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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 27-33

The utility of blood components in the care of sick neonates: An evidence-based review


1 Department of Neonatology, Neonatal Intensive Care Unit, Manipal Hospital, Bengaluru, Karnataka, India
2 Department of Neonatology, Manipal Hospital, Bengaluru, Karnataka, India

Date of Submission11-Mar-2020
Date of Decision24-Mar-2020
Date of Acceptance03-Apr-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
H A Venkatesh
Department of Neonatology, Manipal Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_21_20

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  Abstract 


This article aims to summarize the most current evidence-based practices regarding blood component utility in the care of sick neonates. The indications for transfusion, the transfusion thresholds, and the adverse effects are dealt with in detail. The judicial utilization of blood components is the need of the hour. The right component, right dose, right recipient, right aseptic precautions and constant monitoring of transfusion is very important. Consent for transfuson is another essential step before transfusion.

Keywords: Blood components, evidence, neonatal intensive care unit, transfusion threshold


How to cite this article:
Gupta A, Venkatesh H A. The utility of blood components in the care of sick neonates: An evidence-based review. Glob J Transfus Med 2020;5:27-33

How to cite this URL:
Gupta A, Venkatesh H A. The utility of blood components in the care of sick neonates: An evidence-based review. Glob J Transfus Med [serial online] 2020 [cited 2020 Oct 31];5:27-33. Available from: https://www.gjtmonline.com/text.asp?2020/5/1/27/282731




  Introduction Top


Blood transfusion is of critical importance in neonatal intensive care, particularly the preterm babies. Although they are frequently transfused, there is a need for strong evidence-based data on the thresholds for transfusion. The commonly used blood components in neonatal intensive care units (NICUs) are packed RBCs, platelets, fresh frozen plasma (FFP), albumin, and intravenous immunoglobulin (IVIG). The indications, the threshold level for transfusion, the adverse effects, and monitoring while transfusions have been discussed in detail.


  Data Source Top


This review was performed by searching for the keyword blood transfusion, guidelines, evidence, newborn, thresholds, red blood cells (RBCs), platelets, plasma, albumin, IVIG in PubMed and Google databases, and a thorough search for systematic reviews and meta-analysis was done. Reference lists were cross-checked for relevant citations, and more searches were done until the desired information was gathered.


  Red Blood Cell Transfusion in Neonates Top


RBCs are the most commonly transfused blood products in newborns. Majority of premature and extremely low birth weight (ELBW) neonates will require at least one transfusion in their hospital stay and may even require multiple transfusions. For such critical procedures, we need an evidence-based transfusion threshold.[1],[2] The universally accepted definition of anemia in newborns which necessitates the need for blood transfusion and the treatment thresholds are not standardized.[3] The neonatal RBC transfusions are usually given either to maintain the Hb above a particular threshold or because of the presence of indirect markers of anemia like growth failure, increasing episodes of apnea, or lethargy.[4]

Current evidence and practice

The red cell transfusions (up to 20 mL/kg) are commonly carried out in preterm babies, mainly due to reduced red cell production. Up to 80% of preterm babies weighing less than 1500 g at birth are transfused at least once in their hospital stay.[5] In general, neonates receive RBC transfusions at a dose of 10–15 mL/kg (a maximum of 20 mL/kg), and the transfusion should be completed within 4 h. In general, a dose of 15 ml/kg can be expected to raise the baby's hemoglobin (Hb) concentration by about 20 g/L.[6]

Prerequisites

For blood transfusion, written consent is mandatory. Consent is taken from parents/guardians. The benefits and the possible risks involved in the transfusion and the need for screening the blood for HIV, HbsAg, syphilis, malaria, and hepatitis C virus is explained.

Leukoreduction

The removal of leukocytes from various blood products has been shown to minimize febrile nonhemolytic transfusion reactions, human leukocyte antigen (HLA) alloimmunization, and prevention of transmission of leukotropic viruses such as Epstein–Barr virus and cytomegalovirus. Currently, the best leukoreduction can be achieved with the help of 3rd and 4th generation leukofilters, both in the laboratory and patient bedside.[7]

Irradiation

It is a process of prevention of lymphocyte replication without significantly damaging RBCs. This also helps in the prevention of graft versus host disease (GVHD). The transfused viable lymphocytes (CD4+ and CD8+) attempt to mount an immune response against HLA incompatible host tissue. Normally, host lymphocytes neutralize the response. Lack of host neutralization due to defective cellular immunity, or failure to recognize donor HLA molecule as foreign, may lead to transfusion-associated GVHD (TA-GVHD) mediated by transfused lymphocytes. In neonates, the shelf of life of the irradiated red cell is only 24 h.[8]

Recognition of acute and delayed transfusion reactions and management

Acute reactions may be hemolytic as a result of mismatch, bacterial contamination due to improper handling during processing, transfusion-associated circulatory overload, which may occur if the transfusion is given too rapidly or if renal function is impaired. An anaphylactic reaction is a rare complication of transfusion of blood components or plasma derivatives. The risk is increased by rapid infusion. Transfusion-Related Acute Lung Injury (TRALI) is a severe complication caused by donor plasma that has antibodies against the patient's white blood cells. Rapid failure of pulmonary function occurs usually within 1–4 h of starting transfusion, and diffuse opacities are found on chest X-ray. Intensive respiratory support may be required.

Delayed complications appearing 5–10 days, after the transfusion may include fever, jaundice, anemia, hemoglobinuria, shock, renal failure, and disseminated intravascular coagulation. TA-GVHD occurs in patients such as immunodeficient recipients of bone marrow transplants or immunocompetent patients transfused with blood from individuals with a compatible HLA tissue type, usually blood relatives, particularly 1st degree.

The adverse effects and their management are explained in [Table 1] after, immediately stopping the blood transfusion.
Table 1: The adverse effects of blood transfusion and their management

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There is a concern about the association of morbidities such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity, chronic lung disease (CLD), and mortality with blood transfusion.[9],[10],[11],[12] However, the confusion persists regarding the associated element with NEC, i.e., severe anemia or blood transfusion. Hence, more research is needed in this field as to what is more important, minimizing the risks of blood transfusion or maintaining a higher hemoglobin threshold.

Indications and thresholds

The potential benefits of transfusion in neonates include improved tissue oxygenation and a lower cardiac output to maintain the same level of oxygenation.[13] These benefits need to be weighed against possible adverse outcomes also.

There are three[13],[14],[15] randomized studies evaluating “restrictive” versus “liberal” transfusion thresholds for neonatal red cell transfusion in VLBW babies have been published; and these are included in updated systematic reviews.[16],[17]

The trials in neonates reported a variable reduction in the number of transfusions with restrictive regimens. For the restrictive group (transfused at lower Hbs), at short-term follow-up, the Iowa study (Bell et al., in 2005) reported an increase in episodes of apnea, and at 18–21-month follow-up the PINT study found a statistically significant cognitive delay.[18]

For the liberally transfused group, the Iowa study patients had significantly poorer learning outcomes[19] and reduced brain volume on magnetic resonance imaging.[20] However, information on long-term outcomes is limited, and there is no evidence that restrictive transfusion policies have a significant impact on mortality or major morbidity (Whyte and Kirpalani, 2011).

The approximate lower limits used to define a “restrictive” transfusion policy in these trials are shown in [Table 2]. Many experts now favor a restrictive transfusion policy (Venkatesh et al., in 2012). Further large clinical trials are advocated to address the issues of long-term (including neurodevelopmental) outcomes and cost-effectiveness.
Table 2: The need for red blood cell transfusion in neonates based on oxygen requirement

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For neonates and older children, the transfusion thresholds are dependent on the respiratory requirement (The New British Committee for Standards in Haematology Transfusion Guidelines) and are depicted in [Table 3].
Table 3: Suggested transfusion threshold in neonates depending upon the respiratory status

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Further evidence-based on short-term and long-term outcomes should become available from the multicenter randomized controlled trial (RCT) ETTNO (Effects of Transfusion Thresholds on Neurocognitive Outcome of ELBW infants; ETTNO Investigators, 2012), and the transfusion of premature trial.


  Platelet Transfusion in Newborn Top


Most premature infants have a high risk of developing thrombocytopenia. Platelets are the second most commonly transfused blood component in neonates, next to RBCs.[21]

The incidence of thrombocytopenia is inversely correlated to gestational age, and among the neonates with a birth weight of <1000 g, it is estimated to be as higher than 50%.[22]

There is a considerable difference in the pretransfusion thresholds for platelet count and overall platelet transfusion practices between various hospitals and countries. In general, moderate thrombocytopenia (50–150 × 109/L) is not supposed to be detrimental. In a study on prophylactic platelet transfusion thresholds, over 150 thrombocytopenic neonates <33 weeks' gestation age (weight of 500–1500 g) were randomly assigned to receive platelet transfusions to maintain the platelet count at either >150 × 109/L or greater than 50 × 109/L in the first week of life. This study suggested that the liberal platelet transfusion threshold (150 × 109/L) did not protect against IVH.[23] Another retrospective observational cohort study examined infants with platelet counts of <50 × 109/L in the NICU, and in whom platelet transfusions were withheld, and they did not suffer from serious hemorrhage, which suggested that lower platelet count thresholds can be safe for stable newborns.[24] In a multicenter, retrospective cohort study of 972 VLBW infants from six US NICUs, the pretransfusion count was at least 50 × 109/L for 653 of 998 transfusions. There was neither an association between the severity of thrombocytopenia and the subsequent risk for IVH or a lower risk of IVH due to platelet transfusions. Still, there is a need for RCT evidence to guide the optimal platelet transfusion decisions in premature neonates.[25]

PlaNeT2 is a randomized prophylactic threshold trial randomly assigning neonates to a 25 versus 50 × 109/L transfusion threshold, and the NeoBAT score was used by the PlaNeT2 study. It concluded that among preterm infants with severe thrombocytopenia, the use of a platelet-count threshold of 50,000 per cubic millimeter for prophylactic platelet transfusion resulted in a higher rate of death or major bleeding than a restrictive threshold of 25,000 per cubic millimeter within 28 days after randomization.[26]

In the UK, the current advice is based on expert opinion and the recommendation is that prophylactic platelet transfusion is given to all neonates (term or preterm) with a platelet count <20 × 109/L, to stable preterm infants if the platelet count falls below 30 × 109/L, and to all infants with a birth weight <1000 g if the platelets are below 50 × 109/L during the first week of life. Of note, a threshold of 50 × 109/L is commonly used in the UK for clinically unstable infants, have had a previous major bleed or have other known risk factors.[27] It is widely agreed that the platelet count should not fall below 50,000/μl in preterm neonates who exhibit active bleeding or are at great risk of bleeding.

The current evidence-based guidelines for platelet transfusion are mentioned in [Table 4].
Table 4: Platelet transfusion threshold

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Adverse effects

They also have significant risks of bacterial infections due to storage at room temperature and risks of allergic reaction as well as TRALI due to the plasma component of platelet products.

Random donor platelets or single donor platelets in a neonate

Platelets prepared from whole blood are referred to as random donor platelet (RDP) concentrates. Apheresis platelets are usually called single donor platelets because they are collected from a single donor with an automated cell separator and the returns plasma and red cells to the donor's other arm. A single donor platelet concentrate contains a minimum of 3.0 × 1011 platelets suspended in approximately 200 mL of plasma, which is the equivalent of 6–8 RDP concentrates. Single donor platelets offer several advantages over random donor concentrates including fewer donor exposures, leukocyte reduction during collection, lower risk of bacterial contamination, easier platelet cross-matching, and fewer contaminating RBCs.


  Plasma Transfusion in Neonates Top


The evidence guiding the transfusion of plasma in neonates is the weakest. There are only a few prospective multicenter studies based on plasma use in neonates, but we largely rely on expert opinion for recommendations. The neonatal coagulation system matures slowly after birth, and the reference ranges are quite different from those in adults. Due to the lack of awareness of the different ranges, the transfusion decisions in neonates are made based on the adult ranges which define coagulopathy.

Current evidence

A national audit of transfusion practice from the UK indicated that almost 50% of plasma transfusions are given prophylactically to neonates with abnormal coagulation profile without any evidence of active bleeding, to prevent IVH; however, there is very low-grade evidence to support the effectiveness of this practice.[28]

The current expert opinion supports the therapeutic use of plasma either with active bleeding or during invasive procedures in patients at high risk of bleeding, including those recognized to have an abnormal coagulation profile. An abnormal coagulation profile would be identified as the conventional coagulation parameters, prothrombin time (PT), or activated partial thromboplastin time (aPTT) being significantly above the normal age and gestation adjusted reference ranges.

The British guidelines do not support the prophylactic FFP administration to nonbleeding children with minor prolongation of PT/aPTT, including before surgery and not used as a means for volume replacement or prevention of bleeding (e.g., IVH) in neonates.

The ranges must be established for the classic tests, including PT/aPTT/international normalized ratio, to guide the transfusion practice in newborns. The next step is having a validated bleeding prediction for neonates to standardize the actual bleeding. Correlation of the prolonged values with actual risk for clinically significant bleeding is an important aspect, and no correlation has been established. Finally, there is a need for RCTs to explore the prophylactic use of plasma in neonates deemed at high risk for bleeding or with abnormal coagulation tests.

Adverse effects

Plasma use in neonates could range from a simple allergic reaction secondary to plasma proteins or a febrile nonhemolytic reaction to severe life-threatening reactions, including TRALI, and hemolysis, all of which are under-reported in neonates.

Although plasma is usually transfused for its hemostatic properties, there have been reports of an association between plasma transfusion and venous thrombotic outcomes in the neonatal population.[29]


  Albumin Transfusion in Neonates Top


Intravenous albumin infusion is commonly used to treat hypoalbuminemia in critically ill newborns. Hypoalbuminaemia occurs in many conditions, including prematurity, respiratory distress syndrome (RDS), CLD, NEC, intracranial hemorrhage, hydrops fetalis, and edema.[30] Fluid overload is a potential side effect of albumin administration. Albumin is a blood product and therefore carries the potential risk of infection and adverse reactions. Albumin is also a scarce and expensive resource. There is a lack of evidence from randomized trials to either support or refute the routine use of albumin infusion for premature babies with a low albumin level. In premature infants, the albumin level in the blood can be low hence they are commonly administered albumin.

Guidelines on the use of albumin

It is available as 5% and 25% strength and can be used for hypovolemic shock and hypoproteinemia. For hypovolemic shock, 5% albumin is used at the dose of 0.5–1 g/kg over 10–20 min and 25% for hypoproteinemia over 2–4 h. The possible adverse reactions are volume overload and pulmonary edema, allergic reactions (fever and urticaria), and a rapid increase in serum sodium levels. The hypersensitivity to albumin, severe anemia, cardiac failure, hepatic failure, or renal failure are contraindications.[31]

A meta-analysis by Vincent et al.[32] showed that decreased serum albumin is an independent risk factor for mortality and morbidity. The clinical benefit was observed in four studies with an attained albumin level of more than 30 g/L. In these studies with higher attained albumin levels, the albumin group experienced a shorter time to regain birth weight, fewer morbidities; improved nutritional status, tolerance to enteral feeding, lower incidence of septicemia and pneumonia, and greater relief of hypotension.

In premature neonates, albumin has also been administered in an attempt to decrease pulmonary morbidity. Greenough et al., hypothesized that increasing albumin concentrations would improve diuresis, decreasing lung fluid and improving pulmonary function, but although the albumin-treated infants demonstrated greater weight loss and higher albumin concentrations, this was not associated with a significant decrease in ventilatory support as compared to the placebo group.[33] In a similar study in preterm infants with RDS, albumin was added to the total parenteral nutrition, but there were no effects on the duration of mechanical ventilation.[34] A study of fluid intake in the first week of life in infants less than 33 weeks' gestation found that larger amounts of colloid administration were associated significantly with longer duration of oxygen dependency[35] and on follow-up, these infants were significantly associated with abnormal neurodevelopmental outcome at 1–2 years of age.[36] Thus, the administration of albumin for above-stated indications is still controversial, but its supplementation as the sole management for hypoalbuminemia has not proved to be beneficial.[37],[38],[39]


  Intravenous Immunoglobulin Infusion in Neonates Top


IVIG is manufactured from plasma pooled from more than 1000 healthy blood donors and contains mostly IgG, but traces of IgA also may be present. In the newborn, off-label indications include hemolytic disease of the newborn (HDN), neonatal alloimmune thrombocytopenia, and prophylaxis/therapy against sepsis in LBW or preterm infants.[40],[41],[42],[43] The IVIG also has been used in the treatment of parvovirus B19 infection, neonatal hemochromatosis, neonatal neutropenia and in rare cases of neonatal Kawasaki disease.[44],[45],[46],[47]

Recent studies suggest that its use in the treatment of HDN may be associated with the development of NEC.[48],[49] Although the mechanism of NEC in these infants is still not known. Close attention to flow rate and dosage may limit additional hyperviscosity or thromboembolism, which may function in the pathophysiology of NEC development in these infants.[50] Thus IVIG should be used cautiously in the newborn period.

The adverse reactions in the newborn potentially are related to volume overload, viscosity, osmolarity, pH, and sodium content. IVIG products produced at higher concentrations may reduce the volume required for a specified dose but also may increase the viscosity and osmolarity of the solution which may trigger significant adverse events such as thromboembolic episodes or renal complications. In contrast to plasma osmolarity of 280–296 mOsm/L, the osmolality of commercially available IVIG may exceed 1000 mOsm/L.[51] The optimal pH for the stability of IVIG solutions is 4.0–4.5.[52]

In the presence of IVIG, macrophage receptors are blocked, substantially preventing hemolysis. Clinical studies have shown that high-dose IVIG prevents or decreases hemolysis, as reflected by a rapid decline of carboxyhemoglobin values. Two recently published reviews concluded that early administration of IVIG is the most relevant factor in reducing hyperbilirubinemia and avoiding exchange transfusion.[53],[54] Moreover, a single 0.5 g/kg dose on day 1 is as effective as other proposed therapeutic schemes that have used higher IVIG doses. Thus, in patients in whom total serum bilirubin is rising despite intensive phototherapy or its concentration is within 2-3 mg/dL of the exchange level, 0.5–1 g/kg IVIG can be administered over 2 h and repeated in 12 h, if necessary.[55] However, the American Academy of Pediatrics states that IVIG must not be offered routinely as prophylaxis against hyperbilirubinemia in those who have HDN and should be regarded as an option for hyperbilirubinemia that is refractory to phototherapy and reaches values that put the patient at risk of neurologic damage.[56]

The reduced rate of hemolysis with the use of IVIG has decreased the rate of exchange transfusions substantially. Theoretically, the adverse effects of infections, especially in very preterm infants, could be reduced by the preventive administration of IVIG. The IVIG infusion has been associated with a 3%–4% reduction in sepsis or any serious infection. However, it has not influenced other important outcomes, such as incidence of NEC or intraventricular hemorrhage and length of hospital stay or mortality. From a clinical perspective, a 3%–4% reduction in nosocomial infections without a reduction in mortality or other important clinical outcomes is of marginal importance, as underscored by a recent Cochrane review.[57]

The clinical use of IVIG in newborns has increased substantially in the last few years, although the FDA has not approved its use in newborns. The immunomodulatory, anti-inflammatory, and anti-infectious properties of IVIG may be of benefit for diseases in the newborn, but the dose and volume and rate of infusion should be monitored to avoid acute adverse effects, such as NEC.


  Conclusion Top


Neonates are categories of patients with high transfusion needs even though the number of transfusions given to premature neonates has progressively decreased, and the restrictive approach has been widely accepted. It is essential to establish appropriate transfusion criteria to decrease unnecessary exposure to blood components and minimizing the occurrence of transfusion-related adverse effects.

The scientific contributions on neonatal blood transfusion guidelines are derived predominantly from the consensus of opinions rather than controlled studies, and the lack of clear scientific evidence makes it difficult to formulate high-grade recommendations based on solid levels of evidence. Furthermore, neonatal transfusion medicine is, like all other scientific fields, a continuously evolving discipline. This review summarizes the current evidence-based data defining the utility of commonly used blood components in NICUs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Data Source
Red Blood Cell T...
Platelet Transfu...
Plasma Transfusi...
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Conclusion
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