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Transfusion Medicine

  • Marisa Tucci
  • Jacques LacroixEmail author
  • France Gauvin
  • Baruch Toledano
  • Nancy Robitaille
Chapter
  • 1.8k Downloads

Abstract

Anemia is common in pediatric intensive care units (PICU). Severe anemia can significantly increase the risk of death. Only a red blood cell (RBC) transfusion can rapidly treat a severe anemia. In stable PICU patients, RBC transfusion is probably not required if the hemoglobin concentration is above 7 g/dL, unless the patient has a cyanotic cardiac condition. The trigger or goal that should be used to direct RBC transfusion therapy in unstable critically ill children remains undetermined, although some data suggest that RBC transfusion may help in the early treatment of unstable patients with sepsis if their ScvO2 is below 70 % after mechanical ventilation, fluid challenge, and inotropes/vasopressors perfusions have been initiated. Plasma and platelets are used to prevent or to treat hemorrhage attributable to a coagulopathy, thrombocytopenia or platelet dysfunction. The risks and benefits of plasma and platelet concentrates in PICU patients are discussed. There is almost no evidence at the present time that might permit a strong recommendation with regard to the use of plasma and platelets in PICU. Good knowledge of transfusion reactions is required in order to appropriately estimate the cost/benefit ratio of transfusion. Nowadays, non-infectious serious hazards of transfusion (NISHOT) are more frequent and more challenging for pediatric intensivists than transfusion-transmitted infectious diseases. The decision to prescribe a transfusion must be tailored to individual needs and repeated clinical evaluation of each critically ill child.

Keywords

Anemia Erythrocyte Plasma Platelets Transfusion 

Transfusion of Red Blood Cells

Anemia in the PICU

Anemia—defined as a hemoglobin (Hb) concentration below the “normal” range for age—has been reported to occur up to 74 % of critically ill children with a pediatric intensive care unit (PICU) stay longer than 2 days. Indeed, anemia is already present at the time of PICU admission in 33 % of children, and an additional 41 % develop anemia during their PICU stay [1]. Patients who become anemic gradually over a long period of time and who are chronically anemic are more tolerant of their anemic state than those who develop anemia acutely. The main symptoms and signs of acute anemia are not specific and include pallor, tachycardia, lethargy and weakness. An increased blood lactate level and elevated oxygen (O2) extraction ratio (>40 %) can also be observed in severe cases [2].

The etiology of anemia may be attributable to: (1) blood loss, (2) decreased bone marrow production, which may in part be secondary to a disturbed bone marrow response to erythropoietin [3], (3) decreased RBC survival [4], and (4) anemia due to underlying diseases such as cancer and congenital hemoglobinopathies. However, blood loss is the most important cause of anemia acquired in the PICU. Blood draws account for 70 % of all blood loss (0.32 mL/kg/day in PICU), and procedures and hemorrhage are other causes of blood loss [1].

In healthy animals undergoing acute hemodilution, evidence of heart dysfunction appears only once the Hb concentration drops below 3.3–4 g/dL [5, 6]. However, animals with 50–80 % coronary artery stenosis can show evidence of ischemic insult to the heart with a Hb concentration as high as 7–10 g/dL [7]. In human beings, Carson et al. [8] studied the outcome after surgery in 1,958 patients who declined transfusion for religious reasons; the odds ratio for death started to increase in those with prior ischemic heart disease when their pre-operative Hb concentration decreased below 10 g/dL. Carson et al. [9] also studied the outcome after surgery in 300 patients without prior ischemic heart disease who declined transfusion for religious reasons. The odds ratio for death started to increase when the post-operative Hb concentration dropped below 4 g/dL. There are some data describing the relationship between anemia in severely ill children and mortality. A prospective cohort study in Kenya of 1,269 hospitalized children with malaria showed that RBC transfusions decreased death rate if anemia was severe (Hb level < 4 g/dL) or if some dyspnea was associated with a Hb level < 5 g/dL [10]. In another study conducted in Kenya, Lackritz et al. [11] followed 2,433 hospitalized children younger than 12 years with chronic or acute anemia among which 20 % received RBC transfusions. Some benefit was observed when a RBC transfusion was given to patients with a Hb level below 4.7 g/dL, and if there were signs and symptoms of respiratory disease. Given these results, guidelines were written suggesting that a RBC transfusion should be given to all children with a Hb level < 5 g/dL hospitalized in this Kenyan hospital. Subsequently, Lackritz et al. [12] undertook a prospective study in 1,223 consecutively hospitalized children. The Hb level was <5 g/dL in 303 patients. Of these patients, 116 (38 %) did not receive a transfusion, mostly because packed RBC units were not available. Each of these 303 children with severe anemia was paired with the next child hospitalized with a Hb level > 5 g/dL; none of the latter children with a Hb level > 5 g/dL received a RBC transfusion. Overall mortality was 30 % in the 303 children with a Hb level < 5 g/dL and 19.5 % in those with a Hb level > 5 g/dL (p < 0.01). Among the 303 patients with a Hb < 5 g/dL, mortality in transfused versus non transfused children was respectively 21.4 % and 41.4 % (p < 0.001). These studies suggest that there may be some benefit in keeping the Hb concentration of hospitalized children above 5 g/dL, though a higher threshold Hb concentration may be required in critically ill children.

Severe anemia, as described in the studies above, results in tissue hypoxia, which is likely the main mechanism leading to increased morbidity and mortality in these patients. Of note, tissue hypoxia may be due not only to a low Hb concentration (anemic hypoxia), but also to abnormal blood flow (stagnant hypoxia), decreased Hb saturation (hypoxic hypoxia) or to mitochondrial dysfunction (cytotoxic or cytopathic hypoxia) [13]. Stagnant hypoxia can be caused by dysregulated blood flow in the central circulation (cardiac output), the regional circulation (distribution of blood flow between organs), or the microcirculation (distribution of blood flow within organs) [14, 15, 16].

Adaptive Mechanisms to Acute Anemia in Critically Ill Patients

While the risks of blood transfusion have been extensively characterized, the risks of anemia are poorly understood, especially in critically ill patients. Shander [7] described the consequences of anemia in the critically ill patient and explained the adaptive mechanisms involved. Anemia significantly decreases the O2 carrying capacity of blood. In the normal host, the amount of O2 delivered (DO2) to tissue exceeds resting O2 requirements by a factor of two to fourfold [13, 17]. When the Hb concentration falls below 10 g/dL, several adaptive processes ensure a considerable physiologic reserve that maintains DO2 in spite of major adversity. These adaptive processes include: (1) increased extraction of available O2, (2) increased cardiac output (elevated heart rate and stroke volume as well as decreased peripheral vascular resistance and blood viscosity) [18], (3) redistribution of blood flow from non-vital organs to the heart and brain, at the expense of the splanchnic vascular bed, and (4) a right shift of the oxyhemoglobin-dissociation curve (leading to decreased O2 affinity and therefore increased O2 release) [13, 14, 18, 19]. All these mechanisms facilitate O2 unloading to tissues. Severe anemia triggers additional adaptive mechanisms, which have limited compensation, such as an increase in cellular O2 extraction. Indeed, this explains why there exists a critical threshold of DO2 below which O2 consumption (VO2) begins to fall and selective vasoconstriction is observed, which favors blood flow to critical organs, namely the brain and heart, and deprives other organs, in particular those irrigated by the splanchnic vascular bed [13].

Impairment of Adaptive Mechanisms to Anemia

A number of diseases and host characteristics may impair adaptive mechanisms to anemia in critically ill patients. Cardiac compensation is limited when anemia is associated with hypovolemia or cardiac dysfunction. Disease processes such as sepsis and multiple organ dysfunction syndrome (MODS) affect a number of adaptive mechanisms. In sepsis and MODS there is often a high metabolic rate and increased VO2 that substantially limit the available O2 reserve and may result in a situation where demand is not met if an additional metabolic stress occurs. In addition, these patients may also have impaired left ventricular function [20, 21], and abnormal regulation of vascular tone [22, 23], restricting DO2 and redistribution of blood flow, respectively. Moreover, sepsis and MODS may compound the energy crisis observed in many critically ill patients by causing mitochondrial oxidative dysfunction, decreasing tissue O2 extraction as well as its utilization [14, 18]. Finally, decreased RBC deformability, which can alter microcirculatory function, is also observed with sepsis and MODS.

A number of host characteristics specific to children and infants may also impair their adaptive mechanisms. The energy requirements of young infants are much higher than those of adults [24]. This difference is mostly attributable to growth and implies a greater need for substrates including O2 and nutrients. In addition to increased metabolic demands, there are also major differences in O2 delivery between adults and children in the first years of life. Fetal Hb represents a greater proportion of total Hb during the first few months of life, which can cause a left shift of the Hb saturation curve and thus affect O2 delivery to tissues. Physiologic decrease in Hb concentration is normal in newborns and partially explains the great variability in normal Hb values seen during the first weeks of life. During these weeks, myocardial compliance is decreased, which causes significant impairment in diastolic filling that can limit an increase in stroke volume when needed to maintain O2 delivery. Moreover, the resting heart rate is relatively elevated in newborns (140 ± 20/min) and in infants (130 ± 20/min), which also limits their ability to increase cardiac output via increasing their heart rate. On the other hand, the health status of children prior to PICU entry is usually better than that of adults, which might explain the comparatively low mortality rates seen in PICUs (about 4 %) [25, 26].

Some cardiovascular consequences of anemia are specific to children [27]. Congenital heart disease is frequently observed in the PICUs. The resulting presentation of heart failure and/or postoperative repair can directly impair DO2. Children with cyanotic congenital heart disease can have Hb concentrations as high as 20 g/dL, a rare occurrence in adults. Inversely, certain pathologies frequently seen in adult patients, such as coronary artery stenosis caused by atherosclerosis, are very rare in PICU.

Long-Term Adaptive Mechanisms to Anemia

In the healthy human, anemia activates erythropoiesis almost immediately, but a clinically significant increase in the blood Hb level occurs only after a few days. In the critically ill patient, this process may be delayed and the response to usual stimuli may be blunted or absent. Strong stimuli for erythropoietin production, such as tissue hypoxia, acute blood loss and anemia are often present in the critically ill and would be expected to increase erythropoietin production. Yet, paradoxically, erythropoietin plasma levels are often lower than expected in these patients. Several factors may be involved [28]. Certain inflammatory mediators may decrease and even block the production of erythropoietin. More particularly, in the systemic inflammatory response syndrome (SIRS), which is present in >80 % of PICU patients [29], high interleukin-1 (IL-1) and tumor necrosis factor (TNF) levels can substantially attenuate erythropoietin production [7, 30]. Moreover, the response to erythropoietin is not optimal in patients with systemic inflammation, which could explain why the response to erythropoietin is slow and blunted in critically ill patients [31].

Iron metabolism is also affected in critically ill children. In patients without iron deficiency, iron concentration in blood is low despite increased iron storage, and there is less free iron available for erythropoiesis [32]. In addition, a significant proportion of critically ill adults present some iron (9 %), B12 (2 %) and/or folate deficiency (2 %) [7] These observations explain (or at least partially explain) why anemia persists in critically ill patients, why their erythropoietin levels are lower than expected, and why their response to erythropoietin is not optimal. As a result, RBC transfusion is frequently the only effective way to rapidly increase the Hb level in critically ill patients whose response to usual medical therapies (iron supplements, recombinant erythropoietin, etc.) is suboptimal.

Management of Anemia in the PICU

Each year, ten million RBC units are transfused in the United States of America [33] and 2.18 million units in the United Kingdom (www.shotuk.org). Forty-nine percent of children in a PICU for more than 2 days receive a transfusion during their PICU stay [1]. It is clear that RBCs are useful: they contain Hb, which transports O2 to cells, and cells require O2 to survive. Thus, it might seem reasonable to keep the blood Hb level and hematocrit of critically ill patients in the normal range. However, the safety of RBC transfusion has been increasingly questioned over the last few years, mostly because there is increased awareness among lay people and physicians regarding the risk of contracting infections such as HIV and hepatitis, and to some extent other potential transfusion-related complications such as bacterial contamination and transfusion-related acute lung injury (TRALI). It is less well recognized that transfusion of packed RBC units may modulate the inflammatory process in recipients (transfusion-related immuno-modulation or TRIM), which may increase the risk of developing nosocomial infections, sepsis and MODS [34]. Thus, it is important to ask what the risk/benefit and the cost/benefit ratios of RBC transfusion are in critically ill children.

Effects of Transfused RBC on Oxygen Delivery

Few studies have examined the role of Hb and RBC transfusions as a means of documenting and potentially alleviating O2 supply dependence [27]. There is no doubt that RBC transfusion increases global DO2, but does it increase DO2 to specific organs and does it improve VO2? Global DO2 can be normal in the presence of significant regional ischemia. A number of studies describe the effect of transfused RBCs on the distribution of systemic blood flow to specific organs [14]. For example, Marik and Sibbald [35] showed that RBC transfusion may cause gut ischemia among septic adults, even if it increases global DO2. RBC transfusion can disturb DO2 in the microcirculation (cellular DO2) by many mechanisms, such as increased blood viscosity, lower O2 release, and shunted microcirculatory flow.

It is generally recommended that the hematocrit level be maintained below 0.45 because blood viscosity increases significantly over this threshold [36]. Messmer et al. [37] have suggested that microcirculatory stasis and impaired DO2 to tissues may be directly related to changes in Hb concentration. They theorize that normovolemic hemodilution improves microcirculatory flow and DO2. Other authors have suggested that hematocrit has limited effects on microcirculatory flow [38].

The microcirculatory effects of transfused RBCs may also be attributable to release of inflammatory mediators (cytokines, microparticles, lipids, etc.) in the supernatant of stored RBCs and to increased activation of white blood cells in packed RBCs [39, 40]. These mediators may initiate or enhance an inflammatory reaction, which may result in MODS [41]. They can also mediate vasoconstriction or thrombosis of small vessels, causing local ischemia [42, 43, 44]. Leukocyte reduction should decrease the effects attributable to white blood cells (e.g. cytokine release) and platelet-related microparticles [40], but the impact of microparticles released by RBCs remains to be determined [39, 40, 45, 46, 47].

Transfused RBCs may also have properties that differ from their in vivo counterparts. There are several age-related changes that occur in stored RBCs. Characteristically, older RBC units have lower levels of 2,3-DPG, which alters Hb affinity for O2 [48]. Nevertheless, the decrease in 2,3-DPG during storage appears to be of little clinical significance since 2,3-DPG levels increase (in adults at least) to more than 50 % of normal within several hours, and to normal levels within 24 h of transfusion [49].

Hb molecules interact not only with O2 and CO2, but also with nitric oxide (NO), which is a key mediator of hypoxic vasodilatation [50]. Free vascular Hb causes vasoconstriction, probably by fixing NO, and can substantially reduce NO bioavailability [51]. Free Hb reacts up to 1,000 times faster than Hb found within RBCs [52]. There is increasing hemolysis over time in stored RBC units: the amount of free Hb increases from 0.5 mg/dL in a 1 day-old RBC units to 250 mg/dL in a 25 day-old unit [53]. However, Hess et al. [54] has shown that prestorage leukoreduction decreases free Hb level by 53 %. The clinical impact of RBC hemolysis remains to be determined in leukoreduced RBC units.

Storage-related changes in intra-erythrocyte Hb might be problematic as well. S-nitrosylated Hb (SNO-Hb) is a protein that can bind, activate, and deploy NO [55]. Intra-erythrocyte SNO-Hb regulates small vessels tone and regional blood flow. SNO-Hb reacts almost immediately to local cellular hypoxia by releasing NO, resulting in local vasodilatation. Conversely, RBCs bind more NO if local cellular VO2 seems adequate, leading to local vasoconstriction. This function is almost immediately disturbed by storage (<3 h) [15, 16, 56, 57], and most SNO-Hb is lost within 2 days of storage [55]. Decreased NO bioavailability from RBC could explain the increased morbidity and mortality reported in some patients after RBC transfusion [58].

RBC transfusions indeed improve global DO2, but this does not always result in better regional DO2 and VO2 [59, 60, 61]. RBC transfusions can impair regional blood flow and cellular VO2 by many mechanisms: higher viscosity, vasoconstriction (cytokines, NO-Hb, free Hb) and low 2,3-DPG, which may alter O2 release. As a consequence, transfused RBCs may impair O2 availability and flow in the microcirculation, which may have adverse effects on tissue oxygenation and cellular respiration [59, 60, 61].

Immunologic Effects of Allogeneic RBC Transfusions

Transfusion-related immuno-modulation (TRIM) is another possible concern with regard to RBC transfusion [34]. Both activation and suppression of the immune system have been reported. Blood products such as RBC units, plasma and platelet concentrates contain white blood cells that release inflammatory mediators in concentrations proportional to their number and to storage time. Several pro-inflammatory molecules have been detected in stored non leukocyte-reduced RBC units, including complement activators [62], cytokines [22, 42, 63], O2 free radicals [64, 65], histamine [66], lyso-phosphatidyl-choline species [67] and other bioreactive substances that modulate the inflammatory process. These white blood cells and inflammatory mediators may trigger, maintain or accentuate SIRS in the recipients. SIRS is common in critical care units, which may explain why some data suggest that TRIM is one of the insults occurring in the two-hit hypothesis and may be a risk factor for the development of MODS in critically ill patients [68, 69, 70].

Transfusions of packed RBC units that are not pre-storage leukocyte-reduced have resulted in clinically important immunosuppression in at least some recipients [71, 72, 73, 74, 75, 76]. In particular, before the cyclosporin era, the transfusion of non leukocyte-reduced RBC units was shown to decrease the number of transplanted organ rejection episodes [77, 78, 79], and improve renal and cardiac allograft survival [80, 81, 82]. This effect may be related to alterations in lymphocyte reactivity observed after blood transfusion. These immunosuppressive properties of non leukocyte-reduced blood products may trigger (in contrast to the situation described above), maintain or accentuate compensatory anti-inflammatory response syndrome (CARS) in the recipients. CARS is also common in critically ill patients [83].

Non leukocyte-reduced RBC units contain about 5 × 109 white blood cells per unit. The risk of TRIM may disappear if the RBC unit is leukocyte-reduced, the latter defined as less than 5 × 106 leukocytes per unit [2]. Pre-storage leukocyte-depletion is superior to reduction done by post-storage filtration at the bedside partially because pre-storage leukocyte-reduction is usually done under more rigorously controlled conditions and also because removal of white blood cells prior to storage reduces the time-dependent accumulation of pro-inflammatory mediators in the supernatant fluid [84, 85, 86, 87, 88, 89]. Pre-storage leukocyte reduction is systematically undertaken in many countries (United Kingdom, Canada, etc.); in 2009, 28 out of 33 American blood banks (84.8 %) provided universal leukoreduction [90]. However, pre-storage leukoreduction does not prevent the production of all pro-inflammatory mediators detected in RBC units. For example, stored RBCs shed microvesicles in the supernatant. This process is an integral part of the RBC ageing process, is accelerated in stored RBC units and is not altered by pre-storage leukoreduction. These microvesicles (ectosomes) contain lipids that can amplify an inflammatory reaction [39].

In summary, TRIM may be a risk factor for MODS in critically ill patients [68, 69, 70], and may cause some immunosuppression, thereby increasing the risk of acquiring sepsis and nosocomial infections [91, 92, 93, 94, 95, 96, 97, 98, 99, 100], which may ultimately result in higher mortality rates [70]. In spite of these concerns, the clinical impact of TRIM is still a matter of considerable debate [34]. Moreover the clinical effects of RBC transfusion on the immunological responses of critically ill children remain to be determined, and it is possible that pre-storage leukocyte reduction decreases or eliminates the risk and/or the severity of TRIM [101, 102, 103, 104]. More studies are required to better determine if TRIM is indeed a clinically significant problem, particularly when pre-storage leukocyte-reduced blood products are used.

Length of Storage of RBC Units

RBC units can be stored up to 42 days. The normal average life-span of RBCs is 120 days. RBC ageing is a normal process; it is slowed down in stored RBC units [105]. The storage lesion comprises the time-dependent metabolic, biochemical, and molecular changes that stored blood products undergo over time. Storage lesions changes are observed in all stored RBC units and are not normal processes. They include increased levels in the supernatant of potassium, lactate, PCO2 as well as many inflammatory mediators (cytokines, lipids, CD40, etc.) associated with diminished levels of sodium, low pH and PaO2. Storage-associated RBC abnormalities also include low ATP levels, increased hemolysis with the release of free Hb, iron and lipids, a diminished 2,3-DPG concentration, less RBC deformability, increased RBC adhesiveness and aggregation, disturbed intra-erythrocyte Hb-nitric oxide (NO) interaction and regulation of small blood vessels, etc. [106, 107].

Most of these changes appear within 2–3 weeks of storage. Currently, the average length of storage of RBC units transfused to critically ill children is about 17 days in the USA and Canada [108, 109]. It is unknown whether these in vivo observations translate into clinically significant adverse outcomes. More than 20 observational studies have reported an association between age of blood and the incidence rate of nosocomial infections [110, 111, 112, 113], while others have found no association [114, 115, 116, 117]. Similarly some investigators reported an association between increased RBC length of storage and increased mortality in non-cardiac critically ill adults [44, 110, 118, 119, 120], while others find no association [121, 122, 123]. The same positive [124, 125, 126, 127, 128] and negative observations [115, 116, 129] have also been reported with respect to mortality in cardiac patients.

Tinmouth et al. [106] stated, “There is strong laboratory evidence suggesting that prolonged RBC storage may be deleterious”. The results of many observational studies indeed suggest that an association exists between length of storage and outcome, but the published data are equivocal, and it must be underlined that observational studies overestimate the real benefit of a treatment by 30–60 % [130]. It is important to emphasize that finding an association does not imply a cause-effect relationship. Moreover, the number of RBC units and the severity of illness are also associated with increased mortality in transfused critically ill adults, and they are associated to each other. There is clearly some confounding by indication [131], which further increases the complexity of the relationship between RBC storage time and adverse outcome, and which no multivariate analysis can deconstruct. Only randomized clinical trials can uncouple the relationship between severity of illness, number of transfusions and age of blood, and demonstrate a cause-effect relationship between RBC length of storage and adverse outcome in transfused critically ill patients. Several randomized clinical trials are presently addressing this question. The Age of Blood Evaluation (ABLE) study (ISRCTN44878718) is enrolling 2,510 critically ill adults since 2009 [132]. The Age of Red blood cell In Premature Infants (ARIPI) study (NCT00326924), which recruited 450 premature newborns who were allocated to receive either RBCs stored ≤7 days or transfusion therapy according to standard practice, was completed in Spring 2011 [133]. The “Red Cell Storage Duration and Outcomes in Cardiac Surgery” (NCT00458783) is a single-center RCT comparing outcomes in 2,800 patients allocated to receive RBCs stored for less than 14 or more than 20 days. The Red Cell Storage Duration Study (RECESS) (NCT00991341) is randomizing 1,434 cardiac surgery adult patients to receive either RBC units stored ≤10 days or ≥21 days [134]. The age of blood in children in PICU (ABC-PICU) study is in preparation and plans to recruit more than 1,500 critically ill children. Until hard evidence is available, the use of “fresh” rather than “old” blood cannot be recommended for ICU patients [135].

Practice Patterns: Determinants of RBC Transfusion

Laverdière et al. [136] undertook a survey of pediatric critical care practitioners to investigate stated RBC transfusion practices and clinical determinants that may alter transfusion thresholds in critically ill children. The transfusion threshold chosen by pediatric intensivists varied tremendously for a given scenario, ranging from less than 7 g/dL to more than 13 g/dL. The following patient characteristics were statistically significant stated determinants of RBC transfusion: low Hb concentration, primary diagnosis (bronchiolitis, ARDS, septic shock, corrected tetralogy of Fallot), young age (<2 weeks of age), low PaO2, high blood lactate level, high PRISM score, active bleeding, thrombocytopenia, disseminated intravascular coagulation and emergency surgery. The results of a survey published in 2004 undertaken among European pediatric intensivists were similar [137].

While our beliefs affect what we teach and what we consider standard practice, the reality of what we actually do (observed practice pattern) can be quite different. The same group of investigators undertook an observational cohort study of 303 children consecutively admitted to an academic PICU and noted that 45 children (15 %) had received between 1 and 33 RBC transfusions each, for a total of 103 transfusions. The stated reasons for administering RBCs included the presence of respiratory failure (84/103), active bleeding (67/103), hemodynamic instability (50/103), blood lactate level >2 mmol/L (10/103) or sub-optimal DO2 (6/103). In many cases, more than one reason was specified, but in seven cases, no specific reason was given [138]. In another cohort study involving 985 consecutive critically ill children, the most significant observed determinants of a first RBC transfusion were a low hemoglobin level, an admission diagnosis of cardiac disease, an admission PRISM score >10 and the presence of MODS during PICU stay [139]. The following determinants of perioperative blood product—not only RBC—transfusion were detected in a prospective cohort study of 548 children undergoing cardiac surgery: younger age, higher preoperative hematocrit, complex surgery, low platelet count and longer duration of hypothermia [140].

Goal-Directed RBC Transfusion Therapy

Goal-directed RBC transfusion therapy is frequently advocated. Its basic principle is simple—a RBC transfusion should be given with the aim of attaining a given “physiological” goal. Many goals are suggested in the medical literature. Some are related to biomarkers reflecting global O2 delivery (DO2) and/or O2 consumption (VO2): DO2, VO2, blood lactate, Sv’O2 (mixed venous O2 saturation), ScvO2 (central venous SO2), O2 extraction rate, etc. Some are related to regional (tissue) markers: near-infrared spectroscopy (NIRS), regional or tissue SO2 (rSO2, StO2), regional O2 extraction rate, etc. Other goals have been considered, like heart rate variability, plethysmographic variability [141] and vascular endothelial growth factor levels [142]. Goal-directed RBC transfusion therapy might be the right clinical approach. There are indeed good data supporting goal-directed therapy and using ScvO2 in unstable patients with severe sepsis and septic shock [143, 144], but the role of RBC transfusion in ScvO2-directed goal therapy is unclear. There are no data supporting the use of other goals in other circumstances. Moreover, there is no consensus on what the best choice for a goal would be (maybe ScvO2 in patients in severe sepsis and/or shock), nor any consensus on what threshold should be used for these goals.

There is consensus that the Hb concentration should not be the only marker used in the decision process to prescribe a RBC transfusion. In addition to considering the Hb level, many host-related and disease-related characteristics appear to account for the practice variation observed in PICU. Goal-directed transfusion therapy is a useful concept, but the appropriate goal remains to be determined and validated. There is however some evidence with regard to three potential determinants that deserves further elaboration: threshold Hb concentration, severity of illness (stable versus unstable patients) and case-mix (cardiac patients).

Red Blood Cell Transfusions in Non-cardiac Patients

Stable Critically Ill Children

In critically ill adults, there were no clinical studies documenting the safety of maintaining the Hb at a lower concentration before Hébert et al. [70] published a landmark paper in 1999. This randomized clinical trial involved administration of non leukocyte-reduced RBC units and showed that a conservative strategy (RBC transfusion if the Hb concentration dropped below 7 g/dL to maintain a level between 7 and 9 g/dL) was as safe, in euvolemic critically ill adults, if not safer than a liberal strategy (RBC transfusion if the Hb concentration dropped below 10 g/dL to maintain a level between 10 and 12 g/dL). An adjusted MODS score as well as hospital mortality were statistically lower in the former than in the latter group.

Data from the adult population are important, but cannot be applied to pediatric patients without restriction because many host characteristics are specific to critically ill children and infants (different case-mix, normal range of Hb concentration that varies with age, different cardiovascular physiology, different energy requirements, better health status of children prior to PICU entry, etc.). There have been two randomized clinical trials that evaluated RBC transfusion in severely ill children. The first randomized clinical trial included 106 African children hospitalized for a malarial crisis who had no congenital hemolytic anemia. In these patients with hematocrit levels ranging from 0.12 to 0.17, RBC transfusion did not improve mortality (1/53 vs 2/53) if there was no respiratory or cardiovascular compromise [11].

The second randomized clinical trial, the Transfusion Requirements In Pediatric Intensive Care Units (TRIPICU) study, a large multicenter randomized non-inferiority clinical trial, included only stable or stabilized patients [145]. In this study, children were considered stable or stabilized if their mean arterial pressure was not less than two standard deviations below normal mean for age and if the cardiovascular support (vasopressors, inotropes and fluids) had not been increased for at least 2 h [145]. It must be underlined that in this definition of stable or stabilized patient, the respiratory and neurological status were not taken into account. The basic design of the TRIPICU study was quite simple. All critically ill children who presented a Hb level ≤9.5 g/dL within the first 7 days in the PICU were considered eligible for the study; they were included if they were hemodynamically stable and had no exclusion criteria. Children were randomized either to receive a transfusion only if the Hb was ≤9.5 g/dL (liberal group) or to receive a transfusion only if their Hb concentration was ≤7 g/dL (restrictive group). In the liberal group (320 patients), transfusion aimed for a post-transfusion Hb level of 11–12 g/dL while the aim was 8.5–9.5 g/dL in the restrictive strategic group (317 patients). Only pre-storage leukocyte-reduced packed RBC unit were used. The primary outcome measure was new/progressive MODS and death; all deaths were considered cases of progressive MODS. The number of new/progressive MODS in the restrictive and liberal groups where respectively 38 and 39. The 28-day of mortality was 14 in both groups. These results suggest that a threshold Hb of 7 g/dL can be safely applied to stable critically ill children. Accordingly, the principal recommendation of the TRIPICU study was to adopt “a restrictive transfusion strategy in PICU patients whose condition is stable in the ICU”. One may challenge this recommendation and argue that some patient populations can differ from those in TRIPICU and require more RBC transfusions because they are sicker. Although not hard evidence, subgroup analyses have thus far found no justification to give more RBC transfusion to stable critically ill children even if their PRISM score is higher [145], if patients present with a septic states (sepsis, severe sepsis, septic shock) [146], or if they are in PICU after undergoing a non-cardiac surgery [147]. A before-after study also suggested that a restrictive policy is safe in burn children [148].

Unstable Critically Ill Children

Most experts in critical care medicine and in transfusion medicine believe that RBC transfusion is mandatory in hemorrhagic shock, regardless of the Hb concentration. The Hb level observed while a patient is actively and acutely bleeding does not immediately reflect the volume of blood that has been lost; thus, the Hb concentration is not the best marker to guide transfusion on an emergency basis in such patients. There is no consensus on what must be done in patients who are unstable, but are not actively or acutely bleeding, like critically ill patients with uncontrolled septic shock or uncontrolled intracranial hypertension. Intensivists believe that a higher threshold Hb concentration is required in unstable patients [136, 149]. Few hard data support this point of view, other than two randomized clinical trials conducted in adults with severe sepsis or septic shock by Rivers et al. [143] and in children by de Oliveira et al. [144] These trials suggest that intensivists should try to maintain the ScvO2 over 70 % and that RBC transfusion is required if fluid challenge (up to 80 mL kg within 6 h) and inotropes or vasopressors do not succeed in increasing the ScvO2 above 70 %.

Red Blood Cell Transfusions in Cardiac Patients

Patients with impaired ventricular function cannot increase their cardiac output as efficiently as other patients. Moreover, even at rest, O2 extraction by myocardial cells is elevated, which implies a lessened coping capacity when anemia occurs. Thus, increasing the Hb level may be the only way to increase DO2 and adequately support cardiac function in these patients. Support for this notion can be drawn from a retrospective study involving 1,958 adults who underwent surgery and refused blood transfusion for religious reasons. A substantially increased risk of death was associated with a low preoperative Hb level in cardiac patients when compared to those without cardiovascular disease [8]. In practice, the threshold Hb concentration observed before RBC transfusion is higher in the PICU during the postoperative period of cases of pediatric cardiac surgery than in other PICU patients [139].

Some recent publications question the statement that it is safe to give RBC transfusions to cardiac patients. Laboratory data suggest that RBC transfusion, even with fresh blood, can disturb the capacity of RBCs to release and capture nitric oxide, and to regulate the small blood vessels tone. Some clinical data suggest that critically ill adults with cardiovascular disease need a higher Hb concentration [150], but other data suggest that RBC transfusions can cause more ischemia in patients with cardiac illness. For example, Murphy et al. [151] reported a statistically and clinically significant association between RBC transfusions and ischemia in 8,518 adults transfused during post-operative care of a cardiac surgery: the adjusted odds ratio was 3.35 (95 % CI: 2.68–4.35). This held true regardless of the hematocrit level before transfusion. Indeed, the proportion of patients with a hematocrit <21 % who developed an ischemic episode was 1.9 % in non transfused patients while it was 13.4 % in transfused patients. In comparison, the proportion of patients with a hematocrit over 27 % who developed an ischemic episode was 3.5 % in non-transfused patients and 11.6 % in those who were transfused.

What determinants to use in the post-operative care of pediatric cardiac surgery patients and whether they are useful are matters of great debate. There is consensus that the need for RBC transfusion in patients without cyanotic cardiac disease during the post-operative period must be addressed separately from those of patients with cyanotic heart disease. Many experts in pediatric cardiology believe in maintaining elevated Hb levels in children without cyanotic heart disease and advocate Hb levels of 12–13 g/dL in neonates and 10 g/dL in infants and children [152]. Other experts in Britain and France do not share this view and advocate lower Hb thresholds of 7–8 g/dL in stable children with non-cyanotic heart disease [2, 153]. There is little evidence regarding this issue. In year 2009, Harrington et al. [154] completed a scenario-based survey among Canadian pediatric cardiac surgeons, cardiologists and intensivists in order to ascertain their stated practice pattern with respect to RBC transfusion during the post-operative care after a pediatric cardiac surgery. Two scenarios in the questionnaire involved patients with non-cyanotic heart disease: a 6-day old having undergone arterial switch surgery and a 5-month old having undergone correction of a complete atrio-ventricular canal. Most respondents replied that a Hb lower than 10 g/dL would prompt them to transfuse RBCs in these patients. Their transfusion threshold increased Hb by 2.5 g/dL if the patient was unstable, if he required ECMO, if active bleeding occurred, or if the ScvO2 or the systemic blood pressure dropped suddenly. In the TRIPICU study, 63 patients with non-cyanotic cardiac disease were enrolled in the restrictive group and 62 in the liberal group [155]. New/progressive MODS was observed in eight patients in the former and four patients in the latter (p = 0.36); there were two deaths in each group at 28 days post-randomization. Thus, the only presently available evidence from this subgroup analysis suggests that a Hb level above 7 g/dL is safe for critically ill children with non-cyanotic heart disease if they are stable. A higher threshold Hb level is probably required in unstable patients.

Neonates with cyanotic heart disease present Hb levels that are significantly higher than normal – Hb concentrations as high as 16–20 g/dL are frequently observed in these patients. In the survey by Harrington et al. [154] described above, two scenarios involved patients with post-operative cyanotic heart disease: a 6-day old patient with tetralogy of Fallot and a 5-month old with hypoplastic left heart syndrome – both underwent a Glenn procedure. Most respondents replied that they would prescribe a RBC transfusion for these patients only if their Hb dropped below 12 g/dL. Their transfusion threshold increased by 1.2 g/dL if the patient became unstable, if an active bleeding appeared, if the ScvO2 dropped suddenly, or if the lactate level was high.

Few clinical studies have addressed this question. A case series of seven children with congenital cyanotic heart disease reported a decreased right to left shunt when increasing the Hb concentration from 13.0 to 16.4 g/dL. The authors specifically attributed the benefit seen to a decreased right to left shunt and did not consider the possibility that benefit could have been due to an increased VO2 [61]. Interestingly, experience with bloodless surgery for complex cyanotic defects suggests that cardiac surgery can be safely performed with a lower level of Hb without evidence of increased risk [156, 157]. Cholette et al. [158] published a randomized clinical trial that included children with univentricular physiology among which 33 underwent a Glenn procedure and 27 a Fontan procedure: 30 patients were allocated to a restrictive strategy with a threshold for RBC transfusion of 9 g/dL and 30 patients, to a liberal group with a threshold of 13 g/dL. One death was observed in the liberal group. The median lactate blood level was 1.4 ± 0.05 mmol/L in both groups. Peak blood lactate was also almost identical (3.1 ± 1.5 versus 3.2 ± 1.3 mmol/L). However, the O2 extraction rate was slightly higher in the restrictive group (31 % ± 7 % versus 26 % ± 6 %) with a difference that was statistically significant (p = 0.013), but not necessarily clinically significant. These data suggest that it is safe not to give a RBC transfusion to patients with cyanotic cardiac disease as long as their Hb level is over 9 g/dL.

The evidence that RBC transfusion improves the outcome in children admitted to PICU after cardiac surgery is poor. Some evidence in adults suggests that a RBC transfusion may be detrimental. In spite of this, practitioners believe that a higher Hb threshold is required in children with cardiac disease, more so if a cyanotic heart disease is present. The appropriate transfusion thresholds Hb for children during the post-operative phase of cardiac surgery are unknown for those with non-cyanotic as well as cyanotic heart lesions. Only a subgroup analysis involving 125 patients from the TRIPICU study has provided evidence which suggests that a Hb level of 7 g/dL is well supported by non-cyanotic patients and only one small randomized clinical trial conducted by Cholette et al. [158] has suggested that a Hb level of 9 g/dL is well tolerated by children with cyanotic heart disease. More studies on RBC transfusion must be done in the field of cardiac surgery.

Limiting Blood Product Transfusion

Whenever possible, it is always better not to administer any blood product. The concept of bloodless medicine and blood conservation are two aspects of blood management that all intensivists should integrate into their clinical practice. Blood conservation refers to limiting the volume of blood lost by patients. Repetitive phlebotomy may contribute significantly to blood loss (7.1 ± 5.3 mL/day, 34 ± 37 mL per PICU stay) [159]. Limiting and consolidating blood tests, closed blood sampling, use of pediatric blood collection tubes, and micro-analysis techniques requiring small sample volumes (<0.5 mL) can all be very effective ways to minimize blood loss [160, 161]. The concept of bloodless medicine refers to all the strategies that can be used to provide medical care without allogeneic blood transfusion. Both concepts are discussed in greater detail in a separate chapter in this textbook.

Although bloodless medicine and blood conservation are two concepts involving multiple strategies that should be applied whenever possible, there are several instances when a RBC transfusion must be considered. It is obvious that more research must be undertaken to provide scientific data before one can establish evidence-based guidelines. Meanwhile, decisions related to transfusion should be driven by physiological need rather than a specific Hb trigger, a decision making process advocated by the National Institutes of Health [162], the American College of Physicians [48] and a group of Canadian experts [163]. Because markers of “physiological needs” are not characterized in critically ill patients, the Hb level is still pivotal to the decision making process of intensivists who are considering RBC transfusion [1, 136, 137, 164]. In practice, we recommend the following strategy for hemodynamically stable critically ill children without cyanotic heart disease [165]:
  • Blood gas machines should not be used for Hb estimation on which to base a transfusion request.

  • RBC transfusion is required in most instances if the Hb concentration is <5 g/dL.

  • RBC transfusion is probably useful if the Hb concentration is between 5 and 7 g/dL.

  • For Hb levels ranging from 7 to 9.5 g/dL, there appears to be no overall benefit in transfusing RBCs.

  • No RBC transfusion is required if the Hb concentration is >9.5 g/dL.

It is probably appropriate to consider a higher threshold and/or to have a more aggressive RBC transfusion strategy in critically ill children who are hemodynamically unstable or who have significant cardiovascular disease. There is, however, no consensus on what this threshold should be. It is also possible that a higher Hb concentration may be required early in their course for patients with severe sepsis. Rivers et al. [143] in adults and de Oliveira et al. [144] in children showed that aggressive and early (first 6 h) goal-driven protocol therapy directed at attaining a ScvO2 greater than 70 mmHg (equivalent to 65 mmHg for mixed venous saturation) [166] improves outcome in patients with severe sepsis. In the majority of patients, such early-goal therapy was achieved only if the hematocrit was kept above 0.30 during these six “golden” hours. The recommendations detailed above this paragraph apply after these golden hours, once the patient is stabilized. The decision to prescribe a RBC transfusion must be adapted to specific situations and must take into account determinants other than the Hb concentration, such as the severity of cases or the presence of mitochondrial dysfunction (high blood lactate level), a frequent occurrence in sepsis.

The “Nuts and Bolts” of Packed RBC Transfusion

Packed RBC units are stored in a preservative anticoagulant solution. CPD solution was previously a frequently used preservative that contains sodium citrate (C), citric acid, sodium diphosphate (P) and dextrose (D). In this solution, the dextrose provides energy for RBCs through glycolysis, the phosphate is utilized by RBCs to generate adenosine triphosphate (ATP) and the citrate chelates calcium, which inhibits coagulation, and is then metabolized to bicarbonate, which stabilizes the pH. Most countries have updated the constituents of the solutions used. CPDA–1 (anticoagulant citrate-phosphate-dextrose-adenine) solution contains a higher concentration of dextrose than CPD (2 g vs 1.6 g/63 mL) and some adenine (17.3 mg/63 mL). With this solution, ATP levels remain normal during 21 days of storage and decrease by 50 % after 35 days. Thus units with CPDA–1 can be stored up to 35 days while units with CPD may only be stored for 21 days (28 days fir CPD-2). Additive solutions containing more adenine, such as AS–1 (Adsol®), AS–3 (Nutricel®) and SAG–M are being used with increasing frequency in North American and European countries. The contents of AS–1 and SAG–M are similar to that of CPDA–1 except that they contain mannitol to decrease RBC lysis. Packed RBC units stored in additive solutions have a shelf-life of 35–42 days, depending on country-specific regulations for permitted storage (42 days in North-America, 35–42 in European countries) [167, 168].

The volume of each CPDA–1 unit is 250 mL, which includes 63 mL of preservative solution. Each unit may be diluted with 75 mL of saline immediately prior to administration to the patient (this decreases the hematocrit from 0.70 to 0.55–0.60, allowing an easier administration). The mean volume of each AS–1, AS–3 or SAG–M unit is up to 350 mL, which includes 100 mL of preservative solution. These units have a hematocrit of 0.55–0.60; so they do not need to be diluted with saline prior to administration.

It is common practice to prescribe 10 mL/kg of packed RBCs stored in CPDA–1 and it can be expected that this should increase the blood Hb level by 2–2.5 g/dL if the patient is not actively bleeding. It is frequently unrecognized that these numbers hold true only for undiluted CPD/CPD–1 units: up to 15 mL/kg are required to get the same increase of the Hb concentration with CPD/CPDA–1 units to which saline (75 mL) has been added or RBCs stored in additive solutions. However, the optimal prescription should consider the Hb level prior to transfusion and should adjust the volume of the transfusion to attain a targeted Hb level. This can easily be done if there is no active bleeding by using the formula below to calculate the exact amount (volume) of packed RBCs that should be given:
$$ \begin{array}{c}\mathrm{Volume}\;{(\mathrm{mL})=\{(\mathrm{Hb}}_{\mathrm{targeted}}-{\mathrm{Hb}}_{\mathrm{observed}})\\ {}\kern0.49em \times \mathrm{blood}\;{\mathrm{volume}\}/\{\mathrm{Hb}}_{\mathrm{RBC}\;\mathrm{unit}}\}\end{array} $$
(19.1)
where Hbtargeted is the Hb concentration targeted post-transfusion (for example, 10 g/dL), Hbobserved is the most recently measured Hb concentration of the patient (g/dL), and HbRBC unit is the average Hb concentration in the packed RBC units (g/dL) delivered by the blood bank.

The Hb concentration of RBC units may vary from one center to another and according to the different preservative solutions used. For non leukocyte-reduced RBCs in AS–3, the hematocrit is approximately 0.55, and the HbRBC unit concentration is about 19.5 g/dL (usual range: 18–21 g/dL). For RBCs in CPDA–1, the hematocrit before dilution is about 0.65–0.75 and the HbRBC unit concentration is about 25 g/dL. However, the Hb concentration does vary according to processing methods (e.g. there is RBC loss with leukoreduction filtration, buffy coat removal and/or washing) and between units, variation related to the variability of donor Hb concentrations. Where possible, to use this formula accurately, it is preferable to know the average Hb concentration of the units supplied by the local blood bank.

The blood volume can be calculated according to the formula:
$$ \mathrm{Total}\;\mathrm{body}\;\mathrm{blood}\;\mathrm{volume}=\mathrm{weight}\times \mathrm{blood}\;\mathrm{volume} $$
(19.2)
where weight is expressed in kg, and blood volume in liter/kg (0.08 L/kg for children aged <2 years, 0.07 L/kg for age 2–14 years). For example, in a child weighing 3 kg whose blood volume is 0.24 L (0.08 L/kg × 3 kg), who has a Hb level of 6.5 g/dL and for whom the desired Hb level is 10 g/dL (Hbtargeted), the volume of non leukocyte-reduced packed RBC unit to be transfused (in liters) would be calculated as shown below if the HbRBC unit is 19.5 g/dL (AS-3):
$$ \begin{array}{c}\mathrm{Volume}=\left\{\left(10-6.5\;\mathrm{g}/\mathrm{dL}\right)\times 0.24\;\mathrm{L}\right\}/\Big\{19.5\;\mathrm{g}/\mathrm{dL}\Big\}\\ {}=0.043\;\mathrm{L}=43\;\mathrm{mL}.\end{array} $$
One can also use the following formula:
$$ \begin{array}{c}\mathrm{Volume}\;\left(\mathrm{mL}\right)=\Big\{({\mathrm{Ht}}_{\mathrm{targeted}}-{\mathrm{Ht}}_{\mathrm{observed}})\\ {}\kern0.36em \times \mathrm{blood}\;\mathrm{volume}\Big\}/\left\{{\mathrm{Ht}}_{\mathrm{RBC}\;\mathrm{unit}}\right\}\end{array} $$
(19.3)

In this latter formula, Httargeted is the hematocrit (Ht) targeted post-transfusion (for example, 0.30), Htobserved is the most recently measured Ht of the patient (0.20), and HtRBC unit is the average Ht in the packed RBC units delivered by the blood bank.

In stable patients, RBCs should be administered on a unit-by-unit basis to minimize exposure to multiple donors and to maintain the patient in the appropriate transfusion range. If the volume of packed RBCs needed to reach the Hbtargeted is greater than the volume of one unit of packed RBCs, blood should be transfused one unit at a time and the Hb measured again prior to administration of additional packed RBCs. Given the fact that Hb and Ht values equilibrate within 30 min in transfused patients who are not actively bleeding [169], it would be appropriate to allow for this delay prior to verification of post-transfusion Hb level. A packed RBC unit can be subdivided into smaller units—either half units or four to five aliquots—to avoid waste (Pedi-Pak®, Genesis BPS, is frequently used in North-America). Sterile preparation of these fractionated or partial units may allow for remaining blood to be reserved for the same patient until the expiry date, thus minimizing exposure to multiple donors. A packed RBC unit must be given within 4 h after leaving the hospital blood bank. Fractionated units, which are prepared in a sterile manner, can be kept as long as the original unit.

Table 19.1 summarizes permissible choices of ABO/Rh blood components according to recipient ABO/Rh blood groups. An ABO/Rh blood group is mandatory before any blood component transfusion. In addition a cross-match (electronic or serologic according to institutional policy) is required before a RBC transfusion. It takes 5–10 min to ascertain the ABO and Rh status of a patient (type) and up to 60 min to complete pre-transfusion testing of a recipient including ABO/Rh typing, antibody screening and cross matching. In acute life-threatening situations requiring rapid transfusion, there may not be sufficient time for complete pre-transfusion testing. In these situations, ORh RBC and/or AB plasma should be administered. The risk of severe hemolytic reaction to non cross-matched RBC units is low in patients who have never been exposed to allogenic RBCs (i.e. who have never been transfused or pregnant); however in emergency situations, a reliable medical history is often unavailable. For patients who have been previously transfused or who are pregnant, it is difficult to give a precise figure as to the risk, and this will vary with individual patients (e.g. number of previous transfusions, availability of previous records, nature of the underlying disease like immunosuppressed patient versus a sickle cell patient). The physician must weigh risks and benefits. However, in truly life-threatening situations, most physicians would proceed with transfusion of non cross-matched blood. If large amounts of uncross-matched packed RBC units are transfused, the hospital blood bank might recommend that similar units continue to be administered for a while (a protocol is usually implemented to deal with massive transfusion in most hospitals).
Table 19.1

Choice of ABO and Rh groups for blood product administration in children

Blood product(s) to be transfuseda

Recipient blood group

Red blood cells

Plasma

Platelets b

O

O

O, A, B, AB

O, A, B, AB

A

A, O

A, AB

A, AB

B

B, O

B, AB

B, AB

AB

AB, A, B, O

AB

AB

Rh+

Rh+, Rh

Not applicable

Rh+, Rh

Rh

Rh

Not applicable

Rh− c

Based on data from Refs. [2, 170, 171]

aThe ABO subgroups suggested may not be appropriate in newborns and young infants (<4 months) if maternal antibodies are present in the recipient. The above suggestions also do not apply for bone marrow transplant patients grafted from an ABO mismatched donor [170]

bIn emergency situations, if platelets of the recommended groups are not available, units with low titers of Anti-A or anti-B should be selected, or alternatively the majority of the plasma should be removed from the platelet concentrate

cRh+ platelets can be given to an Rh receiver when no Rh platelets are available. Anti-D immunoglobulins should then be considered, especially in women of childbearing potential

RBC units are stored at 1–6 °C and therefore represent a significant risk of hypothermia. All units are warmed to room temperature (about 20 °C) prior to administration. Warming to body temperature (37 °C) should be considered when significant volumes are given rapidly. In practice, packed RBC units are warmed to 37 °C before transfusion to a small patient (<10 kg) or if the amount given constitutes >20–30 % of the recipient’s blood volume. In other situations (i.e. larger child, slower infusion rate), the blood will warm sufficiently at room temperature while being infused. Warming packed RBCs decreases viscosity (7 % decrease for each 1 °C increase), thus lowering the resistance through the catheter used; the clinical relevance of this remains to be determined. Standard blood-warmer must be used to rise the temperature of whole blood or packed RBC units, not micro-waves oven because they can cause severe hemolysis [172, 173].

All packed RBC units (even leukocyte-reduced units) contain fibrin, platelets and white blood cells, and must be filtered, using a standard blood bank filter with 180–260 μm pores. Some clinicians advocate using microaggregate filters (80 μm or less), but there are no studies that convincingly show an advantage to their use.

Poiseuille’s law regulates the flow through a catheter: Q’ = {π(P1–P2)r4/8 nL} where Q’ is flow (L/min), r is internal radius, (P1–P2) is pressures difference, L is catheter length, and n is viscosity coefficient. Most of the resistance to flow attributable to a catheter is related to its radius (r4) and its length. Moreover, the high viscosity of packed RBC units increases this resistance. It is therefore advisable that the biggest and shortest available catheter be used for RBC transfusion. A 14 G peripheral catheter in adults, a 20 G in infants, or even an intra-osseous catheter are acceptable; 22 G catheters [174] or 1.9 Fr NeoPICC™ [175] are too small unless the flow rate is decreased (<2.5 mL/kg/h) or the intraluminal pressure generated by a pump is increased. Significant hemolysis can occur with intraluminal pressures greater than 300 mmHg [174, 175]. Central vein catheters are appropriate.

A RBC transfusion must be completed within 4 h of removal of the unit from a monitored temperature controlled refrigerator. No medication should ever be administered into the same intravenous access and it is inappropriate to combine transfusion RBCs with a solution that contains dextrose (risk of hemolysis), Ringer lactate or calcium (risk of coagulation) [176]. Only physiologic saline (0.9 % NaCl) is compatible.

Patients should be closely monitored while receiving blood products and transfusion must be immediately stopped if a transfusion reaction is suspected (see section on reactions to blood product transfusion at the end of this chapter). Patient clinical data as well as information regarding the blood products received must be detailed in the hospital chart. If a transfusion reaction is suspected, it is important not to dispose of the remaining blood product as well as any filters and tubing and to forward all items to the blood bank. All possible severe transfusion reactions must be reported to the local blood blank. In some instances, it may be indicated to obtain a blood culture from the patient and from the remaining product, and to assess the patient for hemolysis.

Whole Blood

Whole blood stored for longer than 24 h contains few viable platelets. In addition, levels of Factors V and VIII (the labile coagulation factors) decrease with storage at 4 °C. Levels of the other clotting factors are however well maintained at 4° storage. Whole blood can be reconstituted by combining one unit of packed RBC with a compatible unit of fresh frozen plasma [84]. Worldwide, most blood suppliers do not routinely provide whole blood. However, the transfusion of whole blood could be considered in the following four situations: (1) hemorrhagic shock; (2) exchange transfusion in a newborn; (3) administration of an autologous unit (i.e. blood collected from the patient a few days or weeks prior to re-infusion at the time of elective surgery); (4) administration of blood donated by a family member and dedicated to a given patient. Some investigators have claimed that the use of fresh whole blood is associated with less post-operative blood loss [177]. Whole blood less than 48 h old is systematically used in some hospitals for cardiac surgery, mostly to prime the cardiopulmonary bypass circuit [152]. However a randomized clinical trial has shown that “the use of fresh whole blood for cardiopulmonary bypass priming has no advantage over the use of a combination of packed red cells and fresh-frozen plasma during surgery for congenital heart disease” [178]. In other situations, it is preferable to administer RBC and plasma separately or, in the case of exchange transfusion, as reconstituted whole blood, if both RBC and coagulation factors are required.

Specific Types of Packed RBC Units

While in most instances, standard packed RBCs can be safely used, there exist various other available products indicated for specific clinical situations including washed, irradiated, dedicated, autologous and cytomegalovirus (CMV) seronegative units.

Washed units. – Washed packed RBC units have had more plasma extracted than usual. The hematocrit depends entirely on how much saline is used to reconstitute the solution after washing; it can be as high as 0.70–0.80, but usually is adjusted to give a hematocrit of 0.55–0.60. The volume of washed RBC units depends on the hematocrit. It generally takes 2 or 3 h to complete the washing process and these units must be used within 24 h after entering the unit to begin washing, unless processed with newly available equipment that maintains a close system and thus allows longer (7–14 days) storage post-washing. Washed RBC units can be used to prevent transfusion reactions in patients who have presented severe or recurrent allergic reactions. Some practitioners use washed RBC units because they believe they are free of potassium. However, strong hemolysis is observed in washed RBC units; the concentration of potassium units increased rapidly after they are washed, and get to the pre-washed potassium concentration within 24 h [179].

Irradiated units. – Patients at risk of contracting transfusion-associated graft versus host disease (TA-GvHD) must receive gamma-irradiated cellular blood components. Susceptible patients include those with congenital immunodeficiency, patients receiving immuno-suppressive therapy, recipients of directed transfusions from family members and possibly pre-term infants [152]. However, irradiation does lead to an increased leakage of potassium from the RBCs. The impact of this problem can be minimized if the blood product is administered soon after irradiation.

Autologous units. – A packed RBC unit is autologous when it was collected from the receiver. In the pediatric population, this is possible with older children who are healthy enough to give their own blood a few weeks before elective surgery. It is frequently believed both by lay people and by caregivers that the transfusion of autologous RBC units is absolutely safe. However, there are some complications that may occur with autologous transfusion, including bacterial contamination, transfusion overload and transfusion error.

CMV negative units. – CMV may be transmitted by the transfusion of cellular blood components, and this may cause serious infection in certain categories of transfusion recipients. Because more than 50 % of donors are CMV positive, it is impossible to procure CMV seronegative blood products for all recipients. This blood product is therefore usually reserved for CMV negative future transplant recipients or for already transplanted patients whose donor was CMV negative and who are themselves CMV negative. CMV is transmitted by white blood cells and consequently the risk of contracting a CMV infection is significantly decreased (but not absent) with leukocyte-reduced units.

Transfusion of Frozen Plasma

Plasma for transfusion is prepared from a whole blood donation by separation following centrifugation. Larger volumes of plasma may be collected using automated apheresis techniques. A typical unit of plasma has an approximate volume of 250 mL if obtained from a whole blood donation or approximately 500 mL when obtained by plasmapheresis.

Immediately following collection from a normal donor, plasma contains approximately 1 unit/mL of each of the coagulation factors as well as normal concentrations of other plasma proteins. Coagulation Factors V and VIII, known as the labile coagulation factors, are not stable in plasma stored for prolonged periods at 1–6 °C; consequently plasma is usually stored frozen at −18 °C or lower. Plasma frozen within 8 h of collection, known as fresh frozen plasma (FFP), contains about 87 % of Factor VIII present at the time of collection and, according to standards in most countries, must contain at least 0.70 UI/mL of Factor VIII. Several countries also use plasma frozen within 24 h of collection, known as frozen plasma (FP). Factor VIII levels in frozen plasma are approximately 70–75 % of the levels present at the time of collection. The levels of Factor V as well as the levels of other coagulation factors are not significantly decreased from baseline in plasma frozen within 24 h of collection [180, 181].

FFP and FP units are collected from a single donor, while units of virus inactivated frozen plasma—solvent detergent FFP (SD-FFP) (Octaplas, Octapharma) and methylene-blue treated FFP (MB-FFP)—are constituted from a pool of frozen plasma collected from approximately 700 donors; the SD process is used for inactivation of lipid-enveloped viruses. SD plasma is not currently licensed in the USA, but it is licensed and available in Europe. In some countries, only FP is available, but in many countries including the USA fresh FP is still available in 2011. Depending on the exact temperature at which plasma is stored, applicable national requirements/regulations and the precise product, frozen plasma can be stored from 3 to 24 months.

Indications for Frozen Plasma Transfusion

In 2006, approximately four millions unit of plasma were transfused in the USA [182]. In 2010, 292,884 FFP units and 57,487 SD-FFP units were transfused in the United Kingdom (www.shotuk.org). There is broad, general consensus that the appropriate use of FFP, FP and SD-FFP is limited almost exclusively to the treatment or prevention of clinically significant bleeding due to a deficiency of one or more plasma coagulation factors. Such situations potentially include the presence of (1) a diminution of coagulation factors due to treatment with vitamin K antagonists, (2) severe liver disease, (3) disseminated intravascular coagulation (DIC), (4) massive transfusion, (5) warfarin anticoagulation-related intracranial hemorrhage, (6) isolated congenital coagulation factor deficiencies for which a safer and/or more appropriate product does not exist [183]. A panel of experts could not “recommend for or against transfusion of plasma for patients undergoing surgery in the absence of massive transfusion” [183]. The same experts could not “recommend for or against” a plasma/RBC ratio of 1:3 or more (<1:3) in trauma patients requiring massive transfusion [183].

Plasma exchange with FFP, FP or cryosupernatant as the replacement fluid is the standard therapy for thrombotic thrombocytopenic purpura (TTP). Although no hard evidence supports this, some physicians also advocate plasma administration or exchange transfusion to treat patients with hemolytic uremic syndrome (HUS) who develop neurologic complications [184]. Plasma exchange may be used to treat Guillain-Barré syndrome [185] and acute disseminated encephalomyelitis (ADEM) [186], although intravenous immunoglobulins may be a better option [187]. Plasma exchange is also currently being studied as a therapeutic measure in sepsis [188, 189].

There is also a consensus among the experts developing guidelines that FFP and FP are not indicated in the following situations:
  1. 1.

    Intravascular volume expansion or repletion (where crystalloids, synthetic colloids or purified human albumin solutions are preferred) [84];

     
  2. 2.

    Correction or prevention of protein malnutrition (where synthetic amino acid solutions are preferred);

     
  3. 3.

    Correction of hypogammaglobulinemia (where purified human immunoglobulin concentrates are preferred);

     
  4. 4.

    Treatment of hemophilia A or B and von Willebrand disease (where desmopressin, virus-inactivated plasma-derived or recombinant factor concentrates are preferred);

     
  5. 5.

    Treatment of any other isolated congenital procoagulant or anticoagulant factor deficiency for which a virus-inactivated plasma-derived or recombinant factor concentrate exists;

     
  6. 6.

    Treatment of hemolytic uremic syndrome (HUS) unless plasma exchange is indicated;

     
  7. 7.

    As replacement fluid in therapeutic apheresis procedures for disorders other than TTP/HUS unless proven to be beneficial.

     

The “Nuts and Bolts” of Frozen Plasma Transfusion

The amount of FFP of FP initially prescribed ranges from 10 to 20 mL/kg. The coagulation profile should be verified before further plasma administration. Close monitoring of the respiratory and hemodynamic status of the recipient is mandatory because plasma transfusion is associated with increased risk of developing ALI and transfusion-associated circulatory overload (TACO) [190]. It may be necessary in certain patients to repeat transfusion or to initiate a continuous perfusion (at a rate of 10 mL/kg/h), if there is active bleeding. Repeated measurement of the activity of the coagulation cascade is the best way to determine whether more plasma is required. Indications for continuing plasma administration are the same as for starting plasma.

FFP and FP can be thawed in less than 10 min using microwave ovens specifically manufactured for this purpose. A unit of FFP/FP must be administered within 4 h after thawing. Standard blood administration filter must be used. Plasma prepared from whole-blood derived FFP expires as FFP 24 h after thawing if kept at 1–6 °C, but it can be converted to thawed plasma. This product expires 5 days after thawing if stored at 1–6 °C. Thawed plasma has reduced level of FVIII and is not suitable for Factor VIII replacement. However, concentrations of remaining factors are clinically adequate for transfusion to other patients [168].

Transfusion of Platelets

Three mechanisms combine their effect to stop bleeding from an injured vessel: (1) vasoconstriction, (2) platelet aggregation to form a plug and (3) plug stabilization by a fibrin clot [191]. A low platelet count and/or significant platelet dysfunction therefore places a patient at risk for bleeding because of an impaired ability to form a platelet plug. Platelet dysfunction is common in ICU. In most instances, it is attributable to toxins, drugs (for example, salicylate, nitric oxide), exposure to extracorporeal circulation and renal failure; rarely, unusual causes such as certain inherited diseases can be involved [191]. Treatment of platelet dysfunction, when required, includes administration of certain drugs (for example, antifibrinolytic agents) and/or platelet transfusion.

Thrombocytopenia is defined by a platelet count <150,000/mm3. The prevalence of ICU-acquired thrombocytopenia is 44 % in critically ill adults [192]. Causes of thrombocytopenia in ICU are multiple and include sepsis [193], DIC, massive transfusion, bone marrow histiocytic hyperplasia with hemophagocytosis (acquired hemophagocytosis syndrome) [193, 194], as well as drug-related and heparin-induced thrombocytopenia [195]. Because correction of thrombocytopenia has been shown to be associated with reduced mortality [192], it is reasonable to administer platelet transfusions to critically ill patients with a low platelet count. However, the threshold below which a platelet transfusion should be given is a matter of debate.

Platelet concentrates are prepared from whole blood donations or by apheresis collections. Platelet concentrates prepared from whole blood contain about 55 × 109 platelets per unit, plus 50 mL of plasma, a small quantity of RBCs and about 108 white blood cells/unit. Apheresis platelet concentrates contain about 300 × 109 platelets per unit, plus 250–300 mL of plasma, up to 5 mL of RBCs and about 109/unit white blood cells. In many countries (Canada, United Kingdom, etc.), but not in the USA, all platelet units are leukocyte-reduced pre-storage, either by filtration or (in the case of apheresis platelets) as part of the automated processing. This decreases significantly the risk of HLA alloimmunization, non hemolytic febrile reactions and the transmission of CMV. Both types of platelet concentrates are stored at 20–24 °C for up to 5 days. In many countries, bacterial detection is performed to decrease the risk of bacterial contamination.

Indication for Platelet Transfusion

In 2010, 246,962 platelet units were transfused in the United Kingdom (www.shotuk.org). There is consensus that a platelet transfusion is indicated if the platelet count of a patient with an active hemorrhage falls below 50,000/mm3 [196], or if the hemorrhage is severe and there is platelet dysfunction, as occurs frequently following cardiopulmonary bypass [197]. Many intensivists consider that the risk of pulmonary hemorrhage is significant in mechanically ventilated patients if the platelet count is <50,000/mm3, and most will prescribe platelet transfusion in such instances (although this has never been substantiated by clinical studies). A threshold of 100,000/mm3 is generally recommended for patients with multiple trauma, central nervous system injury [196], or for patients on extracorporeal membrane oxygenation (ECMO) [2, 84]. In patients with thrombocytopenia due to decreased platelet production, prophylactic platelet transfusion should be considered if the platelet count is <10,000/mm3 or if there are additional risk factors for bleeding.

The administration of a large amount of crystalloids, packed RBCs and/or whole blood (more than one blood volume) can have a dilutional effect on the platelet count and warrants close monitoring [198, 199]. Platelets are associated with a sevenfold increased risk of acute transfusion reaction compared to RBC <www.shotuk.org>.

Platelet transfusion should not be used for the treatment of idiopathic thrombocytopenic purpura except in the presence of intracerebral or life-threatening bleeding [200, 201]. Platelets are also contra-indicated in cases of heparin-induced thrombocytopenia and of thrombotic thrombocytopenic purpura [196]. Alternatives to platelet transfusion, such as DDAVP or antifibrinolytic agents, should be considered as first choice therapies when appropriate [202].

The “Nuts and Bolts” of Platelet Transfusion

The amount of platelet concentrate (either whole blood derived or apheresis platelets) generally prescribed ranges from 5 to 10 mL/kg for infants weighing less than 10 kg. For older children weighing more than 10 kg, the usual starting dose is 1 whole blood derived unit per 10 kg (i.e. 1 unit for 11–20 kg child, 2 units for 21–30 kg child, etc.) or approximately 10 mL/kg up to a maximum of 1 pool of platelets if using apheresis or pre-pooled platelets. It can be expected that this should increase the platelet count by 50,000/mm3 unless there is increased platelet consumption [84]. It is standard practice to give no more than five units of whole blood derived platelet concentrates or one apheresis platelet unit per transfusion. The recommended infusion time is 60 min or less. All platelet units must be administered within 4 h after delivery from the blood bank.

Platelets possess intrinsic ABO antigens and extrinsically absorbed A and B antigens [203]. Nevertheless ABO incompatible platelets (i.e. platelets with A and/or B antigens given to a donor with a corresponding antibody) are usually clinically effective. However there are several reports of acute intravascular hemolysis following the transfusion of platelet concentrates containing ABO antibodies incompatible with the recipient’s RBC [203, 204]. Therefore ABO-matched platelets should be used in pediatric patients especially for neonates and small children where the volume of plasma may be relatively large with respect to the patient’s total blood volume. If ABO-matched platelets are not available, units with plasma compatible with the recipient’s RBCs should be chosen. If this is also not possible, units with low titers of anti-A or anti-B should be selected or alternatively the plasma can be removed from the platelet concentrate (i.e. use a volume reduced platelet concentrate) [2]. Platelets do not carry Rh antigen, but concentrates contain RBCs in numbers sufficient to sensitize the recipient. An anti-D vaccine (Win Rho SDR®) should be given if the recipient is a Rh woman of childbearing potential and the donor is Rh+ [2]. Each 120 mcg of Rh-immunoglobulin covers 12 mL whole blood (6 mL RBC) and lasts approximately 21 days [205]. Tobian et al. [206] reported that the incidence of allergic transfusion reactions to unmanipulated apheresis platelets is 5.5 %, and that concentrating and washing reduced this incidence to 0.5 %. Recipients of HLA-matched platelets should receive irradiated platelets in order to prevent graft versus host disease.

Serious Hazards of Transfusion

Labile blood products (RBC units, frozen plasma, platelet concentrates and cryoprecipitate) can cause early onset or late onset reactions and complications (Tables 19.2 and 19.3) [197]. By definition, immediate reactions occur while the transfusion is being given or within 24 h after the end of the transfusion. Late reactions and complications appear days, weeks or even years later. Severe reactions probably attributable to the transfusion of a blood product should be reported to the hospital blood bank.
Table 19.2

Reactions and complications related to blood product transfusions

 

Frequency

1. Early onset reactions (<24 h)

 

 Transfusion-related acute lung injury (TRALI) [207]

1/31,960

 Transfusion associated circulatory overload (TACO) [207]

1/34,091

 Isolated hypotensive reaction [207]

1/102,273

 Major allergic reaction (anaphylaxis) [207]

1/11,117

 Minor allergic reaction [207]

1/100

 Febrile non-hemolytic reaction [207]

1/50–1/200

 Acute hemolytic transfusion reaction [207]

1/26,914

 ABO incompatibility [208]

1/800,000

2. Early onset complications of massive transfusion [199]a

 

 Coagulopathy

Frequent

 Thrombocytopenia

Common

 Hypothermia

Common

 Hypocalcemia, hypomagnesemia, citrate toxicity

Common

 Hyperkalemia

1/20

 Metabolic alkalosis by citrate toxicity, metabolic acidosis

Rare

3. Late onset complications of transfusion

 

 Delayed hemolytic reaction [207]

1/255,682

 Allo-immune thrombopenia

Unknown-rare

 Post-transfusion purpura [207]

1/85,227

 Infections

See Table 19.3

 Transfusion associated graft versus host disease (TA-GvHD) [214]

1/1,000,000

4. Early and late deaths [215]

1/2,845,459

aDefinition of massive transfusion : administration of more than one blood volume of blood products within a 24 h period

Table 19.3

Infections potentially caused by blood product transfusion

Infection

Risk per transfusiona

HIV (AIDS) [207]

1/4,000,000

Hepatitis A [209]

<1/10,000,000

Hepatitis B b [210]

1/282,000–1/357,000

Hepatitis C [207]

1/2,800,000

Other hepatitis (D, E, etc.)

Unknown-rare

HTLV (Health Protection Agency) <www.hpa.org.uk>

1/17,000,000

Cytomegalovirus [209]

Unknown-rare

Parvovirus B19 [207]

1/5,000–1/20,000

TTBI (platelet) [209]

13–44/100,000 platelet pools

TTBI (RBC unit) [209]

0.02/100,000 RBC units

Other infections c

Unknown

HIV human immuno-deficiency virus, HTLV human T-lymphocyte virus, RBC red blood cell, TTBI transfusion transmitted bacterial infection

aRisk per transfusion of blood product: these figures are applicable only in countries where virus testing is systematically performed (testing for HIV, hepatitis B and C is systematically performed in less than 45 % of members states of the World Health Organization [211])

bThe risk for transfusion-transmitted chronic HBV disease in Canada was estimated to be 1 in 2,240,000 transfusion in year 2003 [209]

cOther infections: zoonoses such as babesiosis [210], Colorado tick fever [210], Chagas disease [211], dengue [210], malaria [210], variant Creutzfeldt-Jacob disease [212], West Nile virus [213], etc.

The transfusion of a blood product can result in early as well as late onset death. The overall mortality rate attributed to the transfusion of a blood component dropped to 1/2,845,459 per transfusion in the United Kingdom in 2008 (Serious Hazards of Transfusion Group: (www.shotuk.org). [205]. The risk is higher with platelet concentrates: in 2000, the mortality observed in Canada and attributed to the transfusion of a blood product was 2.2 per 100,000 RBC units and 6.3 per 100,000 platelet pools [209]. The Center for Biologics Evaluation and Research of the Food and Drug Administration receives approximately 60–70 transfusion-related fatality reports per year [216]. The 13 deaths reported in 2010 by the “Serious Hazards Of Transfusion” (SHOT) system of the United Kingdom were caused by TACO (7), TRALI (1), hypotension (1), anaphylactic reaction (1), hyperhemolysis (1) and under-transfusion in a case of hemorrhagic shock.

Acute Reactions

Any unexpected or unexplained change in the clinical condition of a patient during a transfusion or up to 24 h afterwards should be considered (and evaluated) as possibly being due to an acute transfusion reaction, and should be reported to the local blood bank [217].

Transfusion-Related Acute Lung Injury (TRALI)

TRALI is now a well-recognized reaction to transfusion of blood products and also one of the most serious. A TRALI is an acute lung injury (ALI) that appears during or within 6 h after the end of a transfusion. A panel of experts created a list of diagnostic criteria of TRALI that is detailed in Table 19.4. The criterion of “no pre-existing ALI before transfusion” means that TRALI cannot be diagnosed when an ALI is already present. Clinically, TRALI resembles ARDS and involves respiratory symptoms such as hypoxemia, dyspnea and frothy sputum as well as hypotension, tachycardia and fever [216]. Chest radiograph findings are also similar to those seen in ARDS and show generalized opacities. In 90 % of cases, the reaction appears within 1–2 h after a transfusion is started. HLA antibodies and/or granulocyte antibodies are positive in 65–83 % of tested donors [216, 219]. Respiratory symptoms usually disappear within 48–96 h, which is different from the progression typically seen in ARDS [220]. All blood products containing some plasma can cause a TRALI, but frozen plasma (50 %) and packed RBC units (31 %) are more frequently involved than platelet concentrates (17 %) [216].
Table 19.4

Diagnostic criteria of TRALI

The following diagnostic criteria of transfusion-associated acute lung injury (TRALI) were adopted during a Consensus Conference held in Toronto in 2004 [218]

 Diagnostic criteria of TRALI: all six criteria must be present in order to diagnose a TRALI

  1. Acute onset of acute lung injury (ALI)

  2. Hypoxemia

   Research setting:

    PaO2/FiO2 ratio ≤300

    or SpO2 <90 % on room air

   Nonresearch setting:

    PaO2/FiO2 ratio ≤300

    or SpO2 <90 % on room air

    or other clinical evidence of hypoxemia

  3. Bilateral infiltrates on frontal chest radiograph

  4. No evidence of left atrial hypertension (i.e., circulatory overload)

  5. During or within 6 h of transfusion

  6. No temporal relationship to an alternative risk factor for ALI

 Diagnostic criteria of possible TRALI:

  1. ALI

  2. No preexisting ALI before transfusion

  3. During or within 6 h of transfusion

  4. A clear temporal relationship to an alternative risk factor for ALI

The incidence of TRALI was between 1/1,000 and 1/8,000 transfusions in the 90s and the early 2000 [221, 222, 223]. A recent surveillance study completed in 2010 reported an incidence rate of 1.8 TRALI per 100,000 transfusions in Canadian children [224]. In this study, three out of the four cases of TRALI occurred in PICU patients. Furthermore, two cases occurred in neonates who underwent cardiac surgery, raising the possibility that these patients are at greater risk of TRALI.

The mechanisms involved in the physiopathology of TRALI are still being debated. The most popular hypotheses include: (1) a reaction between donor antibodies (anti-granulocyte, anti-HLA class I or II) and recipient antigens that initiates an inflammatory reaction in the lungs; (2) the neutrophils of a recipient primed by surgery, trauma or an infection overreact when exposed to inflammatory activators (anti-leukocyte, biologically active lipids, etc.) that are either present in the donor’s blood or that were produced during storage [225, 226]. Recent studies suggest that the two theories might be somewhat linked [227]. This has lead to the development of a unifying model (the threshold model) by Bux et al. [228] According to this model, the level of priming of neutrophils, either directly or through activation of the pulmonary endothelium, by a patient clinical condition and by substances (including antibodies) present in the transfused component, is responsible for triggering TRALI in a recipient.

The treatment of TRALI involves cessation of the blood product deemed responsible and is otherwise the same as that of ARDS. When a TRALI is suspected, the transfusion must be stopped immediately, and supportive treatment must be started. Oxygen, mechanical ventilation and fluids may be required [229]. Diuretics are not recommended because they increase the risk of severe hypotension [230].

In some countries like the United Kingdom, Canada and USA (American Red Cross), blood collected from multiparous women is not used for transfusion, but sent to fractionation (production of albumin, IVIg) and/or a policy of preferential use of male donors has been implemented, the hypothesis being that this should reduce the exposure of blood receivers to donor antibodies (anti-granulocyte, anti-HLA) [231, 232, 233]. In the United Kingdom, provision of male plasma was associated with a reduction in TRALI reports from 36 in 2003 to 23 in 2004 and 2005 and 10 in 2006 [219]. The mortality rate of TRALI is approximately 6 % [221], but the prognosis is good in most cases. In survivors, resolution is usually rapid (within 96 h) and there are no long-term sequelae [230]. However hypoxemia and pulmonary infiltrates persist more than 7 days in some patients (20 %) [229].

The diagnostic criteria advocated by the panel of experts in 2004 [218] exclude the possibility that a TRALI appears in a patient who already presents an ALI or an ARDS when a RBC transfusion is initiated, which is frequent in the PICU. There is indeed some evidence that a 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. Marik et al. [234] suggested expanding the definition of TRALI in ICU to ALI/ARDS observed within 72 h after the transfusion of a blood product: they reported that such “delayed TRALI syndrome” occurred in up to 25 % of critically ill adults receiving a blood transfusion. Church et al. [235] also reported an association between the transfusion of plasma and/or packed RBC units and ALI/ARDS. The bioactive substances contained in packed RBC and plasma units can cause or add to the severity of cases of ALI/ARDS [235, 236, 237]. Further investigation is required to better characterize the epidemiology, the mechanisms and the clinical impact of transfusion-related delayed TRALI syndrome in PICU.

Transfusion-Associated Circulatory Overload (TACO)

TACO, also named transfusion-associated congestive heart failure, is probably underreported. The incidence rate of TACO collected by the SHOT system is 1/34,091 transfusion, but Popovsky believes that the real incidence rate can be up to 1 % [220], especially after massive transfusions. The incidence rate of TACO in PICU is unknown, but in 2010, TACO was the most common transfusion-related death in UK. According to the British Haemovigilance System (SHOT), a TACO is present if at least four of the five following criteria are met within 6 h after a transfusion: (1) acute respiratory distress; (2) tachycardia; (3) increased blood pressure; (4) acute or worsening pulmonary edema; (5) evidence of positive fluid balance <www.shotuk.org/shot-reports>. All patients with cardiac disease or chronic anemia (Hb < 5 g/dL) are at risk, including newborns. Circulatory overload can be prevented to some extent by slowing the rate of transfusion (to less than 1 mL/kg/h) in patients at risk. Other modalities include pre-emptive diuretics and splitting components into smaller aliquots. Treatment consists in cessation of the transfusion, attention to fluid balance, use of diuretics if necessary and supportive ventilatory measures.

Hypotensive Reaction

Hypotension following transfusion of a blood product is rare (1/102,273 transfusions in Canada [207]), but case reports have been published describing it both in adult and pediatric patients [238]. In most instances, these reactions seem to be caused by a bradykinin modulated metabolic reaction elicited when the blood product is exposed to a negatively charged surface like a transfusion filter. Patients receiving angiotensin conversion enzyme inhibitors as well as patients with an abnormal bradykinin catabolism, a common occurrence in cases of sepsis, are also at risk [197]. Hypotensive reactions usually appear quite soon after the transfusion is initiated and in most instances, there is no fever, although some flushing has been described. These reactions are more frequent after transfusion of platelet concentrates [238]. Pre-storage leukocyte reduction seems to decrease their incidence, although it does not eliminate them entirely [239]. Close monitoring of all patients receiving angiotensin conversion enzyme inhibitors is required.

Fever

Fever is the most frequent reaction to a blood product transfusion. It is not dangerous unless it is caused by a hemolytic reaction or a bacterial contamination. Its frequency after transfusion of a packed RBC unit is about 1 % [163, 240] and can be as high as 10 % after transfusion of platelet concentrates [241]. A febrile non-hemolytic transfusion reaction (FNHTR) is defined as a de novo rise in temperature equal to or greater than 1 °C that cannot be explained by the patient’s clinical condition (i.e. other causes of fever must be ruled out). The fever can be accompanied by dyspnea, tachycardia, headache, anxiety, rigors (shivering) as well as nausea and vomiting [220]. These symptoms usually appear at the end or just after the end of transfusion. FNHTR is thought to be caused primarily by two mechanisms involving white blood cells. Firstly, FNHTR may occur when HLA antibodies present in a recipient react with donor white blood cells present in a RBC or platelet component. This leads to complement activation and cytokine release, which results in the typical symptoms of a FNHTR. Alternately (and likely more commonly, at least in the case of platelet transfusions) cytokines are released from white blood cells during the storage of blood components; when transfused, these cytokines can lead to a FNHTR in the recipient. The proportion of patients with fever episodes decreased from 24.7 % prior to the introduction of the pre-storage leukoreduction program to 22.5 % following its implementation in Canada (OR 0.88; 95 % CI 0.82–0.95; p = 0.001) [242]. It may be useful to use washed blood products for patients with a history of repeated and severe FNHTR to leukocyte-reduced blood products. Acetaminophen can be used to minimize fever, but premedication with acetaminophen, diphenhydramine or steroids is not helpful [243, 244].

Acute Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions are characterized by hemoglobinuria and/or hemoglobinemia (blood level of free Hb above normal range) with at least one of the following symptoms and signs: de novo fever, dyspnea, hypotension and/or tachycardia, anxiety/agitation, pain [220]. Acute hemolytic reactions are rare (1/26,914 according to MacDonald et al. [207]), but may be fatal. The destruction of RBCs in the recipient is attributed to immunological incompatibility (donor RBC antigens reacting with recipient antibodies). Acute hemolytic reactions are usually caused by the transfusion of an incompatible blood product, an adverse event that is attributable to error in 86 % of cases. Acute hemolysis due to ABO incompatibility is the leading cause of severe reaction to RBC transfusion (1/108,968 RBC transfusions) [207]; however, other erythrocyte antigens can be involved (D/d, C/c, E/e, Kell, etc.). Hemolysis is associated with hemoglobinuria and acute anemia. Fever is also frequent, as well as shivering, discomfort and general pain. In severe cases, hypotension, shock, renal insufficiency and DIC can be observed. A mortality rate as high as 10 % is reported [197]. In order to prevent such hemolytic reactions, correct labeling of the blood sample for pre-transfusion testing is essential and, at the time of transfusion, compatibility between donor and recipient including ABO and Rh groups, the identification number of the unit as well as the identity of the recipient (name and hospital chart number) must be meticulously verified and routinely double-checked at the patient’s bedside.

Non-immunologic Hemolysis

Non-immunologic hemolysis can be caused by mechanical trauma to RBCs (transfusion through a very small needle with high pressure), use of a cell-saver device or mechanical warmer (excessive warming), incorrect storage (e.g. if temperature goes below 0 °C), injection using lines that contain a hypotonic solution and bacterial contamination.

Allergic Reactions

Allergic reactions related to type I hypersensitivity reactions can occur when allergens from the donor react with antibodies from the receiver. Such reactions are usually minor (urticaria: 1/100 RBC units [163],) but may be severe (anaphylaxis: 1/20,000 RBC units) [163]. As reported by SHOT (2010 Annual Report <www.shotuk.org/shot-reports>), “anaphylactic reactions… occur most frequently during the first 15 min of a transfusion (mean time to onset 26 min in cases reported in 2010)”, but the risk exists throughout the whole transfusion episode. At least one of the following signs/symptoms is present in severe cases: cardiac arrest, generalized allergic reaction or anaphylactic reaction, angioedema (facial and/or laryngeal), upper airway obstruction, dyspnea, wheezing, hypotension, shock, precordial pain, chest tightness, cardiac arrhythmia or loss of consciousness [220]. The risk for severe allergic reactions is greater in patients with IgA antibodies associated with IgA deficiency. Severe reactions usually occur more rapidly than mild reactions. Fever is usually not observed, but a rash is possible. Severe allergic reaction may be life-threatening [197]. It is advisable to administer antihistamines prior to transfusing patients who have presented repeated minor allergic reactions to blood products; the use of corticosteroids as well as using washed packed RBC units or platelet concentrates may also be considered particularly for severe or repeated reactions that do not respond to premedication with antihistamines. Patients with an IgA deficiency and anti-IgA should receive blood from donors with that same deficit or, in the case of cellular blood components, products that have been thoroughly washed. White blood cell reduction does not prevent allergic reactions.

Infections

All blood product administration involves a potential for transmission of infections. Bacterial contamination of blood products is the cause of 10 % of deaths attributable to transfusions. The risk of bacterial contamination is higher for platelets (1/31,189 units) than for RBC units (1/65,381 units) [207], as platelets are stored at 22 °C while RBCs are stored at 4 °C. Many preventive techniques have been implemented in the last years in order to decrease the risk of bacterial infections caused by platelet transfusions, which have significantly improved the safety of platelets transfusions. For example, the incidence in the Province of Quebec of probable and definite transfusion-transmitted bacterial infections associated with whole blood-derived platelets decreased from 1 in 2,655 in 2000 to 1 in 58,123 five-unit pools in 2008 (p < 0.001) [245]. It is estimated that transfusion-related sepsis occurs in 15–25 % of patients who receive contaminated platelet concentrates [211]. Potential sources of contamination include unrecognized bacteremia in the donor due to Yersinia enterolytica or Salmonella gastroenteritis, Staphylococcus aureus infection caused by dental manipulation, contamination of donated blood by normal skin flora during collection and infection occurring due to manipulation of blood products. The most common germs are: Gram negative bacteria like Klebsiella pneumoniae, Serratia marcescens and Pseudomonas species, and Gram positive like Staphylococcus aureus, Staphylococcus epidermidis and Bacillus cereus. The reaction usually occurs during or within a few hours after transfusion and can cause milder symptoms such as fever and shivering as well as more severe complications such as septic shock. The risk of bacteremia is more important with prolonged storage time. When a bacterial contamination is suspected, the transfusion must be stopped immediately, wide spectrum antibiotics must be given (third generation cephalosporin or beta-lactam in combination with aminoglycoside) and supportive treatment administered. The blood bank must be informed immediately, as other blood products from the same donor may need to be withdrawn. Culture of the blood product itself is indicated. Several blood suppliers now perform bacterial detection studies on platelet concentrates prior to their release into hospital inventories, but even this technique does not detect all contaminated units.

Acute Leukocytosis

Acute leukocytosis is rare after transfusion of leukocyte-reduced RBC units, but may occur after the transfusion of non filtered units [86]. White blood cells can reach values as high as 40 × 109/L, but return to normal within 24 h [86].

Acute Complications of Massive Transfusion

Massive transfusion is defined as the administration of more than one blood volume of blood products within a 24 h period, or more than 50 % of the circulating blood volume in 3 h or less, or ten RBC units in adults [199]. Serious acute complications of massive transfusion include fluid overload, hypothermia, coagulopathy and thrombocytopenia, acidosis, citrate intoxication, hyperkalemia and hypocalcemia [246].

Hypothermia

The massive transfusion of blood products can cause hypothermia, which can lead to problems like tissue hypoxia, arrhythmias, coagulation disorders (increased PT and PTT, platelet dysfunction), increased blood viscosity, high blood lactate level, hyperkalemia and decreased metabolism of drugs. Mortality is higher if the body temperature drops below 34 °C [247]. Treatment and prevention of hypothermia involve warming blood products as well as the patient (blanket, heating lamp, etc.).

Coagulopathy

The coagulopathy and thrombocytopenia observed after massive transfusion of RBC units is attributed to hemodilution, hypothermia, administration of blood products with a prolonged length of storage and DIC [248]. Transfusion-related coagulopathy can be diagnosed if at least one of the following criteria is observed during or shortly after a massive transfusion: INR (international normalized ratio) >2.0; activated partial thromboplastin time (aPTT) >60 s; positive assay for fibrin-split products; D-dimers >0.5 mg/mL [220]. It is frequently recommended to give plasma and platelets if a RBC volume corresponding to 1–1.5 times the circulating blood volume is administered within a short period of time.

Citrate Intoxication

Citrate can cause early onset acidemia, though metabolic alkalosis can also develop due to the liver metabolizing citrate [249]. Citrate intoxication occurs if the metabolic capacity of the liver is overwhelmed, which can occur with administration of packed RBCs at a rate greater than 3 mL/kg/min and of whole blood or plasma at a rate greater than 1 mL/kg/min [250, 251]. Citrate intoxication can cause severe hypocalcemia [252]. Callum et al. [205] recommended the following strategy in order to avoid complications related to massive transfusion: monitor core temperature and prevent hypothermia using a blood warmer for all intravenous fluids and blood components; monitor the coagulation profile and transfuse platelets, plasma or cryoprecipitate to maintain a platelet count >50,000/mm3, an INR < 1.5–2.0 and fibrinogen level over 0.1 g/dL; monitor hyperkalemia, acidosis and hypocalcemia, and give CaCl2 if necessary.

Hyperkalemia

Hyperkalemia is a potential complication with all RBC transfusions, especially if the transfusion is given rapidly. Potassium is released in the supernatant by RBC leak or lysis. Its level increases linearly and is approximately equal to the number of days of storage [253]. Potassium levels have been measured in CPDA-1 and SAGM: it increases from 5.1 to 78.5 mmol/L (1st–35th day) in the former, from 2.1 to 45 mmol/L (1st–42nd day) in the latter [253]. Irradiation further increases the potassium concentration in units stored following irradiation [254]. Monitoring of potassium levels in transfusion recipients is essential, and it is advisable to administer packed RBCs at a rate no greater than 0.3 mL/kg/min whenever possible. Notwithstanding these concerns, the frequency of hyperkalemia caused by RBC transfusion is low. Parshuram et al. [254] have shown that the transfusion of 11 mL/kg of packed RBC units to critically ill children increases the potassium blood level from 3.85 ± 0.55 to 3.94 ± 0.62 mmol/L, a difference that is not clinically, nor statistically significant.

Late Onset Reactions and Complications

Late reactions to transfusion occur days, weeks or even years after the transfusion. Serious late-onset non-infectious complications of blood transfusions include hemolysis (delayed hemolytic transfusion reaction), transfusion-transmitted infections, post-transfusion purpura, allo-immune thrombocytopenia, graft versus host disease, and possibly (though controversial) TRIM (see above).

Delayed Hemolytic Reactions

In 2006, the incidence rate of delayed hemolytic reactions was one per 255,682 transfusions in Canada [207]. Delayed hemolytic reactions are caused by antibodies in the recipient that are not detected during pre-transfusion compatibility testing and that developed either because of prior RBC transfusions or because of exposure to RBCs of fetal origin. The most frequently involved antibodies are: E, Jka, c, Fya, K [255]. The hemolytic reaction usually begins 3–14 days after transfusion. Most cases are mild and resolve spontaneously, but severe cases can occur, especially in sickle cell patients (hyperhemolysis). There is no specific treatment. Erythrocyte alloimmunization following transfusion can occur in 1–8 % of recipients and is a particular concern in young girls who may then be at risk for hemolytic disease of the fetus/newborn in future pregnancies [163].

Post-Transfusion Purpura (PTP)

PTP is rare, but can be severe. It manifests itself by a low platelet count (below 10 × 109/L) any time between 1 and 24 days after transfusion in patients sensitized to platelet antigens by prior transfusion or pregnancy [197]. The pathogenesis is unclear and presumably is related to the presence of platelet-specific antibodies in the recipient following previous exposure to human platelets. These antibodies destroy both transfused platelets and the recipient’s own platelets. Severe hemorrhage can occur in the gut, urinary tract and/or brain. The thrombocytopenia is refractory to platelet transfusion and the mortality rate is reported to be as high as 8 % [256]. Giving platelet concentrates that are free of the implicated platelet antibodies to susceptible patients can prevent this type of reaction. The thrombocytopenia appears suddenly, but it is usually self-limiting. Steroids, plasmapheresis and immunoglobulins may be required in severe cases. The acute onset of severe thrombocytopenia following transfusion can also occur when a plasma-containing component from a donor with anti-platelet antibodies is administered to a recipient possessing the corresponding platelet antigen.

Infections

Nowadays, non-infectious serious hazards of transfusion (NiSHOTs) are more frequent and more challenging to practitioners than transfusion-transmitted infectious diseases [58]. This does not mean that there is no risk. There will always be some residual risk of infections, attributable to the “window period” (time from the beginning of an infection to the time when tests can detect the infection) and to false negative results. Table 19.3 lists the most frequent or most important infections attributable to transfusions. Although transfusion transmitted hepatitis B virus (HBV), hepatitis C virus (HVC) and human immuno-deficiency virus (HIV) have become exceedingly rare, the risk of transfusion transmitted infectious diseases including the risk of bacterial contamination, cytomegalovirus (CMV) transmission and infection with emerging infectious disease agents and with viruses for which testing is not currently performed (e.g. human herpesvirus-8) [257] continues to be a major concern [258]. Transmission of insect-borne zoonosis is also a well-recognized problem (for example: West Nile virus [213], malaria [259], babesiosis [260], Bartonella Quintana [261]) A few cases of prion (agent causing variant Creutzfeld-Jacob disease or vCJD) transmission by a transfusion have been reported [212]. SD plasma has a reduced risk of infection related to enveloped viral pathogens, but the risk for non-enveloped viruses is not affected.

Transfusion Associated Graft Versus Host Disease (TA-GvHD)

TA-GvHD is a rare adverse event that can be extremely severe [214, 262]. The “Serious hazard of transfusion (SHOT) initiative” run in United Kingdom reported that 8 out of 22 deaths (36 %) attributed to a transfusion were caused by a TA-GvHD [263]. TA-GvHD has occurred in two settings. The first clinical setting in which TA-GvHD occurs is severely immunocompromised patients (such as those with congenital immune deficiency syndromes or cancer patients receiving chemotherapy) or preterm infants with immature immune systems unable to reject donor T lymphocytes found in cellular blood components [264]. Hence the donor T lymphocytes are able to engraft, proliferate, and then attack recipient tissues. An ICU group at particular risk is DiGeorge patients undergoing cardiovascular surgery for congenital cardiac anomalies associated with this syndrome. Surprisingly HIV infected patients are not at risk for TA-GvHD. The second clinical setting in which TA-GvHD occurs is the setting in which donor lymphocytes are able to engraft because they are not recognized as foreign by a non-immunosuppressed receiver. This occurs when the donor is HLA homozygous for one of the HLA haplotypes present in an HLA heterozygous recipient. This situation can occur in a population with relative HLA homogeneity (e.g. the Japanese) or in the setting of directed donations from biologic relatives or if HLA-matched platelets are given to treat a patient with immune refractoriness to unmatched platelets [2, 264]. Symptoms usually appear 8–28 days after transfusion and include fever, skin rash, diarrhea and hepatic dysfunction. A severe pancytopenia can be caused by bone marrow dysfunction. TA-GvHD is fatal in 90 % of patients if untreated, a fatality rate that is significantly higher than with GvHD related to bone marrow transplantation [84]. Lymphocyte multiplication can be blocked by irradiation, which dramatically reduces and probably eliminates the risk of contracting TA-GvHD. Leukoreduction of cellular components is not sufficient to prevent TA-GvHD.

Non-specific Treatment of Transfusion Reactions

When a transfusion reaction is suspected, the following actions must be undertaken immediately:
  • Stop the transfusion immediately.

  • Check if the patient received the correct unit.

  • Maintain an intravenous access with NaCl 0.9 %.

  • Insure patient stability.

  • Re-check identification of patient and blood product.

  • Report in detail the clinical data of the event in the hospital chart.

  • Monitor the patient for at least a few hours.

  • Collect blood cultures from the patient if bacteremia is suspected,

  • Measure antibodies, antigens, free Hb or other markers of metabolic disturbance (acidosis, hyperkalemia, hypocalcemia, etc.) if appropriate.

Some attention must also be paid to the transfused unit:
  • Look at the unit and describe your observation in the patient’s hospital chart.

  • Return the unit that was being transfused, the filter and the tubing being used, and the remaining blood product to the blood bank.

All possible transfusion reactions must be immediately reported to the appropriate blood agency, which is the blood blank in many hospitals.

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Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Marisa Tucci
    • 1
  • Jacques Lacroix
    • 2
    Email author
  • France Gauvin
    • 3
  • Baruch Toledano
    • 3
  • Nancy Robitaille
    • 4
  1. 1.Department of PediatricsSainte-Justine Hospital, University of MontrealMontrealCanada
  2. 2.Department of PediatricsSainte-Justine HospitalMontrealCanada
  3. 3.Division of Pediatric Critical Care Medicine, Department of Pediatrics, Faculté de MédecineSainte-Justine Hospital, Université de MontréalMontrealCanada
  4. 4.Division of Hematology-Oncology, Department of Pediatrics, Faculté de MédecineSainte-Justine Hospital, Université de MontréalMontrealCanada

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