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Transfusion of Blood Products Common Issues.pptx
1. Transfusion of blood products
Common Issues
Speaker: Dr Nishant Agarwal, DrNB Resident
Moderator: Dr. Tushar Parikh, Consultant
Institution: KEM PUNE
Date: 05.08.2022
Indian Academy of Neonatology
2. Physiological Benefits of PCV transfusion
• Beneficial to the sick preterm
• Increases circulatory hemoglobin (Hb)
• Improves Tissue oxygenation/Prevents Hypoxia to various organs
• Reduces cardiac output to maintain the same level of oxygenation
• Physiologically sounds well but not proven
J Pediatr 2006;149:301–307
3. Issues with RBC transfusion in Neonate
• Maternal cross reacting antibodies – RBCs should be cross matched with mother’s blood
• Poor immunity - susceptibility to infections
• Immunological complications (GVHD/ TRAGI)
• Risk of hemodynamic instability
• Availability of low volume aliquots
• Multiple blood transfusions with potential to exposure to multiple donors
• Sepsis / NEC predisposing to Hemolysis
4. Indications for transfusion for RBC’s
• Symptoms of anemia (e.g., desaturations, bradycardias, increased oxygen
requirement, and tachycardia) are non-specific
• Certain threshold levels
• Acute blood loss
• Decision for RBCT is made by clinicians based on their clinical judgement
and national or local guidelines
• Benefits outweigh Risks
Blood Transfus 2011;9:86–94, Br J Haematol 2004;124:433–453
6. Choice of ABO group of blood components to administer to a neonate
ABO-incompatible with the mother
ABO Group of
Neonate
ABO group of mother ABO Group that can
be transfused RBC
ABO Group that can
be transfused
Platelets
ABO Group that can
be transfused FFP
O A OR B O O O or AB or A or B
A O OR B O PLASMA FREE O A OR AB
B O OR A O PLASMA FREE O B OR AB
AB O
A
B
O
O or A
O or B
PLASMA FREE O
Plasma free A or O
Plasma free B or O
AB
AB
AB
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
7. Choice of ABO group of blood components to administer to a neonate ABO-
compatible with the mother
ABO blood group of the
neonate
ABO blood group that can
be transfused RBC
ABO blood group that can
be transfused Platelets
ABO blood group that can
be transfused FFP
O O O
AB or A or B
O
AB or A or B
A A
O
A
AB
A
AB
B B
O
B
AB
B
AB
AB AB
O or A or B
AB
Plasma free A or B
AB
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
9. Postnatal Age Respiratory
support and/or O2
dependency
No respiratory
support and off
oxygen
Canadian Pediatric
society
1 week
2 week
3 week or older
11.5 (35)
10(30)
8.5(25)
10 (30)
8.5(25)
7.5(23)
British Committee for
Standards in Hematology
(applicable to preterm
neonates < 32 weeks)
1st 24 h
Day 1 to 7
Day 8 to 14
Day 15 onwards
Invasive Non Invasive
12
10
7.5
7.5
12
12
10
10
12
10
9.5
8.5
French National
Authority for Health
(HAS) (applicable to
preterm neonates < 32
weeks gestational age or
< 1500 g of birth weight)
< 7 Days
≥7 days
Assisted vent/
other support with
FiO2>/= 30%
Spont Vent incl NIV,
nCPAP, HFNC with
FiO2 <30%
7
7
11
10
10
8
Villeneuve A, Arsenault V, Lacroix J, Tucci M. Neonatal red blood cell transfusion. Vox Sanguinis. 2021 Apr;116(4):366-78.
10. NNF Position Statement
• Restrictive threshold packed red blood cell transfusion approach is strongly
recommended in preterm neonates. The panel recommends using above stated
transfusion thresholds. (Strong recommendation, Moderate quality evidence )
Pandita A, Kumar A, Gupta G, Taligasalam V, Tewari VV. Use of Blood Components in Newborns. Journal of Neonatology. 2020 Dec;34(4):199-217.
11. (PINT) Premature Infants in Need of Transfusion
trial
• <1000 g with low or high hemoglobin transfusion thresholds
• Composite primary outcome was death with any of either severe ROP, BPD, or
brain injury on cranial ultrasound
• Fewer infants received one or more transfusions in the low threshold group
(89% low versus 95% high, P = .037)
• Primary outcome were 74.0% in the low threshold group and 69.7% in the
high (P = .25; risk difference, 2.7%; 95% CI -3.7% to 9.2%)
• No statistically significant difference in the primary outcome
J Pediatr. 2006 Sep;149(3):301-307
12. IOWA and PINT
• The Iowa trial revealed more frequent severe cranial ultrasound abnormalities
among the lower threshold infants
• Paradoxically, smaller brain volumes and poorer performance on certain
neurocognitive tests by a small cohort from the higher threshold group at school
age.
• The PINT trial disclosed a nearly significant increase in the OR of cognitive delay
at 18 months for the lower threshold group using the prespecified 2 SD (<75)
cut-off for the Bayley-II Mental Developmental Index (MDI) score.
• When a post hoc analysis was performed using a cut-off of 1 SD (<85), the
increased odds of cognitive delay in the lower threshold group became
significant.
Nopoulos PC, Conrad AL, Bell EF, et al. Long-Term outcome of brain structure in premature infants: effects of liberal vs restricted red blood cell transfusions. Arch
Pediatr Adolesc Med 2011;165:443–50
.
Whyte RK, Kirpalani H, Asztalos EV, et al. Neurodevelopmental outcome of ELBW infants randomly assigned to restrictive or liberal hemoglobin
thresholds for blood transfusion. Pediatrics 2009;123:207–13
13. Low versus high haemoglobin concentration threshold for blood
transfusion for preventing morbidity and mortality in very low birth
weight infants
• 4 trials, 614 infants, compared restrictive vs liberal haemoglobin thresholds
• There were no statistically significant difference in the combined outcomes of death or serious
morbidity at first hospital discharge (typical risk ratio (RR) 1.19
• The use of restrictive threshold modest reductions in exposure to transfusion and in
haemoglobin levels.
• Given the uncertainties of these conclusions, it would be prudent to avoid haemoglobin levels
below the lower limits tested here.
• Further trials are required to clarify the impact of transfusion practice on long term outcome
14. Effects of transfusion Thresholds on Neurocognitive Outcome of
Extremely Low birth Weight Infants (ETTNO Trial)
• 1013 preterm infants with a birth weight less than 1000 g
• Liberal (28%–41%) versus Restrictive (21%–34%) RBC transfusion threshold
• Risk of death or disability (cognitive deficit, cerebral palsy or severe visual
or hearing impairment) at 24 months corrected age
• No difference between liberal vs restrictive transfusion; 44.4% vs 42.9%;
OR 1.05 (95% CI, 0.80– 1.39); P 5 .72
JAMA 2020
15. Transfusion of Premature (TOP) trial
• Restrictive (21%–32%) versus liberal (: 32%–38%) practice for RBC
transfusion
• 1824 premature newborns ,< 29 weeks and birth weight < 1000 g
• Survival, neurodevelopmental impairment at 22–26 months CA
• 50.1 vs. 49.8% survival
• Neurodevelopmental impairment (39.6% and 40.3%, respectively)
• No difference between liberal vs restrictive transfusion
N Engl J Med. 2020 Dec 31;383(27):2639-2651
16. Haemoglobin thresholds (ETTNO/TOP)
Study ETTNO TOP
Transfusion threshold group Higher Lower Higher Lower
Severity Stratum Critical Non
Critical
Critical Non
Critical
Resp
Support
No
Support
Resp
Support
No
Support
Hemoglobin threshold
Week 1 13.7 11.7 11.3 9.3 13.0 12.0 11.0 10.0
Week 2-3(ETTNO) or 2 (TOP) 12.3 10.3 10.0 8.0 12.5 11.0 10.0 8.5
Week >3(ETTNO) or >/=3
(TOP)
11.3 9.3 9.0 7.0 11.0 10.0 8.5 7.0
17. Transfusion thresholds in CHD
In hemodynamically stable critically ill infants and children with
uncorrected CHD, we recommend RBC transfusion to maintain a Hb
concentration of at least 7.0- 9.0 g/dL depending on the degree of
cardiopulmonary reserve.
Weak recommendation, Low quality pediatric evidence (2C)
Cholette JM, Willems A, Valentine S, Bateman S, Schwartz SM. Recommendations on red blood cell transfusion in infants and children with acquired and congenital heart disease from the TAXI.
Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2018 Sep;19(9):S137.
18. How much Blood to transfuse?
• Transfusion criteria used for VLBW babies are based more on consensus
of opinions of “experts” than on scientific evidence
• Transfusion volume
X Neonate weight (Kg) X Neonates Blood Volume (mL/Kg)
Desired Hct – Observed Hct
Packed RBC Hct
Lau W:Neonatal and Pediatric Transfusion: Clinical guide to transfusion [Internet]. Canadian Blood Services. 2017. Available from
https://professionaleducation.blood.ca/fr/transfusion/guide-clinique/pratiques-transfusionnelles-chez-le-nouveau-ne-et-lenfant.
19. Dose and administration
• RBC transfusions at a dose of 10 to 15 mL/kg (a maximum of 20 mL/kg) and the
transfusion should be completed within 4 hours
• Hemoglobin level of the newborn increases by about 2 to 3 g/dL at this dose
NeoReviews. 2015;16:c287–96
• a volume of 15 ml/kg for infants less than 32 weeks GA or ≤1500 g has been suggested
because an association between a greater total volume of infused blood and
transfusion-related NEC is reported in VLBW infants
Marin T, Moore J, Kosmetatos N, et al.: Red blood cell transfusion-related NEC in VLBWt infants: a NIRS investigation.
Transfusion 2013; 53:2650–2658
20. NNF Position Statement
• In neonates requiring packed red blood cell transfusion, smaller volume
(10-15 ml/kg) is preferred
(Weak recommendation, Low quality evidence )
Pandita A, Kumar A, Gupta G, Taligasalam V, Tewari VV. Use of Blood Components in Newborns. Journal of Neonatology. 2020 Dec;34(4):199-217.
21. Risks of Transfusions in neonates
• Metabolic complications: Hypoglycemia, Hyperkalemia, and Hypocalcemia
• Immunologic complications: haemolytic transfusion reactions, allergic
reactions, febrile nonhemolytic reactions, immune-mediated platelet
destruction, transfusion related acute lung injury (TRALI), T-antigen activation,
and TA-GVHD
• Infectious complications: CMV, Bacteria,
• Transfusion-related adverse outcomes: Risk of BPD, ROP, NEC
22. TRANSFUSION-RELATED ACUTE GUT INJURY(TRAGI)
• The greatest controversy surrounding RBCT in preterm infants is its
relationship with NEC.
• Due to the association between NEC and feeding practices, there have
been concerns about the effects of feeding during RBC transfusion.
23. PATHOPHYSIOLOGY
NEC
Normal increase in
postparandial blood flow
in SMA fails to occur
following transfusion in
<1250 g
Stored blood have
depleted NO levels act as
a NO sink causing
vasoconstriction
Ischemia
Arginase from lysed RBCs
Two hit model Initial
injury followed by
exaggerated intestinal
immune response
PRBC Excessive shear
force due to altered
viscosty, poor RBC
deformability
Edmund F. La Gamma, Jonathan Blau Transfusion-Related
Acute Gut Injury:Feeding, Flora, Flow, and Barrier
Defense.Seminars of perinatol, 2012
24. • There have been reports of a temporal association between RBC
transfusion and NEC occurring within 72 h of transfusion.
• 25–35% of NEC cases are temporally associated with RBC transfusion
and the terms “transfusion-related NEC” or “transfusion-related acute
gut injury” have been coined.
Claire Howarth , Jayanta Banerjee, and Narendra Aladangady.
Red Blood Cell Transfusion in Preterm Infants: Current Evidence and
Controversies. Neonatology 2018.
25. • P: 22 infants (25-32 weeks)
• I: Randomized to fed and not-fed groups during a blood transfusion
• O: Superior mesenteric artery blood flow pre and postparandial (30 minutes)
• Result: Increased flow in the superior mesenteric artery lacking immediate post-
transfusion state
• T: October 2005 November2006
Krimmer GA, Baker R, Yanowitz TD: Blood transfusion alters the superior mesenteric artery blood flow velocity response
to feeding in premature infants. Am J Perinatol 2009; 26: 99–105
26. • The average rating for the quality of evidence of individual studies was between
"very low" and "low." On pooling studies for GRADE review
• Inconsistency of results was observed .
• Final overall quality of "very low" for the evidence for an association between
transfusions and necrotizing enterocolitis
28. DEFINITION
A Working Party on Definitions of Adverse Transfusion Events was
established by the European Haemovigilance Network (EHN). :
1) the occurrence of acute respiratory distress during or within 6 hrs of
transfusion;
2) absence of signs of circulatory overload;
3) radiographic evidence of bilateral pulmonary infiltrates
29. TRALI in neonates?
• Very few case reports
• High index of suspicion if acute respiratory worsening distress following
blood transfusion in absence of other signs of fluid overload
• Supportive care
30. • . TRALI TACO
Respiratory distress caused by non cardiogenic
pulmonary edema. ( Normal central venous pressure
and PCWP)
Respiratory distress caused by cardiogenic
pulmonary edema .
Hypotension hypertension caused by volume overload
Usually improves within 48-96 hrs ; require
respiratory support ± vasopressor support.
Diuresis is often required.
31. Silliman, Christopher C., Daniel R. Ambruso and Lynn K. Boshkov. “Transfusion-related acute lung injury.” Blood 105 6 (2005): 2266-73
32. GRAFT VERSUS HOST DISEASE(GVHD)
• TA-GVHD: When an immunosuppressed or immunodeficient patient receives cellular
blood products, which possess immunologically competent lymphocytes.
• Neonates at risk: those with impaired cellular immunity ( eg, SCID, Wiskott Aldrich) ;
receiving IUT/ET; extremely premature neonates
• 3-30 days post transfusion (Median 11 days)
• Fever; generalized, erythematous rash ; watery diarrhea; mild hepatitis to fulminant
liver failure; respiratory distress; pancytopenia.
• Prevented by pre-transfusion gamma irradiation
33. Irradiation
• Blood components must be irradiated with a dose ranging between
25 and 50 Gray (2,500–5,000 rad)
• Once irradiated, the RBC must be transfused within 24 hours
• Irradiation does not change the expiry data of platelet concentrates
34. Irradiation of cellular blood products
• Reduces the incidence of TA-GVHD
• Irradiation increases potassium leakage from stored RBCs and
reduces the shelf life of irradiated RBCs
• Irradiation of blood products does not also prevent TT-CMV
infection
NeoReviews. 2011;12:c13–9
36. How to reduce Risks associated with transfusion?
Leukocyte reduction
• Should be used in all neonates
• Leukoreduction filters can remove approximately 99.9% of white blood cells from
blood cells
• Decreased incidence of BPD (odds ratio [OR], 0.42; 95% CI, 0.25–0.70), ROP (OR,
0.56; 95% CI, 0.33–0.93), and NEC (OR, 0.39; 95% CI, 0.17–0.90) in preterm infants
requiring RBC transfusions
NeoReviews. 2005;6:c351–5, NeoReviews. 2011;12:c13–9
37. Leucodepleted blood components
• Prevents non-haemolytic febrile reactions
• Reduces the risk of alloimmunization
• Lowers the risk of transmission of cytomegalovirus (CMV) infection
Level of evidence IV, Grade of recommendation C
38. Leukocyte reduction
• Usual target is <1 X 106 /unit of PRBC (Pre storage).
• Various methods include buffy coat removal (3800 rpm 7 min), followed
by leukofilteration.
39. }Packed Red Cells
specific gravity~ 1.100
} Buffy Coat
specific gravity ~ 1.075
}Plasma specific gravity ~1.026
Platelets specific gravity ~ 1.058
Centrifugation - Principle
Blood cells have different sedimentation coefficients
due to difference in their specific gravity
40. What type of blood should we use?
• Use irradiated, CMV-negative RBC units
• 25 Gc gamma radiation damages T-lymphocytes, which prevents
them from replicating in an immune weakened or immature
recipient, thereby preventing transfusion-associated graft versus-
host disease (TA-GVHD)
2017. Canadian Blood Services
41. Small Volume transfusion
• Small volume (10 to 15 mL/kg) transfusion requires use of special
equipment such as small bags (satellite packs)
• Blood from a large blood unit (320 to 400 mL) can be transferred into
several small bags in a sterile manner through a closed system(Pentapacks)
• Reduction in donor exposure by increasing the number of transfusions from
a single blood unit
NeoReviews. 2011;12:c13–9
42. Should the number of donors be limited?
• Multiple small-volume transfusions by fractioning RBC units into
multiple smaller aliquots to be reserved for a single neonate for repeat
transfusions until expiry of the unit is reached
• Use Pedipacks
43. What is the optimal storage time?
• 42 days of storage
• Age of Red blood cells In Premature Infants (ARIPI) trial
• 377 premature infants weighing ≤1250 g
• No difference in mortality or a composite outcome that included major
neonatal morbidities (NEC, BPD, IVH and ROP) in patients who received RBCs
stored less versus more than 7 days
• No difference between transfusion with fresher versus older RBCs with regard
to mortality and morbidity
Blood Transfus 2013; 11:419–425 & Cochrane Database Syst Rev. 2015; 5:CD010801
44. Should we use diuretics while transfusing
neonates?
• No effect on other ventilatory and hemodynamic variable
• Adverse effects (electrolyte imbalance, nephrocalcinosis, ototoxicity
• Assess risk of hypervolemia and failure
• Not as routine
Adv Neonatal Care2012;12:369–370
45. Washed versus unwashed red blood cells for transfusion
in Preterms
• Single study
• No significant difference in mortality
• Insufficient evidence to support or refute the use of washed RBCs to
prevent the development of significant neonatal morbidities or
mortality
Cochrane Database Syst Rev. 2016 Jan
46. Stopping enteral feeds for prevention of transfusion-
associated NEC
• Only one RCT involving 22 preterm infants
• No cases of NEC were reported
• Evidence is insufficient
Cochrane Database Syst Rev. 2019 Oct 28;2019
47. Withholding Feeds and Transfusion-Associated Necrotizing
Enterocolitis in Preterm Infants: A Systematic Review.
• 7 non-RCTs (n = 7492)
• showed that withholding feeds during PRBC transfusion significantly
reduced the incidence of TANEC (RR: 0.47; 95% CI: 0.28, 0.80; P =
0.005; I2 = 11%).
• The overall quality of evidence was moderate on GRADE analysis.
• Adequately powered RCTs are needed to confirm these findings.
Jasani B, Rao S, Patole S. Withholding Feeds and Transfusion-Associated Necrotizing Enterocolitis in Preterm Infants: A Systematic Review. Adv Nutr. 2017 Sep
15;8(5):764-769.
48. • Only included RCT by krimmer et al
• No risk of selection bias
• High risk of performance bias
• Care personnel not blinded
• Single study
• GRADE evidence: Very low
Stopping feeds during transfusion cannot be recommended. Needs further studies
49. FEEding DURing red cell transfusion (FEEDUR RCT)
• This was an open, multi-arm, parallel-group, RCT (Australia).
• compared three different enteral feeding regimes during a single red cell transfusion
in preterm infants < 35 weeks gestational age at birth.
• Infants were randomised to either:
– (1) Withholding enteral feeds for 12 h from the start of transfusion or;
– (2) Continuing enteral feeds or;
– (3) Restriction of enteral feed volume to 120 ml/kg/ day (maximum 20 kcal/30 ml) for 12 h.
• Results: There were no episodes of NEC in any infant.
• Conclusions: There were no differences in splanchnic oxygenation when enteral
feeds were either withheld, continued or restricted during a transfusion.
Schindler, T., Yeo, K.T., Bolisetty, S. et al. FEEding DURing red cell transfusion (FEEDUR RCT): a multi-arm randomised controlled trial. BMC Pediatr 20, 346 (2020).
50. Transfusion of RBC’s and effect on ROP
• 18 studies including 15072 preterm infants
• RBC transfusion was significantly associated with ROP (pooled OR =
1.50, 95% CI: 1.27-1.76)
• RBC transfusion was more closely related to ROP in the group with a
gestational age (GA) ≤32 weeks
PLoS One. 2020 Jun 8;15(6):e0234266
51. How can we prevent or reduce blood transfusions?
• Delayed clamping of the cord after birth
• limit iatrogenic blood loss
• use of non-invasive monitoring for parameters like oxygen saturation and
bilirubin level
• Epo not much evidence
• Early (2–3 weeks postnatal age) iron supplementation in LBW infants was
associated with less blood transfusion requirement compared with late
treatment (after 4 weeks postnatal age)
52. • 31 studies, 1651 neonates
• Significant effect on the use of one or more RBC transfusions [RR=0.72, 95% CI
0.65 to 0.79 ]
• Significant reduction in the number of transfusions per infant [MD ‐0.22, 95% CI
‐0.38 to ‐0.06]
• No significant reduction in the total volume (mL/kg) of blood transfused per
infant
• No significant effect on death or ROP
The risk of receiving red blood transfusion is reduced following initiation of
EPO treatment.
53. (PENUT) Preterm Erythropoietin Neuroprotection Trial
• 741 ELBW babies
• Placebo or high-dose EPO
• No significant difference in the incidence of death or severe
neurodevelopmental impairment at 2 years of age
• Significantly decreased volume of RBCs after 10 days of life
N Engl J Med. 2020 Jan 16;382(3):233-243
54. Key Points to remember
• Reduce the number of blood transfusions
• Use special equipment such as small bags (satellite packs) and sterile
connecting devices for small-volume transfusion
• Use leuko-reduced and irradiated cellular blood products
55. Consent
• Parents or legal guardians must give informed consent prior to any
transfusion in their neonate
• Consent requires description of the blood product, possible benefits
and risks, as well as the mention of alternatives to transfusion
56. EXCHANGE TRANSFUSION
• Large volume transfusion
• Indications: severe hyperbilirubinemia, Anemia due to HDFN
• The total volume of reconstituted whole blood (mL) to exchange
("double volume" exchange) is 160 mL/kg for neonates born at term
and 200 mL/kg for those born prematurely.
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
57. Characteristics of the reconstituted whole blood
Characteristics of the red blood cells:
• the same blood group or ABO/Rh compatible with the neonate and the maternal plasma.
– Rh(D) negative in cases of HDFN Rh(D);
– O phenotype in cases of ABO incompatibility neonatal haemolytic disease;
• lacking the antigens against which any irregular antibodies are directed (HDFN due to anti-
c, anti-K, etc.) identified in the mother's or neonate's serum/ plasma;
• fresh (collected within the preceding 5 days).
• cleaned of any additive or preservative, before reconstitution;
• leucodepleted, CMV-safe
• CPD Anticoagulant
• heated to 37 °C, if specific equipment is available
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
58. Characteristics of the reconstituted whole blood
Characteristics of the plasma:
• safe FFP is used (quarantined or inactivated)
• AB Phenotype
The final product must:
• have a Hct between 0.50 and 0.60;
• be irradiated;
• be transfused within 24 hours from the preparation.
• The product has the same metabolic and haemostatic characteristics as fresh,
whole blood but lacks platelets.
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
59. • The volume exchanged each time should be about 5 mL/kg and the rate should not
exceed 2-3 mL/kg/min, in order to avoid rapid fluctuations of intracranial pressure
Level of evidence IV, Grade of recommendation C
61. Platelets - Characteristics
• Group of an identical or compatible ABO phenotype
• Human platelet antigen (HPA)-compatible in the case of alloimmune
thrombocytopenia;
• Leucodepleted/CMV-safe;
• Irrradiated, if indicated
Transfus Med. 2002 Feb; 12(1):35-41
62. Indications for the transfusion of platelet concentrates
• < 25,000 – 30,000 per cmm: Prophylactically
• 30-50,000 per cmm: Consider if
• In first week of life in neonates weighing ≤1,000 g at birth
• Grade 3 intraventricular haemorrhage/intraparenchymal bleeding (in preceding 48-72 h)
• Concomitant coagulopathy
• Critically ill neonate (with sepsis or fluctuating systemic blood pressure)
• During invasive procedures
• 50-99,000 per cmm If Bleeding
63. NNF CPG
Pandita A, Kumar A, Gupta G, Taligasalam V, Tewari VV. Use of Blood Components in Newborns. Journal of Neonatology. 2020 Dec;34(4):199-217.
64.
65. Platelet Transfusion Thresholds in Premature Neonates (PlaNeT-2)
• 2 different platelet transfusion thresholds (50,000/µL vs 25,000/ µL)
• less than 34 weeks, 660 infants;
• 90 % vs. 53% platelet transfusion
• Higher BPD rates 63% vs, 54% ; 95% OR 1.57, 95% CI 1.06-2.32)
• New major bleeding episode or death occurred in 26% of the infants (85 of 324)
in the high-threshold group and in 19% (61 of 329) in the low-threshold group
N Engl J Med. 2019 Jan 17;380(3):242-251.
66. When do we transfuse platelets?
• A reasonable approach for VLBW infants is to transfuse for platelet
levels less than 25,000/µL if not bleeding, > 7 day old, and not having a
procedure in the next 24 hours
• Other babies: clinical severity and risk of bleeding
67. ABO typing in Platelets transfusion
• Importance in platelet transfusions is not clear
• Limited evidence
• Give ABO matched platelets
• improved post-transfusion platelet survival
• reduction in transfusion reactions and RBC alloimmunization
68. How Quickly Should Prophylactic Platelet Transfusions be
Administered?
• Neonatal transfusion treatment guidelines suggest platelets should be
infused rapidly (30-60 minutes)
• Historical practice
69. Platelet transfusion in NICU
• Start immediately after the arrival of Platelets in NICU
• Platelet concentrates must not be stored in the ward’s refrigerator
• A specific venous line must be used for the infusion
• Transfuse within 1 hour
• Pre-transfusion drug treatment is not routinely indicated
• No evidence that the increase in platelet count is greater when 15–20 mL/kg is
transfused compared to 10 mL/kg
Platelets. 2008 Sep; 19(6):428-31
70. SUMMARY
• Prophylactic Platelets < 25,000 per cmm
• Group specific transfusion
• Single donor better but expensive
• Transfuse over 1 hour
72. Indications for the transfusion of fresh-frozen plasma
1. Neonates with ongoing bleeding and significant coagulopathy
2. Neonates with significant coagulopathy who must undergo invasive procedures
3. Congenital deficiency of clotting factors when the specific clotting factor is not
available.
73. Definition of coagulopathy in premature neonates and
neonates born at term, at birth
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
74. Definition of coagulopathy in premature neonates and
neonates born at term, in postnatal period
Blood Transfus 2015; 13; 484-97 DOI 10.2450/2015.0113-15 .
75. NNF CPG RECOMMENDATIONS
• The routine use of prophylactic fresh frozen plasma in preterm neonates is not
recommended. Strong recommendation, Low quality evidence
• Prophylactic fresh frozen plasma transfusion( FFP) in not recommended in non-bleeding
neonates receiving therapeutic hypothermia and having deranged coagulation parameters.
Strong recommendation, Moderate quality evidence
• Transfusion in Neonates with deranged coagulation parameters and planned for surgical or
invasive procedure
Strong recommendation, Very low quality evidence
Pandita A, Kumar A, Gupta G, Taligasalam V, Tewari VV. Use of Blood Components in Newborns. Journal of Neonatology. 2020 Dec;34(4):199-217.
76. SLIDE COURTESY
• Dr Sandeep Kadam, Consultant, KEM Hospital Pune
• Dr Anusha R, DrNB Resident, KEM Pune
77. Indian Academy of Neonatology
https://www.youtube.com/c/IndianAcademyOfNeonatology
Editor's Notes
Anaemia in PT newborns can affect the oxygen supply of the brain, which, combined with intermittent hypoxia and apnoea or circulatory failure at a time of rapid cerebral growth, can contribute to development of brain damage. Red blood cell transfusions are beneficial due to the increase in circulating Hb, which results in improved tissue oxygenation and a decrease in cardiac output.5 On the other hand, there is evidence that they may have a negative impact on neurodevelopment
One non-invasive tool that may be of interest is nearinfrared spectroscopy (NIRS). There is growing interest in intestinal and splanchnic and cerebral oxygen saturation, and it is expected that they may play an important role in the identification of the optimal threshold for transfusion. Both NIRS and the sonographic assessment of perfusion seem to perform well in identifying at-risk anaemic PT newborns. RBC volume and fractional oxygen extraction are not easily measured and, hence, not widely available, and lactic acidemia is a late sign of anaemia that many prefer to avoid.
Measurement of cerebral oxygenation by near-infrared spectroscopy has shown promise but this method requires further evaluation before it can be applied as a clinical tool to aid in transfusion decisions. The use of haemoglobin thresholds to guide transfusion decisions is based on the fact that haemoglobin concentration is one of the main determinants of systemic oxygen transport, along with cardiac output and arterial oxygen saturation, and the main goal of top-up transfusions is to avoid tissue hypoxia and the resultant end-organ injury.
The packed red cells must: be the same ABO/Rh group or a group compatible with the neonate and the mother's serum/plasma (Tables Va and Vb); -lack the antigens against which any irregular antibodies found in the maternal or neonatal serum/plasma are directed;
-thus they must be negative in a cross-match test with maternal or neonatal serum/plasma; - have a final haematocrit of about 0.70; - be leucodepleted/CMV-safe; - be irradiated, if indicated; - be used within 14 days of collection if irradiation is necessary and preferably transfused immediately after irradiation.
Canadian Paeditric society Inspired oxygen requirement in excess of 25% or the need for mechanical increase in airway pressure
PINT 451 infants, mean BW 776, Mean GA 26 weeks
The authors found no differences between groups in the primary outcome, and therefore concluded that in ELBW PT newborns, the application of a higher Hb threshold increased the frequency of transfusion in the absence of strong evidence of any benefits
At a later date, long-term functional outcomes in the PINT study were analysed. The outcome of death or neurodevelopmental impairment at 18 months of corrected age (CA) was observed in 45.2% of the children assigned to the low Hb threshold group compared to 38.5% in the high threshold group, with a P-value of 0.091 in favour of the liberal threshold group. The difference in cognitive delay (<2 standard deviations below the mean) approximated statistical significance (24.4% in the restrictive group vs 17.6% in the liberal group; odds ratio [OR], 1.7; P = .06). This study provides weak evidence of a potential benefit of a higher Hb threshold after a secondary analysis of cognitive delay. The results for this outcome in the statistical analysis neared significance with the post hoc analysis, although the result is thus inconclusive
a study conducted in 56 patients (IOWA trial)from the same cohort at 8---15 years found significant differences between groups, with patients in the restrictive group performing better on measures of associative verbal fluency, visual memory, and reading.
Higher thresholds could increase the risk of hyperviscosity after transfusion, which could compromise blood flow and oxygen delivery to the brain and other organs. Adverse effects on brain size and neurocognitive function were found at school age in a small cohort of children from the higher haemoglobin threshold group in the Iowa transfusion trial, where a haemoglobin transfusion threshold of 15.3g/dL was used for ventilated infants
1013 infants
Mean GA in liberal 26.1; restrictive 26.4
Mean wt in liberal 745; restrictive 750
Multicentre randomized trial from 36 level ¾ NICUs in Europe
Primary outcome @ 24 months CA was death or disability defined as cognitive deficit, CP, or severe visual or hearing impairment
Open multicenter trial
Mean bw 756g, mean GA 25.9
41 NICUs NICHD
Neonatal Research Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), in collaboration with the National Heart, Lung, and Blood Institute (NHLBI)
two large, well-designed trials being published within weeks of each other that show identical and conclusive results, as with the ETTNO and TOP trials
, there is no evidence of any advantage for ELBW infants for maintaining higher haemoglobin levels in the first weeks of life by using higher haemoglobin or haematocrit transfusion thresholds. In particular, there is no evidence to date of any neurological advantage to having higher haemoglobin levels.
We should also reserve the possibility that an advantage in brain development may not be apparent at 2 years but might be evident later. The TOP study infants are now being examined at school age to investigate this possibility
EBV is 100–120 ml/kg in extremely preterm infants and 80–85 ml/kg in term infants .
Hb content of RBCs can vary; in general, each 10–15 ml/ kg transfused is expected to increase the infant’s Hb level by approximately 10–20 g/l
Due to the association between NEC and feeding practices, there have been concerns about the effects of feeding during RBC transfusion
RBC transfusion may eliminate the usual increase in splanchnic blood flow/superior mesenteric artery that follows feeding, placing infants at risk of hypoperfusion
It has been proposed that anaemia causes reduced mesenteric blood flow leading to intestinal hypoxia and subsequent mucosal injury.
There is transient hypoxia followed by re-oxygenation after RBCT and involves a change in blood flow to the bowel leading to NEC, through reperfusion injury .
The association between Hb, tissue perfusion, and oxygen delivery is not clear.
The critical Hb level at which the risk from anaemia outweighs the risk of NEC from RBCT has not been identified.
Although the exact mechanism of TRALI remains uncertain, it is generally believed to be caused by the passive transmission of HLA or neutrophil antibodies
directed against recipient leukocyte antigens. These antibodies activate and sequester recipient neutrophils within the endothelium of the lungs, ultimately leading to the
production of vasoactive mediators and capillary leak. Plasma products (FFP, apheresis platelets) account for the majority of severe TRALI cases, and multiparous women
are the most commonly implicated donors.
Although the exact mechanism of TRALI remains uncertain, it is generally believed to be caused by the passive transmission of HLA or neutrophil antibodies
directed against recipient leukocyte antigens. These antibodies activate and sequester recipient neutrophils within the endothelium of the lungs, ultimately leading to the
production of vasoactive mediators and capillary leak. Plasma products (FFP, apheresis platelets) account for the majority of severe TRALI cases, and multiparous women
are the most commonly implicated donors.
Although the exact mechanism of TRALI remains uncertain, it is generally believed to be caused by the passive transmission of HLA or neutrophil antibodies
directed against recipient leukocyte antigens. These antibodies activate and sequester recipient neutrophils within the endothelium of the lungs, ultimately leading to the
production of vasoactive mediators and capillary leak. Plasma products (FFP, apheresis platelets) account for the majority of severe TRALI cases, and multiparous women
are the most commonly implicated donors.
Two-hit hypothesis
The first hit takes place by priming of neutrophils from who are already ill from shock, sepsis etc. Increased levels of interleukin-8, interleukin-6, and elastase-alpha 1-antitrypsin complex cause neutrophil recruitment to the pulmonary vasculature.
Conformational change in beta-2 integrins allows neutrophil to adhere to pulmonary capillaries.
The second hit comes from the transfusion itself. Antibodies and bioactive lipids stored in blood products activate neutrophils resulting in capillary leakage of intracellular content-releasing proteases and elastases, causing pulmonary edema and endothelial damage.
Another hypothesis is called the threshold hypothesis. There is no first hit involved.
Other possible mechanisms - Several other explanations for TRALI have been suggested.
These include direct injury to pulmonary endothelium,
Immune complex formation with complement activation, and
Cytokine network activation .
Transfusion-associated graft-versus-host disease (ta-GVHD) is a rare and usually fatal complication of blood transfusion in which lymphocytes from the transfused blood component attack the recipient's tissues, especially the skin, bone marrow, and gastrointestinal tract.
the lymphocytes from the transfusion attack the recipient's bone marrow, leading to bone marrow aplasia and profound pancytopenia, which is typically the cause of death. There are no effective treatments, so prevention is essential.
Once irradiated, the RBC must be transfused within 24 hours; if that is not possible, they must be washed with physiological saline in order to remove any excess of potassium and, possibly, in a closed circuit to limit the risk of bacterial contamination. Once washed, the RBC must be transfused as soon as possible and, in any case, not later than 24 hours after preparation. It is good transfusion practice to irradiate the blood component immediately prior to transfusion1
Inactivates donor T cells
leucodepleted (white blood cells <1×106/unit), preferably at the time of collection(pre-storage)
On centrifugation whole blood gets separated into layers, shown in the illustration, due to the different sedimentation coefficients of its constituents
Canadian National Advisory Committee (NAC) on Blood Products recommends the use of irradiated RBCs for who has received an intrauterine transfusion (up to six months after the expected delivery date (40 weeks gestational age)),
for exchange transfusion if this does not cause delay in transfusion – and in VLBW infants (up to 4 months of age)
transfusing a large volume of irradiated RBCs in neonates may increase the risk of hyperkalemia [91]. In such circumstance, fresh RBC units (less than 7 days from collection) should be used and should be transfused within 24 h postirradiation
In the case of transfusion of small volumes, it is good practice to irradiate only the fraction destined for transfusion, rather than the whole unit (Level of evidence IV, Grade of recommendation C). The remaining sub-units should be irradiated within a maximum of 14 days of collection of the parent unit
recommended that only blood components obtained from repeat blood donors are used, as set out in current legislation in Italy
specific clinical situations such as intrauterine transfusion, large-volume transfusion (more than 25 ml/ kg), exchange transfusion, cardiac surgery and use of irradiated blood products may warrant the use of RBCs with shorter storage times [
It has been suggested that washing RBCs could reduce exposure to plasma proteins, additive solution components, electrolytes and inflammatory mediators. However, the process RBCs undergo during the required washing sequences [89] removes not only 98% of plasma, but also up to 20% of RBCs
There were 60 transfusion episodes (20 transfusion episodes in each group) included in the analysis. 41 infants with a median gestational age at birth of 27 weeks (range 23–32 weeks) were enrolled. The median postnatal age was 43 days (range 19–94 days) and the median pre-transfusion haematocrit was 0.27 (range 0.22– 0.32). All three groups were similar at baseline. There were no differences in mean SCOR and mean splanchnic FOE at any of the pre-specified time points. There were also no differences in clinical outcomes.
The primary outcome was mean splanchnic-cerebral oxygenation ratio (SCOR) and mean splanchnic fractional oxygen extraction (FOE) before (1 h prior), during (1 h into transfusion) and after (end of transfusion; 12 and 24 h post) transfusion.
the overall benefit of EPO is reduced as many of these infants had been exposed to donor blood prior to entry into the trials.
systematic reviews and metaanalyses have failed to demonstrate a clear benefit. The time when the need of transfusion is greatest in PT infants is usually the first weeks of life, when administration of EPO offers no benefits. It could be beneficial in reducing late transfusions.
The British Committee for Standards in Haematology does not recommend routine administration of EPO or darbepoetin alfa in PT newborns to reduce the number of transfusions (grade 1B recommendation).9 However, current studies focused on the use of high-dose EPO16 and recombinant human (rhEPO) have found promising results.
In cases in which fresh blood (collected within the preceding 5 days) is not available, products that have been stored for longer can be used, provided they are compatible with irradiation which, by law, must be performed within 14 days of donation, with an additional washing procedure to remove storage residues;
ABO-compatible or ABO-identical platelets are ideally transfused to avoid the transfer of incompatible isohemagglutinins (antiA, anti-B, or anti-A,B antibodies) found in plasma to the recipients, resulting in potential RBC hemolysis
Uk, Ireland, Netherlands
The study demonstrated that a higher threshold for prophylactic platelet transfusion: <50×109/L versus <25×109/L showed increased composite outcome of death and/or major bleeding within 28 days of randomization (26% versus 19%, OR 1.57, 95% CI 1.06-2.32). The study also demonstrated a higher incidence of bronchopulmonary dysplasia in babies transfused at the higher threshold (63% vs, 54%, 95% OR 1.57, 95% CI 1.06-2.32). There was no difference in necrotizing enterocolitis (NEC) or sepsis.
There is little direct evidence for the neonatal platelet transfusion volumes of 10-20ml/kg in current use.[72]. The standard platelet transfusion volume (15 ml/Kg, within the range 10-20 ml/kg) represents common neonatal practice going back several decades.
Andrew et al in 1993 demonstrated an increment of 90×109/L per 10ml/kg platelet transfusion [29] and this has been used historically to support some guidance. The PlaNeT-2 study used 15ml/kg per platelet transfusion,[22]. which was common practice in the UK between 2010 and 2018.
The PlaNeT-3 randomized controlled trial is due to start in 2021 and aims to demonstrate superiority, safety and efficacy of lower volume platelet transfusions in 370 thrombocytopenic preterm neonates less than 32 weeks’ gestation and/or less than 1500g at birth. The trial will compare lower (5mL/kg) or standard volume (15mL/kg) transfusions in babies with platelets <25×109/L.
Significant coagulopathy means prothrombin time (PT) and partial thromboplastin time (PTT) above normal limits or fibrinogen levels below the lower limit of normal for gestational age and post-natal age (Table VII)
A strong recommendation is being made in the presence of low quality evidence because of the serious morbidities associated with transfusions, lack of any benefit and to dissuade the caregiver from this practice.
The decision to give FFP transfusion should not be based only on laboratory investigations; but also take into account the patient’s clinical condition, potential risks (infection, volume overload, adverse effects) and benefits (bleeding prevention, continuing therapeutic hypothermia) of transfusion. procedure should receive Fresh Frozen Plasma.
Surgical and invasive procedures carry a substantial risk of major bleeding in presence of coagulopathy. Hence, a strong recommendation in spite of very low quality evidence.
Cryoprecipitate may be used if there is persistent hypofibrinogenemia (<1.0 g/L) despite FFP transfusion, rapidly falling fibrinogen, or major hemorrhage.
