# RBC Storage Lesion Studies in Humans and Experimental Models of Shock
## 12 Updated Meta-Analysis of the Effects of Stored Blood in Clinical Trials  
Since our investigations began, there has been an increase in the number of clinical studies investigating the effects of length of storage of blood on mortality and several large randomized controlled trials (RCTs) have been completed. Therefore, we updated our prior meta-analysis [21]. In our analysis of the 31 observational studies, we found a significantly increased risk of death (\(p=0.01\), OR 1.13, CI 1.03-1.24) when patients were transfused with longer stored blood, consistent with our original findings. In our updated meta-analysis, we found there were now more than 4000 patients from six RCTs. We did a separate analysis using the data from the six RCTs and found a significantly different overall effect on outcome from the observational studies (\(p=0.02\) for difference between observational and RCTs), with no survival rate differences between older and fresher RBCs (OR: 0.91, 95% CI: 0.77-1.07) in the RCTs. We attribute the different effect on outcome found in the 31 observational studies vs. the six RCTs to differences in the methods used in the two types of study. Observational studies took current transfusion practice and divided it into two groups of longer stored and fresher blood transfusion, with \"longer stored\" blood being that which is stored for up to 42 days. In contrast, the RCTs compare current practice, which consisted of blood stored for an average of two to three weeks, to transfusion of the freshest available RBCs which were stored for between one to 10 days. Therefore, in the observational studies, the median age for both the fresher and older blood arms was significantly higher compared to those same groups in the six RCTs (\(p=0.01\)). Our analysis of RCTs confirms that the transfusion of the freshest RBCs is not superior to standard practice in which RBCs have been stored for intermediate durations of time (two- to three-week-old). Importantly, the RCTs cannot exclude the possibility suggested by the observational studies that older stored units available for transfusion, namely the four- to six-week-old RBCs, increase mortality risk. After the publication of our systematic review, a large randomized controlled trial conducted at six hospitals in four countries randomizing 31,497 subjects to receive either fresher or older RBC was published and produced findings that are consistent with our findings [22]. A Fork in the Road: Haptoglobin--A Novel Therapeutic Approach to Sequester Iron and Limit Bacterial Growth and Tissue Injury? We noted in a randomized controlled trial of our lethal large animal experimental _S. aureus_ pneumonia model that there were marked elevations in plasma CFH levels during sepsis, even in the absence of blood transfusion [23]. Hemolysis resulting in elevated CFH levels has been documented to occur during human bacterial sepsis, and higher CFH levels are associated with a worse outcome [24]. Over the last half-century, the overwhelming majority of research on improving sepsis outcomes has unsuccessfully focused on inhibiting host inflammatory mediators. Preclinical studies have found that infusing plasma proteins that bind to sites on the CFH molecule improve outcomes [25; 26]. This observation suggests that augmenting host clearance of potential toxic elements such as CHF and iron released from RBCs using a plasma protein transfusion therapy could serve as an alternative pathophysiological approach to treating sepsis. This alternative pathophysiological therapeutic approach to remove CFH and thereby iron to treat sepsis is thought to evolve as follows: virulent bacteria produce hemolysisins which disrupt RBCs and result in the release of CFH, heme, and iron into the vascular space [27; 28]. During infection, this can result in injury via multiple mechanisms. CFH itself can scavenge NO, producing vasoconstriction and subsequent tissue and endothelial injury. Free iron serves as an essential bacterial nutrient that promotes bacterial growth and potentially worsens the infection.