Anemia and transfusion thresholds in the critically ill

Incidence of anemia in the ICU

Anemia is all too common among critically ill patients, with 30–50% of patients receiving red cell transfusion. The etiology of anemia in the ICU is multifactorial, contributed by intravenous fluid resuscitation with the resulting hemodilution, repeated blood sampling, low erythropoietin levels induced by inflammatory cytokines, and abnormalities of iron metabolism. A hemoglobin level of 10 gm/dl was proposed by Adam and Lundy among surgical patients in 1942 (1); they averred that “when concentration of hemoglobin is less than 8 to 10 gram per 100 cubic centimeters of whole blood, it is wise to give a blood transfusion before operation.” The 10/30 rule was embraced by clinicians for decades before evidence emerged that supported lower thresholds in most clinical situations, particularly among critically ill patients.

Red cell transfusion and oxygen delivery

Oxygen delivered per minute is the product of the cardiac output and the arterial oxygen content.

Oxygen delivery = cardiac output × [(1.39 × hemoglobin × SaO₂) + (PaO₂ × 0.003)]

According to this equation, a rise in hemoglobin concentration increases oxygen delivery. However, the interplay of several other factors impedes oxygen delivery following transfusion of stored blood. Nitric oxide levels diminish over time with storage, leading to vasoconstriction and reduction in blood flow. The 2,3 diphosphoglyerate levels also decrease during storage, with a shift of the oxygen-dissociation curve to the left, leading to impaired oxygen delivery at the tissue level. Furthermore, transfused red cells may lead to platelet activation and aggregation that may predispose to occlusion of blood vessels (2). 

In the past two decades, a restrictive transfusion strategy has gained ground, with the TRICC trial by the Canadian Critical Care Trials group being the harbinger of change (3). However, does one size fit all, or do we need to tailor transfusion strategy among specific patient populations?

General critically ill patients

Prior to the landmark TRICC trial, it had been customary to aim for higher hemoglobin levels among critically ill patients. In this study, 838 euvolemic critically ill patients were randomized into two groups. In the restrictive group, red cells were transfused below a hemoglobin threshold of 7 gm/dl; the hemoglobin concentration was maintained between 7–9 gm/dl. In the liberal arm, a higher threshold of 10 gm/dl was followed, with a target hemoglobin level between 10–12 gm/dl. There was no difference in the primary outcome, the 30-day mortality, between the two groups (18.7 vs. 23.3%, p = 0.11). A significantly lower mortality was observed with a restrictive strategy among the less severely ill (APACHE II score less than 20) and younger (less than 55 years) patients. Following this trial and the results from several others, a restrictive transfusion strategy has been reasonably established among general critically ill patients (4,5).

Septic patients  

In the early goal-directed therapy (EGDT) trial of patients with severe sepsis and septic shock, red cells were transfused to a hematocrit level of 30% if the central venous oxygen saturation was below 70% during the first 6 hours of septic shock (6). However, the Transfusion Requirements in Septic Shock (TRISS) Trial conclusively established the efficacy of a lower transfusion threshold. In this study, critically ill patients with septic shock were randomized to receive red cell transfusion at a lower threshold of 7 gm/dl compared to 9 gm/dl (4). Among the 998 patients who were analyzed, the restrictive strategy group received a median of 1 unit of blood (IQR: 0–3) compared to 4 units (IQR: 2–7) in the liberal group. The 90-day mortality was similar between the restrictive and liberal strategy groups (43 vs. 45%; relative risk: 0.78–1.09, p = 0.44). In contemporary practice, a lower hemoglobin threshold of 7 gm/dl has been established as standard practice in septic patients and recommended by the Surviving Sepsis Guidelines (7). 

Acute myocardial infarction

Anemia may jeopardize the ischemic myocardium due to impaired oxygen delivery. Patients with acute myocardial infarction are often anemic, and a higher hemoglobin level is often targeted to optimize oxygen delivery in this population. Previous studies using varying hemoglobin thresholds as transfusion triggers had yielded conflicting results. In the CRIT trial, 45 patients with acute myocardial infarction were randomized to a threshold hematocrit of 30% to maintain a range between 30–33% in the liberal group. In the restrictive group, the transfusion threshold was a hematocrit of 24% and the target range between 24–27%. In this pilot study of small sample size, the composite outcome of death in hospital, recurrent myocardial infarction, or new-onset or worsening heart failure occurred more often with a liberal compared to a restrictive transfusion strategy (8). However, in another underpowered randomized controlled trial, a liberal transfusion strategy (hemoglobin >10 gm/dl) revealed a trend towards fewer major cardiac events and mortality compared to a restrictive strategy with red cell transfusion below a threshold of 8 gm/dl.

Against this background, the multicenter REALITY study conducted across 26 centers in France and nine centers in Spain assumes importance. The study was designed to demonstrate the non-inferiority of a restrictive transfusion strategy among patients with acute ST-elevation or non-ST-elevation myocardial infarction who presented with symptoms of cardiac ischemia and elevated biomarkers (9). In the restrictive group, red cells were transfused at a lower threshold of 8 gm/dl to maintain a target range of 8–10 gm/dl; in the liberal group, the transfusion threshold was 10 gm/dl aimed to maintain a minimum target hemoglobin level of 11 gm/dl. Almost all patients (99.7%) in the liberal arm received at least 1 unit of red cells compared to 35.7% patients in the restrictive arm. The incidence of major adverse cardiovascular events (MACE), including all-cause mortality, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization, occurred in 36/327 (11%) patients in the restrictive compared to 45/322 (14%) patients in the liberal arm. These results established the non-inferiority of a restrictive compared to a liberal transfusion strategy in patients with acute myocardial infarction. There was no statistically significant difference in the individual components of MACE between the two groups. Adverse events were uncommon; transfusion-associated acute lung injury occurred in seven patients in the liberal arm compared to one patient in the restrictive arm. Although underpowered to demonstrate superiority, the REALITY trial strongly suggests that MACE events are comparable between a restrictive and liberal transfusion strategy in patients with acute myocardial infarction. 

Stable cardiovascular disease

The TRICC trial also included patients with stable cardiac disease. On subgroup analysis of patients with cardiac disease, there was no difference in the 30-day mortality between a restrictive compared to a liberal strategy (transfusion threshold of 7 vs. 10 gm/dl) (3).  

The Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) investigators randomized 2,016 elderly, high-risk patients with pre-existing coronary artery disease undergoing hip surgery to a liberal vs. restrictive transfusion strategy (transfusion threshold of 8 vs. 10 gm/dl).   Mortality and inability to walk without assistance at 60-day follow-up were similar in both groups (10).

Docherty et al. performed a meta-analysis of transfusion thresholds among patients with stable cardiovascular disease. A transfusion threshold of 8 g/dl revealed a higher risk of acute coronary syndrome; however the 30-day mortality was similar in patients with stable cardiovascular disease who received a restrictive compared to a liberal transfusion strategy (11). The diagnosis of acute coronary syndrome was based on a low quality of evidence and may have confounded the findings of this meta-analysis. The authors recommended a transfusion threshold of 8g/dl in patients with stable cardiovascular disease pending more robust evidence.

Acute gastrointestinal bleeding

Two randomized controlled trials suggest that a lower transfusion threshold may be appropriate among patients with acute upper gastrointestinal bleeding if access to endoscopic intervention is readily available. In a study of 921 patients with acute upper gastrointestinal bleeding, transfusion thresholds of 7 gm/dl vs. 9 gm/dl were compared. All-cause mortality was significantly lower with the lower threshold; besides, fewer complications, less rebleeding, and fewer deaths due to uncontrolled bleeding were encountered in the low threshold group (12). A multicenter cluster randomized controlled trial of 936 patients echoed these findings. The restrictive group with a transfusion threshold of 8 gm/dl received fewer transfusions compared to the liberal group with a threshold of 10 gm/dl; no significant difference was observed in clinical outcomes (13).  

Weaning from mechanical ventilation

He ́bert et al. analyzed the outcomes of a subgroup of 713 patients who received mechanical ventilation from the original TRICC trial (14). The mean duration of ventilation was similar between patients randomized to a restrictive compared to a liberal strategy (transfusion threshold of 7 vs. 10 gm/dl). Ventilator-free days were also similar between groups. After adjusting for confounders, the relative risk of successful extubation was also similar between groups.

In a more recent pilot randomized controlled trial, a liberal vs. restrictive transfusion strategy was evaluated among patients more than 55 years old, requiring more than 4 days of mechanical ventilation (15). The mean hemoglobin level in the restrictive group was 8.19 gm/dl (SD, 0.51) compared to 9.57 (SD, 0.63) g/dl in the liberal group. There was no significant difference in organ dysfunction, duration of mechanical ventilation, infective or cardiovascular complications between groups. A trend towards higher 180-day mortality was observed in the liberal compared to the restrictive group, which persisted after adjustment for age, gender, presence of ischemic heart disease, the APACHE II score, and the non-neurological SOFA score. These studies suggest that a restrictive compared to a liberal transfusion strategy (threshold of 7 vs. 9 g/dl) may be appropriate in patients who require prolonged weaning from mechanical ventilation.

Hematological malignancies

Two small pilot trials compared transfusion thresholds among patients undergoing chemotherapy for hematological malignancies. In one study, a higher hemoglobin level was targeted to evaluate the risk of bleeding compared to a lower hemoglobin level. Two units of red cells were transfused at a hemoglobin level of less than 8 g/dl and compared with an augmented transfusion strategy with transfusion of 2 units red cells at a hemoglobin level of less than 12 g/dl. The incidence of clinically important bleeding was not significantly different between groups in this trial (16). In another pilot randomized controlled trial, a transfusion threshold of 7 gm/dl was compared to 8 gm/dl in patients with acute leukemia. The low threshold arm received a median of 8 units of red cells compared to 11.7 units in the high threshold arm. No significant difference was observed in bleeding episodes or febrile neutropenia between the two groups. Based on the evidence from these pilot studies, a restrictive strategy would be appropriate in patients undergoing treatment for hematological malignancies until more evidence is available from larger studies.

Summary

• Anemia is common among critically ill patients. The etiology is usually multifactorial, including hemodilution resulting from fluid resuscitation, frequent blood sampling, cytokine induced-low erythropoietin levels, and abnormal iron metabolism
• A transfusion threshold of 10 gm/dl was considered appropriate for several decades based on observations in surgical patients; however, robust evidence has emerged suggesting that a one size fit all approach does not apply in most clinical situations
•  The landmark TRICC trial strongly suggested that a hemoglobin concentration of 7–9 gm/dl is adequate compared to 10–12 gm/dl among general critically ill patients. Younger and less severely ill patients had significantly better outcomes at the lower range in this study
• Patients with stable cardiovascular disease do not generally require higher hemoglobin levels to maintain adequate oxygen delivery. Contrary to conventional belief, emerging evidence suggests that a lower threshold of 8 gm/dl may be adequate in patients with acute myocardial infarction
• A transfusion threshold of 7 gm/dl may be appropriate among patients with upper gastrointestinal bleeding who remain hemodynamically stable and have ready access to endoscopic intervention
• Prolonged, difficult weaning from mechanical ventilation does not necessitate higher hemoglobin levels; robust evidence suggests that a hemoglobin level of 7 gm/dl is adequate among these patients
• There is limited evidence from pilot studies that suggests lower thresholds of 7–8 gm/dl would suffice in patients with hematological malignancy

References

1.         Adams RC, Lundy JS. Anesthesia in cases of poor surgical risk: Some suggestions for decreasing the risk. Anesthesiology. 1942;3:603–7.

2.         Silvain J, Pena A, Cayla G, Brieger D, Bellemain-Appaix A, Chastre T, et al. Impact of red blood cell transfusion on platelet activation and aggregation in healthy volunteers: results of the TRANSFUSION study†. Eur Heart J. 2010 Nov 1;31(22):2816–21.

3.         Hébert PC, Martin C, Yetisir E. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. N Engl J Med. 1999;9.

4.         Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381–91.

5.         Hébert PC, Wells G, Marshall J, Martin C, Tweeddale M, Pagliarello G, et al. Transfusion requirements in critical care. A pilot study. Canadian Critical Care Trials Group. JAMA. 1995 May 10;273(18):1439–44.

6.         Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001 Nov 8;345(19):1368–77.

7.         Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304–77.

8.         Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie M, Alcorn KW, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011 Oct 15;108(8):1108–11.

9.         Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, Lemesle G, Cachanado M, Durand-Zaleski I, et al. Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial. JAMA. 2021 Feb 9;325(6):552.

10.       Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011 Dec 29;365(26):2453–62.

11.       Docherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016 Mar 29;352:i1351.

12.       Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11–21.

13.       Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, et al. Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. Lancet Lond Engl. 2015 Jul 11;386(9989):137–44.

14.       Hébert PC, Blajchman MA, Cook DJ, Yetisir E, Wells G, Marshall J, et al. Do blood transfusions improve outcomes related to mechanical ventilation? Chest. 2001 Jun;119(6):1850–7.

15.       Walsh TS, Boyd JA, Watson D, Hope D, Lewis S, Krishan A, et al. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med. 2013 Oct;41(10):2354–63.

16.       Webert KE, Cook RJ, Couban S, Carruthers J, Lee K-A, Blajchman MA, et al. A multicenter pilot-randomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation. Transfusion (Paris). 2008 Jan;48(1):81–91.