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Red Blood Cell Transfusion

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Outline

A history of blood transfusion

The transfusion trials

Pathophysiology of anemia of prematurity

Gaps in knowledge

Summary

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Content prepared by

�Dr. Benjamin Courchia MD

&

Dr. Daphna Yasova Barbeau MD

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History of blood transfusions

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James Blundell MD (1790-1878)

The story takes place in the 1820s in the United Kingdom.

James Blundell was a British obstetrician. During the course of his practice in the early 1800s he witnessed the death of many patients from the dreaded postpartum hemorrhage. And so, to him, the idea of transfusing blood to these mothers sounded quite reasonable. He thus conducted some studies on the process of transfusion in animals and uncovered some remarkable things. He noted that blood had to be transfused quickly after being drawn in order to avoid complications, he also discovered the importance of removing air bubbles from the syringes when administering the blood. lol

And so in 1829 (or was it 1818) Blundell was faced yet again with a case of post partum hemorrhage. He transfused blood from the patient's husband successfully in what we recorded as the first human-human blood transfusion in history. This was extremely lucky considering that the ABO typing system would only be discovered in 1901 by Karl Landsteiner and blood compatibility tests would be described Reuben Ottenberg in 1907 almost one hundred years later. Blundell continued to perform transfusion and over the next five years he documented ten transfusions, five of which showed "positive" results .

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The story takes place in the 1820s in the United Kingdom.

James Blundell was a British obstetrician. During the course of his practice in the early 1800s he witnessed the death of many patients from the dreaded postpartum hemorrhage. And so, to him, the idea of transfusing blood to these mothers sounded quite reasonable. He thus conducted some studies on the process of transfusion in animals and uncovered some remarkable things. He noted that blood had to be transfused quickly after being drawn in order to avoid complications, he also discovered the importance of removing air bubbles from the syringes when administering the blood. lol

And so in 1829 (or was it 1818) Blundell was faced yet again with a case of post partum hemorrhage. He transfused blood from the patient's husband successfully in what we recorded as the first human-human blood transfusion in history. This was extremely lucky considering that the ABO typing system would only be discovered in 1901 by Karl Landsteiner and blood compatibility tests would be described Reuben Ottenberg in 1907 almost one hundred years later. Blundell continued to perform transfusion and over the next five years he documented ten transfusions, five of which showed "positive" results .

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Raju, T. N. K. Historical Perspectives: Cured by the Blood: The Story of the First Neonatal Blood Transfusion. Neoreviews 7, e67–e68 (2006).

On March 4, 1908, a baby girl was born to healthy parents at a New York Hospital. She weighed 8 lb 12 oz. Other than forceps marks over her cheeks, she appeared healthy.

Starting at 12hours of life she developed signs of serious bleeding. She displayed hematoma over her tongue, pallor, irritability, subcutaneous hematoma behind the left ear, extending down to her neck, She passed dark-colored meconium stools, strongly positive for blood.
“Intestinal infection” was diagnosed, and she was treated with 30 minims of castor oil and two grains of calcium lactate.
She deteriorated over the next 3 days, and appeared “hopeless” on the fourth day. Blood oozed continuously from her nose. Her skin was waxen white, mucous membranes were colorless, and pulse was feeble.

It was clear that the child needed a blood transfusion, but this had never been tried in a newborn.
The doctors considered giving her a “direct transfusion” and asked her father to be the donor. He agreed.

Surgeons Alexis Carrel and Geo Brewer were summoned from the Rockefeller Institute.
The infant was strapped to an iron board, and an incision was made at the groin region to expose the popliteal vein. Her father’s left radial artery was exposed.
Dr Carrel carried outa side-to-side anastomosis of the father’s radial artery with the baby’s popliteal vein to effect a transfusion.
The baby recovered fully and went home a week later. At eight weeks of age, she appeared perfectly healthy.

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Karl Landsteiner, discovers the first three human blood groups.

ABO

Reuben Ottenberg: 1st transfusion using blood typing and cross-matching.

Cross Match

Addition of sodium citrate = longer preservation of blood.

Anticoagulant

Karl Landsteiner, Alexander Wiener, Philip Levine and R.E. Stetson.

Rh

1901

1904

1914

1940

https://www.redcrossblood.org/donate-blood/blood-donation-process/what-happens-to-donated-blood/blood-transfusions/history-blood-transfusion.html

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Sacher, R. A., Luban, N. L. C. & Strauss, R. G. Current Practice and Guidelines for the Transfusion of Cellular Blood Components in the Newborn. Transfus Med Rev 3, 39–54 (1989).

From 1989

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https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5941a3.htm

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Hébert, P. C. et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. New Engl J Medicine 340, 409–417 (1999).

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The combined concerned over transfusion complications and data from the adult world opened the door for a series of trials in the newborn intensive care.

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The Transfusion Trials

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Bell, E. F. et al. Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics 115, 1685–1691 (2005).

The University of Iowa study

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Bell, E. F. et al. Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics 115, 1685–1691 (2005).

The University of Iowa study

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Bell, E. F. et al. Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics 115, 1685–1691 (2005).

	Liberal Criteria	Restrictive Criteria
Intubated on mechanical ventilation	Hct < 46%	Hct < 34%
Nasal CPAP or supplemental O2	Hct < 38%	Hct < 28%
No oxygen Support	Hct < 30%	Hct < 22%

The University of Iowa study

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The University of Iowa study

Bell, E. F. et al. Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics 115, 1685–1691 (2005).

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

The primary outcome was a composite of either death before home discharge or survival with severe morbidity.

Severe morbidity was deﬁned as one or more of

retinopathy of prematurity (ROP)
bronchopulmonary dysplasia (BPD)
brain injury on cranial ultrasound.

The primary outcome was a composite of either death before home discharge or survival with severe morbidity.

Severe morbidity was deﬁned as one or more of (1) retinopathy of prematurity (ROP), (2) bronchopulmonary dysplasia (BPD), or (3) brain injury on cranial ultrasound.

Pre-speciﬁed secondary outcomes included hemoglobin level, numbers of RBC transfusions, numbers of donor exposures, rate of growth, and serum ferritin change from early to discharge values. �

Other recorded outcomes included numbers of infants with necrotizing enterocolitis or with apnea requiring treatment and the use of xanthines or doxapram, culture proven infections, or requiring post-natal steroids. We also recorded time in oxygen, time to extubation, and time to discharge.�

Infants were eligible if they were <1000g at birth, gestational age<31weeks at birth, and to be48 hours old at the time of enrollment. Infants deemed non-viable by the attending physician were excluded, as were those with cyanotic heart disease, congenital anemia, acute shock, transfusion after 6 hours of age, or known parental opposition to transfusions, a family history of anemia and hemolytic disease, or where the attending physician anticipated using erythropoietin.

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

	Liberal Criteria		Restrictive Criteria
	Respiratory Support	No Support	Respiratory Support	No Support
1-7 days of life	Hct < 40%	Hct < 35%	Hct < 34%	Hct < 29%
8 – 14 days of life	Hct < 35%	Hct < 29%	Hct < 29%	Hct < 25%
> 15 days of life	Hct < 29%	Hct < 25%	Hct < 25%	Hct < 22%

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

And so the study concludes with: "In extremely low birth weight infants, maintaining a higher hemoglobin level results in more infants receiving transfusions but confers little evidence of beneﬁt."

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

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Kirpalani, H. et al. 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 Pediatrics 149, 301-307.e3 (2006).

The PINT Trial

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Franz, A. R. et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants. Jama 324, 560–570 (2020).

The ETTNO trial

So there is a bit of a gap in the literature between 2006 and the publication of the ETTNO trial in 2020, more than 10 years later.

The ETTNO trial (Effects of Transfusion Thresholds onNeurocognitive Outcomes of Extremely Low-Birth-Weight Infants) was a multicenter trial conducted in Europe.

The premise of the study is trying to address the discrepancy in the evidence in pediatric intensive care/adult intensive care and data from the Pint Trial. In fact, in 2007 a NEJM paper looking at transfusion criteria in pediatric intensive care showed that lower transfusion thresholds were safe and did not increase adverse outcomes.

�

So the question asked by the ETTNO group was: What are the effects of liberal vs restrictive RBCT strategies on survival and neurocognitive outcome at 24 months of corrected age.

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Franz, A. R. et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants. Jama 324, 560–570 (2020).

The ETTNO trial

This was a multicenter study including 36 centers in Europe.

Inclusion criteria was any infant with a BW between 400-999g. Exclusion criteria were GA >29 6/7 wks, major anomalies or malformations requiring surgical correction during the neonatal period; participation in studies precluding participation in this trial; lack of viability; or comfort care.

Babies received a dose of 20 mL/kg of standard whole blood–derived, leukocyte-depleted erythrocyte con- centrate was administered per RBCT in both treatment groups when transfusion criteria were met.

�

Primary outcome of the study was the incidence of death or neurodevelopmental impairment by 24 (±1) months of corrected age measured on the Bayley II.

Secondary outcome measures were the individual components of the composite primary outcome, the incidence of cognitive deficit (defined as an MDI score less than 70), the MDI score, and the PDI score. Further secondary end points were measures of growth at discharge and follow-up, length of hospital stay, and the time intervals from birth to final discontinuation of positive pressure respiratory support, respiratory stimulant (methylxanthine) therapy, and gavage feeding. Further end points were Gross Motor Function Classifica- tion System score and incidence of all major complications of prematurity (ie, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intestinal perforation brain injury on cranial ultrasound, patent ductus arteriosus requiring therapy, and nosocomial infections) as defined in the study protocol.

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Franz, A. R. et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants. Jama 324, 560–570 (2020).

The ETTNO trial

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Franz, A. R. et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants. Jama 324, 560–570 (2020).

The ETTNO trial

The study was able to enroll ˜1000 infants. And as usual, infants in the liberal groups received more transfusions.

The Primary outcome of death or neurodevelopmental impairment at 24 months of corrected age was ascertained in 91.5% patients and 91.7% patients in the liberal and restrictive threshold groups, respectively

The rates of death or neurodevelopmental impairment were 44.4% vs 42.9%, for a risk difference of 1.6% (95% CI, −4.8% to +7.9%) and an odds ratio of 1.05 (95% CI, 0.80-1.39; P = .72) adjusted for center and birth weight stratum

�

Secondary outcomes: There were no statistically significant differences between treatment groups in rates of components of the primary outcome or incidence of cognitive deficit, the MDI score, the PDI score, length of hospital stay, or time intervals from birth to final discontinuation of invasive respiratory support, positive pressure respiratory support, respiratory stimulant therapy, and gavage feeding

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Franz, A. R. et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants. Jama 324, 560–570 (2020).

The ETTNO trial

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Kirpalani, H. et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New Engl J Med 383, 2639–2651 (2020).

The TOP trial

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Kirpalani, H. et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New Engl J Med 383, 2639–2651 (2020).

The TOP trial

The primary outcome of the study was a composite of death or neurodevelopmental impairment in infants at 22 to 26 months of age, corrected for prematurity. Neurodevelopment was measured on the Bayley III

This trial included 41 nicus and included babies with a birth weight of 1000 g or less, a gestational age between 22 weeks 0 days and 28 weeks 6 days, and a postnatal age of 48 hours or less.

Infants were excluded if they were considered to be

nonviable by the attending neonatologist,

had cyanotic congenital heart disease,

had parents who were opposed to blood transfusion,

had a parent with hemoglobinopathy or congenital anemia,

had received a transfusion in utero,

had twin-to-twin transfusion syndrome or isoimmune hemolytic disease,

had received a previous red-cell transfusion after the first 6 hours of life.

had a congenital condition (other than premature birth) adversely affecting life expectancy or neurodevelopment.

�

The primary outcome of the study was a composite of death or neurodevelopmental impairment in infants at 22 to 26 months of age, corrected for prematurity. Neurodevelopment was measured on the Bayley III

�

They had a long list of prespecified outcomes.

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Kirpalani, H. et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New Engl J Med 383, 2639–2651 (2020).

The TOP trial

	Liberal Criteria		Restrictive Criteria
	Respiratory Support	No Support	Respiratory Support	No Support
1-7 days of life	Hct < 38%	Hct < 35%	Hct < 32%	Hct < 29%
8 – 14 days of life	Hct < 37%	Hct < 32%	Hct < 29%	Hct < 25%
> 15 days of life	Hct < 32%	Hct < 29%	Hct < 25%	Hct < 21%

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Kirpalani, H. et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New Engl J Med 383, 2639–2651 (2020).

The TOP trial

So the results revealed A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. Of those, they were able to enroll 1824 infants, of whom data at 22-26mo was available in 1692 infants (93%).

They eventually had 900 babies in each arm.

Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively).

At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.

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Kirpalani, H. et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New Engl J Med 383, 2639–2651 (2020).

The TOP trial

And so the TOP trial concludes: “In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity.”

This trial included 41 nicus and included babies with a birth weight of 1000 g or less, a gestational age between 22 weeks 0 days and 28 weeks 6 days, and a postnatal age of 48 hours or less.

Infants were excluded if they were considered to be

nonviable by the attending neonatologist,

had cyanotic congenital heart disease,

had parents who were opposed to blood transfusion,

had a parent with hemoglobinopathy or congenital anemia,

had received a transfusion in utero,

had twin-to-twin transfusion syndrome or isoimmune hemolytic disease,

had received a previous red-cell transfusion after the first 6 hours of life.

had a congenital condition (other than premature birth) adversely affecting life expectancy or neurodevelopment.

�

The primary outcome of the study was a composite of death or neurodevelopmental impairment in infants at 22 to 26 months of age, corrected for prematurity. Neurodevelopment was measured on the Bayley III

�

They had a long list of prespecified outcomes.

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Pathophysiology of anemia of prematurity

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Polin, Richard A, Steven H. Abman, David H. Rowitch, William E. Benitz, and William W. Fox. Fetal and Neonatal Physiology. , 2017. Print.

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Martin, R. J., In Fanaroff, A. A., & In Walsh, M. C. (2020). Fanaroff and Martin's neonatal-perinatal medicine: Diseases of the fetus and infant.

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Widness, J. A. Pathophysiology of Anemia During the Neonatal Period, Including Anemia of Prematurity. Neoreviews 9, e520–e525 (2008).

So one of the comorbidities seen in preterm infants is AOP. AOP is seen in infants for a number of reasons:

birth occurs before placental iron transport and fetal erythropoiesis are complete, which occurs in the third trimester
Low plasma erythopoietin and low epo output in response to anemia.

I want to talk about innate erythropoeitin production for a second: this is something else that frequently comes up during studying: epo is the essential glycoprotein growth factor for erythropoiesis. It’s primarily produced in the fetal liver and then later in the kidney. Erythropoiesis is related to blood oxygenation, such that as hypoxia occurs, epo production increases. You may note clinically that growth restricted infants or infants with poor uteroplacental perfusion have higher hematocrit levels than their counterparts. Thusly, when a baby transitions to extrauterine life where their paO2 increases significantly and tissue oxygenation improves, there is a dramatic decrease in epo levels causing the nadir which I will discuss shortly. In addition, while epo is still responsive to hypoxia in the preterm neonate it is to a lesser degree than in the full term infant. This is likely related to developmental differences in transcription factors.

Rapid body growth, with limited expansion of blood volume, leading to hemodilution
Other disorders that lead to hemolysis or bleeding. In addition, illness further suppresses epogen productioin.
Shorter lifespan and increased turnover of RBCs

Finally, phlebotomy blood losses taken for laboratory testing. It’s important to remember that with each lab draw for the ELBW, a greater proportion of blood is taken because the lab still needs the same amount of blood. Say you have a 500gram ELBW and you assume 90-100ml/kg of circulating blood volume, that’s only 50 ml total in the whole baby.

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Symptoms of chronic anemia:

- tachycardia

- poor weight gain

- increased FiO2 requirement

- increased episodes of apnea

- increased episodes of bradycardia

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Martin, R. J., In Fanaroff, A. A., & In Walsh, M. C. (2020). Fanaroff and Martin's neonatal-perinatal medicine: Diseases of the fetus and infant.

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Widness, J. A. Pathophysiology of Anemia During the Neonatal Period, Including Anemia of Prematurity. Neoreviews 9, e520–e525 (2008).

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Brody D., Martin C. Neonatology Review Vol V. 3^rd edition

Management options for anemia

Delayed cord clamping
Limited phlebotomy
Erythropoiesis stimulating agents
Blood transfusions

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Martin, R. J., In Fanaroff, A. A., & In Walsh, M. C. (2020). Fanaroff and Martin's neonatal-perinatal medicine: Diseases of the fetus and infant.

Metabolic derangement associated with red blood cell transfusion:

Hypoglycemia
Hyperkalemia
Hypocalcemia

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https://professionaleducation.blood.ca

Finally, transfusion reactions are less common in neonates, though they can still occur. This is potentially a whole additional topic to be discussed and rarely presented in board review materials. However, what is tested is the appropriate definitions for ordering blood.

For example, leukoreduction of blood. This implies filtration or removal of leukocytes in the blood. For neonates this is important because reduces transfusion transmitted CMV in seronegative preterm neonates since the Cytomegalovirus remains latent within leukocytes.

This is different than the need for irradiated blood products which is done to reduce transfusion associated graft versus host disease. The blood product itself is irradiated in an effort to abolish lymphocyte proliferation. In general, while there is still much debate about which neonates need to have irradiated blood, many centers use birthweight <1200 grams and certainly any infant with suspected cellular immunodeficiency. When blood needs to be irradiated for infants it should be done just before transfusion since the procedure increases the free hemoglobin and potassium in the blood product.

��

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One more interesting study….

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Patel, R. M. et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. Jama 315, 889–897 (2016).

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Patel, R. M. et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. Jama 315, 889–897 (2016).

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Patel, R. M. et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. Jama 315, 889–897 (2016).

Of 600 VLBW infants enrolled, 598 were evaluated.
Forty-four (7.4%) infants developed NEC.
Thirty-two (5.4%) infants died (all cause).
Fifty-three percent of infants (319) received a total of 1430 RBC transfusion exposures.

The unadjusted cumulative incidence of NEC at week 8 among RBC transfusion-exposed infants was 9.9% (95% CI, 6.9%-14.2%) vs 4.6% (95% CI, 2.6%-8.0%) among those who were unexposed.
In multivariable analysis, RBC transfusion in a given week was not significantly related to the rate of NEC (adjusted cause-specific hazard ratio, 0.44 [95% CI, 0.17-1.12]; P = .09).
Based on evaluation of 4565 longitudinal measurements of hemoglobin (median, 7 per infant), the rate of NEC was significantly increased among VLBW infants with severe anemia in a given week compared with those who did not have severe anemia (adjusted cause-specific hazard ratio, 5.99 [95% CI, 2.00-18.0]; P = .001).

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Patel, R. M. et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. Jama 315, 889–897 (2016).

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Summary

The etiology of anemia of prematurity is multifactorial
Hemoglobin levels at birth increase with GA
Indications for RBC transfusion in neonates remained nebulous until the early 2000s
The PINT, ETTNO, and TOP trial demonstrated that restrictive transfusion thresholds were a safe practice and should be standard of care
Transfusions are not risk free
RBC transfusions should only be considered to improve distal oxygen delivery
Management of anemia of prematurity in neonates should favor reducing blood losses and improving erythropoiesis before RBC transfusion is considered.

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