Patient Blood Management: Transfusion Therapy

The 1960S

Transfusion medicine has undergone enormous changes in the last 60 years, but the consensus of whether to use whole blood, its components, or both has vacillated every decade or so. In the l960s, most blood given was in the form of whole blood, whereas fresh frozen plasma (FFP) was available for the treatment of coagulopathies.

The 1970S Through The 1980S

Transfusion therapy was characterized in this period by “giving the patient only the component of blood that was needed.” Component transfusion therapy rather than whole blood transfusion was the standard of care. For example, if the patient was anemic, only packed red blood cells (PRBCs) would be transfused, or if thrombocytopenia existed, only platelet concentrates would be given. Caution regarding administration of blood transfusions increased during this time period in part because of concern regarding the infectivity of blood (e.g., hepatitis and human immunodeficiency virus [HIV]). Furthermore, individual clinical decisions regarding blood transfusions were and continue to be monitored by local hospital transfusion committees (as required by regulatory agencies of various countries including the United States). These committees have the responsibility of monitoring the individual and institutional transfusion practices by evaluating clinical appropriateness of transfusion triggers.

1990S Through The 2000S

With improved screening techniques for HIV and other blood-borne pathogens during this decade, the incidence of blood transfusion–related infectious disease transmission decreased 10,000-fold. The focus of blood product safety now shifted to noninfectious serious hazards of transfusion . These hazards include hemolytic transfusion reactions, transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory overload (TACO), to name a few. With an increased awareness of the potential morbidity and mortality associated with blood product administration, research focused on the concept of liberal versus restrictive blood transfusion strategy. Attention now turned to balancing the threats posed by two independent (yet related) risk factors of patient outcome—anemia and transfusion.

Although the strategy of specific component therapy was still prominent, the concept of reconstituted “whole blood” was introduced during this decade. Led by trauma hospitals and the military, FFP and platelets were transfused along with PRBCs, resulting in a transfusion ratio that was similar to that of whole blood. Because the concept of transfusing components that reconstitute whole blood rouses the prior practice of transfusing whole blood, that concept is being reexamined again in the literature and may yet prove beneficial in patients with life-threatening bleeding.

2010 to The Present

The 2010s saw a shift away from simply correcting anemia and coagulopathy, to a more patient-centered, multipronged approach to transfusion medicine. As a result, the term patient blood management (PBM) has become synonymous with modern, evidence-based transfusion medicine. The Society for the Advancement of Blood Management defines PBM as “the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcome.” PBM recognizes transfusions are but a temporary solution to an often complex, multifactorial process that requires attention to the underlying cause of anemia.

Integration of PBM into clinical pathways has reduced the reliance on allogenic blood product transfusion as the only means to avoid anemia and likely explains the continued decrease in transfusions noted in U.S. hospitals over the last decade. In a recent retrospective analysis, implementation of a PBM system with a reduced transfusion threshold from 8 g/dL to 7 g/dL Hb in orthopedic surgical patients reduced the use of erythrocytes by 32% while improving clinical outcomes. Most notably, patients 65 years and older demonstrated the most improved clinical outcomes, including 30-day readmission rates. Comprehensive PBM programs also can include evaluation of preoperative anemia, clinical decision support, educational efforts, improved surgical techniques, and blood conservation strategies.

PBM in many countries has been facilitated by computerized data systems and supply guidelines. A limitation of most of the PBM publications is that they describe mostly nonbleeding, anemic patients and the decision to initiate transfusion. Very little information addresses what guidelines should be used for repetitive transfusions. The anesthesia provider offers insight into these issues and can provide guidance as to how PBM fits into the perioperative clinical environment.

Source of Donors

Significant global disparities exist regarding access to “safe” blood, or blood that is properly collected and tested. According to World Bank definitions, low- and middle-income countries collect 53% of all blood donations worldwide, yet represent 81% of the world’s population. In addition, the prevalence of transfusion-transmissible infections in blood donations from low- and middle-income countries is significantly higher than those from high-income countries, yet low-income countries have less access to basic quality screening procedures. Another issue, particularly in low-income countries, is incentivized donors. The World Health Organization’s (WHO) decision-making body, the World Health Assembly, has issued resolutions and consensus statements that emphasize the need for all member states to develop national blood systems based on voluntary, unpaid donations as a means to ensure a safe, secure, and sufficient supply of blood products. Some experts have suggested that offering economic incentives or rewards to donors should be seriously considered, because limited empirical research exists to support the assumption that incentivized donations, including noncash incentives, either improve recruitment of donors or pose a risk to blood product safety. However, the WHO strongly defends voluntary nonremunerated blood donation as a vehicle to a safer blood supply and increased donor participation.

In the United States, the Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research provides the regulatory oversight for blood banks and donation centers, with most voluntarily obtaining accreditation from the AABB (formerly, American Association of Blood Banks). In Europe, the European Commission sets standards for blood products and their components in the European Blood Directive (Directive 2002/98/EC). These regulatory and professional societies set standards with regard to the donation, collection, testing, processing, storage, and distribution of products.

In the United States, those over the age of 16 and who weigh at least 110 pounds are eligible for screening for potential blood donation. Vital signs are assessed, including temperature, heart rate, and blood pressure. Hb levels are measured, with minimum cutoffs of 13 g/dL for men and 12.5 g/dL for women. Blood is collected either as whole blood and separated by centrifugation or by apheresis, in which only specific components are collected while other components are returned to the donor. An outline of the separation scheme by which various blood components are derived is shown in Fig. 49.1 . Apheresis is particularly helpful in donors with blood type AB, as they represent a rare blood type yet serve as the universal plasma donor. As recipients, patients with blood type AB rarely require AB specific blood, as they can be transfused with any type of red cell. Therefore, if plasma is collected from AB donors while red cells are immediately returned, this may allow for more frequent plasma donation from this small but vitally important group of donors.

Transfusion-Transmissible Infections

Donor screening attempts to reduce the risk of a transfusion-transmissible disease and to protect the donor from an adverse reaction due to donation. Deferment based on medical history includes those considered to be in high-risk categories for potential transmission of an infectious agent, including those with a significant travel history, history of injection drug use, recent tattoos, or men who have had sex with men (MSM) in the previous 12 months. The latter deferment category has been controversial in recent years, given the changing epidemiology of the HIV epidemic and improved screening methods. In this population, some advocate for reducing the time interval between potential exposure and donation to 3 months.

The use of more sensitive screening tests in conjunction with changes in transfusion medicine practices have made infectious risks quite rare. The FDA requires blood products to be tested for hepatitis B and C, HIV (types 1 and 2), human T-lymphotropic virus (HTLV; types 1 and 2), and treponema pallidum (syphilis), West Nile virus, and Zika virus. Testing is recommended for Trypanosoma cruzi (Chagas disease) for first-time donors. Historically, the FDA has published tables on the risks for infectivity, Table 49.1 but because the rates are so infrequent, the last tables published were for data from 2011.

Several blood-safety changes made between the years of 1982 and 2008 have decreased the risk for disease transmission by allogenic blood so that the demand for autologous blood has declined as well. The West Nile virus story illustrates how rapidly our blood banks can respond. In 2002, West Nile virus caused the largest outbreak of arboviral encephalitis ever recorded in the United States (i.e., approximately 4200 patients). Twenty-three cases of transfusion-transmitted infections resulted in seven deaths. In 2003, testing became available that now makes that infection very rare (see Table 49.1 ). The FDA’s response to the 2015 to 2016 Zika virus outbreak was similarly swift—the blood supply was immediately shifted from areas with low risk of infections to areas of known infection; authorization for screening tests was issued within months, and universal screening with a qualitative nucleic acid test (NAT) for the detection of Zika virus ribonucleic acid (RNA) was mandated.

The changes in blood transfusion testing can be appreciated when comparing tests used in 1998 ( Box 49.1 ) with those used in 2018 ( Table 49.2 . The use of nucleic acid technology has decreased the window of infectivity (i.e., time from being infected to a positive test result), which is a major reason for the decrease in infectivity with hepatitis, HIV, West Nile virus, and Zika virus.

Biochemical Changes in Stored Blood

Units of blood collected from donors are usually separated into components (e.g., RBCs, plasma, cryoprecipitate, and platelets; see Fig. 49.1 ). Citrate phosphate dextrose adenine-1 (CPDA-1) is an anticoagulant preservative that is used for blood stored at 1°C to 6°C. Citrate prevents clotting by binding Ca ²⁺ . Phosphate serves as a buffer, and dextrose is a red cell energy source, allowing the RBCs to continue glycolysis and maintain sufficient concentrations of high-energy nucleotides (adenosine triphosphate [ATP]) to ensure continued metabolism and subsequent viability during storage. The addition of adenine prolongs storage time by increasing the survival of RBCs, allowing them to resynthesize the ATP needed to fuel metabolic reactions. This extends the storage time from 21 to 35 days. Without adenine, RBCs gradually lose their ATP and their ability to survive after transfusion. Finally, storage at 1°C to 6°C assists preservation by reducing the rate of glycolysis approximately 40 times the rate at body temperature.

The shelf life of PRBCs can be extended to 42 days when AS-1 (Adsol), AS-3 (Nutricel), or AS-5 (Optisol) is used. Adsol contains adenine, glucose, mannitol, and sodium chloride (NaCl). Nutricel contains glucose, adenine, citrate, phosphate, and NaCl. Optisol contains only dextrose, adenine, NaCl, and mannitol. On a national level, 85% of RBCs are collected in AS-1. In Europe, a solution similar to AS-1 containing saline, adenine, glucose, and mannitol is used. As of 2015, the FDA approved a new additive solution, AS-7, which increases storage time to at least 56 days; however, the solution is not yet commercially available in the United States.

The hematocrit (Hct) of the transfused product depends on the storage method. When CPDA is the anticoagulant used, the Hct is greater than 65%, because most of the plasma is removed, and the resulting volume is approximately 250 mL. When AS-1 is used, most of the plasma is also removed, but 100 mL of storage solution is added, resulting in an Hct of 55% to 60% and volume of 310 mL. The duration of storage is set by U.S. federal regulation and is based on the requirement that at least 70% of the transfused RBCs remain in circulation for 24 hours after infusion.

During storage of whole blood and PRBCs, a series of biochemical reactions occur that alter the biochemical makeup of blood and account for some of the complications. Collectively, these are known as red cell storage lesions and may be responsible for the organ injury associated with red cell transfusion. During storage, RBCs metabolize glucose to lactate; hydrogen ions accumulate, and plasma pH decreases, while increases in oxidative damage to lipids and proteins are noted. The storage temperature of 1°C to 6°C inhibits the sodium-potassium pump, resulting in a loss of potassium ion (K ⁺ ) from the cells into the plasma and a gain of intracellular sodium. Although K ⁺ concentrations appear elevated in 35-day stored RBC concentrates, the total plasma volume in the concentrates is only 70 mL, so total K ⁺ is not markedly elevated. Over time, there are progressive decreases in RBC concentrations of ATP, nitric oxide (NO), and 2,3-diphosphoglycerate (2,3-DPG).

The osmotic fragility of RBCs increases during storage, and some cells undergo lysis, resulting in increased plasma Hb levels. In addition, deformability of RBCs appears impaired in patients who receive allogenic blood cell transfusion, potentially resulting in micro-occlusive events. Frank and associates studied the blood of patients undergoing posterior spinal fusion surgery and found that increased duration of blood storage was associated with decreased RBC deformability, which was not “readily” reversible after transfusion. They speculated that these deformed cells may be defective in delivering oxygen (O ₂ ) to the cells and concluded that both the “age of blood storage” and “amount” of blood given should be considered when giving blood ( Table 49.4 ).

Changes in Oxygen Transport

RBCs are transfused primarily to increase transport of O ₂ to tissues. Theoretically, an increase in the circulating red cell mass will produce an increase in O ₂ uptake in the lungs and a corresponding increase in O ₂ delivery to tissues, but RBC function may be impaired during preservation, making it difficult for them to release O ₂ to the tissues immediately after transfusion.

The O ₂ dissociation curve is determined by plotting the partial pressure of O ₂ (P o ₂ ) in blood against the percentage of Hb saturated with O ₂ ( Fig. 49.2 ). As Hb becomes more saturated, the affinity of Hb for O ₂ also increases. This is reflected in the sigmoid shape of the curve, which indicates that a decrease in the arterial partial pressure of oxygen (Pa o ₂ ) makes considerably more O ₂ available to the tissues. Shifts in the O ₂ dissociation curve are quantitated by the P ₅₀ , which is the partial pressure of O ₂ at which Hb is half saturated with O ₂ at 37°C and pH 7.4. A low P ₅₀ indicates a left shift in the O ₂ -dissociation curve and an increased affinity of Hb for O ₂ . The left shift of the curve indicates that a lower than normal O ₂ tension saturates Hb in the lung, but the subsequent release of O ₂ to the tissues is more difficult, as it occurs at a lower than normal capillary O ₂ tension compared with an unshifted curve. In other words, the increased affinity of Hb for O ₂ makes it more difficult for Hb to release O ₂ to hypoxic tissues. This leftward shift is likely a result of decreased levels of 2,3-DPG in stored RBCs, which can remain low for up to 3 days posttransfusion.

Many of the advances in blood processing and storage are centered on the material of the collections and storage containers. Innovative methods of storing blood are being developed. For example, storing blood in an electrostatic field of 500 to 3000 V decreases hemolysis and attenuates the decrease in pH associated with prolonged storage. Current blood collection and storage systems are made of disposable plastic; these materials must have properties compatible with collection, processing, storage, and administration. Polyvinylchloride (PVC) with use of different plasticizers is commonly used because it is nontoxic, has flexibility, mechanical strength, water impermeability, resistance to temperature extremes for sterilization and freezing, compatibility with blood components, and selective permeability for cellular gas exchange.

Recent animal data suggest that red cells in stored blood can be rejuvenated with solutions of inosine prior to administration, reversing storage lesions and mitigating the potential for organ damage. This could be a promising technique to restore ATP and 2,3-DPG levels, while reducing a recipient’s immune response and transfusion-associated organ injury. However, small clinical trials in humans demonstrating clinical benefit are lacking. Larger trials are ongoing.

Clinical Implications: Duration of Blood Storage

The fact that blood can be stored for 42 days is a mixed blessing. The obvious advantage is the increased availability of blood, but the clinical evidence regarding safety has not been consistent, reflecting the difficulty of conducting a systematic study of patients in varied clinical settings. For decades, many clinicians have tried to establish a firm relationship between the 2,3-DPG levels associated with stored blood and patient outcome. In 1993, Marik and Sibbald found that the administration of blood that had been stored for more than 15 days decreased intramucosal pH, suggesting that splanchnic ischemia had occurred. In addition, an increased incidence of postoperative pneumonia in cardiac patients has been associated with the use of older blood. Yet prolonged storage of blood was not associated with increased morbidity after cardiac surgery. Purdy and colleagues found that patients who received 17-day-old blood (range, 5-35 days) versus 25-day-old blood (range, 9-36 days) had higher survival rates. Koch and colleagues concluded that giving erythrocytes (PRBCs) older than 14 days was associated with an increased risk for postoperative complications, along with reduced short-term and long-term survival in patients undergoing coronary artery bypass surgery. This article also had an accompanying editorial that concluded, “to the extent possible, newer blood might be used in clinical situations that seem to call for it.” In addition, a meta-analysis concluded that older stored blood is associated with an increased risk for death.

However, there is equal data arguing the contrary, and other researchers have not arrived at a clear conclusion and recommended more studies. Weiskopf and associates performed studies in healthy volunteers who were evaluated by a standard computerized neuropsychologic test 2 days and 1 week after acute isovolumic anemia was induced. When correcting the anemia, they concluded that erythrocytes stored for 3 weeks are as efficacious as those stored for 3.5 hours. Spahn wrote an accompanying editorial agreeing with Weiskopf and associates and, furthermore, postulated that 2,3-DPG levels may not be the key factor in determining the delivery of O ₂ (i.e., 2,3-DPG levels are reduced in older blood, but the blood still delivers O ₂ ). Cata and associates also concluded that no change in outcome occurred in patients undergoing radical prostatectomy and receiving older blood. Saager and colleagues also found no relationship between duration of blood storage and mortality in nearly 7000 patients undergoing noncardiac surgery.

Since the publication of the eighth edition of this text, several randomized control trials evaluating the influence of the duration of blood storage have been published. In 2016, Heddle and colleagues published results from the INFOMR trial, a large, pragmatic, randomized controlled trial enrolling adult hospitalized patients in six centers from four countries. Patients were randomized to receive either blood that had been stored for the shortest duration (mean duration of storage 13 days) versus blood stored for the longest duration (mean duration of storage 23 days). Only patients with A and O blood types were included as the less common blood types could not achieve an appropriate difference in mean duration of storage. More than 20,000 patients were included in the primary analysis. No significant differences in mortality were noted between the two groups. In prespecified high-risk categories, including patients undergoing cardiovascular surgery, patients admitted to the intensive care unit (ICU), and those with cancer, the results remained the same.

Similarly, the results of the recent RECESS trial published in 2015 revealed similar mortality rates among those transfused with blood stored less than 10 days (median storage time 7 days) compared with those transfused with blood stored for more than 21 days (median storage time 28 days). Changes in preoperative to 7 days postoperative Multiple Organ Dysfunction Score (MODS) were similar between the two groups, as well. Finally, two randomized controlled trials in critically ill adults evaluating the age of transfused blood on mortality and other outcomes, such as new bloodstream infections, duration of mechanical ventilation, and the use of renal replacement therapy, failed to demonstrate differences between groups transfused with fresher blood compared with those transfused with older blood.

These recent randomized controlled trials demonstrate the safety and noninferiority of “older” versus “younger” blood, but the complete answer may still need further data. First, the measures of outcome may be insufficiently sensitive to detect important and meaningful clinical outcomes. Many studies use mortality as their primary outcome measure. Although this is obviously a critical benchmark, it may not be sensitive enough to detect clinical differences regarding the safe or optimal length of time for the storage of blood. Important adverse clinical outcomes could occur without a change in mortality per se (e.g., duration of hospitalization, cardiovascular events, quality of life, neurocognitive decline). Second, these studies compare moderately young with moderately old blood. Ethical and logistical issues preclude a trial comparing “very” young and “very” old blood or even comparing moderately aged blood to very old blood (e.g., stored for 35-42 days). Because the quality of blood decreases with length of storage, increased morbidity with exposure to more aged red cells is physiologically plausible, but the debate regarding the effectiveness of a blood transfusion and its duration of storage continues. More prospective studies are likely required.

Allogeneic (Homologous) Blood

PRBCs contain the same amount of Hb as whole blood, but much of the plasma has been removed. The Hct value of PRBCs is approximately 60% ( Table 49.5 ). Other than severe hemorrhage, most indications for RBCs can be effectively treated with PRBCs, conserving the plasma and the components for other patients (see Fig. 49.1 ). Many blood banks have conscientiously followed this principle, and whole blood is not available or only available in trauma centers or by special arrangement.

The administration of PRBCs is facilitated by utilizing crystalloid or colloid as a carrier; however, not all crystalloids are suitable. Solutions containing Ca ²⁺ may precipitate clotting. Lactated Ringer solution is not recommended for use as a diluent or carrier for PRBCs because of the Ca ²⁺ ( Table 49.6 ), although several experimental studies found lactated Ringer solution and normal saline to be equally acceptable. A more important factor may be whether the diluent is hypotonic with respect to plasma. In hypotonic solutions, the RBCs will swell and eventually lyse. Solutions that cause hemolysis are listed in Table 49.6 . Recommended solutions compatible with packed erythrocytes are 5% dextrose in 0.45% saline, 5% dextrose in 0.9% saline, 0.9% saline, and Normosol-R with a pH of 7.4.

RBC transfusions are given to increase O ₂ -carrying capacity. Increasing intravascular volume in the absence of significant anemia is not an indication for blood transfusion because volume can be augmented with administration of intravascular fluids that are not derived from human blood (e.g., crystalloids). As such, a sole Hb value should not be the only basis for a transfusion decision. It should be the overall status of the patient that prompts transfusion therapy (e.g., hemodynamics, organ perfusion and oxygen delivery, and anticipated surgical needs). Even so, the Hb value has become the basis for many transfusion strategies. It is the prime criterion for defining restrictive versus liberal transfusion strategies.

When a patient is hemorrhaging, the goals should be to restore and maintain intravascular volume, cardiac output, and organ perfusion to normal levels. By using crystalloids, colloids, or both to treat hypovolemia, normovolemic dilutional anemia may be created. Increasing cardiac output enhances O ₂ delivery to the tissues only to a limited extent. In fact, during normovolemic anemia, Mathru and colleagues found inadequate splanchnic and preportal O ₂ delivery and consumption when the Hb level decreased to 5.9 g/dL. Although the current PBM emphasis is on fewer or even avoidance of blood transfusions, clearly an Hb value exists below which a blood transfusion should be given.

The basis for using the Hb or Hct value as the initial consideration for defining transfusion requirements followed a 1988 National Institutes of Health (NIH) Consensus Conference that concluded that otherwise healthy patients with Hb value more than 10 g/dL rarely require perioperative blood transfusions, whereas patients with acute anemia with a Hb value of less than 7 g/dL frequently require blood transfusions. They also recognized that patients with chronic anemia (as in renal failure) might tolerate an Hb concentration of less than 6 to 7 g/dL. Amazingly, despite many studies, publications, and debates, the fundamental guidelines have not changed substantially in the 30 plus years since this conference.

An excellent editorial by LeManach and Syed outlines key questions that should be considered regarding transfusion triggers, including what we need to learn and the role of databases. Of prime importance is identifying the variables that predict the need for erythrocyte transfusion and the approach that can most accurately estimate the impact of transfusions. Many studies use death rate as their main indicator. Although clearly an important indicator, there are additional obvious factors in between the extremes of life and death, including vital signs, key laboratory values, and other indicators used in critical care units. Several groups working with patients in ICUs have attempted to define the point at which blood transfusions should be given by measures of tissue oxygenation and hemodynamics (e.g., increase in O ₂ consumption in response to added O ₂ content). The O ₂ extraction ratio has been recommended as an indicator for transfusions; however, this technique requires invasive monitoring, and the results were not dramatic between groups who were or were not transfused. No specific measure can consistently predict when a patient will benefit from a blood transfusion. The ultimate determination of the Hb or Hct value at which blood should be given is a clinical judgment based on many factors, such as cardiovascular status, age, anticipated additional blood loss, arterial oxygenation, mixed venous O ₂ tension, cardiac output, and intravascular blood volume ( Table 49.7 ).

Additional Blood Transfusions

To determine whether subsequent units of blood are indicated after the initial administration, the overall condition of the patient and the clinical situation need to be reassessed. The following key components of information to consider include:

• 1.

  Measurement and trend of vital signs

• 2.

  Measurement of blood loss and assessment of anticipated blood loss

• 3.

  Quantitation of intravenous fluids given

• 4.

  Determination of Hb concentration

• 5.

  Surgical concerns.

Measurement of Blood Loss

Measuring blood loss is obviously important when assessing the need for both the initial and subsequent blood transfusions (see Table 49.7 ). A standard approach includes a combination of visualization and gravimetric measurements based on weight differences between dry and blood-soaked gauze pads. A study in patients undergoing spine surgery found that anesthesiologists tended to overestimate blood loss by as much as 40% ( Fig. 49.3 ). On the other hand, optical scanners tended to underestimate blood loss compared with the standard gravimetric calculations. The accuracy of measurements is not uniformly consistent and no “gold standard” for blood loss quantification exists.

Predicting surgical blood loss is also an important component to intraoperative transfusion medicine. As part of the WHO preoperative guidelines to improve the safety of patients undergoing surgery, the anesthesiologist must consider the possibility of a large-volume blood loss prior to the induction of anesthesia. In a prospective trial evaluating both surgeons’ and anesthesiologists’ ability to predict the estimated blood loss prior to incision, members of both these medical professions underestimated the blood loss by greater than 500 mL in 10% of intermediate or major surgeries, which potentially placed those patients at risk for being without adequate intravenous access or appropriate resuscitative volume.