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University of Ottawa Centre for Transfusion Research and the Clinical Epidemiology Program of the
Ottawa Health Research Institute, Department of Medicine, The Ottawa Hospital (General Campus),
501 Smyth Road, Box 201, Ottawa, Ontario K1H 8L6, Canada
b
University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada
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Fig. 1. Preoperative hemoglobin by cardiovascular disease status. Adjusted odds ratio for mortality by
cardiovascular disease and preoperative hemoglobin. (Adapted from Carson JL, Duff A, Poses RM,
Berlin JA, Spence RK, Trout R, et al. Severity of anemia and operative mortality and morbidity. Lancet
1996;348:1055 60; with permission.)
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Benefits of transfusion
Four large observational studies that were specifically designed to compare
clinical outcomes at varying hemoglobin concentration in transfused and nontransfused patients have been conducted in various clinical settings. In the first of
these, Hebert et al [28] used a combined retrospective and prospective cohort
design to examine 4470 critically ill patients admitted to six Canadian tertiary
level intensive care units (ICUs) during 1993. In patients with cardiac diagnoses
(ischemic heart disease, arrhythmia, cardiac arrest, and cardiac and vascular
surgical procedures), there was a trend toward increased mortality when hemoglobin concentrations were < 95 g/L. Furthermore, analysis of a subgroup of
202 patients with anemia, an Acute Physiology and Chronic Health Evaluation
II (APACHE II) score > 20, and a cardiac diagnosis revealed that transfusion of
1 to 3 units or 4 to 6 units of RBCs was associated with a significantly lower
mortality rate when compared with those patients who did not receive transfusion
[55% (no transfusions) versus 35% (1 to 3 units) or 32% (4 to 6 units),
respectively, P = 0.01]. Although the design of the analysis attempted to control
for the confounding influence of disease severity, it is quite possible that the
complex interrelationship between disease severity, the number of transfusions,
and the degree of anemia may have resulted in a spurious association between a
cardiovascular diagnosis and the reported mortality risk with anemia.
Wu et al [29] retrospectively studied Medicare records of 78,974 patients older
than age 65 who were hospitalized with a primary diagnosis of acute myocardial
infarction. The authors then categorized patients according to their admitting
hematocrit. Although anemia defined in the study as a hematocrit < 39% was
present in nearly half the patients, only 3680 patients received a RBC transfusion.
Lower admission hematocrit values were associated with increased 30-day
mortality with a mortality rate approaching 50% among patients with a hematocrit of 27% or lower who did not receive a RBC transfusion. Unfortunately, this
study did not have any data on nadir hemoglobins and their relationship to
mortality. Interestingly, RBC transfusion was associated with a reduction in
30-day mortality for patients who received at least 1 RBC transfusion if their
admitting hematocrit was less than 33%, whereas RBC transfusion was associ-
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ated with increased 30-day mortality for patients whose admitting hematocrit
values were 36.1% or higher. In the analysis, these associations were present even
when adjustments were made for clinical patient factors including APACHE II
scores, location of myocardial infarction and presence of congestive heart failure and treatment factors including use of reperfusion therapies, aspirin, and
b-adrenergic blockade.
In the only study exclusively focusing on the perioperative period, Carson
et al [30] attempted to determine the effect of perioperative transfusion on 30- and
90-day postoperative mortality with a retrospective cohort study involving
8787 patients with hip fractures undergoing repair between 1983 and 1993 in
20 different United States hospitals. This was a large, high-risk, elderly (median
age 80.3 years) population with extensive co-existing disease and with an overall
30-day mortality rate of 4.6%. A total of 3699 patients (42%) received a
perioperative transfusion within 7 days of the surgical repair. After controlling
for trigger hemoglobin concentrations level, cardiovascular disease, and other risk
factors for death, the results suggested that patients who had hemoglobin
concentrations as low as 80 g/L and did not receive transfusion were no more
likely to die than those with similar hemoglobin concentrations levels who received a transfusion. (With hemoglobin concentrations < 80 g/L, nearly all patients received a transfusion which did not allow investigators to draw conclusions
about the effect of transfusion at these lower hemoglobin concentrations levels.)
However, as the authors point out, despite the large sample size, inadequate power
may still explain the inability to detect a reduction in mortality related to
transfusion, and they estimated that the study would need to be 10 times larger
to detect a 10% difference in 30-day mortality with 80% power.
More recently, Vincent et al [31] completed a prospective observational crosssectional study involving 3534 patients admitted to 146 western European ICUs
during a 2-week period in November 1999. Of these patients, 37% received an
RBC transfusion during their ICU admission with the overall transfusion rate
increasing to 41.6% over a 28-day period. For those patients who were transfused, the mean pretransfusion hemoglobin concentration was 84 13 g/L. In an
effort to control for confounding created by illness severity and the need for
transfusion, these investigators used a strategy of matching transfused and
nontransfused patients based on their propensity to receive a transfusion, thereby
defining two well-balanced groups (516 patients in each group) to determine the
influence of RBC transfusions on mortality. Using this approach, the associated
risk of death was increased instead of decreased, by 33% for patients who
received a transfusion compared with similar patients who did not receive blood.
However, as pointed out in the accompanying editorial [32], the results may have
differed if the propensity scores were derived separately for categories of prehemoglobin concentrations (eg, < 80, 80 to 100, and > 100 g/L) instead of
hemoglobin concentrations at ICU admission. For example, if one were to
consider groups of patients with a pretransfusion hemoglobin concentration
< 60 g/L, it is unlikely that the observed 33% increase in mortality would hold
true or blood transfusion would never be recommended.
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Fig. 2. Effect of restrictive transfusion triggers on the need for allogenic RBCs. Forrest plot
describing the effect of restrictive transfusion triggers on the use of allegeneic blood transfusion in
seven published randomized trials. (Adapted from Carson JL, Hill S, Carless P, Hebert PC, Henry D.
Transfusion triggers: a systematic review of the literature. Trans Med Rev 2002;16(3):187 99.)
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sufficient data on potentially relevant clinical outcomes such as stroke, thromboembolism, multi-organ failure, delirium, infection or delayed wound healing to
perform any pooled analysis. Carson and colleagues [33] stated there were
insufficient data to address the full range of risks and benefits associated with
different transfusion thresholds, particularly in patients with coexisting disease.
They also noted that their meta-analysis was dominated by a single trial: the
Transfusion Requirements in Critical Care (TRICC) Trial [34], which enrolled
838 patients and was the only individual trial identified that was adequately
powered to evaluate the impact of different transfusion strategies on mortality
and morbidity.
The TRICC Study [30] documented an overall nonsignificant trend toward
decreased 30-day mortality (18.7% versus 23.3%, P = 0.11) and significant
decreases in mortality among patients who were less acutely ill (8.7% versus
16.1%, P = 0.03) in the group treated using a hemoglobin transfusion trigger
of 70 g/L compared with a more liberally transfused group that received 54%
more red cell transfusions. The investigators also noted that the 30-day mortality
rates were significantly lower with the restrictive transfusion strategy among
patients who were less acutely ill (APACHE II scores < 20) and among patients
who were less than 55 years of age (Fig. 3).
A number of additional questions arose from the TRICC Trial. The investigators were particularly interested in the risks and benefits of anemia and
transfusion in patients with cardiovascular disease and in patients attempting to
wean from mechanical ventilation. In the first of these subgroup analyses [35],
357 patients (43%) were identified with cardiovascular disease. Of these, 160 had
been in the restrictive RBC transfusion group and 197 in the liberal transfusion
strategy group. The two groups were fairly equally balanced with regards to
baseline characteristics and concurrent therapies with a few exceptions: there was
less frequent diuretic use in the restrictive group (43% versus 58%, P < 0.01) and
the use of epidural anesthetics was greater in the restrictive group (8% versus 2%,
P < 0.01). Overall, in this subgroup analysis, there was no significant difference
in the mortality rate between the two treatment groups. However, there was a
nonsignificant (P = 0.3) decrease in overall survival rate in the restrictive group
for patients with confirmed ischemic heart disease, severe peripheral vascular
disease, or severe comorbid cardiac disease.
The subgroup analysis of patients receiving mechanical ventilation was
limited to 713 (85% of the 838 patients in the TRICC Trial who required
invasive mechanical ventilatory support [36]. Of these, 357 had been in the
restrictive RBC transfusion group and 356 in the liberal group. The mean duration of mechanical ventilation was 8.3 8.1 days in the restrictive group and
8.8 8.7 days in the liberal group (P = 0.48). Ventilator-free days were
17.5 10.9 and 16.1 11.4 in the restrictive and liberal RBC transfusion
groups, respectively (P = 0.09). Eighty two percent of the patients in the
restrictive transfusion group were considered successfully weaned and extubated
for at least 24 hours, compared with 78% for the liberal group (P = 0.19).
Amongst the 219 patients who required mechanical ventilation for more than
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Fig. 4. Time remaining on mechanical ventilation in the 283 patients requiring mechanical ventilation
for > 1 week. The time to successful weaning from mechanical ventilation is illustrated using KaplanMeier survival curves in patients who required mechanical ventilation for > 1 week. Weaning success
is defined as remaining off mechanical ventilation, once extubated, during the 30 days of observation.
Hatched line refers to the restrictive group, whereas the solid line refers to the liberal group. Survival
curves were not statistically different when compared using a log rank test (P = 0.08). (Adapted from
Hebert PC, Blajchman MA, Cook DJ, Yetisir E, Wells G, Marshall J, et al. Do blood transfusions
improve outcomes related to mechanical ventilation? Chest 2001;119:1850 7; with permission.)
7 days, there were no differences in the time to successful weaning (Fig. 4). The
independent effects of RBC transfusions and hemoglobin concentration were
also examined. Each additional transfusion was associated with an increased duration of mechanical ventilation (RR = 1.10; 95% CI 1.14 to 1.06, P < 0.01)
adjusting for the effect of age, APACHE II score and co-morbid illnesses.
Hemoglobin concentrations did not influence the duration of mechanical ventilation (RR = 0.99; 95% CI 1.01 to .98, P = 0.45). Complications including
pulmonary edema and adult respiratory distress syndrome (ARDS) were increased in patients in the liberal strategy.
Even though a large randomized clinical trial (RCT) has been completed, a
number of questions remain to be answered. One of the most important questions is why the liberal RBC transfusion strategy failed to improve 30-day mortality and rates of organ failure in critically ill patients? The greater number of
allogeneic RBC units in the liberal group may have significantly depressed
host immune responses [36,37] or resulted in altered microcirculatory flow as a
consequence of prolonged storage times.
Summary
Despite the frequent use of red cell transfusions, only one large randomized
trial has examined red cell administration perioperative and in the critical care
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setting. However, the TRICC Trial does not provide sufficient evidence to
determine optimal transfusion practice in postoperative care, in critically ill
children, or in patients with a myocardial infarction or acute coronary syndromes.
In addition, most transfusion practice guidelines published before the completion
of the TRICC Trial [33 35] are now dated and need to have expert opinion
informed by solid evidence in diverse clinical settings. In the next several years,
several randomized trials will provide additional evidence in support of bedside
decision-making. For example, two transfusion studies will be evaluating
transfusion triggers, including one in premature infants and the other in critically
ill children. At this juncture, high-quality clinical evidence is not yet available for
many decisions related to red cell transfusions. We anticipate that risks and
benefits of red cells and alternatives will be elucidated in the coming years.
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