1093CHAPTER 91 Transfusion Medicine Cytomegalovirus Negative Platelets Platelet concentrates can transmit CMV The indications for CMV negative platelets and RBCs are similar Cryopreserved Platelets Wh[.]
CHAPTER 91 Transfusion Medicine Cytomegalovirus-Negative Platelets Platelet concentrates can transmit CMV The indications for CMV-negative platelets and RBCs are similar Cryopreserved Platelets While cryopreservation of platelets increases product shelf life to years, the storage constraints (–80°C) and thawing protocols may not be conducive to use in all centers.156,157 With respect to in vivo studies, there have been a limited number of trials assessing safety and efficacy of cryopreserved platelets.158 Pathogen-Reduced Platelets Globally, multiple technologies are licensed that prevent the infectious potential from parasites, bacteria, and enveloped viruses in platelet units.159 The increased safety of pathogen-reduced platelets may come at a cost of hemostatic efficacy, as has been reported in children.160 Large multicenter trials are ongoing that will assess efficacy and safety of pathogen-reduced platelets in critically ill children (NCT02549222: https://clinicaltrials.gov) Platelet Transfusion (Why) Over 1.5 million platelet products are transfused in the United States each year.161 Between 3.3% and 7.1% of critically ill children receive at least one platelet transfusion while in PICU.151,162 Approximately two-thirds of all platelet transfusions to PICU patients are for prophylaxis of bleeding in the presence of thrombocytopenia, with an average pretransfusion platelet count of 32 27 109/L (median, 21) The remaining one-third of platelet transfusions in critically ill children are for active bleeding, with an average pretransfusion platelet count of 76 39 109/L (median, 72).162 Most platelet transfusions are administered to increase a low platelet count The prevalence of thrombocytopenia, defined by a platelet count less than 150,000/uL (,150 109/L), is 17.3% on admission into the PICU; 25.3% of children are thrombocytopenic at some point during their PICU stay.163 Thrombocytopenia arises from decreased platelet production, increased platelet destruction, and dilutional or distributional causes In the PICU, most thrombocytopenia is caused by chemotherapy, sepsis, DIC, MODS, or hemolytic uremic syndrome However, heparininduced thrombocytopenia, massive transfusion, and reactive hemophagocytic syndrome are not so rare.164 In critically ill children, thrombocytopenia at PICU entry is associated with increased mortality (17.6% vs 2.5%), bleeding complications, thrombosis, and prolonged PICU and hospital length of stay.163 Pediatric subjects are at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts.165 Platelet dysfunction might be the problem, at least in some instances In PICU patients, platelet dysfunction is typically caused by specific treatments (cardiopulmonary bypass, hypothermia, pentastarch, and hetastarch) or antiplatelet drugs (low-dose aspirin, nonsteroidal antiinflammatory drugs) but it can also be due to hereditary disease (e.g., Bernard-Soulier disease) Transfusion of Platelets: Indications (When) Platelet transfusions are indicated for the prevention or treatment of bleeding in patients with thrombocytopenia or platelet dysfunction As platelet transfusions will result in only modest elevations for to days in patients with persistent thrombocytopenia, 1093 the purpose of platelet therapy is not to eliminate all bleeding but rather to prevent or stop major hemorrhagic events Platelets are contraindicated in patients with thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia because of the increased thrombotic risk Therapeutic platelet transfusions are given to treat clinically significant bleeding associated with a low platelet count or platelet dysfunction There is evidence that correction of thrombocytopenia reduces mortality of critically ill patients,163,166 but a platelet transfusion should be considered only if the platelet count in an actively bleeding patient is less than 50,000/uL.44 However, caregivers must remember that “the principal treatment of ICUassociated thrombocytopenia is to treat the underlying disease.”167 For children with life-threatening bleeding, platelets should be transfused empirically in a ratio between 1:2 to 1:1 (ratio of whole blood–derived platelet unit to RBC unit) until the risk of bleeding resolves When apheresis platelets are transfused, the range of the ratio transfused is 1:5 to 1:10 (apheresis platelet units to RBC units) This recommendation is based on randomized controlled trials in adults and expert opinion.35 More than 50% of platelet transfusions in PICUs are given to prevent bleeding.151 There is insufficient evidence to support a particular threshold for prophylactic platelet transfusion in children.167 Most recommendations come from guidelines developed for adults, based on expert opinion For patients with hypoproliferative thrombocytopenia (e.g., chemotherapy induced), a platelet transfusion threshold of 10,000/uL (10 109/L) is recommended.108 This is based on two clinical trials in adults: Slichter168 reported no increases in bleeding rates when comparing platelet transfusion thresholds of 10,000 versus 20,000/uL; on the other hand, Stanworth et al.169 reported more bleeding in patients with hematologic cancer and a platelet count less than 10,000/uL who did not receive prophylactic platelet transfusion versus those who did On the other hand, Curley et al.170 reported a significantly higher rate of death or major bleeding among preterm infants who received platelet transfusions at a platelet-count threshold of 50,000/uL rather than 25,000/uL In the ICU, higher platelet transfusion thresholds are usually employed Intensivists generally prescribe platelets for patients on ECMO if their platelet count is less than 100,000/uL (10 109/L) The same threshold is frequently used when a central nervous system procedure is undertaken When the platelet count is less than 50,000/uL, platelets are usually given just prior to an invasive procedure (surgery, insertion of central venous catheter, and so on); platelet transfusion can also be considered in mechanically ventilated patients because the risk of pulmonary hemorrhage is significant A threshold of 50,000/uL is recommended for lumbar puncture.136 Increasing the threshold count that would trigger a platelet transfusion may be appropriate if platelets are dysfunctional The capacity of platelets to stop a hemorrhage is not only related to their number but also to their function Many tests can be used to estimate platelet function, such as TEG and devices or systems such as the Sonoclot coagulation analyzer (Sienco, Inc.), the Plateletworks analyzer (Helena Laboratories), the hemostatus platelet function test, the platelet function analyzer, and VerifyNow (Ultegra, Instrumental Laboratories) system.81 However, the results of these tests are not available on an emergency basis in most hospitals.171 Measurement of platelet mass may be a practical alternative There is evidence that larger platelets exhibit increased hemostatic activity.172 The results of a randomized controlled trial conducted in a neonatal ICU suggested that using platelet mass 1094 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology (platelet count mean platelet volume) rather than platelet count alone to trigger a platelet transfusion may reduce the number of transfusions.173 Nevertheless, it must be emphasized that the clinical usefulness of all of these tests remains undetermined in the PICU There is significant diversity in the stated practice pattern with respect to platelet transfusion.174 Most guidelines are based on expert opinion, not on quality data.40 More research is required to refine the indications for platelet transfusion in critically ill children measured 18 to 24 hours posttransfusion.161 Platelet refractoriness can occur due to nonimmune factors such as DIC, in which platelet consumption can be high, acquired hemophagocytic syndrome, drugs such as amphotericin or heparin, or immune factors involving antiplatelet antibodies.161 Treatment of the underlying problem is mandatory in such instances (e.g., discontinuing all heparin administration in heparin-induced thrombocytopenia) Patients with anti-IgA antibodies should receive washed platelets or platelets collected from IgA-deficient donors Transfusion of Platelets: How Whole Blood 11 There are about 3 10 platelets in a unit of apheresis platelets A simple rule of thumb suggests giving or platelet units per 10 kg, but not more than units per transfusion For children weighing less than 10 kg, the platelet dose can be to 10 mL/kg of pooled or apheresis platelet unit Transfusion of one platelet concentrate per square meter (m2) of body surface generally increases the platelet count by 7000 to 11,000/uL By body weight, the administration of one unit per 10 kg should increase the platelet count by 30,000 to 50,000/uL However, a clinical trial in which platelet dose was estimated by body surface area evaluated low-dose (1.1 1012 platelets/m2), medium-dose (2.2 1012/m2), and high-dose (3.3 1012/m2) prophylactic platelet transfusions and did not find any differences in bleeding among adult or pediatric patients.175 Platelets must be used within hours after delivery from the blood bank, but there is some evidence that the platelet count increases more if the unit is given within hour A filter with 80- or 170-micropores must be used to remove aggregates that can form between harvesting and transfusion The volume of a whole blood–derived platelet unit is about 50 mL while that of an apheresis platelet unit ranges from 200 to 300 mL; 90% to 95% of this volume is plasma It is important to note that this plasma is not an adequate source of coagulation factors because factor concentration drops rapidly during platelet storage at room temperature (20°C–24°C) Platelet units can be volume reduced (removal of plasma) prior to transfusion, but this process can decrease the platelet count by 15% to 20%, shortens the storage time to hours, and delays platelet release from the blood bank by approximately hour Volume reduction should be considered only if there is a risk of severe circulatory overload but is not recommended as a standard procedure because it can activate platelets.108 In 2017, 8% of platelet transfusions were volume reduced.151 Unlike RBC units, ABO compatibility is not mandatory with platelets While it is possibly better to use ABO-compatible platelet units if inventory allows, no differences were seen in the incremental change in platelet count or in transfusion reactions when comparing major ABO-incompatible platelet transfusions with ABO-compatible transfusions in a large study of critically ill children.176 In addition, Rh compatibility is desired because all platelet units contain some RBCs Transfusion of an Rh-positive unit to an Rh-negative patient can cause Rh alloimmunization; an anti-D immunoglobulin (e.g., Win Rho SDF, Saol Therapeutics) should be administered within 48 hours to prevent this complication when Rh-positive platelets are given to an Rhnegative patient, particularly if female.161 The percent platelet increment (difference between post- and pretransfusion platelet count) should be higher than 20% if the dose is adequate and if a platelet count is performed 10 to 60 minutes posttransfusion; it should be higher than 10% if Whole Blood: Type of Product The volume of a typical whole blood unit is about 450 to 500 mL It is stored at 2°C to 6°C, with storage duration between 21 and 35 days Some centers limit the storage duration to 14 to 21 days to maximize platelet and RBC function when whole blood is used for only life-threatening hemorrhage.177 Whole blood can be leukoreduced prior to storage with a platelet-sparing filter This filter has minimal effects on reducing platelet count and impairing hemostatic function.178 Whole blood can also be pathogen reduced, which has been shown to decrease rates of malaria transmission in a randomized controlled trial in Africa.179 Pathogenreduced whole blood is not licensed in the United States, Canada, or Europe Whole Blood: Indications The use of whole blood has been advocated mostly for first-line therapy in hemorrhagic shock, as it contains a balanced proportion of RBCs, coagulation factors, and platelets.180,181 Additional benefits of whole blood include platelets stored at 2°C to 6°C, which increases their hemostatic function and reduces the risk of bacterial infection, reduced donor exposures, and the logistic advantage of using one product compared to three.182 The use of whole blood should be considered only for patients with hemorrhagic shock Approximately 15% of children’s hospitals in the United States provide whole blood to children, predominantly for cardiac surgery, liver transplantation, and massive transfusion protocols Whole blood units are also used for some neonatal exchange transfusions.122 Barriers to whole-blood availability have included the need to provide ABO-specific whole blood This limited its availability due to the waste that would occur if each ABO type was maintained in the inventory of the hospital blood bank To address this issue, the use of low-titer group O whole blood (LTOWB) has been adopted based on data showing that the benefits of immediate availability of LTOWB to a patient with severe bleeding outweighs any small risk in non–group O recipients.150,183 The risk of transfusing group O whole blood to a non-O recipient is based on the concern that anti-A or anti-B antibodies will either cause hemolysis or endothelial injury This risk is not different than when non-ABO-matched platelets are transfused or when type A plasma is used in group B or AB severely bleeding patients In recognition of the data supporting the safety of LTOWB, the AABB has changed its standards to allow this product to be used for patients with life-threatening hemorrhage.182 Since this standard change, many trauma centers have implemented LTOWB for patients with severe bleeding.177 Pediatric centers have also begun using LTOWB for children with massive bleeding.184 CHAPTER 91 Transfusion Medicine 1095 Whole Blood: How Transfusions Reactions and Complications Whole blood can be transfused in a rapid infuser and blood warmer for life-threatening hemorrhage It can be given via an intraosseous line and should be transfused with a standard micropore filter The IgM titer of anti-A and anti-B for LTOWB can range from 1:50 to 1:256 Transfusion Reactions Cryoprecipitate Cryoprecipitate is a concentrated source of fibrinogen, factor VIII, factor XIII, and von Willebrand factor It is stored at a minimum of –18°C for a maximum of year Its indication is for fibrinogen replacement It is used in patients with congenital or acquired hypofibrinogenemia and patients with coagulopathy and significant bleeding, mostly in the context of cardiac surgery and/ or DIC in the setting of sepsis.185 It can also be used in patients with von Willebrand disease and hemophilia A if specific factor concentrates are not available The dose is or U/10 kg (maximum, 12 U), which should increase fibrinogen level about 60 to 100 mg/dL.108 A blood filter (80 or 180 micropore) should be used The recommended rate of delivery is 30 minutes (maximum, hours) Transfusion of labile blood products (RBC, plasma, platelets) can cause immediate or delayed transfusion reactions and various complications By definition, immediate reactions usually occur during the transfusion or within hours after the end of the transfusion; delayed reactions can occur after a few days, weeks, or even months or years later The incidences of transfusion reactions (adults and children) and transfusion-transmitted infectious diseases are reported in Tables 91.3 and 91.4, respectively Even though transfusion reactions are underdiagnosed in critically ill children,187 many large-scale studies reported that the risk of transfusion reactions signaled to hemovigilance systems is significantly higher in children than in adults.188–190 TACO and TRALI are the leading causes of transfusion-related morbidity and mortality in North America (Table 91.3)191 and are discussed later Epidemiology and proposed pathophysiology for other common transfusion reactions—including respiratory dysfunction associated with transfusion, hemolytic and nonhemolytic transfusion reactions, febrile and allergic reactions, bacterial contamination, and GVHD—are detailed later TABLE Incidence of Transfusion Reactions, Adults and Children (Risk per Unit of Blood Component) 91.3 All products RBCs FP Plateletsb 1:41,825 1:23,350 1:19,783 1:15,595 1:6,131 1:32,690 1:32,971 1:61,637 — — — 1:23,900 1:108,968 1:98,914 1 — — 1:50,017 1:18,161 — 1:31,189 1:85,227 1:108,968 1:98,914 1:15,595 1:18,017 1:23,350 1:6182 1:3889 1:100 1 1:50 to 1:200 1:300 — 1:10 1:1 million 1 1:78,073 1:163,452 — — Early Transfusion Reactions (Onset Usually ,6 Hours Posttransfusion) Cardiorespiratory Systems TRALI251,252,a TACO 251,252 Transfusion-associated dyspnea 252 Hypotensive transfusion reaction251,252,a,c Cardiac arrhythmias253,d Other Acute Transfusion Reactions and Complicationse Acute hemolytic reaction252,a ABO incompatibility 251,a Severe allergic/anaphylactic reaction Minor allergic reaction (urticaria) Febrile nonhemolytic reaction 251,252,a 220 254 Delayed Transfusion Reactions (Onset Usually Days After Transfusion) TA-GVHD115 Delayed hemolytic transfusion reaction Posttransfusion purpura 251,252,a Transfusion-transmitted infections a 251,252,a 1:1,171,101 1:108,968 — 1:31,189 See Table 91.4 1 Reported in 2003 Risk per pool of units of platelet c Hypotension can be caused by allergic or hemolytic reactions, septicemia, citrate toxicity, reaction to leukocyte reduction filters, and bradykinins in the supernatant of blood products d One retrospective study involving 143 critically ill adults with sepsis or septic shock reported more atrial fibrillation (P 04), cardiac arrest (P 03) and “all cardiac events” (P 001) in recipients of RBC units.253 e Metabolic complications include hypothermia, metabolic alkalosis, hypocalcemia, hypomagnesemia, hyperkalemia, hyponatremia, and hyperglycemia.190 FP, Frozen plasma; RBCs, red blood cells; TACO, transfusion-associated circulatory overload; TA-GVD, transfusion-associated graft versus host disease; TRALI, transfusion-related acute lung injury b 1096 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology TABLE 91.4 Transfusion-Transmitted Infectious Diseases in Canada Infection Risk per Units Componenta Human immunodeficiency virus (HIV)252 252 Hepatitis B in 1.1–1.7 million 252 in 5–7 million Hepatitis C Parvovirus B19 in 8–12 million 252 1:5000 to 1:20,000 Cytomegalovirus252 Rare Syphilis252 ,1 in 100 million Bacterial contamination b Other infections 252 1:292,775 Low a Most transfusion-transmitted infections are attributable to red blood cell units However, there is historical evidence that the following infectious agents can be transmitted by plasma-derived products: HIV, hepatitis B and C, and parvovirus B19, but not cytomegalovirus or parasites.251 b Many other agents can be transmitted by a transfusion, such as West Nile virus and insect-borne zoonoses (e.g., malaria,255 babesiosis,256 Bartonella quintana,257 and variant Creutzfeldt-Jacob disease).258 Immediate Transfusion Reactions The incidence of typical immediate reactions after RBC, FP, and platelet transfusion is reported in Table 91.3 The risk of transfusion reactions is higher in children A report on transfusion reactions observed in children in the United Kingdom estimated the incidence of transfusion-related adverse events to be 13 per 100,000 RBC units issued for adults, 18 per 100,000 RBC units for children less than 18 years of age and 37 per 100,000 RBC units for infants less than 12 months Among the 321 adverse reports in children, 82% were instances of incorrect blood component transfusion and 14% were acute transfusion reactions.188 A Norwegian study reported 106 versus 298 transfusion reactions per 100,000 transfused RBC units in adults and children, respectively.189 Vossoughi et al.190 reported 252 versus 538 reactions per 100,000 RBC units in adults and children, respectively, notably higher for RBC (278 vs 577, P , 001) and platelet transfusions (358 vs 833 per 100,000; P , 001) Allergic reactions seem to be more frequent in children than in adults.189 Transfusion reactions are probably underdiagnosed in critically ill children In a study conducted in the PICU of Sainte-Justine Hospital, all transfusions between February 2002 and February 2004 were prospectively monitored.187 A total of 2509 transfusions were administered to 305 patients Forty acute transfusion reactions (1.6%) occurred: 24 nonhemolytic febrile reactions, minor and major (anaphylactic shock) allergic reactions, isolated hypotensive reactions, bacterial contaminations, hemolytic reaction and TRALI TRALI is one of the most dangerous transfusion reactions Two pathophysiologic mechanisms are currently proposed: antibody-mediated and non–antibody-mediated TRALI.192,193 (1) According to the antibody hypothesis, TRALI is caused by an antigen-antibody reaction.194 The antibodies (granulocyte antibodies and/or HLA class I or II antibodies) are present in the donor plasma and react with the recipient’s WBC antigens (or, rarely, vice versa) The administration of such antibodies can directly injure the lung or can activate neutrophils, monocytes, and complement, creating an inflammatory reaction that may result in pulmonary damage (2) According to the two-hit or neutrophil-priming hypothesis, recipients must first have a predisposing factor that “primes” their neutrophils, such as a septic state or a MODS Then, the recipient’s neutrophils are activated again by donor plasma that contains leukocyte antibody or proinflammatory molecules, such as cytokines and bioactive lipids.195 A panel of experts suggested a consensus definition of TRALI in 2004.196 The list of diagnostic criteria advocated by these experts is detailed in eBox 91.5.186 The diagnosis of TRALI is made on the basis of clinical signs and symptoms, chest radiographs suggestive of pulmonary edema, and time relationship with transfusion (onset per transfusion or within hours posttransfusion) The experts defined TRALI as a new ALI for which no other risk factor than the transfusion can be found They suggested the term possible TRALI if another risk factor can be temporally related to the ALI TRALI is a clinical syndrome, and no laboratory test is pathognomonic, but the presence of HLA and/or neutrophil antibodies in the donor plasma is highly suggestive.192 However, the absence of such antibodies does not exclude a typical case of TRALI Causes of pulmonary edema other than TRALI should also be excluded, such as fluid overload or cardiac dysfunction The incidence rate of TRALI in the PICU is still unknown.197 However, over a 3-year period, Gauvin et al.187 observed one case of TRALI among 305 transfused PICU patients All blood products that contain plasma, even in minute quantities, can cause a TRALI When such a reaction occurs, the transfusion must be stopped immediately and supportive therapy administered Associated hypotension may be unresponsive to fluid administration and may require use of inotropes/vasopressors All suspected TRALI reactions must be reported to the blood bank to determine whether the donor’s other blood products need to be withdrawn The risk of recurrence if the patient gets a subsequent transfusion from another donor is very low The prognosis of cases of TRALI is usually good if the patient survives, but a mortality rate of 6% has been reported In survivors, resolution is usually rapid (within 96 hours), and there are no long-term sequelae.198 The diagnostic criteria advocated by the panel of experts in 2004 exclude the possibility that a TRALI appears more than hours posttransfusion or in patients who already present an ALI or ARDS, a frequent occurrence in the PICU Marik and Corwin199 suggested expanding the definition of TRALI in the ICU to ALI/ARDS observed within 72 hours after the transfusion of a blood product: they reported that this “delayed TRALI syndrome” occurred in up to 25% of transfused critically ill adults Church et al.200 also reported an association between the transfusion of plasma and/or RBC units and ALI/ARDS There is some evidence that TRALI should also be considered in some patients with ALI/ARDS before a transfusion if their respiratory dysfunction deteriorates significantly during or after a transfusion.201 The bioactive substances contained in RBC and plasma units can cause or add to the severity of cases of ALI/ARDS.200,202 Actually, there is a synergistic effect of anemia and RBC transfusion on inflammation and lung injury.203 Further investigation is required to better characterize the epidemiology, mechanisms, and clinical impact of transfusion-related ALI/ARDS in the PICU Respiratory Dysfunction Associated With Transfusion (RDAT). Respiratory complications associated with RBC trans- fusions may be underestimated in the PICU because current definitions exclude patients with preexisting respiratory dysfunction (RD) Kleiber et al.204 undertook a prospective cohort study to determine the epidemiology of new or progressive RD observed after RBC transfusion in critically ill children A respiratory 1096.e1 • eBOX 91.1 Diagnostic Criteria of Transfusion- Related Acute Lung Injury (TRALI) and Possible TRALI186 Diagnostic Criteria of TRALI (all four criteria must be present) Diagnostic criteria ALI: • Acute onset • Hypoxemia: Pao2/Fio2 # 300 or Spo2 ,90% on room air • Bilateral infiltrates on frontal chest radiograph • No evidence of left atrial hypertension (i.e., no circulatory overload) No preexisting ALI before transfusion Onset during or within hours posttransfusion No temporal relationship to an alternative risk factor of ALI (see list of factorsa) Diagnostic Criteria of Possible TRALI 3 4 a ALI No preexisting ALI before transfusion Onset during or within hours posttransfusion A clear temporal relationship to an alternative risk factor for ALI Risk factors of direct lung injury: aspiration, pneumonia, toxic inhalation, lung contusion, near drowning Risk factors of indirect lung injury: severe sepsis, shock, multiple trauma, burn injury, acute pancreatitis, cardiopulmonary bypass, drug overdose Fio2, fraction of inspired oxygen; Pao2, arterial partial pressure of oxygen; Spo2, peripheral capillary oxygen saturation ... patients.175 Platelets must be used within hours after delivery from the blood bank, but there is some evidence that the platelet count increases more if the unit is given within hour A filter with 80-... of an apheresis platelet unit ranges from 200 to 300 mL; 90% to 95% of this volume is plasma It is important to note that this plasma is not an adequate source of coagulation factors because factor... anti-D immunoglobulin (e.g., Win Rho SDF, Saol Therapeutics) should be administered within 48 hours to prevent this complication when Rh-positive platelets are given to an Rhnegative patient, particularly