Parsimonious blood use and lower transfusion triggers: What is the evidence?
ABSTRACT
Evidence supports a parsimonious approach to blood use for managing anemia, contrasting with the long-standing practice of blood transfusion targeting arbitrary hemoglobin levels. Hemodilution studies have demonstrated that humans can tolerate anemia. The cumulative data have confirmed and validated the safety of a conservative approach to transfusion. This has translated into formal national guidelines for blood transfusion as well as patient safety and quality markers supporting blood management stewardship to minimize unnecessary use of blood products.
KEY POINTS
- In critical care patients, transfusion should be considered when the hemoglobin concentration reaches 7 g/dL or less.
- In postoperative patients and hospitalized patients with preexisting cardiovascular disease, transfusion should be considered at a hemoglobin concentration of 8 g/dL or less or for symptoms such as chest pain, orthostatic hypotension, or tachycardia unresponsive to fluid resuscitation, or heart failure.
- Consider both the hemoglobin concentration and the symptoms when deciding whether to give a patient a transfusion.
Meta-analyses and observational studies
Rohde et al26 performed a systematic review and meta-analysis of 17 trials with 7,456 patients, which revealed that a restrictive strategy is associated with a lower risk of nosocomial infection, including pneumonia, wound infection, and sepsis.
The pooled risk of all serious infections was 10.6% in the restrictive group and 12.7% in the liberal group. Even after adjusting for the use of leukocyte reduction, the risk of infection was lower in the restrictive strategy group (RR 0.83, 95% CI 0.69–0.99). With a hemoglobin threshold of less than 7.0 g/dL, the risk of serious infection was 14% lower. Although this was not statistically significant overall (RR 0.86, 95% CI 0.72–1.02), the difference was statistically significant in the subgroup undergoing orthopedic surgery (RR 0.72, 95% CI 0.53–0.97) and the subgroup presenting with sepsis (RR 0.51, 95% CI 0.28–0.95).
Salpeter et al27 performed a meta-analysis and systematic review of three randomized trials (N = 2,364) comparing a restrictive hemoglobin transfusion trigger (hemoglobin < 7 g/dL) vs a more liberal trigger. The groups with restrictive transfusion triggers had lower rates of:
- In-hospital mortality (RR 0.74, 95% CI 0.60–0.92)
- Total mortality (RR 0.80, 95% CI 0.65–0.98)
- Rebleeding (RR 0.64, 95% CI 0.45–0.90)
- Acute coronary syndrome (RR 0.44, 95% CI 0.22–0.89)
- Pulmonary edema (RR 0.48, 95% CI 0.33–0.72)
- Bacterial infections (RR 0.86, 95% CI 0.73–1.00).
Wang et al28 performed a meta-analysis of 4 randomized controlled trials in patients with upper-gastrointestinal bleeding comparing restrictive (hemoglobin < 7 g/dL) vs liberal transfusion strategies. The primary outcomes were death and rebleeding. The restrictive strategy was associated with:
- A lower mortality rate (OR 0.52, 95% CI 0.31–0.87, P = .01)
- A lower rebleeding rate (OR 0.26, 95% CI 0.03–2.10, P = .21)
- Shorter hospitalizations (P = .009)
- Less blood transfused (P = .0005).
Vincent et al,29 in a prospective observational study of 3,534 patients in intensive care units in 146 facilities in Western Europe, found a correlation between transfusion and mortality. Transfusion was done most often in elderly patients and those with a longer stay in the intensive care unit. The 28-day mortality rate was 22.7% in patients who received a transfusion and 17.1% in those who did not (P = .02). The more units of blood the patients received, the more likely they were to die, and receiving more than 4 units was associated with worse outcomes (P = .01).
Dunne et al30 performed a study of 6,301 noncardiac surgical patients in the Veterans Affairs Maryland Healthcare System from the National Veterans Administration Surgical Quality Improvement Program from 1995 to 2000. Multiple logistic regression analysis revealed that the composite of low hematocrit before and after surgery and high transfusion rates (> 4 units per hospitalization) were associated with higher rates of death (P < .01) and postoperative pneumonia (P ≤ .05) and longer hospitalizations (P < .05). The risk of pneumonia increased proportionally with the decrease in hematocrit.
These findings support pharmacologic optimization of anemia with hematinic supplementation before surgery to decrease the risk of needing a transfusion, often with parenteral iron. The fact that the patient’s hemoglobin can be optimized preoperatively by nontransfusional means may decrease the likelihood of blood transfusion, as the hemoglobin will potentially remain above the transfusion threshold. For example, if a patient has a preoperative hemoglobin level of 10 g/dL, and it is optimized up to 12, then if postoperatively the hemoglobin level drops 3 g/dL instead of reaching the threshold of 7 g/dL, the nadir will be just 9 g/dL, far above that transfusion threshold.
Brunskill et al,31 in a Cochrane review of 6 trials with 2,722 patients undergoing surgery for hip fracture, found no difference in rates of mortality, functional recovery or postoperative morbidity with a restrictive transfusion strategy (hemoglobin target > 8 g/dL vs a liberal one (> 10 g/dL). However, the quality of evidence was rated as low. The authors concluded that there is no justification for liberal red blood cell transfusion thresholds (10 g/dL), and a more restrictive transfusion threshold is preferable.
Weinberg et al32 found that, in trauma patients, receiving more than 6 units of blood was associated with poor prognosis, and outcomes were worse when the blood was older than 2 weeks. However, the effect of blood age is not significant when using smaller transfusion volumes (1 to 2 units of red blood cells).
Studies in sickle cell disease
Sickle cell disease patients have high levels of hemoglobin S, which causes erythrocyte sickling and increases blood viscosity. Transfusion with normal erythrocytes increases the amount of hemoglobin A (the normal variant).33,34
In trials in surgical patients,35,36 conservative strategies for preoperative blood transfusion aiming at a hemoglobin level of 10 g/dL were as effective in preventing postoperative complications as decreasing the hemoglobin S levels to 30% by aggressive exchange transfusion.35
In nonsurgical patients, blood transfusion should be based on formal risk-benefit assessments. Therefore, the expert panel report on sickle cell management advises against blood transfusion in sickle cell patients with uncomplicated vaso-occlusive crises, priapism, asymptomatic anemia, or acute kidney injury in the absence of multisystem organ failure.34
Is hemoglobin the most relevant marker?
Most studies that compared restrictive and liberal transfusion strategies focused on using a lower hemoglobin threshold as the transfusion trigger, not on using fewer units of blood. Is the amount of blood transfused more important than the hemoglobin threshold? Perhaps a study focused both on a restrictive vs liberal strategy and also on the minimum amount of blood that each patient may benefit from would help to answer this question.
We should beware of routinely using the hemoglobin concentration as a threshold for transfusion and a surrogate marker of transfusion benefit because changes in hemoglobin concentration may not reflect changes in absolute red cell mass.37 Changes in plasma volume (an increase or decrease) affect the hematocrit concentration without necessarily affecting the total red cell mass. Unfortunately, red cell mass is very difficult to measure; hence, the hemoglobin and hematocrit values are used instead. Studies addressing changes in red cell mass may be needed, perhaps even to validate using the hemoglobin concentration as the sole indicator for transfusion.
Is fresh blood better than old blood?
Using blood that is more than 14 days old may be associated with poor outcomes, for several possible reasons. Red blood cells age rapidly in refrigeration, and usually just 75% may remain viable 24 hours after phlebotomy. Adenosine triphosphate and 2,3-DPG levels steadily decrease, with a consequent decrease in capacity for appropriate tissue oxygen delivery. In addition, loss of membrane phospholipids causes progressive rigidity of the red cell membrane with consequent formation of echynocytes after 14 to 21 days.38,39
The use of blood more than 14 days old in cardiac surgery patients has been associated with worse outcomes, including higher rates of death, prolonged intubation, acute renal failure, and sepsis.40 Similar poor outcomes have been seen in trauma patients.32
Lacroix et al,41 in a multicenter, randomized trial in critically ill adults, compared the outcomes of transfusion of fresh packed red cells (stored < 8 days) or old blood (stored for a mean of 22 days). The primary outcome was the mortality rate at 90 days: 37.0% in the fresh-blood group vs 35.3% in the old-blood group (HR 1.1, 95% CI 0.9–1.2, P = .38).
The authors concluded that using fresh blood compared with old blood was not associated with a lower 90-day mortality rate in critically ill adults.
RISKS ASSOCIATED WITH TRANSFUSION
Infections
The risk of infection from blood transfusion is small. Human immunodeficiency virus (HIV) is transmitted in 1 in 1.5 million transfused blood components, and hepatitis C virus in 1 in 1.1 million; these odds are similar to those of having a fatal airplane accident (1 in 1.7 million per flight). Hepatitis B virus infection is more common, the reported incidence being 1 in 357,000.42
