Rebecca Berger, MD

 

Clinical case

A 48-year-old man with cirrhosis and esophageal varices presents to the emergency department with hematochezia and hematemesis. Upon arrival to the floor, he has another bout of hematochezia and hematemesis. He appears pale. His pulse is 90 beats per minute, his blood pressure is 100/60 mmHg, and his respiratory rate is 14 breaths per minute. A complete blood count reveals a hemoglobin level of 7.8 g/dL and hematocrit of 23.5%. Should he receive a blood transfusion?

Introduction

Anemia is one of the most frequent conditions in hospitalized patients. Anemia is variably associated with morbidity and mortality depending on chronicity, etiology, and associated comorbidities. Before the 1980s, standard practice was to transfuse all patients to a hemoglobin level greater than 10 g/dL and/or a hematocrit greater than 30%. However, with concerns about the potential adverse effects and cost of transfusions, the safety and effectiveness of liberal versus restrictive transfusion thresholds became the subject of many studies.

Tomasz Gierygowski/Thinkstock

Risks of red blood cell (RBC) transfusions include transmission of bloodborne pathogens and, more commonly, immunological reactions and other noninfectious complications. Modern screening methods for HIV, hepatitis B, and hepatitis C infections in developed countries have markedly reduced the incidence of transfusion-related diseases due to these pathogens, such that in the United States the risk of transfusion-related HIV, hepatitis B, or hepatitis C infections is extremely rare (nearly 1 in a million units or less).^1,2 In contrast, noninfectious complications such as febrile transfusion reactions, transfusion associated circulatory overload, and allergic reactions are much more common.¹

The 2016 the AABB (formerly American Association of Blood Banks) guidelines focused on the evidence for hemodynamically stable and asymptomatic hospitalized patients. The guidelines are based on randomized controlled trials that measured mortality as the primary endpoint. Most trials and guidelines reinforce that if a patient is symptomatic or hemodynamically unstable from anemia or hemorrhage, RBC transfusion is appropriate irrespective of hemoglobin level.
 

Overview of the data

Critically ill patients

The Transfusion Requirements in Critical Care (TRICC) trial, published in 1999, was the first large clinical trial examining the safety of restrictive transfusion thresholds in critically ill patients.³

The TRICC trial randomized 838 euvolemic critically ill patients with anemia to a restrictive transfusion strategy (transfusing for hemoglobin less than 7 g/dL) or a liberal strategy (transfusing for hemoglobin less than 10 g/dL). Thirty-day mortality was not significantly different between the two groups, though in prespecified subgroups of less acutely ill patients (APACHE-II score 20 or lower) and younger patients (age less than 55 years), mortality was significantly lower in the restrictive transfusion group. Overall in-hospital mortality was also lower in the restrictive strategy arm.

The subsequent Transfusion Requirements in Septic Shock (TRISS) study involved patients with septic shock and similarly found that patients assigned to a restrictive strategy (transfusion for hemoglobin less than 7 g/dL) had similar outcomes to patients assigned to a liberal strategy (transfusion for hemoglobin less than 9 g/dL). The patients in the restrictive group received fewer transfusions, but had similar rates of 90-day mortality, use of life support, and number of days alive and out of the hospital.⁴

These large randomized controlled trials in critically ill patients served as the basis for subsequent studies in patient populations outside of the ICU.
 

Acute upper GI bleed

Acute upper gastrointestinal bleeding (UGIB) is one of the most common indications for RBC transfusion.

A 2013 single-center study randomized patients with and without cirrhosis who presented with evidence of UGIB, such as hematemesis, melena, or bloody nasogastric aspirate, to either a restrictive or liberal transfusion strategy, with hemoglobin transfusion thresholds of less than 7 g/dL and less than 9 g/dL, respectively. All patients received 1 unit of RBCs before assessing baseline hemoglobin level, and all patients underwent upper endoscopy within 6 hours. Patients in the restrictive-strategy group had significantly lower mortality at 45 days, compared with the liberal-strategy group. This finding persisted in a subgroup of patients with Childs-Pugh class A or B cirrhosis, but not Childs-Pugh class C.⁵

The TRIGGER trial, a cluster randomized multicenter study published in 2015, also found no difference in clinical outcomes, including mortality, between a restrictive strategy and liberal strategy for transfusion of patients with UGIB.⁶

Perioperative patients

Transfusion thresholds have been studied in large randomized trials for perioperative patients undergoing cardiac and orthopedic surgery.

The Transfusion Requirements after Cardiac Surgery (TRACS) trial, published in 2010, randomized patients undergoing cardiac surgery at a single center to a liberal strategy of blood transfusion (to maintain a hematocrit 30% or greater) or a restrictive strategy (hematocrit 24% or greater).⁷ Mortality and severe morbidity rates were noninferior in the restrictive strategy group. Mean hemoglobin concentrations were 10.5 g/dL in the liberal-strategy group and 9.1 g/dL in the restrictive-strategy group. Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications and death at 30 days.

Subsequently, the Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) study enrolled patients aged 50 years and older with cardiovascular disease or coronary artery disease risk factors undergoing hip surgery randomized to either a liberal transfusion strategy (goal hemoglobin 10 g/dL or greater) or restrictive strategy (goal hemoglobin 8 g/dL or greater) was performed.⁸ This study found no difference in outcomes between the two groups, including mortality, inability to walk, or in-hospital complications.

Based on these two trials, as well as other smaller randomized controlled trials and observational studies, the AABB guidelines recommend a restrictive RBC transfusion threshold of 8 g/dL for patients undergoing cardiac or orthopedic surgery.¹

 

Acute coronary syndrome, stable coronary artery disease, and congestive heart failure

Anemia is an independent predictor of major adverse cardiovascular events in patients with acute coronary syndrome.⁹ However, it remains controversial if transfusion has benefit or causes harm in patients with acute coronary syndrome. No randomized controlled trials have yet been published on this topic, and observational studies and subgroups from randomized controlled trials have yielded mixed results.

Similarly, there are no randomized controlled trials examining liberal versus restrictive transfusion goals for asymptomatic hospitalized patients with stable coronary artery disease (CAD). However, patients with CAD were included in the TRICC and FOCUS trials.^3,8 Of patients enrolled in the TRICC trial, 26% had a primary or secondary diagnosis of cardiac disease; subgroup analysis found no significant differences in 30-day mortality between treatment groups, similar to that of the entire study population.³ In a subgroup analysis of patients with “cardiovascular disease” the FOCUS trial found no difference in outcomes between a restrictive and liberal transfusion strategy, although there was a marginally higher incidence of myocardial infarction in the restrictive arm in the entire study population.⁸

Although some studies have included patients with congestive heart failure (CHF) as a subgroup, these subgroups are often not powered to show clinically meaningful differences. The risk of volume overload is one explanation for why transfusions may be harmful for patients with CHF.

Based on these limited available data, the AABB guidelines recommend a “restrictive RBC transfusion threshold (hemoglobin level of 8 g/dL)” for patients “with preexisting cardiovascular disease,” without distinguishing among patients with acute coronary syndrome, stable CAD, and CHF, but adds that the “threshold of 7 g/dL is likely comparable with 8 g/dL, but randomized controlled trial evidence is not available for all patient categories.”¹

Of note, certain patient populations, such as those with end-stage renal disease, oncology patients (especially those undergoing active chemotherapy), and those with comorbid conditions such as thrombocytopenia and coagulopathy are specifically excluded from the AABB guidelines. The reader is referred to guidelines from respective specialty societies for further guidance.
 

Back to our case

This 48-year-old man with cirrhosis and esophageal varices presenting with ongoing blood loss due to hematochezia and hematemesis with a hemoglobin of 7.8 g/dL should be transfused due to his active bleeding; his hemoglobin level should not be a determining factor under such circumstances. This distinction is one of the most fundamental in interpreting the guidelines, that is, patients with hemodynamic insult, symptoms, and/or ongoing bleeding should be evaluated clinically, independent of their hemoglobin level.

Bottom line

Although recent guidelines generally favor a more restrictive hemoglobin goal threshold, in the presence of active blood loss or hemodynamic instability, blood transfusion should be considered independent of the initial hemoglobin level.

Key Points

• The AABB guidelines recommend transfusing stable general medical inpatients to a hemoglobin level of 7 g/dL.
• For patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease, a transfusion threshold of 8 g/dL is recommended.
• Patients with hemodynamic instability or active blood loss should be transfused based on clinical criteria, and not absolute hemoglobin levels.
• Patients with acute coronary syndrome, severe thrombocytopenia, and chronic transfusion–dependent anemia are excluded from these recommendations.
• Further studies are needed to further refine these recommendations to specific patient populations in maximizing the benefits and minimizing the risks of blood transfusions.

Quiz

In which of the following scenarios is RBC transfusion LEAST indicated?

• A. Active diverticular bleed, heart rate 125 beats/minute, blood pressure 85/65 mm HG, hemoglobin 10.5 g/dL
• B. Septic shock in the ICU, hemoglobin 6.7 g/dL
• C. Pulmonary embolism in the setting of stable coronary artery disease and hemoglobin 8.7 g/dL
• D. Lymphoma on chemotherapy, hemoglobin 7.5 g/d, patient becomes dizzy when standing

Answer: C – A hemoglobin transfusion goal of 8.0 g/dL is recommended for patients with cardiovascular disease. The patient in answer choice A has active blood loss, tachycardia, and hypotension, all pointing to the need for blood transfusion irrespective of an initial hemoglobin level greater than 8.0 g/dL. The patient in answer choice B has a hemoglobin level less than 7.0 g/dL, and the patient in choice D is symptomatic, possibly from anemia, as well as on chemotherapy, therefore making transfusion a reasonable option.

Dr. Sampat, Dr. Berger, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. Carson JL et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316:2025-35.

2. Dwyre DM et al. Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century. Vox Sang. 2011;100:92-8.

3. Hébert PC et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-17.

4. Holst LB et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381-91.

5. Villanueva C et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-21.

6. Jairath V et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet. 2015;386:137-44.

7. Hajjar LA et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304:1559-67.

8. Carson JL et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453-62.

9. Sabatine MS et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111:2042-9.

 

Clinical case

A 48-year-old man with cirrhosis and esophageal varices presents to the emergency department with hematochezia and hematemesis. Upon arrival to the floor, he has another bout of hematochezia and hematemesis. He appears pale. His pulse is 90 beats per minute, his blood pressure is 100/60 mmHg, and his respiratory rate is 14 breaths per minute. A complete blood count reveals a hemoglobin level of 7.8 g/dL and hematocrit of 23.5%. Should he receive a blood transfusion?

Introduction

Anemia is one of the most frequent conditions in hospitalized patients. Anemia is variably associated with morbidity and mortality depending on chronicity, etiology, and associated comorbidities. Before the 1980s, standard practice was to transfuse all patients to a hemoglobin level greater than 10 g/dL and/or a hematocrit greater than 30%. However, with concerns about the potential adverse effects and cost of transfusions, the safety and effectiveness of liberal versus restrictive transfusion thresholds became the subject of many studies.

Tomasz Gierygowski/Thinkstock

Risks of red blood cell (RBC) transfusions include transmission of bloodborne pathogens and, more commonly, immunological reactions and other noninfectious complications. Modern screening methods for HIV, hepatitis B, and hepatitis C infections in developed countries have markedly reduced the incidence of transfusion-related diseases due to these pathogens, such that in the United States the risk of transfusion-related HIV, hepatitis B, or hepatitis C infections is extremely rare (nearly 1 in a million units or less).^1,2 In contrast, noninfectious complications such as febrile transfusion reactions, transfusion associated circulatory overload, and allergic reactions are much more common.¹

The 2016 the AABB (formerly American Association of Blood Banks) guidelines focused on the evidence for hemodynamically stable and asymptomatic hospitalized patients. The guidelines are based on randomized controlled trials that measured mortality as the primary endpoint. Most trials and guidelines reinforce that if a patient is symptomatic or hemodynamically unstable from anemia or hemorrhage, RBC transfusion is appropriate irrespective of hemoglobin level.
 

Overview of the data

Critically ill patients

The Transfusion Requirements in Critical Care (TRICC) trial, published in 1999, was the first large clinical trial examining the safety of restrictive transfusion thresholds in critically ill patients.³

The TRICC trial randomized 838 euvolemic critically ill patients with anemia to a restrictive transfusion strategy (transfusing for hemoglobin less than 7 g/dL) or a liberal strategy (transfusing for hemoglobin less than 10 g/dL). Thirty-day mortality was not significantly different between the two groups, though in prespecified subgroups of less acutely ill patients (APACHE-II score 20 or lower) and younger patients (age less than 55 years), mortality was significantly lower in the restrictive transfusion group. Overall in-hospital mortality was also lower in the restrictive strategy arm.

The subsequent Transfusion Requirements in Septic Shock (TRISS) study involved patients with septic shock and similarly found that patients assigned to a restrictive strategy (transfusion for hemoglobin less than 7 g/dL) had similar outcomes to patients assigned to a liberal strategy (transfusion for hemoglobin less than 9 g/dL). The patients in the restrictive group received fewer transfusions, but had similar rates of 90-day mortality, use of life support, and number of days alive and out of the hospital.⁴

These large randomized controlled trials in critically ill patients served as the basis for subsequent studies in patient populations outside of the ICU.
 

Acute upper GI bleed

Acute upper gastrointestinal bleeding (UGIB) is one of the most common indications for RBC transfusion.

A 2013 single-center study randomized patients with and without cirrhosis who presented with evidence of UGIB, such as hematemesis, melena, or bloody nasogastric aspirate, to either a restrictive or liberal transfusion strategy, with hemoglobin transfusion thresholds of less than 7 g/dL and less than 9 g/dL, respectively. All patients received 1 unit of RBCs before assessing baseline hemoglobin level, and all patients underwent upper endoscopy within 6 hours. Patients in the restrictive-strategy group had significantly lower mortality at 45 days, compared with the liberal-strategy group. This finding persisted in a subgroup of patients with Childs-Pugh class A or B cirrhosis, but not Childs-Pugh class C.⁵

The TRIGGER trial, a cluster randomized multicenter study published in 2015, also found no difference in clinical outcomes, including mortality, between a restrictive strategy and liberal strategy for transfusion of patients with UGIB.⁶

Perioperative patients

Transfusion thresholds have been studied in large randomized trials for perioperative patients undergoing cardiac and orthopedic surgery.

The Transfusion Requirements after Cardiac Surgery (TRACS) trial, published in 2010, randomized patients undergoing cardiac surgery at a single center to a liberal strategy of blood transfusion (to maintain a hematocrit 30% or greater) or a restrictive strategy (hematocrit 24% or greater).⁷ Mortality and severe morbidity rates were noninferior in the restrictive strategy group. Mean hemoglobin concentrations were 10.5 g/dL in the liberal-strategy group and 9.1 g/dL in the restrictive-strategy group. Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications and death at 30 days.

Subsequently, the Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) study enrolled patients aged 50 years and older with cardiovascular disease or coronary artery disease risk factors undergoing hip surgery randomized to either a liberal transfusion strategy (goal hemoglobin 10 g/dL or greater) or restrictive strategy (goal hemoglobin 8 g/dL or greater) was performed.⁸ This study found no difference in outcomes between the two groups, including mortality, inability to walk, or in-hospital complications.

Based on these two trials, as well as other smaller randomized controlled trials and observational studies, the AABB guidelines recommend a restrictive RBC transfusion threshold of 8 g/dL for patients undergoing cardiac or orthopedic surgery.¹

 

Acute coronary syndrome, stable coronary artery disease, and congestive heart failure

Anemia is an independent predictor of major adverse cardiovascular events in patients with acute coronary syndrome.⁹ However, it remains controversial if transfusion has benefit or causes harm in patients with acute coronary syndrome. No randomized controlled trials have yet been published on this topic, and observational studies and subgroups from randomized controlled trials have yielded mixed results.

Similarly, there are no randomized controlled trials examining liberal versus restrictive transfusion goals for asymptomatic hospitalized patients with stable coronary artery disease (CAD). However, patients with CAD were included in the TRICC and FOCUS trials.^3,8 Of patients enrolled in the TRICC trial, 26% had a primary or secondary diagnosis of cardiac disease; subgroup analysis found no significant differences in 30-day mortality between treatment groups, similar to that of the entire study population.³ In a subgroup analysis of patients with “cardiovascular disease” the FOCUS trial found no difference in outcomes between a restrictive and liberal transfusion strategy, although there was a marginally higher incidence of myocardial infarction in the restrictive arm in the entire study population.⁸

Although some studies have included patients with congestive heart failure (CHF) as a subgroup, these subgroups are often not powered to show clinically meaningful differences. The risk of volume overload is one explanation for why transfusions may be harmful for patients with CHF.

Based on these limited available data, the AABB guidelines recommend a “restrictive RBC transfusion threshold (hemoglobin level of 8 g/dL)” for patients “with preexisting cardiovascular disease,” without distinguishing among patients with acute coronary syndrome, stable CAD, and CHF, but adds that the “threshold of 7 g/dL is likely comparable with 8 g/dL, but randomized controlled trial evidence is not available for all patient categories.”¹

Of note, certain patient populations, such as those with end-stage renal disease, oncology patients (especially those undergoing active chemotherapy), and those with comorbid conditions such as thrombocytopenia and coagulopathy are specifically excluded from the AABB guidelines. The reader is referred to guidelines from respective specialty societies for further guidance.
 

Back to our case

This 48-year-old man with cirrhosis and esophageal varices presenting with ongoing blood loss due to hematochezia and hematemesis with a hemoglobin of 7.8 g/dL should be transfused due to his active bleeding; his hemoglobin level should not be a determining factor under such circumstances. This distinction is one of the most fundamental in interpreting the guidelines, that is, patients with hemodynamic insult, symptoms, and/or ongoing bleeding should be evaluated clinically, independent of their hemoglobin level.

Bottom line

Although recent guidelines generally favor a more restrictive hemoglobin goal threshold, in the presence of active blood loss or hemodynamic instability, blood transfusion should be considered independent of the initial hemoglobin level.

Key Points

• The AABB guidelines recommend transfusing stable general medical inpatients to a hemoglobin level of 7 g/dL.
• For patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease, a transfusion threshold of 8 g/dL is recommended.
• Patients with hemodynamic instability or active blood loss should be transfused based on clinical criteria, and not absolute hemoglobin levels.
• Patients with acute coronary syndrome, severe thrombocytopenia, and chronic transfusion–dependent anemia are excluded from these recommendations.
• Further studies are needed to further refine these recommendations to specific patient populations in maximizing the benefits and minimizing the risks of blood transfusions.

Quiz

In which of the following scenarios is RBC transfusion LEAST indicated?

• A. Active diverticular bleed, heart rate 125 beats/minute, blood pressure 85/65 mm HG, hemoglobin 10.5 g/dL
• B. Septic shock in the ICU, hemoglobin 6.7 g/dL
• C. Pulmonary embolism in the setting of stable coronary artery disease and hemoglobin 8.7 g/dL
• D. Lymphoma on chemotherapy, hemoglobin 7.5 g/d, patient becomes dizzy when standing

Answer: C – A hemoglobin transfusion goal of 8.0 g/dL is recommended for patients with cardiovascular disease. The patient in answer choice A has active blood loss, tachycardia, and hypotension, all pointing to the need for blood transfusion irrespective of an initial hemoglobin level greater than 8.0 g/dL. The patient in answer choice B has a hemoglobin level less than 7.0 g/dL, and the patient in choice D is symptomatic, possibly from anemia, as well as on chemotherapy, therefore making transfusion a reasonable option.

Dr. Sampat, Dr. Berger, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. Carson JL et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316:2025-35.

2. Dwyre DM et al. Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century. Vox Sang. 2011;100:92-8.

3. Hébert PC et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-17.

4. Holst LB et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381-91.

5. Villanueva C et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-21.

6. Jairath V et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet. 2015;386:137-44.

7. Hajjar LA et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304:1559-67.

8. Carson JL et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453-62.

9. Sabatine MS et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111:2042-9.

 

Clinical case

A 48-year-old man with cirrhosis and esophageal varices presents to the emergency department with hematochezia and hematemesis. Upon arrival to the floor, he has another bout of hematochezia and hematemesis. He appears pale. His pulse is 90 beats per minute, his blood pressure is 100/60 mmHg, and his respiratory rate is 14 breaths per minute. A complete blood count reveals a hemoglobin level of 7.8 g/dL and hematocrit of 23.5%. Should he receive a blood transfusion?

Introduction

Anemia is one of the most frequent conditions in hospitalized patients. Anemia is variably associated with morbidity and mortality depending on chronicity, etiology, and associated comorbidities. Before the 1980s, standard practice was to transfuse all patients to a hemoglobin level greater than 10 g/dL and/or a hematocrit greater than 30%. However, with concerns about the potential adverse effects and cost of transfusions, the safety and effectiveness of liberal versus restrictive transfusion thresholds became the subject of many studies.

Tomasz Gierygowski/Thinkstock

Risks of red blood cell (RBC) transfusions include transmission of bloodborne pathogens and, more commonly, immunological reactions and other noninfectious complications. Modern screening methods for HIV, hepatitis B, and hepatitis C infections in developed countries have markedly reduced the incidence of transfusion-related diseases due to these pathogens, such that in the United States the risk of transfusion-related HIV, hepatitis B, or hepatitis C infections is extremely rare (nearly 1 in a million units or less).^1,2 In contrast, noninfectious complications such as febrile transfusion reactions, transfusion associated circulatory overload, and allergic reactions are much more common.¹

The 2016 the AABB (formerly American Association of Blood Banks) guidelines focused on the evidence for hemodynamically stable and asymptomatic hospitalized patients. The guidelines are based on randomized controlled trials that measured mortality as the primary endpoint. Most trials and guidelines reinforce that if a patient is symptomatic or hemodynamically unstable from anemia or hemorrhage, RBC transfusion is appropriate irrespective of hemoglobin level.
 

Overview of the data

Critically ill patients

The Transfusion Requirements in Critical Care (TRICC) trial, published in 1999, was the first large clinical trial examining the safety of restrictive transfusion thresholds in critically ill patients.³

The TRICC trial randomized 838 euvolemic critically ill patients with anemia to a restrictive transfusion strategy (transfusing for hemoglobin less than 7 g/dL) or a liberal strategy (transfusing for hemoglobin less than 10 g/dL). Thirty-day mortality was not significantly different between the two groups, though in prespecified subgroups of less acutely ill patients (APACHE-II score 20 or lower) and younger patients (age less than 55 years), mortality was significantly lower in the restrictive transfusion group. Overall in-hospital mortality was also lower in the restrictive strategy arm.

The subsequent Transfusion Requirements in Septic Shock (TRISS) study involved patients with septic shock and similarly found that patients assigned to a restrictive strategy (transfusion for hemoglobin less than 7 g/dL) had similar outcomes to patients assigned to a liberal strategy (transfusion for hemoglobin less than 9 g/dL). The patients in the restrictive group received fewer transfusions, but had similar rates of 90-day mortality, use of life support, and number of days alive and out of the hospital.⁴

These large randomized controlled trials in critically ill patients served as the basis for subsequent studies in patient populations outside of the ICU.
 

Acute upper GI bleed

Acute upper gastrointestinal bleeding (UGIB) is one of the most common indications for RBC transfusion.

A 2013 single-center study randomized patients with and without cirrhosis who presented with evidence of UGIB, such as hematemesis, melena, or bloody nasogastric aspirate, to either a restrictive or liberal transfusion strategy, with hemoglobin transfusion thresholds of less than 7 g/dL and less than 9 g/dL, respectively. All patients received 1 unit of RBCs before assessing baseline hemoglobin level, and all patients underwent upper endoscopy within 6 hours. Patients in the restrictive-strategy group had significantly lower mortality at 45 days, compared with the liberal-strategy group. This finding persisted in a subgroup of patients with Childs-Pugh class A or B cirrhosis, but not Childs-Pugh class C.⁵

The TRIGGER trial, a cluster randomized multicenter study published in 2015, also found no difference in clinical outcomes, including mortality, between a restrictive strategy and liberal strategy for transfusion of patients with UGIB.⁶

Perioperative patients

Transfusion thresholds have been studied in large randomized trials for perioperative patients undergoing cardiac and orthopedic surgery.

The Transfusion Requirements after Cardiac Surgery (TRACS) trial, published in 2010, randomized patients undergoing cardiac surgery at a single center to a liberal strategy of blood transfusion (to maintain a hematocrit 30% or greater) or a restrictive strategy (hematocrit 24% or greater).⁷ Mortality and severe morbidity rates were noninferior in the restrictive strategy group. Mean hemoglobin concentrations were 10.5 g/dL in the liberal-strategy group and 9.1 g/dL in the restrictive-strategy group. Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications and death at 30 days.

Subsequently, the Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) study enrolled patients aged 50 years and older with cardiovascular disease or coronary artery disease risk factors undergoing hip surgery randomized to either a liberal transfusion strategy (goal hemoglobin 10 g/dL or greater) or restrictive strategy (goal hemoglobin 8 g/dL or greater) was performed.⁸ This study found no difference in outcomes between the two groups, including mortality, inability to walk, or in-hospital complications.

Based on these two trials, as well as other smaller randomized controlled trials and observational studies, the AABB guidelines recommend a restrictive RBC transfusion threshold of 8 g/dL for patients undergoing cardiac or orthopedic surgery.¹

 

Acute coronary syndrome, stable coronary artery disease, and congestive heart failure

Anemia is an independent predictor of major adverse cardiovascular events in patients with acute coronary syndrome.⁹ However, it remains controversial if transfusion has benefit or causes harm in patients with acute coronary syndrome. No randomized controlled trials have yet been published on this topic, and observational studies and subgroups from randomized controlled trials have yielded mixed results.

Similarly, there are no randomized controlled trials examining liberal versus restrictive transfusion goals for asymptomatic hospitalized patients with stable coronary artery disease (CAD). However, patients with CAD were included in the TRICC and FOCUS trials.^3,8 Of patients enrolled in the TRICC trial, 26% had a primary or secondary diagnosis of cardiac disease; subgroup analysis found no significant differences in 30-day mortality between treatment groups, similar to that of the entire study population.³ In a subgroup analysis of patients with “cardiovascular disease” the FOCUS trial found no difference in outcomes between a restrictive and liberal transfusion strategy, although there was a marginally higher incidence of myocardial infarction in the restrictive arm in the entire study population.⁸

Although some studies have included patients with congestive heart failure (CHF) as a subgroup, these subgroups are often not powered to show clinically meaningful differences. The risk of volume overload is one explanation for why transfusions may be harmful for patients with CHF.

Based on these limited available data, the AABB guidelines recommend a “restrictive RBC transfusion threshold (hemoglobin level of 8 g/dL)” for patients “with preexisting cardiovascular disease,” without distinguishing among patients with acute coronary syndrome, stable CAD, and CHF, but adds that the “threshold of 7 g/dL is likely comparable with 8 g/dL, but randomized controlled trial evidence is not available for all patient categories.”¹

Of note, certain patient populations, such as those with end-stage renal disease, oncology patients (especially those undergoing active chemotherapy), and those with comorbid conditions such as thrombocytopenia and coagulopathy are specifically excluded from the AABB guidelines. The reader is referred to guidelines from respective specialty societies for further guidance.
 

Back to our case

This 48-year-old man with cirrhosis and esophageal varices presenting with ongoing blood loss due to hematochezia and hematemesis with a hemoglobin of 7.8 g/dL should be transfused due to his active bleeding; his hemoglobin level should not be a determining factor under such circumstances. This distinction is one of the most fundamental in interpreting the guidelines, that is, patients with hemodynamic insult, symptoms, and/or ongoing bleeding should be evaluated clinically, independent of their hemoglobin level.

Bottom line

Although recent guidelines generally favor a more restrictive hemoglobin goal threshold, in the presence of active blood loss or hemodynamic instability, blood transfusion should be considered independent of the initial hemoglobin level.

Key Points

• The AABB guidelines recommend transfusing stable general medical inpatients to a hemoglobin level of 7 g/dL.
• For patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease, a transfusion threshold of 8 g/dL is recommended.
• Patients with hemodynamic instability or active blood loss should be transfused based on clinical criteria, and not absolute hemoglobin levels.
• Patients with acute coronary syndrome, severe thrombocytopenia, and chronic transfusion–dependent anemia are excluded from these recommendations.
• Further studies are needed to further refine these recommendations to specific patient populations in maximizing the benefits and minimizing the risks of blood transfusions.

Quiz

In which of the following scenarios is RBC transfusion LEAST indicated?

• A. Active diverticular bleed, heart rate 125 beats/minute, blood pressure 85/65 mm HG, hemoglobin 10.5 g/dL
• B. Septic shock in the ICU, hemoglobin 6.7 g/dL
• C. Pulmonary embolism in the setting of stable coronary artery disease and hemoglobin 8.7 g/dL
• D. Lymphoma on chemotherapy, hemoglobin 7.5 g/d, patient becomes dizzy when standing

Answer: C – A hemoglobin transfusion goal of 8.0 g/dL is recommended for patients with cardiovascular disease. The patient in answer choice A has active blood loss, tachycardia, and hypotension, all pointing to the need for blood transfusion irrespective of an initial hemoglobin level greater than 8.0 g/dL. The patient in answer choice B has a hemoglobin level less than 7.0 g/dL, and the patient in choice D is symptomatic, possibly from anemia, as well as on chemotherapy, therefore making transfusion a reasonable option.

Dr. Sampat, Dr. Berger, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. Carson JL et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316:2025-35.

2. Dwyre DM et al. Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century. Vox Sang. 2011;100:92-8.

3. Hébert PC et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-17.

4. Holst LB et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381-91.

5. Villanueva C et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-21.

6. Jairath V et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet. 2015;386:137-44.

7. Hajjar LA et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304:1559-67.

8. Carson JL et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453-62.

9. Sabatine MS et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111:2042-9.