Blood transfusion for upper gastrointestinal bleeding: is less more again?

Abstract

Background

The hemoglobin threshold for transfusion of red blood cells in patients withacute gastrointestinal (GI) bleeding is controversial. We compared theefficacy and safety of a restrictive transfusion strategy with those of aliberal transfusion strategy.

Methods

Objective: The objective was to prove that the restrictivethreshold for red blood cell transfusion in patients with acute upper GIbleeding (UGIB) was safer and more effective than a liberal transfusionstrategy.

Design: A single-center, randomized controlled trial wasconducted.

Setting: Patients with GI bleeding were admitted to the de la SantaCreu i Sant Pau hospital in Barcelona, Spain.

Subjects: The subjects were adult intensive care unit patientsadmitted with high clinical suspicion of UGIB (hematomemesis, melena, orboth). Patients were excluded if they had massive exsanguinating bleeding,acute coronary syndrome, symptomatic peripheral vascular disease,stroke/transient ischemic attack, transfusion within the previous 90 days,recent trauma or surgery, lower GI bleeding, or a clinical Rockall score of0 with hemoglobin higher than 12 g/dL.

Intervention: A total of 921 patients with severe acute UGIB wereenrolled. Of these, 461 were randomly assigned to a restrictive strategy(transfusion when the hemoglobin level fell to below 7 g/dL) and 460 to aliberal strategy (transfusion when the hemoglobin fell to below 9 g/dL).Random assignment was stratified according to the presence or absence ofliver cirrhosis.

Outcomes: The primary outcome was rate of death from any causewithin the first 45 days. Secondary outcomes were further bleeding, definedas hematemesis or melena with hemodynamic instability or hemoglobin decreaseof 2 g/dL or more, and in-hospital complications.

Results

In total, 225 patients assigned to the restrictive strategy (51%) and 65assigned to the liberal strategy (15%) did not receive transfusions(P <0.001). The probability of survival at 6 weeks washigher in the restrictive-strategy group than in the liberal-strategy group(95% versus 91%; hazard ratio (HR) for death with restrictive strategy,0.55; 95% confidence interval (CI) 0.33 to 0.92; P = 0.02). Furtherbleeding occurred in 10% of the patients in the restrictive-strategy groupand in 16% of the patients in the liberal-strategy group (P =0.01), and adverse events occurred in 40% and 48%, respectively (P= 0.02). The probability of survival was slightly higher with therestrictive strategy than with the liberal strategy in the subgroup ofpatients who had bleeding associated with a peptic ulcer (HR 0.70, 95% CI0.26 to 1.25) and was significantly higher in the subgroup of patients withcirrhosis and Child-Pugh class A or B disease (HR 0.30, 95% CI 0.11 to 0.85)but not in those with cirrhosis and Child-Pugh class C disease (HR 1.04, 95%CI 0.45 to 2.37). Within the first 5 days, the portal-pressure gradientincreased significantly in patients assigned to the liberal strategy(P = 0.03) but not in those assigned to the restrictivestrategy.

Conclusions

Compared with a liberal transfusion strategy, a restrictive strategysignificantly improved outcomes in patients with acute UGIB.

Commentary

The annual incidence of hospitalization for acute UGIB is 1 in 1,000 people in NorthAmerica, translating to 300,000 admissions yearly [1] and a total annual expenditure of $2.5 billion [2]. The mortality from UGIB is approximately 10% and may reach 35% inpatients hospitalized with another medical condition [3].

In the critically ill, a more restrictive strategy has been used for bloodtransfusion on the basis of a growing body of data indicating worse outcomes withred blood cell transfusions in this population [4, 5]. However, the threshold for blood transfusion in patients with UGIB hasbeen controversial since hemoglobin values may underestimate the blood loss. Overthe past decade, consensus guidelines suggested using a more conservative approachbased on experimental studies, trials in other populations, and physiologic data [6, 7]. A prospective observational study in patients with UGIB showed thatblood transfusion in the first 12 hours in patients presenting with hemoglobin ofmore than 8 g/dL increased mortality and rebleeding rates in comparison withpatients not receiving blood transfusion in the first 12 hours [8]. A recent Cochrane meta-analysis of randomized controlled trialsexamining red blood cell transfusion for the management of UGIB found only threetrials and showed higher mortality and rebleeding rates for a liberal transfusionstrategy. However, these studies had design flaws and were underpowered [9].

The Transfusion Strategies for Acute Upper Gastrointestinal Bleeding trial [10] is a randomized controlled trial testing liberal and conservativestrategies for patients with UGIB. The authors hypothesized that a restrictivethreshold for red blood cell transfusion (transfusion when hemoglobin was below 7g/dL with a goal of 7 to 9 g/dL) was safer and more effective than a liberaltransfusion strategy (transfusion when hemoglobin was below 9 g/dL with a goal of 9to 11 g/dL). Patients with low mortality and low risk of rebleeding were excluded byusing the Rockall score, which is based on age, presence or absence of shock,comorbidities, reason for bleeding, and major stigmata of recent hemorrhage [11]. The primary end-point was all-cause mortality rate at 45 days. Secondaryoutcomes were rebleeding rate and adverse events. The random assignment wasstratified by the presence or absence of cirrhosis. Twenty-eight percent in therestrictive group and 31% in the liberal group were in shock upon enrollment. Therestrictive-strategy group had a lower mortality rate than the liberal group (5%versus 9%, P = 0.02) at 45 days, and the relative-risk reduction was 45%and the number needed to treat was 25 patients for the restrictive strategyintervention. In addition, the liberal-strategy group had higher frequency ofrebleeding, interventions (transjugular intrahepatic portosystemic shunt forvariceal bleeding and surgery in non-variceal bleeding), and cardiac and pulmonaryadverse effects.

The study had several strengths. First, it used a randomized controlled design and apatient-centered outcome with an adequate number of patients. The protocol was welldevised for hemoglobin checks and management of complications. The study also had afew concerns. The protocol allowed the physicians to transfuse in the presence ofsigns and symptoms of anemia in case of a massive bleed and if a surgicalintervention was planned. However, protocol violations in transfusing blood occurredin both arms, and more violations occurred in the restrictive group (9% versus3%).

Multiple mechanisms have been suggested by previous animal and physiologic studies toexplain the increased mortality and morbidity with a liberal transfusion strategy [12–14]. These include clot rupture, coagulopathy, changes in stored red bloodcells (the storage lesion), and immunomodulation. The duration of storage of redblood cells was similar in the two groups, and the coagulation laboratory testresults were also similar in the two groups [15], suggesting that these pathways may not solely explain differences inoutcomes.

Although this study was conducted only in patients with UGIB, a similar restrictiveapproach should be considered by physicians caring for critically ill patientspresenting with other acute bleeding episodes, such as lower GI bleeding andretroperitoneal bleeding. However, physicians should be careful about extrapolatingthese results to patients with massive bleeding or those with bleeding and acutecoronary syndrome.

Recommendation

A restrictive strategy for blood transfusions should be used for UGIB. The results ofthis study reinforce the growing notion that ?less is more? for a blood transfusionstrategy in the critically ill.