Historically, reported incidence rates for TACO have been based upon passive reporting. Reliance on these mechanisms suggested that TACO is a relatively rare event (incidence <1 %) [20]. However, in 2005 blood centers began reporting TACO to the FDA as a specific cause of transfusion-related death [4]. Since this time, TACO has received increased recognition as an important cause of transfusion-related morbidity and mortality. Indeed, more contemporary investigations utilizing active surveillance have suggested TACO incidence rates ranging from 4 to 8 % [11, 21]. As an example, in a single-center, 1-month prospective cohort study evaluating patients transfused with plasma outside of the operating room and emergency department environments, Narick and colleagues identified a TACO incidence rate of 4.8 % [11]. Of concern, none of the cases identified by the investigating authors had been reported to the hospital blood bank by the responsible clinical team. Similarly, using highly sensitive TACO screening algorithms followed by manual review of all screen-positive cases, the authors of this chapter recently identified a TACO incidence rate of 4.3 % following intraoperative blood product administration (unpublished results). Again, none of the confirmed cases had been reported by the clinical service. Importantly, similar temporal trends are noted when evaluating the impact of TACO on patient-important outcomes. While initially accounting for as little as 2 % of all transfusion-related fatalities reported to the FDA, data from 2012 puts this figure at 21 % [4]. This makes TACO the second leading cause of transfusion-related fatalities, trailing only TRALI. Similarly, the 2012 SHOT report from the UK found TACO to be the leading cause of transfusion-associated deaths, accounting for six out of the nine (67 %) reported fatalities that year [22].

Regarding the incidence of TACO in critically ill populations, there again remains significant uncertainty. In 2011, Li and colleagues reported that 51 of 901 (6 %) patients transfused in a tertiary ICU setting developed TACO [23]. In comparison, other publications have reported incidence rates up to 11 % [24]. The difficulty in identifying cases of TACO is likely one reason why there have been such discrepancies in reported incidence rates. Bearing this in mind, the true incidence of TACO is likely best represented by the upper limits of the reported range. Together with our heightened awareness of TACO, refined diagnostic criteria as well as improved case ascertainment strategies will likely play an important role in improving our future understanding of the true epidemiology of this syndrome. Of note, a consistent finding is that TACO appears to be more common in patients who are transfused in the ICU setting as compared to the general hospital ward [11, 25]. This may in part be explained by the higher prevalence of comorbid conditions that are thought to be risk factors for TACO, such as advanced age as well as cardiovascular and renal disease. In addition, ICU populations frequently require large-volume resuscitation and high transfusion rates, both known risk factors for TACO [23].

Since its earliest reports more than 70 years ago [10], TACO’s clinical manifestations of dyspnea, hypoxia, and hypertension have been suggested to result from hydrostatic pulmonary edema [10, 26]. Simply stated, transfusing too large a volume of blood at too fast an infusion rate has been postulated to result in hypervolemia, elevated left atrial pressures, alveolar flooding, and respiratory distress [23]. While this mechanism holds clear biologic plausibility, it is of interest to note that a growing number of investigations suggest the potential for TACO development in patients receiving low-volume transfusion. In 1996, Popovsky and colleagues noted that the orthopedic surgical patients who developed TACO frequently received only one or two units of RBCs [21]. Since this observation, several other authors have similarly noted that TACO can occur in the setting of low-volume or even single-unit blood-product transfusion [8, 27, 28]. While it has been postulated that such patients are simply more susceptible to circulatory overload due to preexisting cardiac dysfunction [23], additional potentially synergistic mechanisms have been proposed as well [23].

In 2005, Singel et al. hypothesized that impaired nitric oxide (NO) metabolism in stored RBCs may lead to posttransfusion microcirculatory NO trapping [29]. Consequently, increases in vascular resistance may precipitate left ventricular dysfunction, ultimately resulting in hydrostatic pulmonary edema (TACO). These findings have been corroborated by a growing number of investigations and may partly explain the relationship between TACO and the characteristic acute hypertensive response [15, 30]. More recently, as has been described in the congestive heart failure literature [31], inflammatory mediators have been implicated in the pathogenesis of TACO [32]. This notion gained reverence in 2010 when Blumberg et al. noted a dramatic 49 % reduction in the incidence of TACO following the introduction of universal prestorage leukoreduction of RBCs [33]. It was postulated that this effect was the result of an attenuated accumulation of leukocyte- and platelet-derived inflammatory mediators due to the leukoreduction procedures. These results are perhaps further supported by the findings of Andrzejewski et al. who noted the frequent occurrence of fever in those who developed TACO [15, 32]. While interesting and hypothesis generating, the results of studies such as these will clearly require further validation. Indeed, the exact mechanism or mechanisms underlying TACO remain an area of ongoing investigation. To this point, the National Institutes of Health is currently supporting studies investigating the roles of biological and inflammatory mediators, microparticles, and free hemoglobin on pulmonary inflammation and vascular dysfunction.

Though the precise mechanisms underlying TACO remain under investigation, a number of risk factors for its development have been described. Some of the earliest reported recipient risk factors, including extremes of age (<3 or >60 year), severe chronic anemia, and plasma transfusion for the reversal of oral anticoagulant therapy, are still broadly considered predisposing characteristics for TACO [23, 26]. Chronic anemia and hemorrhagic shock are believed to be risk factors for TACO due to an associated hyperdynamic state and the relative intolerance of the cardiovascular system to acute increases in circulating blood volume. Plasma transfusion for the reversal of oral anticoagulant therapy is presumed related to TACO due to the large volume of plasma required to achieve the desired end points (frequently greater than 1–2 L). More recently, Murphy et al. associated chronic renal failure, heart failure, and transfusion in a setting of hemorrhagic shock with risk for TACO [25]. Additionally the number of blood products administered and a positive fluid balance were associated with increased rates of TACO as well [25]. Importantly, while the extremes of age appear to be at heightened risk, data from the Quebec Hemo-vigilance study highlight the fact that TACO can occur in all age groups [28]. Specifically, this investigation noted that 9 % of TACO cases occurred in transfusion recipients who were <50 years of age, 15 % in those <60 year, and approximately 7 % occurred in those aged 18–49 years [28].

If TACO is suspected, the transfusion should be discontinued immediately and the institutional transfusion medicine service and/or blood bank contacted in order to initiate an appropriate workup [32, 34, 35]. This should include reserving any remaining portion of the blood product for possible laboratory testing. Treatment of the transfusion recipient remains supportive as there are no known effective therapeutic interventions for established TACO. Therefore, current treatments are geared toward managing these events as you would a patient with acute decompensated heart failure, including oxygen supplementation, ventilator support when needed, and, as hemodynamic status will allow, measures to achieve a negative fluid balance [36]. In light of the fact that most patients with TACO present with hypertension, the use of intravenous diuretics to enhance urine output and foster negative fluid balance is generally recommended. Noninvasive ventilation with continuous positive airway pressure has been shown to reduce the need for endotracheal intubation as well as mortality in patients with acute hypoxemic respiratory insufficiency resulting from congestive heart failure [37, 38]. As such, we would recommend the consideration of noninvasive ventilatory strategies in TACO cases as well, provided the patient remains hemodynamically stable. For patients with a concomitant respiratory and/or metabolic acidosis or associated shock, more controlled ventilatory strategies should be considered [39, 40]. When invasive ventilatory support is required, lung-protective ventilation strategies should be employed using low tidal volume ventilation (≤6 ml per kg of ideal body weight) while maintaining an inspiratory plateau pressure of ≤30 cm H₂O [41, 42]. Data relating to appropriate levels of positive end expiratory pressure (PEEP) are insufficient to provide meaningful evidence-based recommendations in the setting of TACO. Although elevated PEEP levels (>5 cm H₂O) are often utilized in the setting of congestive heart failure, there is little data to suggest that this provides substantial benefit in the setting of TACO.