Christopher L. Carroll, MD, MS, FCCP

 

Blood transfusions are common in critically ill patients; two in five adults admitted to an ICU receive at least one transfusion during their hospitalization (Corwin HL, et al. Crit Care Med. 2004;32[1]:39). Recently, there has been growing concern about the potential dangers involved with prolonged blood storage. Several provocative observational and retrospective studies found that prolonged storage time (ie, the age of the blood being transfused) negatively affects clinical outcomes (Wang D, et al. Transfusion. 2012;52[6]:1184). But now, some newly published trials on blood transfusion practice, including one published in late September 2017 (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017) seem to debunk much of this literature. Was all of the concern about age of blood overblown?

The appeal of “fresh” blood is intuitive. As consumers, we’re conditioned that the fresher the better. Fresh food tastes best. Carbonated beverages go “flat” over time. The newest iPhone® device is superior to your old one. So, of course, it follows that fresh blood is also better for your health than older blood.
But, in order to have a viable transfusion service, blood has to be stored. Blood is a scarce resource, and blood banks need to keep an adequate supply on hand for expected clinical necessities, as well as for emergencies. Donors can’t be on standby, waiting in the hospital to provide immediate whole blood transfusion. Also, blood needs to be tested for infections and for potential interactions with the patient, and whole blood must be broken down into individual components for transfusion. All of this requires time and storage.

Vlad/Fotolia

According to the US FDA, blood can safely be stored for up to 42 days, requiring that there be less than 1% hemolysis at the end of storage, and that more than 75% of the red blood cells remain in circulation 24 hours after the transfusion. But some have suggested that these specifications aren’t comprehensive enough, citing studies that have linked prolonged storage to the development of “red blood storage lesion.” Red blood storage lesion has been theorized to have a variety of effects, including altered immunologic response and defective oxygen carrying capacity (Spinella PC, et al. Transfusion. 2011;51[4]:894). But do these changes have clinical implications?

In a randomized study of 100 critically ill adults supported by mechanical ventilation, 50 were randomized to receive “fresh” blood (median storage age 4 days, interquartile range 3-5 days) and 50 were randomized to receive “standard” blood (median storage age 26.5 days, interquartile range 21-36 days) (Kor DJ, et al. Am J Respir Crit Care Med. 2012;185[8]:842). The primary outcome was gas exchange, as prolonged storage of red blood cells could potentially lead to an increased inflammatory response in patients. However, the authors found no difference in gas exchange between the two groups, and there were no differences in immunologic function or coagulation status.

The ABLE (Age of Blood Evaluation) trial was a randomized, blinded trial of transfusion practices in critically ill patients (Lacroix J, et al. N Engl J Med. 2015;372:1410). In 64 centers in Canada and Europe, 2,430 critically ill adults were randomized to receive either “fresh” blood (mean storage age 6.1 ± 4.9 days) or “standard” blood (mean storage age 22.0 ± 8.4 days). The primary outcome was 90-day mortality, with a power of 90% to detect a 5% change in mortality between the two groups. The investigators found no statistically significant difference in 90-day mortality between the “fresh” and “standard” groups (37% vs 35.3%; hazard ratio 1.1; 95% CI 0.9 – 1.2). Additionally, there were no differences in secondary outcomes, including multiorgan system dysfunction, duration of supportive care, or development of nosocomial infections.

The INFORM (Informing Fresh versus Old Red Cell Management) trial was a randomized study of patients hospitalized in six centers in Canada, Australia, Israel, and the United States (Heddle NM, et al. N Engl J Med. 2016;375[2]:1937). A total of 24,736 patients received transfusions with either “fresh” blood (median storage age 11 days) or “standard” blood (median storage age 23 days). The primary outcome was in-hospital death, with a 90% power to detect a 15% lower relative risk. When comparing the 8,215 patients who received “fresh” blood and the 16,521 patients who received “standard” blood, the authors found no difference in mortality between the two groups (9.1% vs 8.8%; odds ratio 1.04; 95% CI 0.95 to 1.14). Furthermore, there were no differences in outcomes in the high-risk subgroups that included patients with cancer, patients in the ICU, and patients undergoing cardiovascular surgery.

A meta-analysis examined 12 trials of patients who received “fresh” blood compared with those who received “older” or “standard” blood (Alexander PE, et al. Blood. 2016;127[4]:400); 5,229 patients were included in these trials, in which “fresh” blood was defined as blood stored for 3 to 10 days and “older” blood was stored for longer durations. There was no difference in mortality between the two groups (relative risk 1.04; 95% CI 0.94 - 1.14), and no difference in adverse events (relative risk 1.02; 95% CI 0.91 - 1.14). However, perhaps surprisingly, “fresh” blood was associated with an increased risk of nosocomial infections (relative risk 1.09; 95% CI 1.00 - 1.18).

And finally, in the recently published TRANSFUSE trial (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017), 4,994 critically ill adults were randomized by 59 centers in five countries to receive transfusions stored for a short-term (median storage of 11 days) or long-term (median 21 days). Similar to the other three randomized trials, there was no difference in mortality between the two groups at both 90 and 180 days.

So, can we stop worrying about the age of the blood that we are about to transfuse? Probably. Taken together, these studies suggest that differences in the duration of red blood cell storage allowed within current US FDA standards aren’t clinically relevant, even in critically ill patients. At least, for now, the current practices for age of blood and duration of storage appear unrelated to adverse clinical outcomes.

Dr. Carroll is Professor of Pediatrics, University of Connecticut, Division of Critical Care, Connecticut Children’s Medical Center, Hartford, Connecticut.

 

Blood transfusions are common in critically ill patients; two in five adults admitted to an ICU receive at least one transfusion during their hospitalization (Corwin HL, et al. Crit Care Med. 2004;32[1]:39). Recently, there has been growing concern about the potential dangers involved with prolonged blood storage. Several provocative observational and retrospective studies found that prolonged storage time (ie, the age of the blood being transfused) negatively affects clinical outcomes (Wang D, et al. Transfusion. 2012;52[6]:1184). But now, some newly published trials on blood transfusion practice, including one published in late September 2017 (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017) seem to debunk much of this literature. Was all of the concern about age of blood overblown?

The appeal of “fresh” blood is intuitive. As consumers, we’re conditioned that the fresher the better. Fresh food tastes best. Carbonated beverages go “flat” over time. The newest iPhone® device is superior to your old one. So, of course, it follows that fresh blood is also better for your health than older blood.
But, in order to have a viable transfusion service, blood has to be stored. Blood is a scarce resource, and blood banks need to keep an adequate supply on hand for expected clinical necessities, as well as for emergencies. Donors can’t be on standby, waiting in the hospital to provide immediate whole blood transfusion. Also, blood needs to be tested for infections and for potential interactions with the patient, and whole blood must be broken down into individual components for transfusion. All of this requires time and storage.

Vlad/Fotolia

According to the US FDA, blood can safely be stored for up to 42 days, requiring that there be less than 1% hemolysis at the end of storage, and that more than 75% of the red blood cells remain in circulation 24 hours after the transfusion. But some have suggested that these specifications aren’t comprehensive enough, citing studies that have linked prolonged storage to the development of “red blood storage lesion.” Red blood storage lesion has been theorized to have a variety of effects, including altered immunologic response and defective oxygen carrying capacity (Spinella PC, et al. Transfusion. 2011;51[4]:894). But do these changes have clinical implications?

In a randomized study of 100 critically ill adults supported by mechanical ventilation, 50 were randomized to receive “fresh” blood (median storage age 4 days, interquartile range 3-5 days) and 50 were randomized to receive “standard” blood (median storage age 26.5 days, interquartile range 21-36 days) (Kor DJ, et al. Am J Respir Crit Care Med. 2012;185[8]:842). The primary outcome was gas exchange, as prolonged storage of red blood cells could potentially lead to an increased inflammatory response in patients. However, the authors found no difference in gas exchange between the two groups, and there were no differences in immunologic function or coagulation status.

The ABLE (Age of Blood Evaluation) trial was a randomized, blinded trial of transfusion practices in critically ill patients (Lacroix J, et al. N Engl J Med. 2015;372:1410). In 64 centers in Canada and Europe, 2,430 critically ill adults were randomized to receive either “fresh” blood (mean storage age 6.1 ± 4.9 days) or “standard” blood (mean storage age 22.0 ± 8.4 days). The primary outcome was 90-day mortality, with a power of 90% to detect a 5% change in mortality between the two groups. The investigators found no statistically significant difference in 90-day mortality between the “fresh” and “standard” groups (37% vs 35.3%; hazard ratio 1.1; 95% CI 0.9 – 1.2). Additionally, there were no differences in secondary outcomes, including multiorgan system dysfunction, duration of supportive care, or development of nosocomial infections.

The INFORM (Informing Fresh versus Old Red Cell Management) trial was a randomized study of patients hospitalized in six centers in Canada, Australia, Israel, and the United States (Heddle NM, et al. N Engl J Med. 2016;375[2]:1937). A total of 24,736 patients received transfusions with either “fresh” blood (median storage age 11 days) or “standard” blood (median storage age 23 days). The primary outcome was in-hospital death, with a 90% power to detect a 15% lower relative risk. When comparing the 8,215 patients who received “fresh” blood and the 16,521 patients who received “standard” blood, the authors found no difference in mortality between the two groups (9.1% vs 8.8%; odds ratio 1.04; 95% CI 0.95 to 1.14). Furthermore, there were no differences in outcomes in the high-risk subgroups that included patients with cancer, patients in the ICU, and patients undergoing cardiovascular surgery.

A meta-analysis examined 12 trials of patients who received “fresh” blood compared with those who received “older” or “standard” blood (Alexander PE, et al. Blood. 2016;127[4]:400); 5,229 patients were included in these trials, in which “fresh” blood was defined as blood stored for 3 to 10 days and “older” blood was stored for longer durations. There was no difference in mortality between the two groups (relative risk 1.04; 95% CI 0.94 - 1.14), and no difference in adverse events (relative risk 1.02; 95% CI 0.91 - 1.14). However, perhaps surprisingly, “fresh” blood was associated with an increased risk of nosocomial infections (relative risk 1.09; 95% CI 1.00 - 1.18).

And finally, in the recently published TRANSFUSE trial (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017), 4,994 critically ill adults were randomized by 59 centers in five countries to receive transfusions stored for a short-term (median storage of 11 days) or long-term (median 21 days). Similar to the other three randomized trials, there was no difference in mortality between the two groups at both 90 and 180 days.

So, can we stop worrying about the age of the blood that we are about to transfuse? Probably. Taken together, these studies suggest that differences in the duration of red blood cell storage allowed within current US FDA standards aren’t clinically relevant, even in critically ill patients. At least, for now, the current practices for age of blood and duration of storage appear unrelated to adverse clinical outcomes.

Dr. Carroll is Professor of Pediatrics, University of Connecticut, Division of Critical Care, Connecticut Children’s Medical Center, Hartford, Connecticut.

 

Blood transfusions are common in critically ill patients; two in five adults admitted to an ICU receive at least one transfusion during their hospitalization (Corwin HL, et al. Crit Care Med. 2004;32[1]:39). Recently, there has been growing concern about the potential dangers involved with prolonged blood storage. Several provocative observational and retrospective studies found that prolonged storage time (ie, the age of the blood being transfused) negatively affects clinical outcomes (Wang D, et al. Transfusion. 2012;52[6]:1184). But now, some newly published trials on blood transfusion practice, including one published in late September 2017 (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017) seem to debunk much of this literature. Was all of the concern about age of blood overblown?

The appeal of “fresh” blood is intuitive. As consumers, we’re conditioned that the fresher the better. Fresh food tastes best. Carbonated beverages go “flat” over time. The newest iPhone® device is superior to your old one. So, of course, it follows that fresh blood is also better for your health than older blood.
But, in order to have a viable transfusion service, blood has to be stored. Blood is a scarce resource, and blood banks need to keep an adequate supply on hand for expected clinical necessities, as well as for emergencies. Donors can’t be on standby, waiting in the hospital to provide immediate whole blood transfusion. Also, blood needs to be tested for infections and for potential interactions with the patient, and whole blood must be broken down into individual components for transfusion. All of this requires time and storage.

Vlad/Fotolia

According to the US FDA, blood can safely be stored for up to 42 days, requiring that there be less than 1% hemolysis at the end of storage, and that more than 75% of the red blood cells remain in circulation 24 hours after the transfusion. But some have suggested that these specifications aren’t comprehensive enough, citing studies that have linked prolonged storage to the development of “red blood storage lesion.” Red blood storage lesion has been theorized to have a variety of effects, including altered immunologic response and defective oxygen carrying capacity (Spinella PC, et al. Transfusion. 2011;51[4]:894). But do these changes have clinical implications?

In a randomized study of 100 critically ill adults supported by mechanical ventilation, 50 were randomized to receive “fresh” blood (median storage age 4 days, interquartile range 3-5 days) and 50 were randomized to receive “standard” blood (median storage age 26.5 days, interquartile range 21-36 days) (Kor DJ, et al. Am J Respir Crit Care Med. 2012;185[8]:842). The primary outcome was gas exchange, as prolonged storage of red blood cells could potentially lead to an increased inflammatory response in patients. However, the authors found no difference in gas exchange between the two groups, and there were no differences in immunologic function or coagulation status.

The ABLE (Age of Blood Evaluation) trial was a randomized, blinded trial of transfusion practices in critically ill patients (Lacroix J, et al. N Engl J Med. 2015;372:1410). In 64 centers in Canada and Europe, 2,430 critically ill adults were randomized to receive either “fresh” blood (mean storage age 6.1 ± 4.9 days) or “standard” blood (mean storage age 22.0 ± 8.4 days). The primary outcome was 90-day mortality, with a power of 90% to detect a 5% change in mortality between the two groups. The investigators found no statistically significant difference in 90-day mortality between the “fresh” and “standard” groups (37% vs 35.3%; hazard ratio 1.1; 95% CI 0.9 – 1.2). Additionally, there were no differences in secondary outcomes, including multiorgan system dysfunction, duration of supportive care, or development of nosocomial infections.

The INFORM (Informing Fresh versus Old Red Cell Management) trial was a randomized study of patients hospitalized in six centers in Canada, Australia, Israel, and the United States (Heddle NM, et al. N Engl J Med. 2016;375[2]:1937). A total of 24,736 patients received transfusions with either “fresh” blood (median storage age 11 days) or “standard” blood (median storage age 23 days). The primary outcome was in-hospital death, with a 90% power to detect a 15% lower relative risk. When comparing the 8,215 patients who received “fresh” blood and the 16,521 patients who received “standard” blood, the authors found no difference in mortality between the two groups (9.1% vs 8.8%; odds ratio 1.04; 95% CI 0.95 to 1.14). Furthermore, there were no differences in outcomes in the high-risk subgroups that included patients with cancer, patients in the ICU, and patients undergoing cardiovascular surgery.

A meta-analysis examined 12 trials of patients who received “fresh” blood compared with those who received “older” or “standard” blood (Alexander PE, et al. Blood. 2016;127[4]:400); 5,229 patients were included in these trials, in which “fresh” blood was defined as blood stored for 3 to 10 days and “older” blood was stored for longer durations. There was no difference in mortality between the two groups (relative risk 1.04; 95% CI 0.94 - 1.14), and no difference in adverse events (relative risk 1.02; 95% CI 0.91 - 1.14). However, perhaps surprisingly, “fresh” blood was associated with an increased risk of nosocomial infections (relative risk 1.09; 95% CI 1.00 - 1.18).

And finally, in the recently published TRANSFUSE trial (Cooper DJ, et al. N Engl J Med. Published online, September 27, 2017), 4,994 critically ill adults were randomized by 59 centers in five countries to receive transfusions stored for a short-term (median storage of 11 days) or long-term (median 21 days). Similar to the other three randomized trials, there was no difference in mortality between the two groups at both 90 and 180 days.

So, can we stop worrying about the age of the blood that we are about to transfuse? Probably. Taken together, these studies suggest that differences in the duration of red blood cell storage allowed within current US FDA standards aren’t clinically relevant, even in critically ill patients. At least, for now, the current practices for age of blood and duration of storage appear unrelated to adverse clinical outcomes.

Dr. Carroll is Professor of Pediatrics, University of Connecticut, Division of Critical Care, Connecticut Children’s Medical Center, Hartford, Connecticut.