Anemia and oxygen delivery

Oxygen delivery in the critically ill

Variables related to oxygen delivery and consumption, and hemodynamic adaptive mechanisms related to anemia, are explained in more detail in Chapters 23 , 28 , and 34 .

Anemia decreases the capacity of blood to deliver O ₂ because of lower Hb content. Systemic (global) D o ₂ is dependent on cardiac output and the arterial concentration of O ₂ (Ca o ₂ ):

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Do2=cardiac output (stroke volume×heart rate)×Cao2

Ca o ₂ (mL O ₂ /100 mL) is defined by the formula:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='(Hb×Sao2×1.34)+(0.003×Pao2)’>(Hb×Sao2×1.34)+(0.003×Pao2)(Hb×Sao2×1.34)+(0.003×Pao2)
(Hb×Sao2×1.34)+(0.003×Pao2)

where Sa o ₂ is arterial oxygen saturation and Pa o ₂ is partial pressure of arterial oxygen. Because systemic D o ₂ is directly linked to Hb concentration, the most rapid and effective way of increasing D o ₂ (within minutes) in anemic patients is by giving an RBC transfusion.

The ultimate goal of RBC transfusion is to improve cellular energy production, that is, ATP production, which translates into V o ₂ . An adequate O ₂ delivery to cells does not imply necessarily that V o ₂ is adequate and that cells produce enough energy. V o ₂ depends on substrate availability and metabolic demands; it can be amplified by increasing cellular O ₂ extraction rate (O ₂ ER), or by increasing D o ₂ if there is V o ₂ /D o ₂ dependence.

The relationship between O ₂ delivery and consumption is characterized by two phases: a directly linear relationship between V o ₂ and D o ₂ up to a “critical threshold” (often referred to as the critical D o ₂ ) and a flat section above this threshold ( eFig. 91.1 ). Above this threshold, a fall in D o ₂ does not cause a drop in V o ₂ because it is compensated by mechanisms such as an increase in O ₂ ER. These mechanisms are limited, though, and there is a critical threshold of D o ₂ under which O ₂ ER cannot increase any further, and below which V o ₂ diminishes if D o ₂ decreases.

Relationship between oxygen delivery (D o ₂ ) and O ₂ consumption (V o ₂ ) in normal patients (black line) , between D o ₂ and blood lactate level in normal patients (blue dashed line) , and between D o ₂ and V o ₂ in septic critically ill patients (red dotted line) . Under the critical threshold D o ₂ (arrow) , V o ₂ diminishes and blood lactate level increases. Over this threshold, a fall in D o ₂ does not cause a drop in V o ₂ because it is compensated for by an increase in O ₂ extraction and/or an increased cardiac index. In critically ill patients, V o ₂ is frequently higher than normal. Then, the level of the D o ₂ /V o ₂ curve (red dotted line) is shifted upward; the critical threshold may also be shifted to the right, which may explain why pathologic O ₂ supply dependence is reported in some critically ill patients.

The stress of critical illness increases metabolic rate and V o ₂ , which shifts the critical level of D o ₂ to the right and upward. However, compensatory mechanisms are limited in anemic critically ill patients.

Oxygen kinetics in the critically ill

Tissue hypoxia from low D o ₂ may be due to low Hb concentration (anemic hypoxia), low cardiac output (stagnant hypoxia), or low Hb saturation (hypoxic hypoxia) or some intoxications (e.g., toxic hypoxia caused by carbon monoxide). RBC transfusions are typically administered to increase D o ₂ in critically ill children. RBC transfusion increases D o ₂ in the central circulation, but it does not always increase tissue D o ₂ and global V o ₂ in ICU patients. ^, Several mechanisms may explain this. Mitochondrial dysfunction can impede O ₂ utilization in critically ill patients. Moreover, peripheral D o ₂ is impaired in ICU patients, and there is some evidence that RBC transfusion may worsen this problem.

Regulation by red blood cells of oxygen delivery to tissue

While RBC transfusion certainly increases systemic D o ₂ in the central circulation, this does not imply that regional D o ₂ is improved. There is evidence that RBC transfusion may disturb local D o ₂ . However, data on regional D o ₂ are inconsistent, their clinical significance remains to be determined, and the underlying mechanisms, which may involve blood viscosity, microcirculatory flow, local D o ₂ , and cellular respiration, are not well characterized.

Resistance to blood flow increases rapidly if the hematocrit level exceeds 0.45, which corresponds to an Hb of 15 g/dL. RBC transfusion increases blood viscosity, which can lead to microcirculatory stasis and impaired D o ₂ to tissues.

Activation of white blood cells (WBCs) in RBC units and cytokine generation in the supernatant of transfused RBC units may also have a microcirculatory effect: some cytokines can mediate vasoconstriction or thrombosis of small vessels and cause local ischemia. Most RBC units are now prestorage leukocyte reduced, which significantly decreases cytokine levels in the supernatant. The clinical impact of cytokines on regional D o ₂ remains to be determined.

There is evidence that RBC transfusion can cause vasoconstriction of microvasculature via an interaction between intracellular Hb and uptake by RBCs of nitric oxide released by blood vessels. With local tissue hypoxia, Hb in the microvasculature releases nitric oxide and triggers local vasodilation. Conversely, if there is sufficient O ₂ in the microvasculature, Hb traps nitric oxide and causes vasoconstriction. This regulatory mechanism is almost immediately lost once RBCs are stored: it has been shown that in vitro exposure of blood vessels to RBC units stored 3 hours or more causes vasoconstriction. The clinical significance of these observations is not clear; nonetheless, they suggest that regional D o ₂ can be disturbed by RBC transfusion (see also Chapter 87 ).

RBC units undergo several changes during storage, which are generally referred to as storage lesions. ^, For example, the concentration of 2,3-diphosphoglycerate (2,3-DPG) in stored RBCs decreases over time and can induce a left shift in the oxy-Hb dissociation curve, which impedes O ₂ release to tissues even if systemic D o ₂ is increased. In addition, RBC deformability decreases after 2 or 3 weeks of storage, which may alter their capacity to pass through the capillary bed. Furthermore, hemolysis in older RBC units releases substantial amounts of free Hb, ranging from 0.5 mg/dL in 1-day-old RBC units to 250 mg/dL in 25-day-old units. Moreover, microparticles are released by RBCs stored more than 2 or 3 weeks. Free intravascular Hb and microparticles tightly bind nitric oxide and therefore cause vasoconstriction.

Thus, while RBC transfusions certainly increase systemic D o ₂ , some evidence suggests that impaired microcirculatory flow and O ₂ availability can occur, which may have adverse effects on tissue oxygenation and cellular respiration.

Risks of anemia

Severe anemia is associated with a higher risk of mortality. Carson et al. combined the data of two studies involving bloodless surgery in adults and reported that the unadjusted mortality rate was 0.9% when the nadir Hb level was 7 g/dL or greater, 9% if it was between 5 and 7 g/dL, 29.8% if it was between 4 and 5 g/dL, and 41% if it was less than 4 g/dL. Clearly, the risk of mortality increases when the Hb falls below 5 g/dL. It is less obvious when to transfuse if the nadir Hb level is between 5 and 7 g/dL. It is important to recognize that the relationship between anemia and outcomes does not mean that transfusion to treat anemia will necessarily improve outcomes.

There are less data on the relationship between anemia and adverse outcomes in children. Lackritz et al. followed 2433 anemic African children, 20% of whom received a whole-blood transfusion. Transfusion seemed beneficial if the Hb was below 4.7 g/dL and if the patient presented with respiratory distress. Given these data, local guidelines were implemented, recommending that whole blood should be transfused to hospitalized children if their Hb was less than 5 g/dL. Lackritz subsequently enrolled 303 children with a Hb less than 5 g/dL. Mostly because blood products were not available, 116 (38%) did not receive a transfusion. Each child with severe anemia was matched with the next child hospitalized with a Hb greater than 5 g/dL. Death rates were 19.5% in 303 patients with a Hb greater than 5 g/dL who were not transfused, 21.4% in 187 patients with a Hb less than 5 g/dL who were transfused, and 41.4% in 116 patients with a Hb less than 5 g/dL who were not transfused. English et al. completed a prospective cohort study of 1269 children with malaria hospitalized in Kenya. Whole-blood transfusion seemed to decrease mortality if anemia was severe (Hb <4 g/dL), or if a Hb less than 5 g/dL was associated with dyspnea. These studies suggest that the risk of mortality increases significantly among children ill enough to require hospitalization if their Hb is less than 5 g/dL, particularly if respiratory symptoms are present.

Hemorrhagic shock or severe bleeding (node 1)

The first node of the decision tree is about hemorrhagic shock and life-threatening bleeding. In such instances, RBC transfusions are clearly indicated, with plasma and platelets (ratio: 1/1/1 or 2/1/1). ^, The decision to prescribe RBC transfusions should be based on physiologic state, estimated amount of blood loss (Canadian Blood Services recommends a transfusion if there is an acute blood loss >15% blood volume ) and risk of ongoing life-threatening hemorrhage, more than on Hb concentration, coagulation tests, and platelet counts. A systematic approach to treat hemorrhagic shock and to activate massive transfusion protocols is recommended.

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  Severe anemia in PICU patients without severe bleeding (node 2): The TAXI recommendation is that a RBC transfusion should be prescribed in PICU patients with Hb concentration less than 5 g/dL, and that practitioners prescribe RBC transfusion using their experience and clinical data, such as severity of illness and evidence of decreased O ₂ consumption if the Hb concentration is between 5 and 7 g/dL. It is recommended to move to node 3 in critically ill children with Hb level of 7 g/dL or greater.

PICU patients with severe anemia without severe bleeding (node 2)

RBC transfusion is more questionable if there is no severe bleeding. Pediatric intensivists have stated in two surveys that their decision to prescribe an RBC transfusion would be based on reasons such as low D o ₂ or V o ₂ , cardiovascular insufficiency, respiratory failure or use of certain specific technologies such as ECMO, hemodialysis, hemofiltration, plasmapheresis, or exchange transfusion. Nonetheless, the most frequent reason to transfuse RBCs was reported to be a low Hb concentration, ^, which is the core of node 2 in the decision tree. The Hb level that should prompt a pediatric intensivist to prescribe RBC transfusion remains a matter of debate, but there is some evidence in the medical literature that can guide practitioners.

Hemodynamically stable noncardiac patients (node 4)

What should prompt intensivists to prescribe an RBC transfusion in hemodynamically stable noncardiac PICU patients with an Hb level of 7 g/dL or greater? Some high-quality studies have addressed this question. Two randomized controlled trials evaluated RBC transfusion strategies in children. The first study was performed in 106 African children with malaria crisis (hematocrit 12%–17%). Whole-blood transfusion did not improve mortality rate (1 in 53 vs. 2 in 53) in patients without respiratory or cardiovascular compromise. In the TRIPICU study, a randomized controlled trial involving 637 stable critically ill children with an Hb level of 9.5 g/dL or less, 320 patients were allocated to an RBC transfusion threshold of 7 g/dL of Hb (restrictive group) and 317 to a threshold of 9.5 g/dL (liberal group). A statistically significant noninferiority was found: 38 and 39 patients, respectively, developed new or progressive MODS, and there were 14 deaths within 28 days postrandomization in both strategy groups. The conclusion was that a restrictive strategy is as safe as a liberal strategy in stable critically ill children. Moreover, 174 patients (54%) in the restrictive group received no RBC transfusion compared with 7 (2%) in the liberal group ( P < .0001), and patients in the restrictive group received 54% fewer RBC transfusions. These data and the primum non nocere principle support adopting a restrictive transfusion strategy for stabilized critically ill children.

Is there anything else than the Hb level that should guide RBC transfusion strategy in hemodynamically stable PICU patients with an Hb level of 7 g/dL or greater? Guidelines from many organizations emphasize that the decision to administer RBCs should not be based solely on Hb levels but should involve sound clinical judgment and good common sense. , ,

Should we use physiologic markers to guide RBC transfusion in PICU patients? Goal-directed transfusion therapy using such markers is frequently advocated. While it is theoretically rational to base the decision to transfuse RBCs on physiologic need, it is still a matter of debate as to what parameters best determine that need. It has been suggested that an RBC transfusion is indicated for patients with symptomatic anemia, but most critically ill children are unable to report these symptoms. Some have suggested that systemic markers of oxygenation deficit, such as systemic V o ₂ , V o ₂ /D o ₂ dependence, blood lactate level, S cvo ₂ , mixed venous O ₂ saturation or O ₂ ER, might be useful. Others have proposed that parameters reflecting regional oxygenation deficit—such as brain tissue O ₂ pressure, gastric tonometry, tissue O ₂ saturation measured by near-infrared spectroscopy, or digital O ₂ ER measured by noninvasive devices—may be more reliable. Actually, it is presently not known which markers are best suited to guide RBC transfusion therapy and what cutoff values should be used to determine the need for RBC transfusion. The concept of goal-directed transfusion therapy is laudable but is presently vaguely defined and not supported by hard data. Specific recommendations for goal-directed transfusion therapy remain undetermined at the present time. ^,

In practice, a low Hb concentration remains the most frequent and primary justification for pediatric intensivists to prescribe an RBC transfusion. Therefore, it makes sense that the Hb concentration be the first parameter assessed when an RBC transfusion is considered. Given the available evidence, critically ill children must receive an RBC transfusion if their Hb level is below 5 g/dL. In stable patients—including septic patients, patients having undergone noncardiac surgery, severely burned children, and trauma patients —it is suggested to consider RBC transfusion if the Hb concentration is less than 7 g/dL, but a transfusion is not recommended if the Hb concentration is above this threshold. However, determinants other than the Hb concentration must be considered, including age, severity of illness, or evidence of organ dysfunction or O ₂ dependency, such as elevated blood lactate level or low S cvo ₂ . For example, it would seem appropriate to consider a higher threshold and a more aggressive RBC transfusion strategy in unstable patients for whom the optimal and safe lower limit of the transfusion threshold has not been established. Moreover, any recommendations made must also factor in specific considerations for disorders such as sickle cell disease and cardiac conditions (node 5).

In summary, the TAXI recommendation in noncardiac PICU patients is “In critically ill children or those at risk for critical illness, who are hemodynamically stable and who have an Hb concentration ≥7 g/dL, we recommend not administering a RBC transfusion.” Can we apply this recommendation to all noncardiac PICU patients, whatever their basic disease?

TAXI members concluded that an RBC transfusion should not be given in hemodynamically stable noncardiac PICU patients with an Hb level of 7 g/dL or greater if they belong to any of the following subpopulations: noncardiac postsurgery, respiratory failure (excluding severe pediatric ARDS), nonhemorrhagic shock, non-life-threatening hemorrhage, ECMO, VAD, or RRT.

Should PICU patients with respiratory dysfunction receive more RBC transfusions? In the TRIPICU study, 234 and 246 patients with respiratory dysfunction were enrolled in the restrictive and liberal group (threshold Hb for RBC transfusion: 7.0 and 9.5 g/dL, respectively). The number of cases of new/progressive MODS was similar, 33 and 35, respectively. Duration of mechanical ventilation was also comparable in these 480 patients (6.4 ± 6.0 vs. 6.3 ± 5.3 days; absolute risk difference: –0.16; 95% CI, –1.2 to 0.9; P = .75), including 73 with an acute lung injury (ALI; 7.2 ± 6.5 vs. 7.1 ± 6.2 days; absolute risk difference: –0.12; 95% CI, –3.1 to 2.9; P = .94) and 48 with ARDS (10.5 ± 9.2 vs. 8.5 ± 7.2 days; absolute risk difference: –2.0; 95% CI, –6.8 to 2.8, P = .40). Thus, targeting higher Hb thresholds does not improve outcome in stable critically ill children with respiratory problems if their Hb level is greater than 7 g/dL.

There is little evidence supporting the belief that a higher Hb level is required in severely ill septic patients. The outcome of 137 septic children (34 in septic shock, 31 with severe sepsis) allocated in the TRIPICU study to a restrictive or liberal transfusion strategy was similar, with 13 of 69 versus 13 of 68, respectively, developing new/progressive MODS (absolute risk difference: 0.3%; 95% CI, –12% to 14%). Holst randomized 1005 adults with septic shock to receive an RBC transfusion only if their Hb level fell below 7 or 9 g/dL. Some of these patients were hemodynamically unstable. The 90-day mortality was similar (43.0% vs. 45.0%; relative risk: 0.94; 95% CI, 0.78–1.09; P = .44). Thus, a threshold Hb of 7 g/dL can probably be safely applied in critically ill children with sepsis, severe sepsis, and septic shock.

The optimal Hb level to trigger RBC transfusion in brain-injured patients and oncologic patients has not been defined yet. Members of TAXI recommended to consider giving an RBC transfusion in critically ill children with acute brain injury if the Hb level is 10 g/dL or less and in patients with oncologic diagnoses or with stem cell transplant if their Hb level is 8 g/dL or less.

TAXI suggests using clinical judgment in PICU patients with alloimmune or autoimmune anemia, with severe pediatric ARDS.

RBC exposure is very large in children under ECMO or VAD. This practice is not without risks. ^, TAXI suggests using clinical judgment in children under ECMO or VAD.

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  Cardiac patients (node 5): TAXI suggests a postoperative Hb level of 7 g/dL in pediatric cardiac patients when there is good postoperative cardiac function in the absence of persisting cyanotic heart disease and a postoperative Hb level of 9 g/dL in PICU patients with persisting cyanotic heart disease. TAXI suggests using clinical judgment in PICU patients with acquired myocardial dysfunction or pulmonary hypertension. The experts added, “there is no evidence that transfusion above 10 g/dL is beneficial.” ^,

Cardiac patients (node 5)

Critically ill children with cardiac disease receive more RBC transfusions than other PICU patients. ^, There is no evidence indicating that this strategy improves outcomes. On the contrary, anecdotal experience with bloodless cardiac surgery for congenital heart disease in children whose families refuse transfusion suggests that a lower Hb level may be well tolerated. ^, eTable 91.1 summarizes the available data on this question.

Prevention of anemia and red blood cell transfusion

“Bloodless medicine” is a popular concept; it refers to all strategies that can be used to provide medical care without allogeneic RBC transfusion, including blood conservation. Many strategies can prevent or significantly decrease the number of RBC transfusions and exposure to transfusion. These strategies are integrated into the concept of a “patient blood management program,” which includes measures to prevent anemia and to limit the number of transfusions. ^{, , ,} Adopting a restrictive RBC transfusion policy in stable critically ill children is one of these strategies. Other strategies could include raising the Hb concentration before elective surgery, using blood products only when necessary, limiting blood loss, and administering the patient’s own blood.

Standard red blood cell units

Storage of RBC units is made possible by refrigeration at about 2°C to 6°C and by storage in preservative anticoagulant solutions that contain dextrose, sodium citrate, citric acid, and sodium diphosphate. RBCs use dextrose and phosphate to generate ATP, which is essential for their survival. Citrate blocks coagulation by chelating calcium; it is also transformed into bicarbonate, which stabilizes the stored RBC unit pH above 6.4. RBCs in CPDA-1 (citrate-phosphate-dextrose-adenine) solution can be stored up to 35 days because the level of ATP is normal after 21 days of storage and is about 50% after 35 days. RBC units are prepared by removing 200 to 250 mL of plasma and platelets from one unit of whole blood after centrifugation. To support the nutrient needs of RBCs after plasma is removed, additive solutions were developed, such as AS-1 (Adsol), AS-3 (Nutricel) and AS-5 (Optisol), and saline-adenine-glucose (SAG) or SAG-mannitol (SAGM). These additive solutions further decrease RBC lysis and allow for storage up to 42 days.

The volume of a CPDA-1 unit is about 250 mL, including 63 mL of preservative solution; it must be diluted with 75 mL of NaCl 0.9% before transfusion (final volume: 325 mL). Volumes of an AS-3 unit and a SAGM unit are about 350 mL and 300 mL, respectively; both include approximately 100 mL of preservative solution and do not require any dilution.

Other types of red blood cell units

Many other types of RBC units are available: collected by apheresis, leukocyte-reduced, washed, irradiated, cytomegalovirus (CMV) negative, autologous, and directed.

Blood types

Table 91.2 describes the compatibility of different blood products. A complete cross-match is mandatory before any transfusion is given, with few exceptions. Transfusion of group O Rh-negative RBCs can be life-saving, but this must be reserved for very severe and acute situations. It takes 15 to 20 minutes to type a patient for ABO and Rh. If there are no RBC antibodies, fully compatible blood or immediate spin cross-match may be issued quickly. In the case of RBC antibodies or other anomalies, a lengthier full serologic cross-match is required. The risk of severe reaction to typed, but not cross-matched, RBC units is about 1 in 1000 if the patient has never received a transfusion; the risk is decreased by 10-fold if a cross-match is performed. Repeat verification that the correct blood unit has been delivered to a given patient is essential because blood mismatch is the most important cause of severe transfusion reaction.

For high-risk elective procedures, type and cross-matching, completed prior to any bleeding, allows for compatible RBC units to be reserved. If an unforeseen emergency transfusion is required for an actively bleeding patient, it is impossible to deliver RBC units that are typed and cross-matched within a reasonable time frame, in which case group O Rh-negative RBC units can be administered (some hospitals also deliver group O Rh-positive RBC units for men and for women after menopause). STAT ordering a transfusion means that transfusion is required within a few minutes; this is not indicated unless the patient is actively bleeding.

Volume and number of red blood cell units

Prescribing the right volume of RBC units is important, as this prevents cardiac overload and limits exposure to several donors.

An easy, albeit simplistic, rule of thumb exists suggesting that administration of 10 mL/kg of RBC units increases the Hb level by 2 to 3 g/dL. If the volume prescribed is greater than the volume of 1 unit of RBCs, blood should be transfused 1 unit at a time to minimize exposure to multiple donors. Prior to the administration of additional RBCs, the Hb concentration should be measured after allowing at least 30 minutes posttransfusion for Hb and hematocrit values to equilibrate. The transfusion can be completed with another unit or partial unit if a reasonable Hb level is not attained.

If the volume of RBCs required is less than 1 unit, a partial unit can be given. Whole RBC units can be subdivided in half (standard division) or in small pediatric 75-mL transfer packs (Pedi-Pak). Partial units prepared nonsterilely expire 24 hours after preparation. On the other hand, partial units prepared sterilely can be kept as long as the original unit (up to 42 days for AS–3). A small volume of RBC unit placed in a syringe must always be administered within 24 hours.

Length of storage

Regulatory agencies and scientific societies, such as the US Food and Drug Administration (FDA) and the European counterpart to the FDA, mandate that RBC units can be stored up to 42 days based on the criterion that at least 75% of transfused RBCs will be alive 24 hours posttransfusion and that hemolysis will be less than 1%. However, a storage lesion, detailed previously, occurs over time, which raises many concerns. ^,

There are safety concerns for transfusion of fresh RBCs as well, including the risk of transmission of some infectious diseases (malaria, Chagas disease, intracellular viruses), cell-free DNA, microchimerism, TA-GVHD, and risk of in-hospital mortality.

Five randomized controlled trials addressed the question of whether the transfusion of fresher rather than older RBC units improves the outcome of critically ill patients. All reported that fresher RBC units do not improve outcome; the three larger trials rather showed consistent, but not statistically significant, trends against the use of fresher blood. ^{, ,} Many intensivists believe that children should receive fresher RBC units, especially for pediatric cardiac surgery patients. A large randomized controlled trial, the Age of Blood in Children in PICU study, enrolling 1538 transfused PICU patients to address this question. The use of fresh compared with standard-issue RBCs (median length of storage, 5 vs 18 days) did not reduce the incidence of new or progressive MODS (147 vs. 133) or PICU mortality (33 vs. 26). Presently, there is no justification to require fresh RBC units for critically ill children, even for cardiac surgery patients.

There are less data informing us on the effect on outcomes with the transfusion of old RBC units, such as those stored for 5 weeks or longer, but available evidence suggests that transfusion of blood stored for 35 days or longer has no effect on in-hospital mortality. ^,

Perfusion, warming, and filtration

An RBC transfusion must be completed within 4 to 6 hours (4 hours in the United States) after the unit is delivered by the hospital blood bank. An RBC unit is usually given over 1 to 3 hours but can be given more slowly (up to 4 hours) or divided into two transfusions if there is some risk of cardiac overload. RBCs can also be given through a rapid infuser in a few minutes for life-threatening bleeding.

The viscosity of RBC units is high, which implies that it is preferable to use larger-bore needles to administer them. No drugs should be given in the line used for RBC unit perfusion. There is in theory a risk of hemolysis if RBCs are given with 0.2% saline or dextrose 10%, but the coinfusion of RBCs and hypotonic or hypertonic solution seems safe if it is short lasting (a few minutes). On the other hand, coinfusion of dextrose-containing fluids with RBC units is safe. It is inappropriate to mix RBC units with Ringer’s lactate (risk of coagulation) or calcium salts.

RBC units must be warmed before administration to diminish the viscosity of the blood product and to avoid hypothermia. Blood viscosity decreases by about 7% for each 1°C increase, reducing resistance and making it easier to administer blood products through catheters. RBC units are stored at 2°C to 6°C and could cause significant hypothermia if given to a patient without warming. Blood products are warmed to room temperature (about 20°C) before delivery to the bedside unless the RBC units are required on an emergency basis (e.g., in a case of hemorrhagic shock). Warming to body temperature (37°C) may be required for patients weighing less than 10 kg or if large volumes need to be given (>20%–30% of the circulating blood volume). RBC units can be warmed by ambient temperature or by active warming with a device. Standard blood-warming devices are used to raise the temperature of whole blood or RBC units and not microwave ovens, which can cause severe hemolysis.

Because all RBC units (even prestorage leukocyte-reduced RBC units) contain fibrin, platelets, and WBC aggregates, a filter (with 80-, 179- or 260-micropores) must always be used to filter these aggregates before they are administered. Although their cost-usefulness has not been determined, filters with 20- to 40-micropores are more effective, and some evidence suggests that they can prevent cases of TRALI. Filters with smaller micropores are not considered standard treatment.

Types of plasma

Plasma is separated from RBCs after collection of whole blood or collected using an apheresis machine. It is then frozen for storage to preserve coagulation factors. The term fresh frozen plasma (FFP) is used if the unit is refrigerated within 8 hours of collection; the term frozen plasma (FP) is used if refrigerated within 24 hours of collection. There is a slight reduction in factor VIII levels in FP. In clinical practice, however, these two types of plasma are presumed to be essentially interchangeable. FP (frozen plasma) is used in this section to designate both types of plasma units.

FP units are collected from a single donor, while units of solvent detergent (SD) plasma (Octaplas, Octapharma) are constituted from a pool of FP collected from approximately 630 to 1520 donors and processed using SD for inactivation of lipid-enveloped viruses. In many countries, only FP may be available, but FFP is still available in some countries.

FP units are systematically leukocyte reduced by filtration before storage in many countries, but not in the United States. FP volume is about 200 to 250 mL/U, while the volume of SD plasma is about 200 mL/U. On average, FP contains 1 U/mL of all coagulation factors, but there is significant variability among individual units, which is attributable to biological variation in factor levels among individual donors and differences in processing, storage, and preparation for transfusion. The levels of coagulation factors in SD plasma are more standard with little variation among units, as it is a pooled plasma product. FP is stored at –18°C up to 1 year after collection. SD plasma can be stored for up to 48 months. Compared with FFP, SD plasma is practically cell free and contains significantly lower residual platelet concentrations and negligible amounts of microparticles due to its manufacturing process.

Multiple dried plasma products are currently used in a few European countries to allow for immediate availability of plasma for severely bleeding patients. Dried plasma products maintain hemostatic and endothelial repair properties similar to that of FP products. ^, The licensing of dried plasma for adults and children is anticipated soon in the United States.

Epidemiologic studies reported that adults transfused with plasma are more prone to contract ventilator-associated pneumonia, bloodstream infection, and septic shock (relative risk for all infections, 2.99; 95% CI, 2.28–3.93; P = .02). A prospective cohort study involving 831 critically ill children reported an increased incidence rate of morbidity and nosocomial infections. The adjusted odds ratios were 3.2 (95% CI, 1.6–6.6) and 2.3 (95% CI, 1.0–5.3), respectively. There was also a significant difference in the adjusted length of PICU stay. Plasma transfusions are associated with adverse clinical outcomes; this might be attributable to their immunomodulative properties or due to confounding by indication given that plasma is transfused to patients with increased severity of illness. It also might be that the association between plasma and outcomes is due to severity of illness and not due to the plasma.

In a secondary analysis of a prospective observational study that included 443 critically ill children who received plasma transfusions, FFP and SD plasma were associated with similar reductions in INR ( P = .80). However, ICU mortality was significantly lower with SD plasma compared with FFP (14.5% vs. 29.1%, P = .02).

Transfusion of plasma: Indications (when)

Generally, FP is transfused to correct multiple coagulation factor deficiencies (or single-factor deficiencies when no recombinant or plasma-derived coagulation factor concentrates are available) in patients with active bleeding or prior to invasive procedures when no alternative therapies are available or appropriate. Common coagulopathies for which FP may be given include liver disease and symptomatic disseminated intravascular coagulation (DIC). FP can be given for the emergency reversal of warfarin or vitamin K deficiency when prothrombin complex concentrates are not available. FP is also given to prevent bleeding in patients with abnormal coagulation tests. Guidelines suggest transfusing FP only when the INR, prothrombin time (PT), or activated partial thromboplastin time (aPTT) is more than 1.5 times normal, as coagulation factors are generally adequate for hemostasis below this level. However, recent data suggest that FP is not very effective at normalizing mild abnormalities of coagulation tests, and the potential clinical benefit of FP transfusion seems minimal when the INR is less than 2.5 or an aPTT is less than 60. Plasma is also indicated for plasma exchange therapies for certain conditions, such as thrombotic thrombocytopenic purpura.

FP should be administered empirically during massive transfusion for life-threatening bleeding. A randomized controlled trial in adults revealed that the early use of FP in the prehospital setting for severe traumatic bleeding improved 24- and 30-day survival. Some experts advocate early replacement of FP in a 1:1 or 1:2 ratio with RBC units in trauma patients with massive transfusion. ^{, ,} According to two systematic reviews, application of a thromboelastography (TEG or rotational thromboelastometry [ROTEM])–guided transfusion strategy reduces the amount of bleeding in patients with massive transfusion, blood product utilization, and renal failure, and seems to improve morbidity and mortality. ^, However, these results were primarily based on trials of elective cardiac surgery involving cardiopulmonary bypass, and the level of evidence was low.

Many pediatric intensivists state that abnormal coagulation tests (INR, TEG, and so on) could prompt them to prescribe FP even if the patient is not bleeding. Actually, there is no evidence that FP should be given in prophylaxis to nonbleeding patients. For decades, there has been consensus that plasma should not be used as a volume expander; crystalloids, synthetic colloids, or purified human albumin solutions are preferred. This concept is currently being challenged by some who are considering reexamination of the use of plasma for volume resuscitation of patients who are in hypovolemic or septic shock. In vitro and animal data in septic models support the concept that plasma improves preload more effectively than crystalloids, can correct both hyper- and hypocoagulable states, repair endothelial injury, and is, in fact, less inflammatory than crystalloids. Until trials are performed in humans, plasma should not be routinely used for volume resuscitation even in patients with hypovolemic shock.

Epidemiologic studies reported that adults transfused with plasma are more prone to contract ventilator-associated pneumonia, bloodstream infection and septic shock (relative risk for all infections: 2.99; 95% CI, 2.28–3.93; P = .02). A prospective cohort study involving 831 critically ill children reported an increased incidence rate of morbidity, nosocomial infections, and duration of stay associated with FP transfusion.

In a secondary analysis of a prospective, observational study that included 443 critically ill children who received plasma transfusions, FFP and SD plasma were associated with similar reductions in INR ( P = 0.80). However, ICU mortality was significantly lower with SD plasma compared with FFP (14.5% vs. 29.1%, P = .02).

Transfusion of plasma: How

The typical dose of plasma in nonmassively bleeding children ranges between 10 and 15 mL/kg. The effectiveness of FP transfusion should be estimated by clinical judgment of ongoing bleeding and functional measurements of hemostasis when time allows. For life-threatening bleeding, FP is empirically transfused without guidance from laboratory measurements of hemostasis due to the inherent delay in reporting of these parameters. In patients with non–life-threatening bleeding, FP may be indicated by functional measures of hemostasis that indicate a hypocoagulable state. Karam et al. reported that a dose-response relationship was found in patients only with an INR greater than 2.5; patients with a lower INR had no significant change in coagulation tests. Normalization of coagulation tests often does not occur and therefore should not be used as the only guide for additional FP transfusions.

FP transfusions should be ABO compatible but do not require cross-matching. In contrast to RBCs, group AB–positive plasma is the universal plasma donor and can be given in emergency situations when a blood group is not available. When group AB plasma is not available, evidence data in adults indicate that it is safe to use group A plasma for emergency release for patients with life-threatening bleeding. ^, Cross-matching is not required, as FP units are screened for antibodies against non-ABO and Rh antibodies, which may cause hemolytic reactions.

FP must be thawed prior to transfusion (20–30 minutes with the water bath method). Thawing FP can be shortened to 7 minutes using microwave ovens specifically designed for this task. A thawed unit of FP is ideally transfused within 4 hours, but thawed plasma can be relabeled and stored for up to 5 days (American Association of Blood Banks [AABB] Technical Manual). The clinical indications for thawed plasma are similar to FP but there is some decrease in the labile coagulation factors (factor V and VIII), and reduction in thrombin generation capacity. An 80- or 170-micropore filter must be used.

Types of platelet products

Platelet transfusion (why)

Over 1.5 million platelet products are transfused in the United States each year. Between 3.3% and 7.1% of critically ill children receive at least one platelet transfusion while in PICU. ^, Approximately two-thirds of all platelet transfusions to PICU patients are for prophylaxis of bleeding in the presence of thrombocytopenia, with an average pretransfusion platelet count of 32 ± 27 × 10 ⁹ /L (median, 21). The remaining one-third of platelet transfusions in critically ill children are for active bleeding, with an average pretransfusion platelet count of 76 ± 39 × 10 ⁹ /L (median, 72).

Most platelet transfusions are administered to increase a low platelet count. The prevalence of thrombocytopenia, defined by a platelet count less than 150,000/uL (<150 × 10 ⁹ /L), is 17.3% on admission into the PICU; 25.3% of children are thrombocytopenic at some point during their PICU stay. Thrombocytopenia arises from decreased platelet production, increased platelet destruction, and dilutional or distributional causes. In the PICU, most thrombocytopenia is caused by chemotherapy, sepsis, DIC, MODS, or hemolytic uremic syndrome. However, heparin-induced thrombocytopenia, massive transfusion, and reactive hemophagocytic syndrome are not so rare. In critically ill children, thrombocytopenia at PICU entry is associated with increased mortality (17.6% vs. 2.5%), bleeding complications, thrombosis, and prolonged PICU and hospital length of stay.

Pediatric subjects are at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. Platelet dysfunction might be the problem, at least in some instances. In PICU patients, platelet dysfunction is typically caused by specific treatments (cardiopulmonary bypass, hypothermia, pentastarch, and hetastarch) or antiplatelet drugs (low-dose aspirin, nonsteroidal antiinflammatory drugs) but it can also be due to hereditary disease (e.g., Bernard-Soulier disease).

Transfusion of platelets: Indications (when)

Platelet transfusions are indicated for the prevention or treatment of bleeding in patients with thrombocytopenia or platelet dysfunction. As platelet transfusions will result in only modest elevations for 1 to 3 days in patients with persistent thrombocytopenia, the purpose of platelet therapy is not to eliminate all bleeding but rather to prevent or stop major hemorrhagic events. Platelets are contraindicated in patients with thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia because of the increased thrombotic risk.

Therapeutic platelet transfusions are given to treat clinically significant bleeding associated with a low platelet count or platelet dysfunction. There is evidence that correction of thrombocytopenia reduces mortality of critically ill patients, ^, but a platelet transfusion should be considered only if the platelet count in an actively bleeding patient is less than 50,000/uL. However, caregivers must remember that “the principal treatment of ICU-associated thrombocytopenia is to treat the underlying disease.” For children with life-threatening bleeding, platelets should be transfused empirically in a ratio between 1:2 to 1:1 (ratio of whole blood–derived platelet unit to RBC unit) until the risk of bleeding resolves. When apheresis platelets are transfused, the range of the ratio transfused is 1:5 to 1:10 (apheresis platelet units to RBC units). This recommendation is based on randomized controlled trials in adults and expert opinion.

More than 50% of platelet transfusions in PICUs are given to prevent bleeding. There is insufficient evidence to support a particular threshold for prophylactic platelet transfusion in children. Most recommendations come from guidelines developed for adults, based on expert opinion. For patients with hypoproliferative thrombocytopenia (e.g., chemotherapy induced), a platelet transfusion threshold of 10,000/uL (10 × 10 ⁹ /L) is recommended. This is based on two clinical trials in adults: Slichter reported no increases in bleeding rates when comparing platelet transfusion thresholds of 10,000 versus 20,000/uL; on the other hand, Stanworth et al. reported more bleeding in patients with hematologic cancer and a platelet count less than 10,000/uL who did not receive prophylactic platelet transfusion versus those who did. On the other hand, Curley et al. reported a significantly higher rate of death or major bleeding among preterm infants who received platelet transfusions at a platelet-count threshold of 50,000/uL rather than 25,000/uL.

In the ICU, higher platelet transfusion thresholds are usually employed. Intensivists generally prescribe platelets for patients on ECMO if their platelet count is less than 100,000/uL (10 × 10 ⁹ /L). The same threshold is frequently used when a central nervous system procedure is undertaken. When the platelet count is less than 50,000/uL, platelets are usually given just prior to an invasive procedure (surgery, insertion of central venous catheter, and so on); platelet transfusion can also be considered in mechanically ventilated patients because the risk of pulmonary hemorrhage is significant. A threshold of 50,000/uL is recommended for lumbar puncture. Increasing the threshold count that would trigger a platelet transfusion may be appropriate if platelets are dysfunctional.

The capacity of platelets to stop a hemorrhage is not only related to their number but also to their function. Many tests can be used to estimate platelet function, such as TEG and devices or systems such as the Sonoclot coagulation analyzer (Sienco, Inc.), the Plateletworks analyzer (Helena Laboratories), the hemostatus platelet function test, the platelet function analyzer, and VerifyNow (Ultegra, Instrumental Laboratories) system. However, the results of these tests are not available on an emergency basis in most hospitals. Measurement of platelet mass may be a practical alternative. There is evidence that larger platelets exhibit increased hemostatic activity. The results of a randomized controlled trial conducted in a neonatal ICU suggested that using platelet mass (platelet count × mean platelet volume) rather than platelet count alone to trigger a platelet transfusion may reduce the number of transfusions. Nevertheless, it must be emphasized that the clinical usefulness of all of these tests remains undetermined in the PICU.

There is significant diversity in the stated practice pattern with respect to platelet transfusion. Most guidelines are based on expert opinion, not on quality data. More research is required to refine the indications for platelet transfusion in critically ill children.

Transfusion of platelets: How

There are about 3 × 10 ¹¹ platelets in a unit of apheresis platelets. A simple rule of thumb suggests giving 1 or 2 platelet units per 10 kg, but not more than 6 units per transfusion. For children weighing less than 10 kg, the platelet dose can be 5 to 10 mL/kg of pooled or apheresis platelet unit. Transfusion of one platelet concentrate per square meter (m ² ) of body surface generally increases the platelet count by 7000 to 11,000/uL. By body weight, the administration of one unit per 10 kg should increase the platelet count by 30,000 to 50,000/uL. However, a clinical trial in which platelet dose was estimated by body surface area evaluated low-dose (1.1 × 10 ¹² platelets/m ² ), medium-dose (2.2 × 10 ¹² /m ² ), and high-dose (3.3 × 10 ¹² /m ² ) prophylactic platelet transfusions and did not find any differences in bleeding among adult or pediatric patients. Platelets must be used within 4 hours after delivery from the blood bank, but there is some evidence that the platelet count increases more if the unit is given within 1 hour. A filter with 80- or 170-micropores must be used to remove aggregates that can form between harvesting and transfusion.

The volume of a whole blood–derived platelet unit is about 50 mL while that of an apheresis platelet unit ranges from 200 to 300 mL; 90% to 95% of this volume is plasma. It is important to note that this plasma is not an adequate source of coagulation factors because factor concentration drops rapidly during platelet storage at room temperature (20°C–24°C). Platelet units can be volume reduced (removal of plasma) prior to transfusion, but this process can decrease the platelet count by 15% to 20%, shortens the storage time to 4 hours, and delays platelet release from the blood bank by approximately 1 hour. Volume reduction should be considered only if there is a risk of severe circulatory overload but is not recommended as a standard procedure because it can activate platelets. In 2017, 8% of platelet transfusions were volume reduced.

Unlike RBC units, ABO compatibility is not mandatory with platelets. While it is possibly better to use ABO-compatible platelet units if inventory allows, no differences were seen in the incremental change in platelet count or in transfusion reactions when comparing major ABO-incompatible platelet transfusions with ABO-compatible transfusions in a large study of critically ill children. In addition, Rh compatibility is desired because all platelet units contain some RBCs. Transfusion of an Rh-positive unit to an Rh-negative patient can cause Rh alloimmunization; an anti-D immunoglobulin (e.g., Win Rho SDF, Saol Therapeutics) should be administered within 48 hours to prevent this complication when Rh-positive platelets are given to an Rh-negative patient, particularly if female.

The percent platelet increment (difference between post- and pretransfusion platelet count) should be higher than 20% if the dose is adequate and if a platelet count is performed 10 to 60 minutes posttransfusion; it should be higher than 10% if measured 18 to 24 hours posttransfusion. Platelet refractoriness can occur due to nonimmune factors such as DIC, in which platelet consumption can be high, acquired hemophagocytic syndrome, drugs such as amphotericin or heparin, or immune factors involving antiplatelet antibodies. Treatment of the underlying problem is mandatory in such instances (e.g., discontinuing all heparin administration in heparin-induced thrombocytopenia). Patients with anti-IgA antibodies should receive washed platelets or platelets collected from IgA-deficient donors.

Whole blood: Type of product

The volume of a typical whole blood unit is about 450 to 500 mL. It is stored at 2°C to 6°C, with storage duration between 21 and 35 days. Some centers limit the storage duration to 14 to 21 days to maximize platelet and RBC function when whole blood is used for only life-threatening hemorrhage. Whole blood can be leukoreduced prior to storage with a platelet-sparing filter. This filter has minimal effects on reducing platelet count and impairing hemostatic function. Whole blood can also be pathogen reduced, which has been shown to decrease rates of malaria transmission in a randomized controlled trial in Africa. Pathogen-reduced whole blood is not licensed in the United States, Canada, or Europe.

Whole blood: Indications

The use of whole blood has been advocated mostly for first-line therapy in hemorrhagic shock, as it contains a balanced proportion of RBCs, coagulation factors, and platelets. ^, Additional benefits of whole blood include platelets stored at 2°C to 6°C, which increases their hemostatic function and reduces the risk of bacterial infection, reduced donor exposures, and the logistic advantage of using one product compared to three. The use of whole blood should be considered only for patients with hemorrhagic shock. Approximately 15% of children’s hospitals in the United States provide whole blood to children, predominantly for cardiac surgery, liver transplantation, and massive transfusion protocols. Whole blood units are also used for some neonatal exchange transfusions.

Barriers to whole-blood availability have included the need to provide ABO-specific whole blood. This limited its availability due to the waste that would occur if each ABO type was maintained in the inventory of the hospital blood bank. To address this issue, the use of low-titer group O whole blood (LTOWB) has been adopted based on data showing that the benefits of immediate availability of LTOWB to a patient with severe bleeding outweighs any small risk in non–group O recipients. ^, The risk of transfusing group O whole blood to a non-O recipient is based on the concern that anti-A or anti-B antibodies will either cause hemolysis or endothelial injury. This risk is not different than when non-ABO-matched platelets are transfused or when type A plasma is used in group B or AB severely bleeding patients. In recognition of the data supporting the safety of LTOWB, the AABB has changed its standards to allow this product to be used for patients with life-threatening hemorrhage. Since this standard change, many trauma centers have implemented LTOWB for patients with severe bleeding. Pediatric centers have also begun using LTOWB for children with massive bleeding.

Whole blood: How

Whole blood can be transfused in a rapid infuser and blood warmer for life-threatening hemorrhage. It can be given via an intraosseous line and should be transfused with a standard micropore filter. The IgM titer of anti-A and anti-B for LTOWB can range from 1:50 to 1:256.

Transfusion reactions

Transfusion of labile blood products (RBC, plasma, platelets) can cause immediate or delayed transfusion reactions and various complications. By definition, immediate reactions usually occur during the transfusion or within 6 hours after the end of the transfusion; delayed reactions can occur after a few days, weeks, or even months or years later. The incidences of transfusion reactions (adults and children) and transfusion-transmitted infectious diseases are reported in Tables 91.3 and 91.4 , respectively. Even though transfusion reactions are underdiagnosed in critically ill children, many large-scale studies reported that the risk of transfusion reactions signaled to hemovigilance systems is significantly higher in children than in adults. TACO and TRALI are the leading causes of transfusion-related morbidity and mortality in North America ( Table 91.3 ) and are discussed later. Epidemiology and proposed pathophysiology for other common transfusion reactions—including respiratory dysfunction associated with transfusion, hemolytic and nonhemolytic transfusion reactions, febrile and allergic reactions, bacterial contamination, and GVHD—are detailed later.

TABLE 91.3

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