Transfusion and Infections in the Burn Patient

Transfusion in Burn Resuscitation

Blood transfusion has been utilized in burn injury treatment for more than 100 years. Early reports cited the use of blood transfusion in overwhelming toxic shock in children who were burned, theorizing that replacing the patient's infected blood with a transfusion would diminish the infectious toxemia [12]. Whole blood transfusion was recommended during the burn resuscitative phase in the early 1920s, extending into early 1940 [13–15]. Whole blood administration during burn shock was recommended based on the theory that whole blood best approximated the losses of red cells, plasma proteins, water, and electrolytes that occurred in circulating blood immediately post-injury. Additionally, whole blood transfusion was purported to help restore nitrogen balance [16]. Of note, during this period the major cause of death after burn injury was hypovolemic shock in the resuscitation period. Hence, the infectious potential of transfusion was not a major consideration.

The recommendation for whole blood transfusion during resuscitation was supplanted by plasma in World War II, citing that plasma better matched the extracellular losses associated with burn injury [17]. Pooled plasma use for burn resuscitation was at its peak during this time, in which plasma was a mainstay for fluid resuscitation in trauma and burns. Pooled plasma, diluted 50% with normal saline, was also used extensively in non-military settings, for example, in the Cocoanut Grove nightclub disaster in 1942 [18]. Several burn resuscitation formulas, including the Evans formula and Brooke formula, initially included plasma. Hepatitis transmission caused by plasma infusion was identified, spurring a transition to a combined crystalloid/colloid approach using albumin [19]. Ironically, plasma use in resuscitation declined with increasing concerns for cost and infection, similar to the previous abandonment of whole blood use in resuscitation.

The use of crystalloid in burn resuscitation gained momentum in the late 1960s, with the evaluation of extracellular fluid losses and replacement [20]. Consensus guidelines for resuscitation focused on crystalloid solutions, and the Parkland formula gained popularity. Unfortunately, resuscitation with the Parkland formula has resulted in “fluid creep,” with crystalloid resuscitation far exceeding the patient need [21]. The increased use of crystalloid volumes has resulted in hemodilution. However, it is rare for a burn patient to require a blood transfusion during resuscitation in the absence of other traumatic injuries or development of coagulopathy [10].

Recent interest in the use of plasma and albumin for burn resuscitation may yet again swing the resuscitation paradigm back to colloid and blood product transfusion [22,23]. Fresh frozen plasma has been demonstrated to stabilize the glycocalyx in animal models of severe trauma and burn resuscitation, and there have been several retrospective clinical reports citing a reduction in resuscitation requirement when using fresh frozen plasma (FFP) [18]. Hepatitis contamination of plasma, which ultimately restricted plasma use 100 years ago, has been reduced substantially, thus providing an opportunity for further investigation [24]. Randomized trials using FFP administration in burn resuscitation are underway to evaluate the efficacy of these strategies during resuscitation.

Yet another blood-product–derived colloid being examined by prospective trial is albumin, which is a pooled plasma-derived product. Albumin is a key plasma protein that helps regulate drug levels, enzymatic reactions, and electrolyte concentrations [25]. Although an early study cited increased interstitial pulmonary edema with albumin resuscitation in resuscitation, subsequent reports have described improved outcomes and decreased fluid requirements [26,27]. A prospective randomized trial of albumin in resuscitation is in progress. Both the albumin and plasma resuscitation trials focus on fluid volume and survival rather than infection risk, hence, their infection potential will require further investigation.

Transfusion During the Acute Phase of Burn Care

Although recommendations for the use of transfusion during the acute resuscitation phase have varied widely, the need for transfusion after initial resuscitation occurs primarily for two reasons: symptomatic anemia and acute blood loss. Acute anemia after burn injury is multifactorial: circulatory dilution from resuscitation, augmented red cell destruction, reduced erythropoiesis, erythropoietin-resistant iron deficiency, and frequent phlebotomy all contribute to the development of anemia [28,29]. Another insidious cause of anemia in the burn patient is blood loss through donor sites and healing wounds, particularly if wound healing is delayed. As a result, transfusion for anemia has occurred in patients with burns as little as 10% total burn surface area (TBSA) [30]. Increases in hepcidin post-burn injury contribute to impaired erythropoiesis [31]. Elevated hepcidin levels inhibit efficacy of oral iron absorption after burn injury. The use of intravenous iron has been hampered by reports of increased infection rates and mortality with intravenous iron use [32]. Although recent meta-analyses suggest that intravenous iron may be safe and effective in acute inflammatory states, further evidence is needed prior to recommending its use in burns [33,34].

The second major event leading to transfusion post-burn, surgical excision, and grafting, has long been acknowledged as a necessary evil. Early excision and grafting of the burn wound are the current standard of care for major third-degree burns because they improve mortality and decrease infection rates [35–37]. Conservative estimates for blood loss during burn excision range from 2% of a patient's blood volume per percent excised for trunk and extremity burns to 5% blood volume for the face [38,39]. Some authors have suggested that surgical blood loss for adults with major burn injury approaches 0.8 mL/cm² of excised and grafted skin [40]. The majority of burn transfusions occur within 24 hours of an operation, because of both the surgical excision as well as insidious losses through the donor site. As a result, patients with major burn injury receive 20–40 units of red blood cells during their hospitalization [10].

Although blood transfusion salutary effects include increased oxygen delivery, red cell mass, and restoration of circulatory volume, blood transfusion also has well-described infectious complications. These complications occur both as a result of contamination of the blood itself as well as the immunosuppressive potential of blood products on the host. Infectious contamination has been well documented in the literature and is common to all transfusions. Blood products, particularly platelets stored at room temperature, may be contaminated with bacteria, with an incidence of bacterial contamination in platelets reported as high as 1 in 2,000–3,000 platelet transfusions [41,42]. Other infections also can be transmitted via blood transfusion, including hepatitis C (<1 per 1 million), human immunodeficiency virus (HIV; <1 per 1 million) and hepatitis B (1 per 3,000,000) [43]. Hence, the transfusion may directly cause blood stream infection because of direct administration of an infectious agent. Cytomegalovirus infections have likewise been reported after blood transfusion and allograft placement in burn patients [44].

The belief that blood transfusion increases infection in burn patients because of its immunomodulatory effects has dominated the literature. Indeed, there have been a host of retrospective studies that establish an association between blood transfusion and infection in major burns. An early retrospective study of 594 burn patients described a relation between infectious morbidity and number of transfusions in adults with major burn injury [45]. A large multicenter retrospective study of transfusion in burn patients reported that each unit of red blood cells increased infection risk by 11% [9]. Retrospective analysis of the association of blood transfusion and infection of severely burned children treated at a single center likewise demonstrated increased risk of infection, particularly in patients with inhalation injury [46]. In addition, a study focusing on children with major burns reported a decreased probability of meeting sepsis criteria over time after burn injury utilizing a restrictive transfusion strategy [47]. Retrospective publications citing an association of blood transfusion and infection continue even today [48]. However, these retrospective studies suffer from the same major limitation: association does not ensure causation. Do burn patients get infections because of the immunosuppressive effects of blood transfusion or do burn patients with infections require more transfusions because they have an infection?

The landmark multicenter, randomized, prospective Transfusion Requirement in Burn Care Evaluation (TRIBE) trial perhaps has a part of the answer [10]. The aim of TRIBE was to determine if a restrictive transfusion strategy (transfuse if hemoglobin <7 g/dL) had better outcomes than a traditional strategy (transfuse if hemoglobin <10 g/dL). The primary outcome measure for TRIBE was blood stream infection, with secondary outcome measures of pneumonia, urinary tract infection (UTI), mortality, ventilator days, wound healing, and hospital length of stay. More than 9,000 units of blood were transfused in 356 patients. No difference in any outcome measure, most notably infection (blood stream, pneumonia, UTI, wound) occurred. This may be caused by several factors, not the least of which include that the vast majority of blood transfused in the TRIBE study was leuko-reduced. Studies in trauma patients have suggested that leukoreduction reduces infectious complications [49]. Another reason that TRIBE may not have reported a difference in infection rates lies in the challenge of identifying infection in the burn patient, in which the systemic inflammatory response, present in virtually all major burns, reduces the efficacy of traditional sepsis markers. Finally, the development of sepsis in a burn patient likely occurs due to the combination of factors, not just a single event. For example, a patient receiving a transfusion may not develop an infection just because they were transfused, but if transfusion occurred during a period of transient bacteremia, then host defense reduction may allow infection to ensue. Likewise, subsequent studies demonstrated no difference in infection based on amount of blood transfused for massive burns, increased blood age, or inhalation injury [50,51].

The use of massive transfusion protocols in trauma have been shown to decrease blood utilization and improve survival [52]. Given the extent of blood loss in a major burn excision, the use of FFP and platelets have increased during burn excision and grafting. A retrospective study in children with major burn injury demonstrated that non-survivors received more FFP, platelets, red blood cells, and cryoprecipitate than survivors [53]. The ensuing prospective trial comparing outcomes for children randomized to receive either a 1:1 or a 4:1 red blood cell to FFP ratio during massive transfusion demonstrated no difference in blood stream infection or pneumonia among the two strategies [54]. However, this study did not examine the potential infectious impact of platelet or cryoprecipitate transfusions on infectious outcomes in burn patients. The use of whole blood during the massive blood loss has regained popularity, as whole blood contains coagulation factors that could mitigate bleeding [56]. Early studies in children report that massive whole blood transfusion is safe and effective [57]. Evaluation of the long-term infectious complications of a massive transfusion protocol during burn excision and grafting will require further study.

Care must be taken in evaluating the association between infection and blood product transfusion trials in burns due to the unique pathophysiology accompanying major burn injury. Pyrexia, tachycardia, and tachypnea, which are components of most sepsis scoring systems, are common hypermetabolic responses in burn patients. Burn sepsis guidelines have been published to assist in diagnosing infection in burn patients [55]. Although these guidelines are helpful, further validation and refinement will assist in assuring the veracity of prospective trials assessing infection in burns. Likely the relation between transfusion and infections in burns is multifactorial, and future studies leveraging artificial intelligence analysis of electronic medical record data may be required to tease out these associations.

Conclusions

Blood transfusion is commonplace after burn injury. Historically transfusion was used in resuscitation, however, this practice dissipated with increased recognition of the complications of transfusion including infection, circulatory overload, transfusion related lung injury, and transfusion related immunomodulation. Prospective randomized trials of transfusion in burn injury treatment have failed to demonstrate a cause–effect relation between infection and blood transfusion, despite commonly held beliefs to the contrary, although the difficulty in identifying sepsis in burns may detract from infection identification. The correlation of other blood products, such as FFP, cryoprecipitate, and platelets with infection in burns has had limited study. Although retrospective reviews suggest an association between infection and blood product administration, a single randomized prospective trial in children did not demonstrate an increased infection rate in burn patients related to the use of blood products. Blood and blood product transfusion in burn patients should be limited to symptomatic anemia, blood loss, or active hemorrhage, and all patients monitored for infectious complications. Transfusion has become an integral component of burn care. Optimizing its use in the future using interactive technologies will be essential in improving the burn outcomes of the future.