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10 1056@NEJMra1612789 PDF
10 1056@NEJMra1612789 PDF
Review Article
A
pproximately 11 million units of red cells are transfused an- From the Department of Medicine, Divi-
nually in the United States, making red-cell transfusion one of the most sion of General Internal Medicine, Rutgers
Robert Wood Johnson Medical School,
common medical interventions. Red cells are typically administered as a New Brunswick, NJ ( J.L.C.); the Division
concentrate, called packed red cells, with a preservative solution (hematocrit, 60%) of Transfusion Medicine, Department of
that allows up to 42 days of refrigerated storage. On average, transfusion of 1 unit Pathology, University of Pittsburgh, Pitts-
burgh (D.J.T.); and the Department of
of red cells, which has a volume of 350 ml, results in a hemoglobin increment of Pathology, Division of Transfusion Medi-
1 g per deciliter in an adult with stable blood volume. cine, Johns Hopkins University School of
In this review, we describe the evidence underlying current transfusion guide- Medicine, Baltimore (P.M.N.). Address
reprint requests to Dr. Carson at Rutgers
lines, trends in use, the infectious and noninfectious risks of transfusion, and ongo- Robert Wood Johnson Medical School,
ing research. We describe the effects of transfusion in adults who have cardiovas- 125 Paterson St., New Brunswick, NJ 08901,
cular disease or gastrointestinal bleeding, who are critically ill, or who are or at jeffrey.carson@rutgers.edu.
undergoing orthopedic surgery, as well as the effects in children. Discussions of N Engl J Med 2017;377:1261-72.
the safety of transfusion in resource-poor countries and the efficacy of transfusion DOI: 10.1056/NEJMra1612789
Copyright © 2017 Massachusetts Medical Society.
in premature infants, pregnant women, and patients with hemorrhagic shock or
congenital anemias are beyond the scope of this review.
Figure 1. Clinical Trials Comparing the Effect of Restrictive versus Liberal Transfusion on 30-Day Mortality.
Data are from a meta-analysis of 31 studies, of which 23 reported 30-day mortality.1 Risk ratios were calculated with
the use of the Mantel–Haenszel test. The blue boxes indicate risk ratios, and the size of each box is proportional to
the sample size of the corresponding study. CI denotes confidence interval, and df degrees of freedom; I2 is the per-
centage of total variation that is due to heterogeneity rather than chance.
0.94; 95% CI, 0.80 to 1.11), myocardial infarc- involved patients with various diagnoses. There-
tion (risk ratio, 1.08; 95% CI, 0.74 to 1.60), and fore, it may not be appropriate to generalize the
congestive heart failure (risk ratio, 0.78; 95% CI, results of trials that used the lower threshold to
0.45 to 1.35). In addition, long-term mortality, clinical settings in the trials using the higher
with a mean of 3.1 years of follow-up, was similar threshold. It is possible that mortality is not in-
in the two groups (hazard ratio for liberal trans- fluenced by a lower transfusion threshold, but
fusion as compared with restrictive transfusion, the rate of myocardial infarction (in patients
1.09; 95% CI, 0.95 to 1.25) in one trial.8 with preexisting cardiovascular disease or in
Many trials have used a restrictive transfusion those undergoing cardiac surgery) or recovery
threshold of 7 g per deciliter or 8 g per deciliter.9 of functional capacity (in patients undergoing
Among the trials assessing 30-day mortality, the orthopedic surgery) could be adversely affected
results with a threshold of 7 g per deciliter were by a transfusion threshold of 7 g per deciliter
similar to those with a threshold of 8 g per deci- rather than 8 g per deciliter.
liter (test for differences, P = 0.56; I2 = 0%). How-
ever, most of the trials using 7 g per deciliter as Indications for Subgroups of Patients
the threshold for restrictive transfusion involved Adults with Cardiovascular Disease
patients in intensive care units (ICUs), whereas The risk of death is strongly associated with the
the trials using 8 g per deciliter as the threshold level of anemia and is increased among patients
with cardiovascular disease.10,11 Thus, it follows but an increase in the risk of myocardial infarc-
that patients with cardiovascular disease might tion, acute coronary syndrome, or cardiac arrest
benefit from a higher transfusion threshold. was associated with restrictive transfusion (4.5%
Overall, restrictive transfusion is not associ- vs. 2.5%; risk ratio, 1.78; 95% CI, 1.18 to 2.70).14
ated with an increased risk of myocardial infarc- These results should be interpreted with caution
tion; however, there is some evidence supporting because not all trials that enrolled patients with
a benefit of liberal transfusion in patients with cardiovascular disease were included in this analy-
underlying cardiovascular disease. In a trial in- sis. Furthermore, it may not be appropriate to
volving 2007 patients undergoing cardiac surgery, combine data from patients who had preexisting
90-day mortality was higher in the restrictive- coronary artery disease with data from those
transfusion group than in the liberal-transfusion with acute coronary syndromes, since the risks
group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% associated with anemia and efficacy of transfu-
CI, 1.00 to 2.67; P = 0.045), although short-term sion may be different; patients with active ische
outcomes (30-day mortality, myocardial infarc- mia often undergo cardiac interventions and in-
tion, and others) were similar in the two groups.7 tensive pharmacologic treatment, whereas those
In a pilot trial involving 110 patients with acute with preexisting cardiovascular disease are hetero-
ischemic heart disease, 7 deaths occurred in the geneous with respect to disease severity and may
restrictive-transfusion group, as compared with have undefined cardiovascular disease. This analy-
1 death in the liberal-transfusion group (absolute sis also did not include patients undergoing
risk difference, 11.2 percentage points; 95% CI, cardiac surgery.
1.5 to 20.8; P = 0.08 with adjustment for age).12 In
a cluster-randomized trial involving 936 patients Adults with Gastrointestinal Bleeding
with gastrointestinal bleeding, there was a trend Three trials involving a total of 1522 patients
toward increased mortality among patients with with gastrointestinal bleeding showed that mor-
underlying ischemic heart disease; mortality was tality was lower with a restrictive transfusion
3% with liberal transfusion but 12% with re- threshold than with a liberal transfusion thresh-
strictive transfusion (absolute difference, 10.7 per- old (risk ratio, 0.65; 95% CI, 0.43 to 0.97; dif-
centage points; 95% CI, −9.8 to 31.2; P = 0.11 for ference in rate of transfusion, 24.5 percentage
interaction).13 In contrast, in a trial involving points).1,5,13,15 Rebleeding also was lower with a
2016 patients with cardiovascular disease or risk restrictive transfusion threshold (risk ratio, 0.54;
factors for it who were undergoing hip-fracture 95% CI, 0.51 to 0.93). The rebleeding rate in the
repair, mortality was similar with liberal transfu- liberal-transfusion group may have been higher
sion and restrictive transfusion (5.2% and 4.3%, because of increased intravascular pressure from
respectively; odds ratio, 1.23; 95% CI, 0.71 to 2.12).4 a higher volume of fluid (blood), leading to rup-
Several trials are under way to address this ques- ture of thrombus at the site of the bleeding vessel.
tion of restrictive versus liberal transfusion in
patients with cardiovascular disease: Transfu- Other Subgroups of Adults
sion Requirements in Cardiac Surgery III (TRICS Five trials involving a total of 2840 patients in
III; ClinicalTrials.gov number, NCT02042898), with ICUs, including 998 patients with septic shock,6
a projected sample of 5000 patients; Cost-Effec- showed no significant difference in mortality
tiveness and Cost-Utility of Liberal vs. Restrictive between the two transfusion thresholds (risk
Red Blood Cell Transfusion Strategies in Patients ratio with restrictive transfusion, 0.97; 95% CI,
with Acute Myocardial Infarction and Anaemia 0.75 to 1.25; absolute difference in rate of trans-
(REALITY; NCT02648113), with a projected sam- fusion, 36.3 percentage points).1 Similarly, the
ple of 630 patients; and Myocardial Ischemia and mortality rates in five trials involving a total of
Transfusion (MINT; NCT02981407), with a pro- 2831 patients undergoing orthopedic surgery were
jected sample of 3500 patients. similar with the two transfusion thresholds, al-
A meta-analysis of selected trials that pro- though they were slightly higher with restrictive
vided data on patients with cardiovascular dis- transfusion (risk ratio, 1.27; 95% CI, 0.72 to
ease showed no difference in mortality between 2.25; absolute difference in rate of transfusion,
the liberal and restrictive transfusion thresholds, 54.7 percentage points).1
ditional capacity to reduce unnecessary blood red cells stored in refrigerators.47 U.S. donors are
transfusions (Fig. 3). However, U.S. medical prac- not tested for malaria, but infectious donors
tice, with major programs for trauma resuscita- are eliminated on the basis of travel exclusions.48
tion and aggressive programs of solid-organ and Babesia infection is becoming recognized as a
stem-cell transplantation, may explain the persis- growing problem (associated with 15 to 20%
tently high rates of red-cell transfusion in the mortality) in some areas of the United States,
United States. such as New England, and testing programs are
currently being evaluated for possible implemen-
tation.49-51 Other agents also under study include
Improv ing S a fe t y
dengue virus,52 chikungunya virus,53 and hepatitis
Transfusion-Transmitted Diseases E virus.54
In developed countries, the risk of a disease
transmitted by transfused red-cell concentrates Pathogen Reduction
has become very small (Fig. 4), with a risk of less Pathogen-reduction technology represents a pro-
than 1 in 1 million for the pathogens of greatest active approach to improving blood safety by
concern, including the human immunodeficiency broadly inactivating potential infectious agents
virus (HIV) and hepatitis C virus (HCV).38 Al- in the blood component. This technology is now
though it is always possible that a new infec- available in the United States for platelets and
tious agent will be introduced into the blood plasma.55 Several systems are under study for the
supply, current blood-collection programs use a treatment of red cells, using chemical process-
combination of a medical history from volunteer ing with an alkylating agent (S-303) and gluta-
donors, limited physical examinations, geograph- thione (Intercept, Cerus) or a combination of
ic and travel exclusions for areas where disease riboflavin and ultraviolet light (Mirasol, Terumo
is known to be endemic and testing is not prac- BCT). Neither system is licensed in the United
tical or of proven efficacy, and a battery of sero- States. The advantages of pathogen-reduction
logic and nucleic acid tests to reduce the risk of technology would include reduction of residual
infectious complications. Volunteer blood dona- infections with viruses, bacteria, or parasites that
tions in the United States are tested for syphilis are not detected by current testing systems and
(despite the absence of recent documented cases),39 prevention of some infections that have not yet
hepatitis B virus (HBV),40 HIV,41 human T-cell been recognized as transmitting disease through
lymphotropic virus,42 HCV,41 West Nile virus,43 and transfusion. Pathogen-reduction technology will
Chagas’ disease,44 with the recent addition of also inactivate white cells in blood that are not
testing for Zika virus.45 Although the tests are removed by leukoreduction filters, eliminating
performed to eliminate infectious units from the the need to irradiate red cells in order to prevent
blood supply, some of the tests are more likely transfusion-associated graft-versus-host disease
to identify previous infections (in particular, and potentially reducing the risk of febrile non-
syphilis or hepatitis B, with the latter indicated hemolytic transfusion reactions.56 It is also antici-
by the presence of hepatitis B core antibody). pated that pathogen-reduction technology could
Initial testing for these agents is performed with eliminate some of the current donor travel exclu-
the use of serologic methods that have been sions and testing for some agents for which the
enhanced over time with new generations of as- risk of breakthrough infections is very low. In
says that have improved sensitivity and specific- vitro studies have shown that pathogen-reduction
ity. For additional recipient safety, nucleic acid technology kills high levels of viruses and bac-
testing is performed for HBV, HCV, HIV, West teria in red cells, and a clinical study showed
Nile virus, and Zika virus. Donor red cells can that whole blood treated with riboflavin and
also be tested for antibody to cytomegalovirus ultraviolet light reduced malaria transmission.57
for patients at high risk, but leukoreduced red These safety advantages of treating red cells with
cells are considered equally safe with respect to pathogen-reduction technology will need to be
the risk of cytomegalovirus.46 Bacterial infections, weighed against some degree of cell damage
a major problem in platelets that are stored at and the likelihood of increased costs of such
room temperature, are not a major concern in treatment.
Sponsor and Year Recommended Hemoglobin Concentration as Threshold for Transfusion Comments
diovascular disease
National Guideline Centre, Restrictive transfusion threshold of Patients with major hemorrhage, Consider a transfusion threshold of Transfuse single unit in patients
201616 7 g/dl, with target of 7–9 g/dl for acute coronary syndromes, or 8 g/dl, with target of 8–10 g/dl after without active bleeding; re
patients without major hemor- chronic anemia are excluded transfusion for patients with acute assess after each single-unit
rhage coronary syndromes; further re- transfusion
search required for patients with
chronic cardiovascular disease
American Society of Restrictive transfusion threshold of Transfuse single unit; multimodal
Anesthesiologists, 6–10 g/dl, with consideration of protocols or algorithms may
201517 potential or ongoing bleeding, in- help reduce use of blood prod-
travascular volume status, signs ucts; however, no single algo-
of organ ischemia, and adequacy rithm or protocol can be rec
of cardiopulmonary reserve ommended at this time
n e w e ng l a n d j o u r na l
Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
American College of Guidelines focused on patients with Use threshold of 7–8 g/dl in hospital-
Physicians, 201320 heart disease; current evidence ized patients with coronary heart
does not support benefit of liberal disease, including patients with
transfusion in patients with as- acute coronary syndromes
ymptomatic anemia and heart
disease
Sponsor and Year Recommended Hemoglobin Concentration as Threshold for Transfusion Comments
Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
* KDIGO denotes Kidney Disease: Improving Global Outcomes, and MI myocardial infarction.
1267
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Figure 3. Transfusion Rates in the United States in 2013 and 2015, as Compared with Rates in Other Developed
Countries.
The number above each bar is the number of transfused red-cell units per 1000 population. Transfusion rates in the
United States in 2013 and 2015 are compared with the most recent data on transfusion rates in Europe (2013).33 The
U.S. rate of transfusion in 2013, 41.0 units per 1000 population, is the midpoint of the rates estimated separately on
the basis of the 2013 AABB Blood Collection, Utilization, and Patient Blood Management Survey28 (40.3 units per 1000)
and the 2013 Centers for Disease Control and Prevention (CDC) NBCUS (41.7 units per 1000).29 The U.S. rate of trans-
fusion in 2015, 34.5 units per 1000, is based on the 2015 NBCUS.30 The data shown are for distributed (D) or transfused
(T) units of blood, which are typically nearly equivalent.
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