1 July–15 December 95 (n = 167) Microanalyser January 96–30 June 96 (n = 123) Transfusion practice 15 July–31 December 96 (n = 119)

Question 2 Cellular blood products intended for neonates of less than 1250 g are irradiated at issue with a cesium source blood irradiator at a dose designed to deliver 2500 cgy at the midplane of the canister. This methodology and dose has been validated in our laboratory [1,2]. Standards of the AABB (www.aabb.org) [3] and the Food and Drug Administration (www.fda.gov) support the dosing; many institutions irradiate and store products rather than irradiating at issue. Question 3 No pathogen-inactivation is as yet approved for use in the USA. Question 4 Many transfusion services use small volume splits to reduce exposure. At Children's National Medical Center, we produce as many as 25 splits (mean of 4) from a single unit for neonatal use. We implemented this process prior to 1982, and presented our findings as an SPR (Society for Pediatric Research) abstract and during lectures. Table 1 appended below. Question 5 There are no national recommendations on RBC additive solution. We have published the commentary on this topic [4]. Our institutional policy is to issue CPDA-1 or additive solution units for small-volume neonatal transfusions. For large-volume neonatal transfusions, we use CPDA-1 units. For neonatal cardiovascular surgery (CVS), we utilize the freshest units (less than 5 days) available in CPDA-1 or additive solution when CPDA-1 is not available. We do not wash or hand pack additive units. Question 6 For neonatal exchange transfusions, the Hct is determined based on the infant’s Hct and discussions between the neonatologist and transfusion medicine specialists. Whole blood is unavailable in our country; reconstituted CPDA-1 packed cells with plasma is usually provided for neonatal exchange with the Hct determined as delineated

Transfusions per patient transfused (mean ± SD day)

Donors per patient transfused (mean ± SD day)

66 (39·5)

4·9 ± 6·98

4·12 ± 5·48

46 (37·4)

5·20 ± 6·53

4·53 ± 5·19

40 (33·6)

5·62 ± 5·33

1·95 ± 1·32a

P < 0·05 for comparison between periods 2 and 3.

a

© 2008 The Author(s) Journal compilation © 2008 International Society of Blood Transfusion, Vox Sanguinis (2009) 96, 62–85

84 International Forum

above. For CVS surgery, additive RBCs are provided along with FFP that is used during the pump prime with an Hct determined by the CVS team. For neonatal ‘top-up’ transfusions, additive RBCs with an average Hct of 60% are used at a dose of 15 ml/kg/transfusion. Question 7 Directed donations are permitted but not encouraged. All directed donors must fulfill FDA-mandated donor criteria and testing. Any unit collected as a family directed donor of any degree is irradiated (see Question 2) and tagged for the exclusive use of that infant. Question 8 For fiscal year 2006, 327/726 neonatal admissions (45% or 450/1000) received transfusions. We prepared 1724 split RBC products for 327 neonates, averaging 5·3 splits per neonate. During fiscal year 2007, 333/813 neonatal admissions (41% or 410/1000) received transfusions. We prepared 2177 split RBC products for 333 neonates, averaging 6·5 splits per neonate. Note that our NICU is the major regional high-risk NICU specializing in ECMO and neonatal surgery. Question 9 We have established institutional guidelines that are based on published recommendations [5] and our own experience. These guidelines are in the process of revision based on new published data, but are as follows: Packed blood cells: • Hct ≤ 40–45% for neonates with congenital heart disease, persistent pulmonary hypertension, pre-ECMO/ECMO; • Hct ≤ 40% in the setting of acute blood loss with shock; • Hct ≤ 35% on CPAP or mechanical ventilation with pulmonary artery wedge pressure ≥ 6–8 cm H2O and/or receiving > 35% supplemental oxygen; • Hct ≤ 30% and any of the following: • receiving > 35% supplemental oxygen by hood/ CPAP/mechanical ventilation with pulmonary artery wedge pressure < 6 cm H2O; • increase in rate or severity of apnoea or bradycardia (> 10 episodes in 24 h or two episodes in 24 h requiring bag and mask ventilation while receiving therapeutic doses of methylxanthines); • Heart rate > 180/min or respiratory rate > 80/min persisting for 24 h; • weight gain < 10 g/day observed over 4 days while receiving > 100 Kcal/kg/day; and • undergoing surgery with general anaesthesia; • Hct 25–30% and receiving supplemental oxygen by nasal cannula; • Hct ≤ 20% and reticuloctye count < 4% in asymptomatic infant; and • ECMO pump prime.

Platelets: • platelet count < 20 000 in a stable term infant; • platelet count < 50 000: (i) in a sick term infant; (ii) in an infant requiring a minor invasive procedure; and (iii) patient at risk for intracranial or organ haemorrhage; • platelet count < 100 000: • platelet count 50–100 000 in a sick preterm infant; • in an infant requiring a major invasive procedure; • in diffuse intravascular coagulopathy as evidenced by clinical bleeding and either specific coagulation abnormalities or fibrin degradation products; and • patient on ECMO; • platelet count < 200 000, patient on ECMO, and bleeding or at risk for bleeding; • bleeding with an established qualitative platelet defect; • cardiopulmonary bypass surgery confirmed with Maximum Surgical Blood Ordering Schedule; and • cardiopulmonary bypass surgery with unexplained intra or immediate postoperative excessive bleeding. Fresh-frozen plasma: • specific quantitative factor deficiency of < 35% of normal, confirmed with age-related ‘normals’ for neonates for which a specific factor concentrate is not available; • diffuse intravascular coagulopathy and active bleeding with one of the following: (i) fibrinogen < 100 mg/dl; and (ii) fibrin degradation products present. • blood replacement in excess of two blood volumes; and • cardiopulmonary bypass surgery confirmed with Maximum Surgical Blood Ordering Schedule. Question 10 We do not have data from multicentre audits. Question 11 There are no national or regional guidelines for administration of blood products. Question 12 There is no national reporting system. However, the Department of Health and Human Services of the US Department of Health has agreed to establish an interagency working group on biovigilance (www.hhs.gov/bloodsafety/presentations). The charge of the group will be to develop strategies to improve safety for both transfusion and transplantation and will include both governmental and private sector representation. Included will be over 28 agencies who represent blood and tissue collection, licensing, regulatory, physician and consumer groups. Question 13 Specific measures to reduce errors in patient identification are included in the Joint Commission’s National Patient Safety Goal #1 ‘Improve the accuracy of patient identification’

© 2008 The Author(s) Journal compilation © 2008 International Society of Blood Transfusion, Vox Sanguinis (2009) 96, 62–85

International Forum 85

(www.jointcommission.org). It states: ‘Use at least two patient identifiers when providing care, treatment or services.’ We use a three part identifier for blood collection: name, medical record number and date of birth. At time of transfusion, a complex nursing protocol of identification and witnessing is used. Other institutions have implemented RFID systems but none are specific for neonates. Question 14 Erythropoietin is not used at our institution for neonates to avoid/limit/diminish transfusion. Question 15 IVIG is used as an adjunct in the treatment of haemolytic disease of the newborn. American Academy of Pediatrics Clinical Practice Guideline 7.1.4 recommends: ‘In alloimmune haemolytic disease, administration of intravenous gammaglobulin (0·5–1 g/kg over 2 hours) is recommended if TSB is rising despite intensive phototherapy or the total serum bilirubin level is within 2 to 3 mg/dL (34–51 μmol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours’ [6].

References 1 Pelszynski MM, Moroff G, Luban NLC, Taylor B, Quinones R: Effect of γ-irradiation of red blood cell units on T-cell inactivation as assessed by limiting dilution analysis: Implications for preventing transfusion-associated graft-versus-host disease. Blood 1994; 83:1683–1689 2 Luban NLC, Fearon T, Leitman SF, Moroff G: Absorption of gamma radiation in simulated blood components using cesium (Cs) irradiators. Transfusion 1995; 35:635 3 Silva MA (ed.): AABB Standards, 24th edn. Bethesda, MD, AABB Press, 2006:16 4 Luban NLC, Strauss RG, Hume HA: Commentary on the safety of red cells preserved in extended-storage media for neonatal transfusion. Transfusion 1991; 31:229–235 5 Roseff SD, Luban NLC, Manno CS: Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 2002; 42:1398–1413 6 AAP Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297–316 N. L. C. Luban & W. Paul Department of Laboratory Medicine Children’s National Medical Center 111 Michigan Avenue, NW Washington, DC 20010 USA E-mails: [email protected]; [email protected]

© 2008 The Author(s) Journal compilation © 2008 International Society of Blood Transfusion, Vox Sanguinis (2009) 96, 62–85

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