Pediatric Blood Transfusion Therapy and Patient Blood Management

By Norma J. Klein, MD
Clinical Professor
University of California, Davis

A SPA workshop on pediatric blood transfusion therapy and patient blood management (PBM) was led by experts in PBM at the 2019 SPA/AAP meeting in Houston, Texas.  The recent evidence-based research guidelines regarding pediatric PBM were presented, and some practical aspects of intraoperative pediatric blood product transfusions were discussed. 

The workshop opened with a panel presentation by Drs. Susan Goobie, Mark Yazer, and Jonathan Waters. 

Dr. Goobie (Boston Children’s) gave an overview of Pediatric PBM and noted that a blood transfusion can be either life-saving or life-threatening for children.  Bleeding and blood transfusion are associated with increased morbidity and mortality in children, which is significantly higher than in adults. The reported incidence of serious hazards of transfusion (SHOT) has increased, particularly in infants and especially non-infectious transfusion-associated complications.(1) There are two cases of death in children reported for every 100,000 blood products transfused. Children have a higher incidence of adverse reactions during transfusion of blood products, with nearly two times the adult rate in children and three times the adult rate in infants.(2)  

Pediatric PBM involves using multimodal blood conservations strategies to reduce exposure to blood transfusion.  PBM is defined as, “The timely application of evidence based medical concepts designed to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcomes.”(3)  Pediatric PBM may include the following measures: (4-7)

• Timely preoperative anemia diagnosis and management
• Minimizing blood draws and sample size
• The use antifibrinolytics to stabilize the blood clot and decrease blood loss
• Use of restrictive blood transfusion algorithms
• Surgical techniques to minimize blood loss
• Avoidance of hemodilution by careful fluid management
• Cell salvage
• Viscoelastic testing (Rotem and TEG) to guide hemostasis management
• Use of massive hemorrhage protocol to guide goal-directed treatment of bleeding

While PBM programs are well-recognized in the adult setting, they are quite far from standard-of-care in the pediatric patient population. Adult PBM standards cannot be uniformly applied to children and there currently is significant variation in transfusion practices nationally across and within hospitals. Data suggest restrictive transfusion strategies should be employed for neonates, infants and children.  Evidence based and expert consensus guidelines are currently available to guide the implementation of PBM techniques, taking into consideration optimum oxygenation requirements, hemoglobin thresholds and blood transfusion strategies for patients with active bleeding, hemodynamic instability, unstable cardiac disease and cyanotic cardiac disease. 

Dr. Jonathan Waters (University of Pittsburgh Medical Center), an authority on autotransfusion, discussed the use of intraoperative cell salvage.(8) The collection of shed surgical blood, its filtration and its subsequent reinfusion was first pioneered in 1874. In this era, the blood was simply filtered with gauze prior to reinfusion. In the mid-1970’s, washing was added to the processing of this shed blood. The first machine was the “cell saver”, manufactured by Haemonetics®. Now there are multiple manufacturers of intraoperative blood collection and reinfusion devices. Rather than use the brand name of “cell saver” to refer to this process, many have chosen a more generic term, “autotransfusion”, to describe this process.

Typical 40-micron blood filter

Many contraindications have been discussed over the years but many of these contraindications relate to FDA labeling rather than being true contraindications. For instance, widespread use of autotransfusion takes place with obstetrical care, trauma care and even in cancer surgery. Using special filters, many contaminants can be removed. A leukocyte depletion filter is effective at removing anything with DNA which would include cancer cells, bacteria or fetal squamous cells. The filter (~150 micron) in the collection reservoir is effective in sifting out macroaggregates such as fat, bone fragments, tissue, and gauze fibers.  Other soluble substances, such as heparin, free hemoglobin, and potassium, are removed in the “wash out” phase.  All cell-saver blood must be infused with a 40-micron “microaggregate” filter.  This 40-micron filter is in addition to the standard 170 to 200-micron filter that comes in the standard blood infusion tubing.  The 40-micron filter is one final safety net to filter out both macro- and microaggregates. 

While studies comparing outcomes between autologous and allogeneic transfusion are limited, many of the complications associated with allogeneic blood are eliminated by autotransfusion. Additionally, in a busy service, a unit of autologous blood can be provided at a lower cost than an allogeneic unit.(9)  Until recently, the ability to cell salvage was limited by the larger volumes of blood necessary for cell washing.(10)  New technology now supports cell salvage through incorporation of smaller collection bowls, less than 100 ml in size.(11, 12)  If the final hemoglobin goal is 15 to 25 g/dL per cell saver unit, the volume of collected blood should be at least three times the bowl size.  

Cold stored whole blood administration has re-emerged as a viable alternative to conventional components for patients who require transfusions early in their resuscitation.  Dr. Mark Yazer, a hematopathologist who has published extensively on whole blood implementation,  presented the benefits of low-titer, type O, whole blood (LTOWB).  These benefits include simplified logistics facilitating early transfusion in casualty resuscitation, less dilution of the final product compared to reconstituted whole blood, and reduced bacterial contamination risk that is associated with platelets stored at room temperature. 

Whole blood used in pediatric cardiac surgery patients may also significantly reduce donor exposure when these patients are transfused during surgery.  Furthermore, studies in both military and civilian populations have demonstrated that recipients of LTOWB do not have worse outcomes compared to recipients of conventional components, and that the early administration of blood products improves mortality.(13, 14)

 At the University of Pittsburgh, Drs. Leeper, Yazer, and colleagues recently treated 18 pediatric trauma patients (mean age 11, IQR 5-14) with LTOWB blood in the resuscitation phase of care.(15)  The primary objective of the study was to evaluate patients for indicators of hemolysis (serum creatinine, potassium, and LDH) during the three days post-transfusion.  A major concern with administering type O whole blood to non-group type O recipients is that it must contain compatible RBCs but potentially incompatible plasma.  The plasma of patients who have blood type O blood contains naturally-occurring A- or B-type antibodies. Therefore, type O RBCs in plasma that has low titer anti-A and anti-B antibodies is a logical, and in fact required, choice for safe whole blood administration. 

Under current US standards, whole blood for transfusion does not need to be blood type “identical”; the AABB (formerly American Association of Blood Banks) standard now requires that the RBCs in the whole blood product be “compatible” with the recipient’s blood type.  In Dr. Leeper’s study, there was no evidence of hemolysis amongst the non-group O recipients compared to the group O, LTOWB recipients. 

Dr. Destiny F. Chau (Children's Hospital of The King's Daughters) discussed acute normovolemic hemodilution (ANH) as a blood management strategy and demonstrated associated techniques for pediatric patients. Although current evidence is insufficient to support its routine use, ANH has been utilized for the successful reduction of allogenic blood transfusion requirements in specific pediatric patients undergoing elective surgeries with anticipated significant blood loss (e.g., 50% of blood volume).(16-19)  ANH also offers a blood management alternative to patients who refuse all blood products.(20) 

Other potential advantages include the use of fresh autologous whole blood containing all coagulation factors and reduced risk of allogeneic blood-related detrimental effects such as transfusion-transmitted infection (TTI).  Institutional guidelines should be available if performing ANH to ensure patient safety.   Autologous blood collection is usually performed via central or peripheral venous lines with the withdrawal of 10 - 20 ml/kg (body weight less than 5 kg) or up to 20% of estimated blood volume (body weight greater than 5 kg) over 20 to 30 minutes while the patient is fully monitored for signs of intolerance. Crystalloid or colloids are infused to maintain normovolemia. The blood is collected into pre-prepared containers with citrate-phosphate-dextrose-adenosine (CDPA) anticoagulant at a CPDA to blood ratio of approximately 1:7 to 1:10.(21)  The blood is maintained at room temperature and transfused back to the patient towards the end of the surgery.  Contraindications to ANH include, but are not limited to, patients with impaired end-organ function and those who present with preoperative anemia.

Dr. Nitin Wadhwa (Children’s Memorial Hermann) presented examples of various transfusion devices including blood warmers, rapid infusers, and blood filters.(22, 23)  All blood products should be transfused through a 170 – 260 micron filter, included in all standard blood administration sets.  The 40-micron filter, however, is intended for cell saver use and should not be used to transfuse platelets or any other blood product administered under pressure due to increased likelihood of hemolysis. 

Specialized “needleless” neonatal syringe sets (150-micron filter) are now available for single use and small aliquot delivery by syringe.  Blood should be infused through a fluid warmer during large volume transfusions (e.g., 15 ml/kg), during exchange transfusions, and in patients with cold agglutinin disease.  The enFlow® warmer (GE Medical), a welcomed solution to the need for a small volume, low infusion rate blood warming device, was recalled from the market secondary to concerns over aluminum leakage from the inline cartridge during fluid administration.  Rapid infuser devices have not been validated for safety in children.  The Level 1 Hotline suits slower, low-volume blood replacement; the Belmont, however, should be reserved for larger children (e.g., > 40 kg) experiencing rapid and massive blood loss.(24) Air embolus and TACO (transfusion-associated circulatory overload) are risk factors of rapid infuser systems.

Dr. Norma Klein (UC Davis Children’s Hospital) conducted a PBLD on blood transfusions in low resource environments.  The World Health Organization estimates that 65% of transfusions in low-income countries are administered to patients less than five years of age.(25) Access to a safe and immediate blood supply in developing countries is limited due to a lack of centralized infrastructure, a reliable donor source, and prohibitive cost.  Half of the world’s donated blood originates in countries that contain less than 20% of the global population. 

Recognizing that blood transfusions can save lives, the World Health Organization (WHO) recommends that there should be a reserve of blood at facilities performing surgery.  Anemia is so prevalent in developing countries such as India and Africa (and the blood supply is so scarce) that the WHO advises red blood cell (RBC) transfusion in children at a Hgb of 4 g/dL in the absence of other symptoms such as respiratory distress or heart failure.(26) However, despite the presence of operating rooms, a pharmacy, and large hospital wards, many hospitals in low resource areas do not contain a blood bank and blood products are often not immediately available.(27) 

This problem has led many communities into what are called the “replacement” or family donation scheme:  If a patient urgently requires blood from a blood storage facility, the patient’s family finds a suitable replacement in exchange for immediately available stored blood.  As an alternative to the family or replacement system, an unbanked directed blood transfusion system (UDBT) has been increasingly proposed.(28)  UDBT is similar to the buddy or “walking blood bank” system used in the field by the military.(29) This blood supply system was made illegal in India in 1998, with government concerns that such a blood source may encourage professional donors (who may not be forthcoming about high-risk behavior). 

Blood group screening, when performed through standardized procedures and under quality oversight, requires resources such as a centralized infrastructure and consistent supplies that may not be present in low resource settings.  As part the walking blood bank adaptation in low resource areas, local hospital employees may know their own blood type and may even wear it on their employee badge.  Under austere or emergency conditions, a bedside rapid test has gained popularity and, on some medical missions, the Eldonâ card has become part of the team supply.  However, predetermined blood types and bedside donor blood group testing do not necessarily ensure a safe blood product. The WHO recommends routine testing of all donor blood for HIV, HCV, HBV, and syphilis.(30).  In addition to TTI testing and blood group typing for compatibility, the donor blood is ideally “crossmatched” with the intended recipient’s blood.

Massive transfusion protocols (MTP) were adopted in the US years ago for the adult patient population.   In pediatrics, MTP’s are just being developed and the definition of massive blood loss, similar to the adult world, may vary.  Dr. Francois Trappey, a surgeon, led a PBLD discussion on a recently developed consensus-based pediatric MTP protocol for trauma patients, defining massive blood loss at 40 ml/kg body weight.(31, [EMID:a11bdd26c8205dc0]). Following unsuccessful hemodynamic resuscitation using crystalloid 20 ml/kg along with other measures, blood dosing is guided using a Broselow-based transfusion table, with the preferential order of product administration of PRBC, then plasma, then platelets in a volume ratio of 2 : 1 : 0.5.  When the protocol is deactivated in a stable, nonbleeding patient, coagulation parameter goals include hemoglobin 7 g/dL, INR < 2.0, and a platelet count of 20,000/µL.  Further work appearing in the literature will help to define the optimal MTP definition, blood product ratios, and outcomes in children requiring MTP administration.

Dr. Amy Rahm (UC Davis Children’s Hospital), a pediatric cardiac surgeon, conducted a PBLD on blood conservation in pediatric cardiac surgery, covering the pre-, intra-, and postoperative phases of care.  Preoperatively, a careful family history of bleeding diatheses and anemia management are crucial to avoiding perioperative blood transfusions.(32) ANH in select cases reduces allogeneic donor exposure and provides a fresh source of whole blood replete with clotting factors.  Intraoperatively, retrograde arterial and venous line primes, cell salvage, miniaturized bypass circuits, ultrafiltration and low-dose antifibrinolytic therapy (particularly neonates and repeat cases) can be utilized to minimize transfusion requirements.(33)  Blood sampling should be minimized and microtubes should be used when possible. 

Postoperatively, high chest tube output can be returned through cell salvage.  On the day of surgery, antifibrinolytics (tranexamic acid, aminocaproic acid, desmopressin) can be utilized in the postoperative phase for continued bleeding.  Coagulation monitoring using TEG, ROTEM, or traditional laboratory testing is essential to reduce arbitrary transfusion decisions.  Restrictive RBC transfusion goals should be adopted, although the exact cutoff for cyanotic and non-cyanotic patients is unclear (e.g., 7 g/dL vs. 9 g/dL), requiring a balance of clinical considerations.(33, 34)

Dr. Amy Denise Graham-Carlson (Children’s Memorial Hermann) presented a brief review of the use of thromboelastography (TEG) and thromboelastometry in pediatric patients.  Characteristic waveforms of the TEG and what each value represents were discussed. While the use of TEG has not yet been validated in pediatric patients, there are a few articles that cite its utility in pediatric trauma, liver, and cardiac patients in directing transfusion of blood products as well as antifibrinolytics and coagulation factors.(34, 35)  The use of TEG may also be useful in predicting mortality in pediatric trauma patients.(36, 37)

References

1. Harrison E, Bolton P. Serious hazards of transfusion in children (SHOT). Paediatr Anaesth. 2011;21(1):10-3.
2. Delaney M, Wendel S, Bercovitz RS, Cid J, Cohn C, Dunbar NM, et al. Transfusion reactions: prevention, diagnosis, and treatment. Lancet. 2016;388(10061):2825-36.
3. SABM Administrative and Clinical Standards for Patient Blood Management Programs. Society for the Advancement of Blood Management; 2018.
4. Faraoni D, DiNardo JA, Goobie SM. Relationship Between Preoperative Anemia and In-Hospital Mortality in Children Undergoing Noncardiac Surgery. Anesth Analg. 2016;123(6):1582-7.
5. Goobie SM, Faraoni D. Tranexamic acid and perioperative bleeding in children: what do we still need to know? Curr Opin Anaesthesiol. 2019;32(3):343-52.
6. Valentine SL, Bembea MM, Muszynski JA, Cholette JM, Doctor A, Spinella PC, et al. Consensus Recommendations for RBC Transfusion Practice in Critically Ill Children From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med. 2018;19(9):884-98.
7. Goobie SM, Gallagher T, Gross I, Shander A. Society for the advancement of blood management administrative and clinical standards for patient blood management programs. 4th edition (pediatric version). Paediatr Anaesth. 2019;29(3):231-6.
8. Waters JH. Intraoperative blood recovery. ASAIO J. 2013;59(1):11-7.
9. Waters JR, Meier HH, Waters JH. An economic analysis of costs associated with development of a cell salvage program. Anesth Analg. 2007;104(4):869-75.
10. Golab HD, Scohy TV, de Jong PL, Takkenberg JJ, Bogers AJ. Intraoperative cell salvage in infants undergoing elective cardiac surgery: a prospective trial. Eur J Cardiothorac Surg. 2008;34(2):354-9.
11. Overdevest EP, Lanen PW, Feron JC, van Hees JW, Tan ME. Clinical evaluation of the Sorin Xtra(R) Autotransfusion System. Perfusion. 2012;27(4):278-83.
12. Seyfried TF, Gruber M, Streithoff F, Mandle RJ, Pawlik MT, Busse H, et al. The impact of bowl size, program setup, and blood hematocrit on the performance of a discontinuous autotransfusion system. Transfusion. 2017;57(3):589-98.
13. Seheult JN, Bahr M, Anto V, Alarcon LH, Corcos A, Sperry JL, et al. Safety profile of uncrossmatched, cold-stored, low-titer, group O+ whole blood in civilian trauma patients. Transfusion. 2018;58(10):2280-8.
14. Yazer MH, Seheult J, Kleinman S, Sloan SR, Spinella PC. Who's afraid of incompatible plasma? A balanced approach to the safe transfusion of blood products containing ABO-incompatible plasma. Transfusion. 2018;58(2):532-8.
15. Leeper CM, Yazer MH, Cladis FP, Saladino R, Triulzi DJ, Gaines BA. Use of Uncrossmatched Cold-Stored Whole Blood in Injured Children With Hemorrhagic Shock. JAMA Pediatr. 2018;172(5):491-2.
16. Sebastian R, Ratliff T, Winch PD, Tumin D, Gomez D, Tobias J, et al. Revisiting acute normovolemic hemodilution and blood transfusion during pediatric cardiac surgery: a prospective observational study. Paediatr Anaesth. 2017;27(1):85-90.
17. Jamnicki M, Kocian R, van der Linden P, Zaugg M, Spahn DR. Acute normovolemic hemodilution: physiology, limitations, and clinical use. J Cardiothorac Vasc Anesth. 2003;17(6):747-54.
18. Crescini WM, Muralidaran A, Shen I, LeBlan A, You J, Giacomuzzi C, et al. The use of acute normovolemic hemodilution in paediatric cardiac surgery. Acta Anaesthesiol Scand. 2018;62(6):756-64.
19. Simon TL, McCullough J, al e. Rossi's Principles of Transfusion Medicine. 5th ed. West Sussex, UK: Willey Blackwell; 2016.
20. Ratliff TM, Hodge AB, Preston TJ, Galantowicz M, Naguib A, Gomez D. Bloodless pediatric cardiopulmonary bypass for a 3.2-kg patient whose parents are of Jehovah's Witness faith. J Extra Corpor Technol. 2014;46(2):173-6.
21. Barcelona SL, Thompson AA, Coté CJ. Intraoperative pediatric blood transfusion therapy: a review of common issues. Part II: transfusion therapy, special considerations, and reduction of allogenic blood transfusions. Paediatr Anaesth. 2005;15(10):814-30.
22. Barcelona SL, Vilich F, Coté CJ. A comparison of flow rates and warming capabilities of the Level 1 and Rapid Infusion System with various-size intravenous catheters. Anesth Analg. 2003;97(2):358-63, table of contents.
23. AABB. Technical Manual. 19th ed. Fung M, editor. Bethesda, MD: Amerian Association; 2017.
24. Blum RH CC. A Practice of Anesthesia for Infants and Children. 4th ed. Cote L, Todres, editor. Philadelphia: Saunders Elsevier; 2009.
25. Blood Safety and Availability [Internet]. World Health Organization. 2017. Available from: Found at: https://www.who.int/news-room/fact-sheets/detail/blood-safety-and-availability.
26. Roberts DJ, Field S, Delaney M, Bates I. Problems and Approaches for Blood Transfusion in the Developing Countries. Hematol Oncol Clin North Am. 2016;30(2):477-95.
27. Kralievits KE, Raykar NP, Greenberg SL, Meara JG. The global blood supply: a literature review. Lancet. 2015;385 Suppl 2:S28.
28. Sood R, Raykar N, Till B, Shah H, Roy N. Walking blood banks: an immediate solution to rural India's blood drought. Indian J Med Ethics. 2018;3(2):134-7.
29. Strandenes G DPM, Hervig TA, et al. Emergency Whole Blood use in the Field: A Simplified Protocol for Collection and Transfusion. Available from: Found at: https://prolongedfieldcare.files.wordpress.com/2014/11/emergency-wb-protocol.pdf.
30. Jenny HE, Saluja S, Sood R, Raykar N, Kataria R, Tongaonkar R, et al. Access to safe blood in low-income and middle-income countries: lessons from India. BMJ Glob Health. 2017;2(2):e000167.
31. Neff LP, Cannon JW, Morrison JJ, Edwards MJ, Spinella PC, Borgman MA. Clearly defining pediatric massive transfusion: cutting through the fog and friction with combat data. J Trauma Acute Care Surg. 2015;78(1):22-8; discussion 8-9.
32. Sarangi SN, Acharya SS. Bleeding Disorders in Congenital Syndromes. Pediatrics. 2017;139(2).
33. Faraoni D, Meier J, New HV, Van der Linden PJ, Hunt BJ. Patient Blood Management for Neonates and Children Undergoing Cardiac Surgery: 2019 NATA Guidelines. J Cardiothorac Vasc Anesth. 2019.
34. Cholette JM, Faraoni D, Goobie SM, Ferraris V, Hassan N. Patient Blood Management in Pediatric Cardiac Surgery: A Review. Anesth Analg. 2018;127(4):1002-16.
35. Sujka J, Gonzalez KW, Curiel KL, Daniel J, Fischer RT, Andrews WS, et al. The impact of thromboelastography on resuscitation in pediatric liver transplantation. Pediatr Transplant. 2018;22(4):e13176.
36. Vogel AM, Radwan ZA, Cox CS, Cotton BA. Admission rapid thrombelastography delivers real-time "actionable" data in pediatric trauma. J Pediatr Surg. 2013;48(6):1371-6.
37. Kalkwarf KJ, Jensen SD, Allukian M, Harting MT, Cox CS, Fox EE, et al. Can We Identify Futility in Kids? An Evaluation of Admission Parameters Predicting 100% Mortality in 1,292 Severely Injured Children. J Am Coll Surg. 2018;226(4):662-7.