Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients

This document aims to summarize the current literature guiding the use of red cell transfusion in critically ill patients and provides recommendations to support clinicians in their day-to-day practice. Critically ill patients differ in their age, diagnosis, co-morbidities, and severity of illness. These factors influence their tolerance of anaemia and alter the risk to benefit ratio of transfusion. The optimal management for an individual may not fall clearly within our recommendations and each decision requires a synthesis of the available evidence and the clinical judgment of the treating physician. This guideline relates to the use of red cells to manage anaemia during critical illness when major haemorrhage is not present. A previous British Committee for Standards in Haematology (BCSH) guideline has been published on massive haemorrhage (Stainsby et al, 2006), but this is a rapidly changing field. We recommend readers consult recent guidelines specifically addressing the management of major haemorrhage for evidence-based guidance. A subsequent BCSH guideline will specifically cover the use of plasma components in critically ill patients. The World Health Organization (WHO) defines anaemia in men and women as a haemoglobin (Hb) 99% of O2 is transported bound to haemoglobin. Tissue hypoxia can occur during critical illness as a result of problems at all stages in the O2 cascade, including airway and pulmonary disease, inadequate cardiac function and reduced or maldistributed microvascular flow. Anaemia reduces O2 carrying capacity and there is strong biological plausibility in the belief that it causes tissue hypoxia. When tissue DO2 falls, O2 supply is maintained by compensatory mechanisms that increase O2 extraction. However, there is a critical DO2 at which these compensatory mechanisms are overwhelmed and O2 transport becomes directly proportional to O2 supply. In such circumstances, severe tissue hypoxia is much more likely to occur. Studies using normovolaemic haemodilution indicate that young adults can maintain an O2 supply at Hb concentrations of 40–50 g/l by increasing cardiac output and O2 extraction (Weiskopf et al, 2006). The heart and brain have high O2 extraction ratios, which limits these compensatory mechanisms. In addition, O2 consumption is increased in the critically ill. Therefore anaemia may be less well tolerated during critical illness. An assessment of the risk to benefit ratio of transfusion to improve O2 carrying capacity is a key consideration to optimise patient outcomes. The strongest evidence guiding transfusion policy in adult critically ill patients comes from the Transfusion Requirements In Critical Care (TRICC) study (Hebert et al, 1999). Patients with a Hb ≤90 g/l were randomized to either a relatively high Hb transfusion trigger of <100 g/l with a target of 100–120 g/l, the ‘liberal’ group, or a lower trigger of <70 g/l with a target of 70–90 g/l (the ‘restrictive’ group). Mortality was compared at 30 and 60 d, and a range of secondary outcomes compared. The restrictive group received 54% fewer units of blood and 33% received no blood transfusions in the ICU, whereas all of the liberal group were transfused. Thirty-day mortality in the liberal group was typical of general ICU populations (23·3%), but there was a non-significant trend towards lower mortality for the restrictive group (18·7%, P = 0·11). In two pre-defined subgroups, younger patients (aged < 55 years) and patients with lower illness severity Acute Physiology and Chronic Health Evaluation (APACHE) II score < 20, the risk of death during 30-d follow up was significantly lower with the restrictive strategy. For patients aged <55 years those in the restrictive group had a 5·7% mortality vs. 13·0% for those in the liberal group 95% confidence interval (CI) for the absolute difference 1·1–13·5%; P = 0·028. Similarly, for patients with an APACHE II score < 20, those in the restrictive group had an 8·7% mortality vs. 16·1% for the liberal group (95% CI for the absolute difference: 1·0–13·6%; P = 0·03). These differences represented a number needed to treat to benefit from restrictive over liberal transfusion of about 13 patients for these sub-groups. Overall, there were also lower rates of new organ failures in the restrictive group and a trend towards higher rates of Acute Respiratory Distress Syndrome in the liberal group (7·7% vs. 11·4%). These findings support using transfusions to maintain a Hb of 70–90 g/l. Concerns about the applicability of these results include the introduction of leucodepletion of red blood cells (RBCs), the storage age of RBCs, and risk of selection bias; few patients with cardiac disease were enrolled and there was a high clinician refusal rate. The results of the TRICC study have been corroborated by two recent studies. The Transfusion Requirements After Cardiac Surgery (TRACS) study found no difference in a composite end-point of 30-d mortality and severe comorbidity in cardiac patients prospectively randomized to a liberal or restrictive transfusion strategy (Hajjar et al, 2010). Most recently the ‘FOCUS’ (Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair) study of liberal or restrictive transfusion in high-risk patients after hip surgery showed no difference in mortality or mobility in the group assigned to the restrictive transfusion strategy (Carson et al, 2011). Importantly, although patients in the FOCUS trial were not critically ill, they were elderly and had a high prevalence of cardiovascular disease. Taken together the recent literature consistently shows no clear advantage with a liberal transfusion strategy. A suggested approach to transfusion in critical care is summarised in Fig 1. Critically ill patients do not generate a physiological increase in erythropoietin concentration in response to anaemia (Corwin et al, 1999, 2002, 2007; Hobisch-Hagen et al, 2001; Corwin, 2004; Shander, 2004; Hebert Belova Arroliga et al, 2009; Bateman et al, 2009). Several trials have evaluated the efficacy and effectiveness of erythropoietin administration in critically ill patients. Methodological variations including different patient populations, and varying dosage regimens of both erythropoietin and iron therapy makes interpretation of these trials complicated. It appears on balance that a combination of iron supplementation and erythropoietin therapy can modestly decrease transfusion requirements, but the benefits become negligible when a transfusion trigger of 70 g/l is used (Corwin et al, 2007). No difference in patient outcomes has been demonstrated, except for a possible decrease in mortality among trauma patients. Erythropoietin therapy increases deep vein thrombosis, especially when prophylaxis is not used. Erythropoietin is not licenced for use in anaemic critically ill patients. The inflammatory response complicates the interpretation of iron indices in critical illness (Walsh Munoz et al, 2008). There are no large randomized trials of iron monotherapy in critically ill patients, and excess iron may increase susceptibility to infection (Maynor Corwin et al, 1995; Zimmerman et al, 1997). Studies examining the magnitude of blood loss associated with routine phlebotomy indicate typical daily blood loss of approximately 40 ml (Foulke Fowler MacIsaac et al, 2003; Corwin, 2005; Chant et al, 2006; Harber et al, 2006; Sanchez-Giron MacIsaac et al, 2003; Mukhopadhyay et al, 2010). One study (Mukhopadhyay et al, 2010) showed a reduction in the severity of anaemia and reduced RBC use with the Venous Arterial blood Management Protection (VAMP) system (Edwards Lifesciences, Irvine, CA, USA). Use of this device was associated with decreased requirements for RBC transfusion (control group 0·131 units vs. active group 0·068 units RBC/patient/d, P = 0·02). The intervention group also had a smaller reduction in Hb during ICU stay, 14·4 ± 20·8 vs. 21·3 ± 23·2 g/l; P = 0·02 (Mukhopadhyay et al, 2010). No cost-effectiveness evaluations of these systems in routine practice have been published. The use of small volume paediatric sampling bottles has also been consistently associated with reduced phlebotomy-related blood loss, without affecting assay quality (Harber et al, 2006; Sanchez-Giron et al, et al, et al, 2007). adverse or to transfusion be and to risk the of Transfusion group and the and the Blood and defines as with pulmonary increased blood and evidence of a balance after a blood transfusion et al, 2010). the of is to the of a A large study the of in critically ill patients, the as the of pulmonary within of transfusion with a ratio of or of on on a in the of et al, The different criteria used in these studies may for the differences in varying from in units of RBCs to the et al, which of to RBCs, but only as highly is as the of pulmonary within of transfusion with a ratio of in on a in the of was first in but did not receive more transfusion support et al, It is to and can occur after transfusion of or et the of as in in Blood in are typically women have during Blood Transfusion have a policy of plasma from which has reduced the of et al, 2009). When be a suggested is summarized in Table Cohort studies have the between the age of blood and clinical outcomes, including and of these studies is of the problems of and also of control of the RBC storage but not studies have found between the transfusion of RBCs and adverse clinical outcomes et al, et al, 2002; et al, et al, 2011). There are no randomized trials RBCs with either RBCs or are in et al, 2011). storage are on RBCs function within of transfusion into the The of storage from to d between ICU patients receive RBCs stored for in part blood RBCs as they to be transfused after RBC storage results in that O2 and decreased increased to of in the also have adverse effects, especially in RBCs et al, 2006). is the for to the ICU in the for of et al, 2006), with mortality from to et al, 2001). is associated with tissue DO2 a range of including cardiac function and of microvascular flow. The physiological for using blood transfusions is to in capacity in anaemic patients. Tissue hypoxia is during the stages of include and cardiovascular The is to a DO2 and tissue O2 Evidence of benefit from RBC transfusion in comes from a study of et al, 2001). groups in the study received and to a and arterial The therapy group were during the first of by the oxygen saturation In where the was patients received blood transfusions to maintain a of to increase cardiac output et al, 2001). This intervention decreased the absolute risk of death in by vs. One major difference between the groups was the use of blood vs. this was a intervention it is to clinical benefit to a However, when patients are anaemic and there is evidence of inadequate DO2 during sepsis, a target Hb of g/l is In sepsis, oxygen saturation or concentration are with the of tissue hypoxia although this may not be the for patients with more clinical trials are the of therapy in The evidence for RBC transfusions in patients during the stages of critical illness resulting from is The use of RBC transfusion and to for DO2 has been et al, et al, evidence suggests that using RBC transfusions to a Hb higher 70–90 g/l has no clinical benefit the patient has organ the A of patients with severe infection in the TRICC trial to benefit from liberal transfusion, with more in the transfused group restrictive group vs. liberal group Hebert et al, 1999). Cohort studies have also the association between RBC transfusion and clinical outcomes in patients. Studies carried the introduction of leucodepletion between RBC transfusion and higher whereas those after leucodepletion have lower the possibility that this may influence the risk to benefit of transfusion in these patients (Hebert et al, Vincent et al, 2002, Corwin et al, trials are restrictive liberal transfusion practice for patients with transfusion practice when a patient with critical illness a of severe during an ICU stay, such as or is – no trials are available to management in this these clinicians use in available physiological of O2 such as and together with clinical to transfusion practice. evidence not support transfusion to a Hb g/l. DO2 is from the blood and the arterial O2 brain factors to including raised of and of The tissues for a fall in DO2 by increasing their oxygen extraction ratio but this compensatory has limits and brain tissue with a high is to and secondary of brain tissue O2 that is consistently associated with outcomes brain and DO2 to is to the management of critically ill patients. anaemia is in patients admitted to the ICU brain the of the to maintain DO2 increasing the increases O2 carrying there is an between and blood and high have been to and may to et al, 2006). There are few studies that have to the optimal in critically ill patients and current is from studies and expert the use of a restrictive transfusion strategy may improve outcomes in most critically ill it these findings can be to neurocritical care patients (Hebert et al, Vincent et al, 2002; Corwin et al, There is evidence that blood transfusion in anaemic patients with brain and transfusion appears to be associated with outcomes in studies. The evidence is in the of brain haemorrhage and ischaemic is a major of secondary et al, 2009). of are of in these patients et al, et al, et al, of DO2 and of is et al, 2002; et al, 2002; et al, 2008). to maintain on and the of raised The has published guidelines on the management of the 2007). These guidelines no on the optimal Hb target to A number of studies suggest that anaemia is associated with outcomes et al, 2001; et al, 2001; et al, 2004; et al, 2006; et al, Sanchez-Giron et al, 2007). RBC transfusion in most anaemic patients with the is small and appears to decrease in patients transfusion et al, 2005; et al, 2006; et al, 2009). It has been that this in clinical effect may be to the storage age of but this et al, 2008). The influence of RBC transfusion on the of is Transfusion is associated with but in studies this be to et al, 2006; et al, 2008). A of the TRICC which patients with to severe suggested no significant in mortality in patients randomized to a liberal 100–120 as compared to restrictive 70–90 transfusion strategy (Hebert et al, et al, 2006). this suggests a restrictive transfusion strategy may be in this group of patients. The approach to the management of a combination of to the and the blood brain including RBC transfusion to maintain a Hb g/l; a small study has suggested outcomes using this but the use of this et al, In there is evidence to an evidence-based on the optimal Hb Anaemia is consistently associated with in patients with and it is transfusion et al, 2007; et al, 2006; et al, 2008). transfusion DO2 in anaemic patients with it may decrease brain tissue in et al, Transfusion has been associated with reduced mortality in two studies et al, 2009; et al, 2011). A small randomized in which patients with were randomized to a Hb target of either or g/l, has suggested only a trend towards secondary outcomes, reduced and rates of functional with restrictive transfusion, but large randomized studies are studies have suggested an association between RBC transfusion and et al, 2004; et al, 2005; et al, et al, 2008). a of approximately has been used in combination with and in the and of et al, 2006). studies the efficacy of therapy are and it is reduced blood reduced Hb are for the benefits et al, 2010). The optimal Hb in patients with has not been defined. It the use of RBC transfusion outcomes. studies in patients with ischaemic suggest that the effect of on is with both high and Hb associated with et al, 2003; et al, 2008). high to and reduced have to significant benefit from haemodilution 2002; et al, An study examining in patients with ischaemic suggests that DO2 is with a of a similar range to that in et al, Hebert et al, 1997). In both studies a Hb g/l was associated with excess These were corroborated by between anaemia and higher mortality in general populations, among patients et al, 2001; Kulier et al, 2007). In the TRICC there were no excess adverse cardiac in the patients with a restrictive transfusion strategy. The of patients a was higher in the liberal group vs. P = and cardiac adverse were also higher vs. P < In a of patients were as from at there was a non-significant trend towards lower 30-d mortality among patients with the liberal strategy in 30-d (95% CI to these suggested possible benefit from liberal blood use in patients with but the sub-group was In the recently published FOCUS study in elderly patients hip which compared a liberal strategy < with a restrictive strategy anaemia or Hb < found no difference in mortality or cardiovascular of patients (Carson et al, 2011). Similarly, the study compared similar liberal and restrictive transfusion in patients cardiac surgery and found no differences in 30-d mortality or severe between the groups (Hajjar et al, 2010). these trials were not in critically ill patients, both patients at high risk of There are no large randomized trials of transfusion for patients with A recent small study in patients compared liberal and transfusion in patients with an et al, 2011). The of or of cardiac in patients in the liberal group and in the vs. P = The majority of our current evidence is on the physiological for a higher blood O2 and from studies. patients an have outcomes (Guralnik et al, An the use of together with blood loss during have increased the prevalence of anaemia among patients with Wu et approximately patients in the database aged years with After for transfusion 30-d mortality for patients with a < the benefit of transfusion among those patients with most severe anaemia et al, 2001). In were from trials of for et al, 2004; et al, anaemia was associated with patient outcomes, these studies found no benefit from transfusion at lower and transfusion was associated with outcomes. Wu et compared the impact of transfusion in patients with and In this anaemia < was associated with increased mortality in and RBC transfusions were associated with decreased for anaemia was associated with increased but RBC transfusions were associated with increased recent studies also did not clinical benefit from transfusion when the Hb was g/l et al, et al, 2009). studies are by and the quality of evidence is of from mechanical and to improve the and of weaning are of they are likely to be both and cost Depending on up to of patients and to at 30 d 1995; et al, is associated with a increase in mortality et al, 1997; DO2 by increasing the Hb using transfusion arterial O2 content and is the physiological of using RBC transfusion to et and chronic pulmonary disease patients and that transfusion reduced the of in the A patient by the suggested transfusion may be in weaning anaemic patients et al, However, studies in a more group of patients have either no benefit from transfusion, or suggested that it is associated with a et al, Hebert et al, et al, The two studies are of other studies – TRICC and Hebert et al, Corwin et al, provide evidence they were not to weaning or the effect of RBC transfusion on weaning and suggested that transfusion was associated with an increased of mechanical Available evidence not strong recommendations specific to transfusion and weaning from mechanical ventilation, but do not support the use of a liberal transfusion strategy. Anaemia is prevalent in the critically ill and is associated with adverse outcomes. At there are no or to RBC transfusion for rapidly increasing the Hb and O2 carrying The and that is available consistently suggests that transfusion of RBCs when the Hb is within the 70–90 g/l range has no effect on clinical outcomes either in the general critical care or in specific patient sub-groups for a physiological for reduced anaemia tolerance Importantly, it is the of effectiveness of blood transfusions in this is anaemia not outcomes or the associated with current stored red cell transfusions physiological In the large well randomized control trials are to the risk to benefit balance of RBC transfusion in a range of resulting in critical illness. the and in these guidelines is to be and at the of to the the British Society for Haematology the for the content of these of the literature used to the guideline and provide the key recommendations patients blood randomized control patients Patients randomized to either units d or units d Hb <90 g/l randomized patients Patients randomized to receive RBCs d therapy patients study patients received blood d patients received blood d patients Transfusion of 2 units RBCs in patients on a ICU patients to of two transfusion – Hb maintained g/l – Hb maintained at 70–90 g/l randomized control patients of including patients Transfusion of units of RBCs patients Patients received of RBCs for each g/l that their Hb was g/l