Why normal saline with blood transfusion

Infectious Risks of Transfusion

Although the infectious disease risks of allogeneic blood transfusions are extremely low, transfusions must be given judiciously because “emerging infections,” such as Ebola or Zika virus, when they first arise, pose a potential threat until they are studied definitively and, accordingly, are of constant concern, and testing is not done for every microorganism possibly transmitted by blood transfusions (Table 501.1 andFig. 501.1). Taking nucleic acid amplification testing (NAT) and all other donor-screening activities (antibody and epidemiology screening) into account, a current estimate of the risk of transfusion-associatedHIV infection is approximately 1 per every 2 million donor exposures. Similarly, with NAT, the risk of hepatitis C virus (HCV) infection is 1 per every 1.5-2 million donor exposures (Table 501.1). NAT identifies circulating microbial nucleic acids that appear in the window before antibodies develop, and NAT is used routinely to detect HIV, HCV, and West Nile virus, hepatitis B virus,Trypanosoma cruzi, Babesia microti, and Zika virus.

Transfusion-associated cytomegalovirus (CMV) has been nearly eliminated by transfusion of leukocyte-reduced cellular blood products or by selection of blood collected from donors who are seronegative for antibody to CMV. Although it is logical to hypothesize that first collecting blood components from CMV-seronegative donors and then removing the white blood cells (WBCs) might further improve safety, little data are available to document the superior efficacy of this combined approach. However, in a recent prospective birth cohort study of premature infants with birthweight ≤1500 g, a combined approach of leukoreduction and CMV-seronegative cellular blood components yielded 0% transfusion transmission of CMV (15.3% cumulative incidence at 12 wk of maternal breast milk transmission from CMV-seropositive mothers) in >300 transfused infants studied. Similar uncontrolled reports of hematopoietic stem cell transplant patients found 0% transmission of CMV from leukoreduced blood products from donors of unknown CMV antibody status. Therefore, considerable care must be taken not to place children at risk of delayed or missed transfusions while awaiting/searching for blood from CMV-seronegative donors, then to leukoreduce (i.e., risks must not be taken for practices with no established benefits).

Further data on these 2 mitigation strategies revealed that large quantities of CMV viral material are present “free” in the plasma of healthy-appearing donors during the early phase of primary infection (while CMV antibodies are either absent [“window” phase] or are newly emerging and at low, inconsistently detected levels in plasma), rather than being leukocyte associated, as occurs with CMV as substantial quantities of IgG antibodies appear. As a result of this biology of CMV primary infection, plasma “free” virus will not be removed by leukoreduction during early infection, and CMV-seronegative donors who may be asymptomatic or deny symptoms of infection during blood donor screening will be misclassified as being CMV safe. They are not necessarily as safe because antibody is below the limits of detection, while plasma “free” CMV is plentiful during early infection. Because almost all plasma “free” CMV disappears and becomes almost exclusively cell associated, once donors are CMV seropositive with antibody present for several months, some propose that the best method to reduce CMV risk may be leukoreduction of blood from donors known to be CMV seropositive for at least 1 yr. However, data to prove the efficacy of this proposal are lacking, and in practice, several studies have shown that the most efficacious method currently available to prevent transfusion-transmitted CMV is to perform leukoreduction in the blood center/bank without regard for the CMV antibody status of the donor/unit (i.e., leukoreduction alone performed by the blood center/bank, not at the bedside, is sufficient in most cases).

Specific hazards of massive blood transfusion

Massive blood transfusion may be defined in several ways:

replacement of the circulating volume in 24 hours

>4 units of blood in 1 hour with continuing blood loss

loss of 50% of circulating blood volume within 3–4 hours.

Any patient receiving massive blood component therapy is likely to be seriously ill and have multiple problems. Many adverse effects must be considered in conjunction with the injuries and multi-organ dysfunction. It is not always possible to define the complications caused or aggravated by massive blood transfusion.

Role of Blood Transfusions

Premature infants are at higher risk of needing packed red blood cell (pRBC) transfusions, with some studies estimating that about 90% of infants with birth weight below 1500 g receive at least one.11 This highly prevalent intervention has long been under scrutiny for its potential role in NEC pathogenesis. Distinguishing whether transfusions predispose preterm infants to NEC or whether NEC is related to a pretransfusion deteriorating status remains difficult. Transfusion guidelines are not uniform and changes in the clinical status of the infant frequently trigger laboratory evaluations with subsequent pRBC transfusions. This subset of NEC is called transfusion-associated NEC (TANEC).

Studies that found associations between pRBC transfusion and development of NEC prompted the development of the term transfusion-associated gut injury (TRAGI).13,48 This association was reinforced by a systematic review of 12 retrospective studies, although only part of those studies were included in calculation of odds ratios.55 Only 5 out of 12 included studies reported unadjusted estimates of infants’ exposure to transfusion in the previous 48 hours, and NEC and only 4 studies reported adjusted estimates of such exposure.55 Several mechanisms were proposed to explain the role of transfusions in the development of NEC: (1) reperfusion injury due to transfusion; (2) immunologic reactions and injury of intestinal mucosa triggered by cytokines, fragmented RBCs, and free hemoglobin; and (3) transient mesenteric ischemia after blood transfusion. A prospective observational study found significant elevation of proinflammatory cytokines (IL-1β, IL-8, IFN-γ, IL-17, MCP-1, IP-10, and ICAM-1) at different time points following blood transfusion in preterm infants less than 32 weeks of gestation.18

Alternatively, evidence has also accumulated about the lack of association between pRBC transfusions and NEC.83,91 Moreover, some studies found that blood transfusions are associated with a lower risk for NEC.7,84 In a recent prospective multicenter study, secondary analysis revealed that severe anemia (Hb <8 g/dL), but not blood transfusion, was associated with development of NEC.70 In one meta-analysis, authors found that data from RCTs conflict with the results of observational studies. The RCTs show that blood transfusions are associated with lower risk for NEC, and the observational studies show that transfusions are associated with NEC.41 A large ongoing randomized controlled trial, Transfusion of Prematures, should provide additional information about this controversial topic (ClinicalTrials.gov identifier: NCT01702805).

Administration of enteral feedings during blood transfusion is another daunting issue. A small case-control study found that implementation of a policy for withholding of enteral feedings during pRBC transfusion was associated with reduction of NEC incidence.21 Another small study looked at trends of mesenteric tissue oxygenation during and after pRBC transfusions relative to feeding status.50 This study found that infants who received enteral alimentation during pRBC transfusions had negative trends in postprandial mesenteric tissue oxygenation for up to 15 hours after the transfusion compared to infants who were not fed. There was no difference in mesenteric oxygenation during the transfusion between the groups. The authors suggested a relative postprandial ischemia after transfusion in infants who were fed. It is important to note that in this study the majority of infants who were fed during transfusion were getting formula feedings (6 out of 8) and the majority of infants whose feeds were held during transfusion were receiving breast milk feedings (7 out of 9).50 This difference could have had significant impact on the difference in the NEC incidence by itself. A systematic review recently evaluated the evidence for withholding enteral feedings during pRBC transfusions.38 This review showed that the practice of withholding enteral feedings during pRBC transfusions significantly reduced the incidence of transfusion-associated NEC with RR of 0.47; 95% CI: 0.28-0.80 (P = 0.005). No RCTs were included in this review since they were not found. Conclusions were drawn by comparing rates of transfusion-associated NEC before and after implementation of the practice to withhold feedings in the peri-transfusion period.38 Authors stated that the quality of the generated evidence was moderate.38 In summary, controlled and adequately powered studies are needed to generate better evidence to determine the association between withholding enteral feedings during pRBC transfusions and NEC.

IV. Complications of Blood Transfusion

A.

Iatrogenic. Administration of incompatible blood or use of an incompatible carrier can lead to transfusion complications.

TABLE 10-1. BLOOD PRODUCTS

Improper patient infusion and clerical errors are important causes of inappropriate transfusion.

When hypotonic or calcium-containing solutions are used (e.g., 5% dextrose or lactated Ringer's solution), red blood cell clumping, hemolysis, and clot formation may occur.

Blood should be infused through lines carrying isotonic fluid, such as normal saline or Plasmalyte.

Immunologic. The incidence of hemolytic reactions is 0.03% to 2% per unit. It is fatal in 1/100,000.

Acute hemolytic reaction is the result of transfusion of ABO-incompatible blood.

Hypotension, fever, chills, hemoglobinuria, confusion, chest pain, back pain, dyspnea, and bleeding diathesis mark this reaction.

The transfusion should be stopped and the patient's blood sent for free hemoglobin and haptoglobin levels and a Coomb's test.

Treatment is supportive, with maintenance of good urine output.

Delayed hemolytic reaction is due to prior sensitization in a patient who has a nondetectable level of antibody at the time of typing.

These patients present with indirect hyperbilirubinemia and hemoglobinuria several days after transfusion.

This reaction is generally well tolerated and milder than the former.

Febrile reactions are probably due to antileukocyte antibodies and are seen in patients who have had prior transfusions. Although this is a mild reaction, an acute hemolytic reaction must be ruled out before transfusion is continued.

Nonhemolytic allergic reactions are seen in 1% to 4% per unit transfusion. These reactions generally occur in patients who have not had previous transfusions and may be caused by reaction to leukocytes or plasma proteins.

The reaction is usually mild, with urticaria, fever, hives, and bronchospasm, but may be severe and may even present with anaphylaxis.

Treatment is supportive: antihistamine (diphenhydramine, 25 mg IV), epinephrine (1:1000; 0.1 to 0.5 mg IM or SC every 10 to 15 minutes), and IV steroids (hydrocortisone, 40 to 100 mg) may be indicated.

Immunosuppression is becoming a more recognized complication of blood transfusion.

Data from cardiac surgery, colon cancer, and renal transplant studies show decreased T-lymphocyte proliferation, reversed CD4/CD8 ratio, depression of natural killer cells, decreased B-lymphocyte reactivity against antigens, and decreased macrophage phagocytosis.

Given these findings, the risks of immunosuppression should be taken into consideration when deciding to transfuse. However, fear of immunosuppression should not override the need for appropriate blood replacement in the acute setting.

Infections. The advancement of technologies dedicated to the screening of infectious diseases has greatly increased the safety of the blood supply. Nucleic amplification testing (NAT) is now performed on virtually all blood collected in the United States for detection of HIV and hepatitis C. Future advances in screening techniques will likely lead to a lower incidence of hepatitis B.

Viral contamination per unit transfusion is reported as:

HIV: 1/1 to 2 million

Hepatitis B: 1/200,000

Hepatitis C: 1/1 to 2 million

Human T-cell lymphocytotrophic virus (HTLV) types I and II: 1/1 to 2 million

West Nile virus: 1/1 million in endemic areas

Cytomegalovirus (CMV) is the most common virus transmitted with transfusions in the United States. Because it is endemic, routine screening for CMV is not performed. However, CMV transmission by transfusion requires transfer of infected leukocytes, and with the transition to an all-leukocyte-reduced blood supply, CMV transmission is becoming less frequent.

Immunocompromised patients (e.g., transplant patients) should receive leukocyte-reduced or CMV-screened blood products.

Bacterial contamination per unit transfusion is reported as:

Transfusions of products with bacterial contaminants (e.g., syphilis, malaria, Yersinia enterocolitica, Babesia microti, Trypanosoma cruzi): 1/5 million

The onset of fever, chills, and hypotension shortly after transfusion make the distinction from acute allergic or hemolytic reaction difficult. These patients may become very ill and may need to be treated with broad-spectrum antimicrobial agents and supportive care.

Metabolic complications

Potassium

Packed red blood cells contain 30 to 40 mEq per unit after 3 weeks of storage secondary to cell lysis. Hyperkalemia can be induced in the setting of massive transfusion.

Calcium

Citrate, the preservative used in blood products, binds to calcium to prevent clotting during storage.

At infusion rates >1 unit per 5 minutes, hypocalcemia may occur. This may cause hypotension, myocardial depression, arrhythmias, and coagulopathy.

Treatment is slow IV calcium gluconate (0.45 mEq elemental calcium) per 100 mL of citrated blood transfused.

Acid-base

Stored PRBCs contain citrate, which is converted by the liver to bicarbonate, thus perpetuating an alkalotic effect.

Hypothermia

Defined as temperature <34°C (PRBCs are stored at 1° to 6°C and have a shelf-life of 35 days.)

Infusion of cold blood products augments heat loss caused by exposure and has several detrimental effects including:

Acidosis

Leftward shift of the oxygen dissociation curve

Increased oxygen affinity

Impaired platelet function

Myocardial depression

Arrhythmias

Respiratory depression

Thus, when transfusing large amounts of blood products, heated IV tubing should be used.

Disseminated intravascular coagulation (DIC)

Red blood cell adenosine diphosphate (ADP) and membrane phospholipoprotein activate the procoagulant system via factor XII and complement. Diffuse microvascular thrombosis, consuming platelets and coagulation factors, occurs. Simultaneous fibrinolysis releases fibrin split products into the circulation.

The etiology of DIC includes:

Massive transfusion

Sepsis

Crush injury

Multiple injuries

Clinical features include:

Fever

Hypotension

Acidosis

Proteinuria

Hypoxia

Laboratory features include:

Thrombocytopenia (<80,000/mm3)

Decreased fibrinogen (0.8 g/L)

Prolonged PT and PTT

Elevated fibrin-degradation products or D-dimers

Fragmented red blood cells on smear

Treatment involves aggressive hemodynamic support and removal of underlying cause (transfusion of compatible washed PRBCs). If these measures fail we have used IV heparin infusion (titrated to maintain international normalized ratio (INR) between 1.1 and 1.5), antithrombin III, or epsilon-aminocaproic acid (Amicar) with variable success. The onset of DIC portends a poor prognosis. Mortality is high mainly due to end-organ damage and failure.

Transfusion related acute lung injury (TRALI). TRALI is defined as noncardiogenic pulmonary edema temporally related to transfusion therapy.

Diagnosis requires exclusion of other diagnoses (such as sepsis, volume overload, cardiogenic pulmonary edema).

Pathogenesis may be explained by a two-hit hypothesis, with the first hit being a predisposing inflammatory condition and the second hit involving the passive transfer of neutrophil or HLA antibodies from the donor or the transfusion of biologically active lipids from older cellular blood products.

The first hit involves priming the adherence of neutrophils to the pulmonary endothelium. Examples of the first hit can include surgery, sepsis, trauma, massive transfusions, cardiac disease, and possibly multiparity.

The second hit activates these primed neutrophils, resulting in the release of the reactive oxygen species that cause capillary leak and pulmonary edema.

Treatment is supportive with outcomes better than for most other causes of acute lung injury. Management should be guided by the use of a pulmonary artery catheter (PAC) to show that fluids are not needed within a normal wedge. Volume overload must be excluded to differentiate TRALI from phenomena such as shock lung or adult respiratrory distress syndrome after massive transfusion.

Mortality rate can be as high as 5% to 8%.

Acute respiratory distress syndrome (ARDS)

This syndrome occurs in patients with an average incidence of 0.02% per unit blood transfused.

It can occur with any blood product containing plasma, and signs usually appear during transfusion or within 3 to 4 hours.

The clinical features include fever, chills, hypotension, and progressive respiratory insufficiency.

Hypoxemia is refractory to supplemental oxygen, and ARDS can be avoided by transfusing washed PRBCs in symptomatic patients.

Treatment consists of aggressive pulmonary support and possibly mechanical ventilation.

The syndrome follows a milder course when caused by transfusion, usually resolving within 48 to 96 hours.

The mortality rate is significantly lower than mortality of ARDS associated with other etiologies (10% vs 60%).

Scope of Blood Transfusion

According to estimates from the World Health Organization (WHO), more than 112 million units of blood were collected in 2013.11 Less than half of donated blood is collected in developing and transitional countries, which are home to about 80% of the world's population. Of the 156 countries providing data to WHO for 2013, 13 were not able to screen all of their donated blood for one or more of the four infections (HIV, HBV, HCV, and syphilis) that are most widely recognized to be transmitted through blood and are recommended by WHO to be screened at donation.11 A total of 126 countries have national guidelines on the appropriate clinical use of blood, and 70 countries have a national hemovigilance system to monitor adverse events associated with transfusion.11

Surveys to determine blood product use in the United States, led by the National Heart and Lung Institute (now called the National Heart, Lung, and Blood Institute), began in 1971.12 In the United States, surveys have reported the frequency of blood collection and utilization since the late 1980s, most recently through the National Blood Collection and Utilization Survey (NBCUS), which has been conducted biannually since 1998.12–14 In the 2017 NBCUS report, reflecting data collected in 2015, there were nearly 11 million whole-blood and 3.7 million apheresis collections, with approximately 19 million blood components transfused.14 In 2015, 11.33 million whole-blood and RBC units, 2.7 million units of plasma, 1.8 million units of apheresis platelets, 0.17 million units of whole-blood–derived platelets (measured in apheresis equivalent units), and 1.2 million units of cryoprecipitate were given.14 The number of RBC transfusions has continued to decline since 2008, perhaps reflecting the growing adoption of more aggressive hospital blood management practices. The number of transfused platelets has remained approximately the same, but transfusion of apheresis platelets has continued to increase, while the amount of whole-blood–derived or pooled platelets has continued to decline. In addition to contributions from the voluntary donor pool, plasma units also are collected annually from paid donors and are used to prepare immune globulin, albumin, and various other plasma-derived products. By 1987, the cost of collecting, processing, and transfusing patients exceeded $3 billion; since then, costs have increased steadily with the addition of new screening tests and the implementation of leukoreduction.12 In 2015, the mean price paid by a hospital was $217 for a unit of leukocyte-reduced RBCs, $60 for fresh-frozen plasma, and $537 for apheresis platelets, so current costs are likely to exceed $4 billion annually.14,15

It has been estimated that the annual likelihood of an individual's receiving a transfusion increases dramatically with age; in 2015, the transfusion rate in the US population was 35.3 units per 1000 people.14 Because of concern about contracting an infectious disease, there has been historic interest in autologous and donor-directed blood donation. However, donor-directed units, usually given by family members for a specific patient, have been shown to have higher rates of various infectious agents. There has been movement away from donor-directed donation and toward building a dedicated, voluntary repeat donor population.14,15 Viral infections are much less common among repeat donors compared with first-time whole-blood donors, and they may be even less common among donors associated with apheresis collection.16,17

Blood transfusion services are an important part of the health-care system since blood transfusion is required in a number of frequently occurring clinical situations: Major surgical procedures, including treatment of trauma patients; obstetric care with major bleeding during child birth; and treatment of several medical diseases, especially hematological diseases. This article outlines the essential safety aspects of blood transfusion from the proper selection of the unpaid blood donor to processing and appropriate testing of the blood unit to safety aspects of transfusion, which include the appropriate clinical use of blood and blood components. The importance of accurate reporting of any adverse reactions to blood transfusion, which form the basis for a hemovigilance system, is reviewed.

Apparent hemoglobinopathy after blood transfusion

Blood transfusion history is essential in interpreting abnormal hemoglobin pattern because small peaks of abnormal hemoglobin may appear from blood transfusion. Apparent hemoglobinopathy after blood transfusion is rarely reported, but it may cause diagnostics dilemma resulting in repeated unnecessary testing. Kozarski et al. reported 52 incidences of apparent hemoglobinopathies out of which 46 were Hb C, 4 were Hb S, and 2 were Hb O-Arab. The percentage of abnormal hemoglobin ranged from 0.8% to 14% (median: 5.6%). The authors recommended identifying and notifying the donor in such event [16].

Impact of Blood Transfusion

Blood transfusion can be required to control anemia and hemodynamic compromise. However, there is ongoing controversy about its real efficacy and safety in the context of NSTE-ACS. Blood transfusion has been shown to be associated with an increased risk of death, MI, and refractory ischemia.50

It is not clearly understood why transfusion may be associated with adverse outcome. Alterations in erythrocyte, nitric oxide biology in stored blood, and high hemoglobin oxygen affinity due to a low rate of 2,3-diphosphoglyceric acid, leading to decreased oxygen delivery to tissues, have been put forward, as well as increases in inflammatory mediators.

All in all, the information about the efficacy of and the indications for blood transfusion needs to be critically considered. In mild to moderate anemia (hematocrit > 25% or hemoglobin levels >8 g/dL), blood transfusion may be associated with increased risk of death at 30 days and should be avoided if anemia is hemodynamically well tolerated. Below these hematocrit/hemoglobin levels blood transfusion should be given.50

5. Blood Loss and Transfusion

Blood loss and transfusion were shown to interfere with several aspects of CMI, including cytokine levels, NK cell activity, and T-cell blastogenesis (Klein, 1999). Blood transfusion (BT) was suggested to be an independent risk factor for tumor recurrence in cancer patients (Klein, 1999), although the specific mechanisms are yet unclear. In an ongoing study in rats, we found that BT that is based on standard clinical procedures promotes MADB106 metastasis and the progression of the CRNK-16 leukemia. Surprisingly, our findings also indicate a critical role for red blood cells in mediating these effects of BT, rather than a role for leukocyte or soluble factors. We suspect that donors’ deteriorating red blood cells disrupt the normal host anti-tumor response, presumably through preoccupying host immunocytes (Atzil et al., 2004).

Blood Transfusion

Blood transfusion, which is frequently used to correct anemia or treat hemorrhage, is associated with significant immunomodulation, termed transfusion-related immunomodulation (TRIM). Observational studies in human cohorts have shown allogeneic blood transfusion to be associated with immunosuppressive cytokine profiles in elective surgical patients.56 Blood transfusion may be immunomodulatory through a number of mechanisms, including deficient natural killer cell function, altered antigen presentation, and impaired macrophage phagocytosis.57-59 Whether these immune changes alter the inflammatory profile and increase the risk of infection24 and/or recurrence of cancer remain controversial.60 These associations may merely reflect patient comorbidity and/or intraoperative hemorrhage.