The purpose of our study was to determine whether RBC transfusion administered in the ICU is associated with outcomes among patients with a recent diagnosis of ALI, sepsis and shock. We found that RBC transfusion in this period occurred in approximately one in five patients. The proportion of patients receiving RBC transfusions was similar in the subgroup of patients meeting our specified transfusion criteria. After adjusting for predetermined confounders, we found no significant, independent association between RBC transfusion and mortality or VFDs. The 95% CIs surrounding our risk estimates argue that the lack of statistical significance should be interpreted cautiously, as our risk estimates included clinically relevant differences in the direction of both benefit and harm.
Our study failed to show benefit or harm when RBC transfusion was administered to patients with a new diagnosis of ALI, sepsis and shock. There are several potential explanations for this result. First, RBC transfusion in this study was administered to patients in the ICU up to 72 hours after they met the criteria for sepsis and ALI. The clinical setting and/or timing of RBC transfusion may in fact be important in determining its benefit or harm [5
]. A single randomized trial published by Rivers et al
] showed a mortality benefit when RBC transfusion was administered to patients with severe sepsis in the emergency department as part of a larger goal-directed resuscitation strategy that included fluid and vasopressor support. This resuscitation protocol was administered to enrolled subjects in an emergency department setting within 6 hours after a sepsis diagnosis. Thereafter, subjects were admitted to an ICU and underwent care as determined by their physicians. Notably, 64% of subjects in the treatment arm of the Rivers et al
. trial were exposed to RBC transfusion within the first 6 hours of therapy. In contrast, observational studies in the ICU have not consistently demonstrated that RBC transfusion improves oxygen delivery in fluid-replete septic subjects [28
] and instead raises concern regarding increased complications, including nosocomial infection [2
], ALI [3
] and death [3
]. In an observational study of 160 ICU patients with septic shock, delayed goal-directed resuscitation and transfusion up to 48 hours after diagnosis were associated with higher risk of ALI [5
]. Similarly to these observational studies, our findings may reflect a lack of benefit when transfusion is administered beyond the initial 6-hour resuscitation window or for reasons other than protocol-driven resuscitation in severe sepsis. Finally, RBC transfusion may carry minimal beneficial effects or even harmful effects on patient outcomes independently of other resuscitative strategies, such as volume resuscitation or vasopressor support.
Despite our efforts to identify a subset of subjects with shock whom transfusion might benefit, we observed no improvement in outcomes with RBC transfusion. Although transfusion criteria were met in one of four subjects, we observed no treatment association when adjusting for these factors in subgroup analysis. Consistent with prior work [28
], our study suggests that physiological indicators may not necessarily identify those patients likely to benefit from RBC transfusion. While randomized data in patients with septic shock are lacking, there is growing experimental evidence that transfusion of stored RBCs can potentially harm patients with preexisting inflammation or impaired microvascular perfusion. According to the current "two-hit" hypothesis of transfusion injury [34
], RBC units may contain bioactive particles capable of influencing the cellular injury that leads to organ failure in susceptible patients with preexisting insults such as sepsis or mechanical ventilation [4
]. In addition, in vivo
models have demonstrated that older RBC units exhibit reduced deformability [36
], which may actually impair capillary flow and oxygen delivery in an already compromised microvascular system [38
]. It is therefore possible that RBC transfusion administered beyond the first 6 hours of illness may paradoxically be harmful in the very patients that we hope will benefit.
Our study has several limitations. First, transfusion data for a significant number of subjects were missing. Because complete case analysis in the setting of missing data may be limited by both reduced power and residual bias [23
], we performed a sensitivity analysis using multiple imputation of missing values, which provided results similar to our primary analysis. The combination of missing RBC transfusion data and the small proportion of patients who met our "shock" definition limited our study's power to detect statistically significant associations between transfusion and outcomes (minimum detectable difference in mortality = 19% based on an overall mortality rate of 30% and two-sided α = 0.05). While pooled blood products such as fresh frozen plasma (FFP) may also have an effect on patient outcomes, missing data and low FFP transfusion rates in our cohort precluded our ability to include FFP as a meaningful covariate. Furthermore, we cannot exclude the possibility of residual bias related to unignorable missing data (missing not at random) or other covariates either not present or insufficiently captured in the database, including age of transfused blood [40
], the indication for transfusion, concomitant therapies such as fluid administration and the manner in which transfusion was administered. Though we carefully defined sepsis, shock and physiological criteria on the basis of objective measures within a fixed time period, misclassification of shock due to etiologies other than sepsis is a potential limitation of our study. We also could not determine the reason why physicians chose to transfuse individuals or whether transfusion was administered concomitantly with other resuscitation strategies. The decision to administer RBC transfusion may depend on a host of factors, including patient-, hospital- and provider-level characteristics [1
]. Understanding factors that contribute to transfusion practice variability is an important avenue of future study, because blood products are a limited and costly health care resource. Last, our study cannot determine whether RBC transfusion is a meaningful component of early goal-directed therapy within the first 6 hours of severe sepsis. It is important to note that our patients likely differed significantly, with regard to their stage of illness, indication for transfusion and concomitant therapy, from those enrolled in the randomized trial evaluating early goal-directed therapy in the emergency department setting [9
]. Nonetheless, some form of goal-directed resuscitation likely extends beyond the first 6 hours of severe sepsis into the ICU period. Previous work suggests that delayed goal-directed therapy may be associated with increased complications in critically ill septic patients [5
]. Despite its limitations, our study builds on previous work suggesting that RBC transfusion beyond 6 hours of presentation may not improve mortality in critically ill patients with septic shock and coexistent ALI and that physiological criteria may not identify those patients likely to benefit from transfusion in the ICU setting.