Anemia, transfusions and hospital outcomes among critically ill patients on prolonged acute mechanical ventilation: a retrospective cohort study

Patients requiring prolonged acute mechanical ventilation (PAMV), defined as 96 hours of mechanical ventilation (MV) or longer, are a group with high hospital utilization intensity [1]. Although constituting roughly one-third of all hospitalized MV patients, they account for about two-thirds of all the hospital resources allocated to the MV group [1]. For example, in the USA in 2003, PAMV patients occupied 6,728,819 hospital days, at an aggregate annualized hospital cost of over $16 billion [1]. At the same time their hospital mortality of 35% is similar to that observed among ventilated patients who require fewer than 96 hours of MV. Based on age-adjusted and disease-specific incidence rates, this population is projected to more than double by the year 2020, thus mandating increased emphasis on efficiency of health care delivery to patients requiring PAMV [2].

Anemia is a frequent complication of critical illness, and its etiology is multifactorial [3‐5]. Despite evidence from a large randomized controlled trial suggesting that tolerating a lower hemoglobin among critically ill patients results in unimpaired outcomes, more recent observational data indicate that adherence to this recommendation is poor across the board, and is worst among patients requiring MV [3, 5, 6]. At the same time, a large body of work specifically addressing the critically ill points to a strong association of exposure to allogeneic blood with such complications as acute lung injury (ALI), ventilator-associated pneumonia, and blood stream infection (BSI) [7‐11], and morbidity and attendant hospital resource utilization stemming from such complications may be avoided by more restrictive use of allogeneic blood [12‐15].

Because by virtue of having a prolonged critical illness the PAMV population is at greater risk for exposure to packed red blood cell (pRBC) transfusions [16], we hypothesized that in this population more liberal use of allogeneic blood is associated with worse clinical and economic outcomes. Conversely, it would follow that a more restrictive approach to transfusions might result in fewer complications, better outcomes, and thus better quality health care and more efficient health care delivery.

In the present study we have demonstrated that transfusions are commonly used among patients requiring PAMV, occur at relatively liberal hemoglobin triggers, and are associated with worsened hospital outcomes, including mortality, LOS, and costs. We have also shown that PAMV patients undergoing a transfusion are less likely to be discharged home and, despite a high transfusion burden, leave the hospital with a lower hemoglobin level than those not undergoing a transfusion. Specifically, we have documented a 67% transfusion rate among these patients, with the attendant attributable mortality, LOS, and cost increases of 21%, 6.3 days, and $48,972, respectively. Importantly, these numbers reflect the adjustment for potential contributions to these outcomes of such high risk and costly events as nosocomial infections (HAP and BSI) and gastrointestinal bleeding, and cardiac, abdominal and orthopedic surgeries.

Health care costs in the USA have reached an unprecedented $2.1 trillion, representing 16% of the gross domestic product [19]. A large proportion of this price tag, approximately one-third, is attributed to hospital expenses, and these have been rising steadily [20]. The intensive care unit (ICU), in turn, is a high-intensity use area of the hospital, whose utilization by the Medicare population alone has grown by over 12% in a recent 5-year period [21]. MV, whose attributable cost is $1,500/day in 2002 US dollars, is the single greatest driver of the ICU costs [22]. Illustrating this, the 2003 aggregate hospital costs for all patients undergoing any MV were $25 billion, 64% of which (or $16 billion) was consumed by patients requiring PAMV [1]. Furthermore, given the historic approximately 6% crude annual growth in the volume of PAMV in US hospitals, age-specific incidence change in PAMV over time, and the age-adjusted US population growth, PAMV patients are likely to number over 600,000 cases by year 2020, more than doubling their current numbers [2]. Such substantial utilization of health care resources demands closer scrutiny.

Given that hospital survival rate among patients on PAMV is comparable to that among patients requiring shorter term ventilatory support [1], institution of measures that are directed at optimizing efficiency of health care delivery to this population are critical. Allogeneic blood transfusion is one area of health care delivery in which the penetration of evidence-based practices has remained suboptimal [3, 5]. Despite the fact that a randomized controlled trial performed a decade ago confirmed safety of reducing hemoglobin transfusion triggers among critically ill from the traditional 10 g/dl to 7 g/dl [23], the mean pretransfusion hemoglobin remains in the region of 8.5 g/dL among all ICU patients, and is even higher among those requiring MV [3, 5, 6]. Our study demonstrates nonadherence not only to this recommendation but also to the guidance supporting the administration of only 1 unit of pRBCs per transfusion episode, as was done in the TRICC (Transfusion Requirements in Critical Care) trial [23], because we have observed that on average a transfused PAMV patient receives more than 3 units of blood in a single transfusion episode.

Unfortunately, this nonadherence to recommendations based on the best evidence is not without consequences. Evidence points to a strong association between exposure to blood transfusions and such complications as ventilator-associated pneumonia and BSIs [9, 10, 24], as well as multiple other infectious and immune complications [25‐27]. Evidence for the connection between acute respiratory distress syndrome (ARDS) and transfusion exposure is also mounting. For example, not only did the difference in the ARDS incidence nearly reach statistical significance in the TRICC trial (P = 0.06), with the more favorable results in the restrictive arm [23], but also several prospective cohort studies have strengthened this association [7, 8, 11], particularly because some were able to detect a dose-response relationship between the magnitude of blood exposure and risk for subsequent development of ARDS [7, 11]. Giving further credence to this causal relationship is a recent report from the Mayo clinic [13], in which adherence to a restrictive transfusion protocol along with the use of a lung-protective ventilation strategy resulted in a reduction in ALI incidence from 28% to 10%. In general, it is estimated that adopting restrictive triggers more ubiquitously could result in avoidance of nearly 40,000 acute complications associated with transfusions, and, more specifically, approximately 17,000 cases of ARDS alone [14, 15]. This may even be an under-estimate, given the results of the nested case-control study conducted by Gajic and coworkers [28], in which ALI was prospectively observed in 8% of all patients exposed to blood products. Our study, by focusing on the population of MV patients at greatest risk for transfusions (namely those receiving PAMV), deepens our understanding not only of transfusion practices in PAMV patients but also of how altering these practices in line with the best evidence might result in lower costs and better outcomes for patients. Given that more than a half of all of the observed transfusion episodes were administered at or above a hemoglobin concentration of 8 g/dl, and given the noted contribution of allogeneic pRBC exposure to mortality, hospital LOS, and costs in the PAMV population, there is a substantial opportunity to improve these outcomes via an evidence-driven reduction in transfusion triggers.

Our study has a number of limitations. First, its retrospective nature lends itself to multiple forms of bias, the most important of which is a selection bias. We have mitigated this possibility by employing uniform inclusion criteria that are based on a strict definition of the population, as well as by following all patients to the hard end-points of hospital discharge or death. Second, having been performed in a single health care system, the underlying population characteristics may limit the generalizability of our findings. Third, the accuracy of the identification of hospital complications (HAP and BSI) and such processes of care as the surgical procedures we adjusted for may be at least somewhat questionable, because we utilized administrative coding, and not clinical data, to define these conditions. Although it is possible that the first two are prone to being over-reported in the hospital's billing system, particularly for the sicker patients, the reporting of surgical procedures is less likely to have an inherent bias. Fourth, because of its observational nature, and although we attempted to adjust for confounders, the possibility of residual confounding remains. Finally, our study was performed before widespread utilization of leukoreduction, and thus it may overestimate the association between transfusions and such adverse outcomes as infectious complications or ALI. However, this potential inflation of the association, if present, is likely to be small, because a recent randomized controlled trial failed to observe a reduction in the incidence of either infection or ALI in the group exposed to leukoreduced blood [29, 30].

In summary, we have demonstrated that two-thirds of all patients on PAMV are exposed to allogeneic blood during their hospitalization. Furthermore, the total amount of blood is, on average, a staggering 9 units per transfused patient. Even with a pretransfusion hemoglobin of >7 g/dl, the number of units administered per one episode of transfusion is over 3. This potential overuse of allogeneic blood is associated with a 21% increase in adjusted hospital mortality, and an incremental hospital LOS and costs of 6.3 days and $48,972, respectively. Our data support the idea that evidence-based transfusion practices in this population of critically ill patients may be one of the ways to improve quality and efficiency of health care delivery.