- Email: [email protected]
Anaemia and blood transfusion
PERIOPERATIVE MANAGEMENT
Oxygen content of blood ¼ ðO2 carried by HbÞ þ ðO2 in solutionÞ
Anaemia and blood transfusion
¼ ð1:34 Hb SpO2 0:01Þ þ ð0:023 PaO2 Þ The haemoglobin dissociation curve (Figure 1) describes the relationship between oxygen saturation and the partial pressure of oxygen. Its sigmoid shape can be explained as follows. Each haemoglobin molecule is able to bind up to four oxygen molecules. There is a reduced tendency for the first and fourth oxygen molecules to bind (the lower and upper plateau portions of the graph, respectively) and an increased tendency for the second and third oxygen molecules to combine with haemoglobin (the steep portion of the curve). The upper plateau portion corresponds with the high PO2 (around 13 kPa) at the pulmonary capillaries when there will be little drop in oxygen carriage until the PO2 drops to less than 7.5 kPa (approximately 55 mmHg). The steep portion represents the environment at the systemic capillaries where a small drop in PO2 will result in a large release of oxygen from the haemoglobin to attempt to ensure oxygen delivery meets demand. The strength with which oxygen combines with haemoglobin is further affected by other environmental factors. Increased affinity for oxygen is represented by a leftward shift of the curve and reduced affinity (and therefore increased delivery of oxygen to the tissues) is represented by a right shift. This has numerous clinical implications. An example is in the systemic inflammatory response where temperature and metabolic activity are often increased, causing CO2 and lactic acid formation. This hypercarbia and lactataemia shifts the oxygen dissociation curve to the right, allowing more oxygen to be released to the tissues for a given PO2.
Barry Paul Ian Nesbitt
Abstract Anaemia is a common diagnosis in surgical practice. It may impair oxygen delivery to tissues and cause significant complications. This article discusses definitions, critical levels of anaemia (along with transfusion triggers), an overview of the manufacture provision, and use of various blood products along with novel agents and research areas for the future.
Keywords Anaemia; blood products; complications; transfusion
Anaemia is a common problem encountered in surgical patients. We will provide an overview of why, and what level of anaemia is important, and the value of transfusion triggers under different clinical circumstances. We will then move on to transfusion itself and describe both established and novel products available with an evaluation of when and how they are best used.
Overview of oxygen carriage Oxygen delivery to the tissues is an essential process and is dependent on cardiac output and the oxygen content of the blood. Oxygen is carried in the blood in two forms. 1. A very small amount is dissolved in the plasma. The actual quantity depends on the partial pressure of oxygen (PO2) according to the formula 0.023 ml O2/100 ml blood/kPa PO2, and, in a healthy patient breathing room air, only 3 ml of oxygen is dissolved in every litre of plasma. Supplementation of inspired oxygen increases this by only a small degree, although hyperbaric oxygen can significantly increase plasma oxygen carriage. 2. Most of the oxygen in the circulation combines with haemoglobin to form oxyhaemoglobin. Each gram of haemoglobin is capable of carrying 1.34 ml of oxygen and so a patient fully saturated with oxygen with a haemoglobin concentration of 15 g/dl would carry approximately 200 ml of oxygen for every litre of blood. Hence, the total oxygen content of a sample of blood may be calculated as:
When is anaemia significant? Anaemia is defined as a haemoglobin below the expected value when age, gender, pregnancy and environmental factors (such as
The oxygen–haemoglobin dissociation curve
Oxyhaemoglobin (%)
100
75
Temperature pH CO2 2,3-DPG
50
25
0
Barry Paul MB.BS MRCP FRCA EDIC FFICM is a Consultant in Anaesthesia and Intensive Care Medicine at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Conflicts of interest: none.
0
5
10
15
20
PO2 (kPa)
Ian Nesbitt MB.BS FRCA DICM FFICM is a Consultant in Anaesthesia and Intensive Care Medicine at Freeman Hospital, Newcastle upon Tyne, UK. Conflicts of interest: none.
SURGERY --:-
Temperature pH CO2 2,3-DPG
2,3-DPG, 2,3-diphosphoglycerate.
Figure 1
1
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
patients.4,5 Ninety-five per cent of patients spending more than 3 days in critical care develop anaemia.6 This is due in a large degree to an ‘acute anaemia of chronic disease’ e a blunted reticulocyte count for the degree of anaemia, along with cytokine mediated low levels of erythropoietin, and functional iron deficiency, along with a variable element of bone marrow dysfunction. The issue of trying to establish an appropriate transfusion trigger in this group was addressed by the TRICC trial in 1998.7 This compared a restrictive target haemoglobin of 7.0e9.0 g/dl and a trigger of <7 g/dl with a more liberal strategy of aiming for 10.0e12.0 g/dl and a trigger of 10.0 g/dl during the first 3 days of a patient’s stay in ICU. The investigators found no difference in mortality at 30 and 60 days in both groups but subgroup analysis suggested a lower mortality with the restrictive strategy (trigger <7 g/dl). This, perhaps counter-intuitive result, may be partly explained by potential immunomodulation caused by transfusion, particularly the white cell component. These findings have been supported by several other similar studies and a Cochrane review,8 and for most critical care patients, a transfusion trigger of 7 g/dl is widely accepted. Possible exceptions to the use of a restrictive strategy include patients with ischaemic heart disease where there is evidence of active myocardial ischaemia9 (consider transfusion to a haemoglobin of 9.5 g/dl) and in early severe sepsis (aim for haemoglobin >10 g/dl) to ensure central venous oxygen saturations are >70%.10
WHO grading of anaemia severity Grade
Severity
Hb range (g/dl)
0 1 2 3 4
None Mild Moderate Severe Life threatening
>11 9.5e10.9 8.0e9.4 6.5e7.9 <6.5
Table 1
altitude) have been considered. The World Health Organization (WHO) defines anaemia as a haemoglobin <13 g/dl (haematocrit <39%) for adult males and <12 g/dl (haematocrit <36%) for non-pregnant adult females.1 The WHO also grades severity of anaemia for patients with cancer using the scale detailed in Table 1. Whilst a cause for anaemia should always be considered (Box 1), there is variation in practice as to when and how anaemia should be treated. A critical value for anaemia is reached when oxygen delivery fails to provide the oxygen demand under specific clinical circumstances. For young, healthy patients, it is unclear what this critical value is e survivors of extreme anaemia (Hb < 1 g/dl) have been reported, but these are the exception.2 For the majority of patients, a complex interaction of cardiac co-morbidity, age, degree of anaemia and actual blood loss exists. The risks of complications and death increase with all these variables, but a marked increase in mortality has been seen with haemoglobin levels lower than 6 g/dl.2 For many patients, however, the risk of complications remains significant at higher haemoglobin levels. Thus, a specific trigger for transfusion will depend on individual patient assessment to a large degree. Even decades after the introduction of the arbitrary traditional 10/30 ‘rule’ (haemoglobin 10 g/dl or haematocrit 0.3), it is not possible to provide a simple answer. General recommendations are that few adult patients require a haemoglobin greater than 10 g/dl, and few should be denied transfusion with a haemoglobin below 6 g/dl.3
Established blood products available for transfusion Until the late 1970s, most blood was transfused without being processed into its constituents and was termed ‘whole blood’. While this is still common practice in some countries, in the UK almost all donations are now processed into red cells, platelets and plasma after screening for infectious agents and removing white cells (leucodepletion) (Figure 2). The donor blood is drawn into a bag containing 63 ml of an anticoagulant preservative solution, normally CPDA1 (citrate, phosphate, dextrose and adenine). The citrate binds calcium, acting as an anticoagulant while the other components support red cell metabolism. Each donation is tested to determine the ABO and RhD group of the donor’s red cells. Anti-A and anti-B antibody titres are also checked on donations from blood group O to minimize the risk of transfusion reactions.
Anaemia in the critically ill Red cells A standard unit of red cells contains approximately 20 ml of plasma with the rest replaced by 100 ml of a storage solution. This solution has been improved over time, and currently contains saline, adenine, glucose and mannitol (SAGM). The total volume ranges from 180 ml to 350 ml with a mean of 282 ml. Mean haematocrit is 57%. The red cells are stored between 2 and 6 C for up to 35 days and the product must be compatible with the recipient’s ABO (and usually RhD) type. During the storage process, RBCs undergo numerous changes which may be deleterious to their intended function of carrying oxygen in the recipient patient. These include haemolysis, decreased concentrations of 2,3 DPG, NO and ATP, intracellular acidosis and leakage of potassium. The erythrocyte consequently becomes irregular (an echinocyte) with a less deformable cell
Anaemia is a common problem in critical care patients, affecting approximately 60e70% of patients on admission, with moderate to severe anaemia (<9 g/dl) affecting around a quarter of
Causes of anaemia in surgical and critically ill patients C C C C C C C
Blood loss Haemodilution Frequent phlebotomy B12 or folate deficiency Reduced red cell survival or production Low erythropoietin levels Functional iron deficiency
Box 1
SURGERY --:-
2
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Production of blood products and plasma derivatives Education Recruitment Selection Donation
Platelet pheresis
Test for: HIV Hepatitis B Hepatitis C HTLV Syphillis ABO + RhD Other phenotypes Red cell antibodies (CMV HbS, malaria)
Process into blood components Filter to remove leucocytes
Red cells
Pooled platelets Fresh frozen plasma
Plasma (from non-UK source)
Fractionation
35 days Confirm compatibility 4˚C
5 22˚C days (Pool)
24 –30˚C months Plasma (Thaw) derivatives e.g. albumin, immunoglobulin
Patient 14 Reproduced with permission from the Handbook of Transfusion Medicine . CMV, cytomegalovirus; HIV, human immunodeficiency virus; HTLV, human T-lymphotropic virus.
Figure 2
membrane and reduced oxygen carrying capacity. This was of particular concern given that in the UK, the average age of blood administered is 14 days.11 This resulted in two major trials e RECESS12 and ABLE13 being undertaken and recently published. They both showed that age of blood did not correlate with organ dysfunction or mortality.
Platelets are either derived either from the buffy coat of whole blood pooled from four donors or by single donor aphaeresis which has the advantage of exposing the recipient to the blood of fewer donors. They are stored at 22 C with agitation to ensure function is maintained and should ideally be ABO and RhD compatible with the recipient, due to the plasma present.
Platelets Platelet transfusions are for the prevention and treatment of haemorrhage in patients with thrombocytopaenia or in those with platelet dysfunction (e.g. aspirin and clopidogrel therapy).
Fresh frozen plasma (FFP) Fresh frozen plasma is indicated for the replacement of coagulation factors in specific circumstances and for thrombotic thrombocytopaenia. It refers to plasma that has been
SURGERY --:-
3
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
centrifuged, separated and frozen at 30 C within 8 hours of collection. Each unit of FFP is obtained from a single donor. It is no longer used in haemophilia now that concentrated forms of coagulation factor are available for use. FFP should be ABO matched to avoid the risk of haemolysis from donor anti-A or anti-B but does not need to be RhD matched. It can typically be stored for up to 2 years. Once thawed, plasma can be stored at room temperature for 4 hours without loss of activity, or for 5 days at 1e6 C.
multiple other antigens, modern cross-matching to ensure minimal risk has become a much more complex process. Bacterial contamination Although rare, this is more likely to occur with platelet transfusions as they are stored at higher temperatures. The clinical features are similar to haemolytic reactions, with a rapid onset. Examination of the donor bag to confirm the diagnosis and identify the offending organism is important to guide antibiotic therapy.
Cryoprecipitate Cryoprecipitate is produced after controlled thawing of FFP to precipitate the high molecular weight proteins, namely fibrinogen, factor VIIIc and von Willebrand factor. A typical adult dose of 110e250 ml, derived from 5 units of FFP, will perhaps raise the fibrinogen level by about 1 g/l.
Transfusion-related lung injury (TRALI) Characteristically occurring six hours after transfusion, the patient develops dyspnoea, hypoxia, cough and bilateral infiltrates on chest X-ray. Treatment is supportive. Although TRALI may occur after any blood product (or similar, such as intravenous immunoglobulin), platelets and FFP are both most strongly implicated. The donors are almost always parous women with antibodies that react strongly against the recipient’s leucocytes.
Acute complications of transfusion Acute haemolytic reaction The ABO blood groups are divided into groups A, B, AB and O based on which antigen the individual’s red cells carry. IgM antibodies are produced from early childhood against either the A or B antigens depending on what the red cell expresses. Therefore if incompatible blood is administered, the transfused cells will be destroyed with resultant haemolysis and the liberation of inflammatory cytokines (TNF, IL-1, IL-8) causing vasodilation, hypotension, bleeding and organ failure. Mortality from such reactions has been quoted at 5e10%. The variation in severity is thought to be due to the different potency of antibodies produced and in particular the relative lack of potency in group A or B individuals compared to group O. The reaction is usually most severe when group A blood is transfused to a group O patient. Haemolytic reactions are usually prevented by means of the group and screen. This involves characterizing the patient’s ABO and RhD group and screening for any additional antibodies that could haemolyse donor red cells. A traditional grid of donor-recipient compatibility is shown in Table 2. However, with increased testing and recognition of
Transfusion-associated circulatory overload (TACO) This tends to occur when patients receive high volumes of blood products quickly in the setting of heart failure. It can be treated with supportive treatment and diuresis. Allergic reactions Most allergic reactions are mild and can be treated with antihistamines and steroids if necessary. Anaphylaxis is rare. Figure 3 shown below summarizes the NHS Blood and Transplantation (NHSBT) guidelines for the management of acute reactions to transfusion in the UK.
Delayed complications of transfusion Delayed haemolytic transfusion reaction (DHTR) This is a delayed reaction (more than 24 hours) after a transfusion in a patient who has previously been immunized to a red cell antigen either by transfusion or pregnancy. Rhesus antibodies and Kidd antibodies are most often implicated with typical features being jaundice, fever, falling haemoglobin concentration and even renal failure. Characteristically, there will be haemolysis on the blood film with raised LDH and a positive direct Coombs test.
A+ AB+ BAB+ ABO+ O-
A+
A-
safe
safe safe
B+
Red Cell Donor BAB+
safe safe
safe safe
safe
safe safe safe safe
AB-
O+
O-
safe
safe safe safe safe safe safe safe safe
safe safe
safe safe
safe safe
Transfusion-associated graft-versus-host disease This occurs 1e2 weeks after transfusion and is caused by donor lymphocytes damaging recipient cells carrying HLA antigens. Although rare, it is more common in patients who are immunocompromised or those receiving a transfusion from a close relative. The condition causes multi-organ failure and is associated with a high mortality. For this reason, all patients at risk of GvHD should receive irradiated blood products to inactivate donor lymphocytes.
AB+ “The universal recipient”
Recipient
Traditional blood group compatibility
O negaƟve “The universal donor”
Post-transfusion purpura This is caused by platelet-specific alloantibodies and is more common in female patients. Symptoms start to appear approximately 1 week after exposure with spontaneous bleeding
Table 2
SURGERY --:-
4
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Acute transfusion reactions Symptoms/signs of acute transfusion reaction Fever; chills; tachycardia; hyper-or hypotension; collapse; rigors; flushing; urticaria; bone, muscle, chest and/or abdominal pain; shortness of breath; nausea; generally feeling unwell; respiratory distress
Stop the transfusion and call a doctor • Measure temperature, pulse, blood pressure, respiratory rate, O2 saturation • Check the identity of the recipient with the details on the unit and compatibility label or tag
Febrile non-haemolytic transfusion reaction • If temperature rise less than 1.5°C, the observations are stable and the patient is otherwise well, give paracetamol • Restart infusion at slower rate and observe more frequently
Urticaria Mild fever
Reaction involves mild fever or urticarial rash only
Mild allergic reaction • Give chlorphenamine 10 mg slowly IV and restart the transfusion at a slower rate and observe more frequently
ABO incompatibility • • • • • • •
Stop transfusion Take down unit and giving set Return intact to blood bank Commence IV saline infusion Monitor urine output/catheterize Maintain urine output at › 100 ml/hr Give furosemide if urine output falls/ absent • Treat any DIC with appropriate blood components • Inform hospital transfusion department immediately
NO Severe allergic reaction YES Suspected ABO incompatibility
NO YES Severe allergic reaction
Haemolytic reaction/bacterial infection of unit • Stop transfusion • Take down unit and giving set • Return intact to blood bank along with all other used/unused units • Take blood cultures, repeat blood group/ cross-match/FBC, coagulation screen, biochemistry, urinalysis • Monitor urine output • Commence broad spectrum antibiotics if suspected bacterial infection • Commence oxygen and fluid support • Seek haematological and intensive care advice
Fluid overload • Give oxygen and frusemide 40–80 mg IV
NO
YES
Bronchospasm, angioedema, abdominal pain, hypotension • Stop transfusion • Take down unit and giving set • Return intact to blood bank along with all other used/unused units • Give chlorphenamine 10 mg slow IV • Commence O2 • Give salbutamol nebulizer • If severe hypotension, give adrenaline (0.5 ml of 1 in 1000 intramuscular)* • Clotted sample to transfusion laboratory • Saline wash future components (* equivalent to 0.5 mg IM)
Other haemolytic reaction/bacterial contamination NO
Acute dyspnoea/ hypotension Raised Monitor blood gases Perform CXR CVP Measure CVP/ pulmonary capillary pressure
TRALI Normal CVP
• Clinical features of acute LVF with fever and chills • Discontinue transfusion • Give 100% oxygen • Treat as ARDS – ventilate if hypoxia indicates
Reproduced with permission from the Handbook of Transfusion Medicine.14 ARDS, acute respiratory distress syndrome; CVP, central venous pressure; CXR, chest X-ray; DIC, disseminated intravascular coagulation; FBC, full blood count; IM, intramuscular; IV, intravenous; LVF, left ventricular failure; TRALI, transfusion-related lung injury.
Figure 3
SURGERY --:-
5
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
associated with severe thrombocytopenia. High dose IV immunoglobulin is the treatment of choice.
Preoperative autologous blood transfusion (PABD) This involves the patient donating their own blood for storage up to 5 weeks before their operation. Starting haemoglobin concentration should be >10 g/dl for females and >11 g/dl for males. At least 2 units, but usually 3e5, are donated and the patient is subsequently given iron therapy and erythropoietin to accelerate recovery. Whilst this strategy reduces the risk of developing red cell antibodies and acquiring viral infections, it does not reduce (and may actually increase) the risk of bacterial contamination or wrong blood errors. The optimal strategy for PABD is for patients having elective major surgery with a high predicted blood loss, but without intraoperative blood salvage.
Transfusion and cancer recurrence rates The issue of whether transfusing blood products during or after cancer surgery increases recurrence rates has been debated for over 20 years. Chung et al.15 published a meta-analysis of 100 observational studies in 1993 of patients with colorectal, head and neck, breast, gastric, lung, cervical and prostate cancer. They reported that the odds ratio of adverse clinical outcome was significant (p < 0.05) in the transfusion group for all sites except the cervix. Brand and Houbiers16 performed a further metaanalysis 6 years later for colorectal patients. They found no association between perioperative transfusion and cancer recurrence (p ¼ 0.55) or death due to cancer recurrence (p ¼ 0.19) but found a relationship between perioperative transfusion and higher overall mortality (p < 0.001). There are a number of possibilities for the above findings. Firstly, patients who require allogeneic blood transfusion are likely to have more significant disease, suffer a greater physiological insult during treatment and are therefore more likely to have an adverse outcome. Secondly, publication bias may exist which means the studies that were included into both metaanalyses may be skewed in favour of showing adverse outcomes with transfusion. Thirdly, it is possible that a transfusionrelated immunomodulatory (TRIM) effect contributed to the results. If so, since the advent of leucodepletion of blood products in many countries, this seems less likely to be a continuing issue. As yet, no adequately designed trial has demonstrated a causal relationship between cancer recurrence and allogeneic blood transfusion. Therefore, a pragmatic viewpoint should be taken and no patient who absolutely requires transfusion should have this withheld based on the risk of cancer recurrence.
Acute normovolaemic haemodilution This involves withdrawing several units of blood from the patient at induction of anaesthesia and replacing the circulatory volume with colloid or crystalloid. Total red cell mass lost during the operation is therefore reduced and the withdrawn blood from the patient can be replaced postoperatively. Acute normovolaemic haemodilution is an unproven technique and is rarely used in the UK. Cell salvage Allogeneic transfusion is a limited resource with associated risks as described and significant cost implications. As a result, autologous transfusion with intraoperative and postoperative cell salvage, when possible, should be considered as this may reduce allogeneic transfusion by around 40%.18 In this process, blood from the surgical field is collected and anticoagulant is added. It is then filtered and washed (usually by centrifugation) to remove contaminants. Red cells remain whilst plasma, platelets, heparin and inflammatory mediators are discarded to give a product with a haematocrit of 50e70%. Cell salvage should be considered for operations where the intraoperative blood loss is predicted to be >1 litre or >20% of blood volume. It should also be specifically considered in certain patient groups such as those with rare blood groups or antibodies, patients with preoperative anaemia or where there is patient refusal to receive allogeneic blood transfusion. The views of individual Jehovah’s Witnesses to allogeneic and autologous blood transfusion vary and so this should be discussed with each patient on a case by case basis. Although cell salvage for cancer surgery is not recommended by the manufacturers due to the possibility of reinfusion of cancer cells, the UK National Institute for Health and Care Excellence (NICE) has approved cell salvage for surgery involving urological malignancies following a trial in patients undergoing radical prostatectomy and cystectomy which showed no difference in recurrence rates.19 Other concerns exist with cell salvage during bowel surgery (due to potential infection risk) and obstetric haemorrhage (due to potential amniotic fluid embolization and rhesus sensitization). As a result, with bowel surgery, cell salvage should commence after decontamination of the infected area and by using broad-spectrum antibiotics. In the obstetric setting, there should be separate suctioning of amniotic fluid and blood.
Reporting adverse reactions (SHOT/SABRE) All adverse reactions or events associated with transfusion should be reported. In the UK, the Medicines Health Related Agency (MHRA) has set up a reporting system called SABRE (Serious Adverse Blood Reactions and Events) that is linked to SHOT (Serious Hazards of Transfusion), an independent haemovigilance body set up and run by professionals working within the transfusion service. Both systems are designed to analyse such incidents and respond in a positive way so that patient safety can be improved. Similar systems exist in many other countries.
Alternative strategies for managing anaemia Ferrous sulphate Ferrous sulphate can be taken orally at a dose of 200 mg three times daily when iron deficiency is proven and there is no sinister cause. Correction will be achieved at 1 month in 90% of cases but is often poorly tolerated by patients. The PREVENTT Trial17 (Preoperative Intravenous Iron to Treat Anaemia in Major Surgery) is currently recruiting patients to assess if intravenous iron reduces the need for perioperative transfusion of red cells. B12 and folate replacement can be instituted if deficiency of either is found to be the cause.
SURGERY --:-
6
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Summary
Blood substitutes Advantages
Disadvantages
Not limited by number of donors If mass produced could be cheaper Significantly reduced infective complications Fewer ethical objections Longer storage time No need to refrigerate Allow for full immediate oxygen carrying capacity
Currently expensive Not widely available for commercial use Novel therapies that are as yet unproven Many substitutes withdrawn due to unacceptable adverse CVS and renal events
Anaemia is a common problem encountered in surgical patients. The management is not always straightforward and difficult cases should ideally be managed within a multidisciplinary approach tailored to the individual patient. Where transfusion is necessary, clear communication should ensue with the haematology team to ensure that optimal patient care is delivered and that adverse incidents are minimized. Where they do occur, reporting is mandatory. Research is active in developing alternatives strategies to blood products, but remain largely outwith standard clinical practice at present. A REFERENCES 1 Emmanuel JE, McClelland B, Page R, eds. The clinical use of blood in medicine, obstetrics, paediatrics, surgery anaesthesia, trauma & burns. World Health Organization, 1997; 337. 2 Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107(S1): i41e59. 3 Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger. Vox Sang 2010; 98: 2e11. 4 Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288: 1499e507. 5 Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically illdcurrent clinical practice in the United States. Crit Care Med 2004; 32: 39e52. 6 Corwin HL, Rodriguez RM, Pearl RG, et al. Erythropoietin response in critically ill patients. Crit Care Med 1997; 25(suppl 1): A82. 7 Hebert PC, Wells G, Martin C, et al. Canadian survey of transfusion practices in critically ill patients. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Crit Care Med 1998; 26: 482e7. 8 Carless PA, Henry DA, Carson JL, Hebert PP, McClelland B, Ker K. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2010. Art. No.:CD002042. 9 Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med 2001; 29: 227e34. 10 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368e77. 11 Nee PA, Bonney SC, Madden P, et al. Transfusion of red blood cells in critical illness. JICS 2010; 4: 240e4. 12 Steiner ME, Ness PM, Assman SF. Effect of red cell storage duration on patients undergoing cardiac surgery. NEJM 2015; 372: 1419e29. 13 Lacroix J, Hebert PC. Fergusson DA age of transfused blood in critically ill adults. NEJM 2015; 372: 1410e8. 14 McLelland DBL. Handbook of transfusion medicine. 4th edn. 2007. 15 Chung M, Steinmetz OK, Gordon PH. Perioperative blood transfusion and outcome after resection for colorectal carcinoma. Br J Surg 1993; 80: 427e32.
Table 3
Blood substitutes (Table 3) With an ageing population in many countries, allied to expanding surgical interventions in the elderly and a reduced number of younger donors, the availability of blood is reducing. The cost of a unit of blood varies significantly (currently around £135/unit in the UK), but has increased with the introduction of additional processing and testing (HIV, uncommon antibodies, leucodepletion, etc.). Thus, there is an ongoing requirement for a safe and reliable red cell substitute. Blood substitutes can be classified as haemoglobin-based oxygen carriers (HBOC) such as or perfluorocarbon-based oxygen carriers (PFBOC). The first such product was approved more than twenty years ago but their use is still confined to specialist areas particularly within the field of trauma in Russia and South Africa. Much work, however, continues across the world in developing such products and it is anticipated that future developments will follow. Other products to prevent intraoperative bleeding The CRASH-2 trial from 201020 was an international multicentre trial which showed a mortality benefit from the early intravenous use of the antifibrinolytic drug, tranexamic acid in the context of trauma. This has led to its widespread use in this setting. It has also largely replaced aprotinin in the context of reducing blood loss during cardiopulmonary bypass and is increasingly now used in the orthopaedic setting, particularly in joint replacements. It acts by competitively inhibiting the activation of plasminogen to plasmin, thus preventing the breakdown of fibrin clots. For life-, limb- or sight-threatening bleeding within the context of a coagulopathy (most commonly, the use of warfarin), prothrombin complex concentrate (PCC) can be considered and used after discussion with a haematologist. PCC is a combination of high doses of the clotting factors II, VII, IX, X and proteins C and S. It works quickly to reverse the coagulopathy. It should not be used, however, for the routine reversal of warfarin.
SURGERY --:-
7
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
16 Brand A, Houbiers JGA, Vamvakas EC, Blajchman MA, eds. Clinical studies of blood transfusion and cancer. Immunomodulatorys effects of blood transfusion. Bethesda, MD: AABB Press, 1999; 145e90. 17 https://clinicaltrials.gov/ct2/show/NCT01692418 Preoperative Intravenous Iron to treat Anaemia in Major Surgery (PREVENTT). 18 Carless PA, Henry DA, Moxey AJ, O’Connell DL, Brown T, Fergusson DA. Cell salvage for minimising perioperative allogeneic blood transfusion (review). Cochrane Database Syst Rev 2006. Art. No.:CD001888.
SURGERY --:-
19 Neider AM, Carmack AJK, Sved PD, Kim SS, Manoharan M, Soloway MS. Intraoperative cell salvage during radical prostatectomy is not associated with greater biochemical recurrence rate. Urol 2005; 65: 730e4. 20 Shakur H, Roberts I, Bautista R. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 23e32.
8
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
Oxygen content of blood ¼ ðO2 carried by HbÞ þ ðO2 in solutionÞ
Anaemia and blood transfusion
¼ ð1:34 Hb SpO2 0:01Þ þ ð0:023 PaO2 Þ The haemoglobin dissociation curve (Figure 1) describes the relationship between oxygen saturation and the partial pressure of oxygen. Its sigmoid shape can be explained as follows. Each haemoglobin molecule is able to bind up to four oxygen molecules. There is a reduced tendency for the first and fourth oxygen molecules to bind (the lower and upper plateau portions of the graph, respectively) and an increased tendency for the second and third oxygen molecules to combine with haemoglobin (the steep portion of the curve). The upper plateau portion corresponds with the high PO2 (around 13 kPa) at the pulmonary capillaries when there will be little drop in oxygen carriage until the PO2 drops to less than 7.5 kPa (approximately 55 mmHg). The steep portion represents the environment at the systemic capillaries where a small drop in PO2 will result in a large release of oxygen from the haemoglobin to attempt to ensure oxygen delivery meets demand. The strength with which oxygen combines with haemoglobin is further affected by other environmental factors. Increased affinity for oxygen is represented by a leftward shift of the curve and reduced affinity (and therefore increased delivery of oxygen to the tissues) is represented by a right shift. This has numerous clinical implications. An example is in the systemic inflammatory response where temperature and metabolic activity are often increased, causing CO2 and lactic acid formation. This hypercarbia and lactataemia shifts the oxygen dissociation curve to the right, allowing more oxygen to be released to the tissues for a given PO2.
Barry Paul Ian Nesbitt
Abstract Anaemia is a common diagnosis in surgical practice. It may impair oxygen delivery to tissues and cause significant complications. This article discusses definitions, critical levels of anaemia (along with transfusion triggers), an overview of the manufacture provision, and use of various blood products along with novel agents and research areas for the future.
Keywords Anaemia; blood products; complications; transfusion
Anaemia is a common problem encountered in surgical patients. We will provide an overview of why, and what level of anaemia is important, and the value of transfusion triggers under different clinical circumstances. We will then move on to transfusion itself and describe both established and novel products available with an evaluation of when and how they are best used.
Overview of oxygen carriage Oxygen delivery to the tissues is an essential process and is dependent on cardiac output and the oxygen content of the blood. Oxygen is carried in the blood in two forms. 1. A very small amount is dissolved in the plasma. The actual quantity depends on the partial pressure of oxygen (PO2) according to the formula 0.023 ml O2/100 ml blood/kPa PO2, and, in a healthy patient breathing room air, only 3 ml of oxygen is dissolved in every litre of plasma. Supplementation of inspired oxygen increases this by only a small degree, although hyperbaric oxygen can significantly increase plasma oxygen carriage. 2. Most of the oxygen in the circulation combines with haemoglobin to form oxyhaemoglobin. Each gram of haemoglobin is capable of carrying 1.34 ml of oxygen and so a patient fully saturated with oxygen with a haemoglobin concentration of 15 g/dl would carry approximately 200 ml of oxygen for every litre of blood. Hence, the total oxygen content of a sample of blood may be calculated as:
When is anaemia significant? Anaemia is defined as a haemoglobin below the expected value when age, gender, pregnancy and environmental factors (such as
The oxygen–haemoglobin dissociation curve
Oxyhaemoglobin (%)
100
75
Temperature pH CO2 2,3-DPG
50
25
0
Barry Paul MB.BS MRCP FRCA EDIC FFICM is a Consultant in Anaesthesia and Intensive Care Medicine at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. Conflicts of interest: none.
0
5
10
15
20
PO2 (kPa)
Ian Nesbitt MB.BS FRCA DICM FFICM is a Consultant in Anaesthesia and Intensive Care Medicine at Freeman Hospital, Newcastle upon Tyne, UK. Conflicts of interest: none.
SURGERY --:-
Temperature pH CO2 2,3-DPG
2,3-DPG, 2,3-diphosphoglycerate.
Figure 1
1
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
patients.4,5 Ninety-five per cent of patients spending more than 3 days in critical care develop anaemia.6 This is due in a large degree to an ‘acute anaemia of chronic disease’ e a blunted reticulocyte count for the degree of anaemia, along with cytokine mediated low levels of erythropoietin, and functional iron deficiency, along with a variable element of bone marrow dysfunction. The issue of trying to establish an appropriate transfusion trigger in this group was addressed by the TRICC trial in 1998.7 This compared a restrictive target haemoglobin of 7.0e9.0 g/dl and a trigger of <7 g/dl with a more liberal strategy of aiming for 10.0e12.0 g/dl and a trigger of 10.0 g/dl during the first 3 days of a patient’s stay in ICU. The investigators found no difference in mortality at 30 and 60 days in both groups but subgroup analysis suggested a lower mortality with the restrictive strategy (trigger <7 g/dl). This, perhaps counter-intuitive result, may be partly explained by potential immunomodulation caused by transfusion, particularly the white cell component. These findings have been supported by several other similar studies and a Cochrane review,8 and for most critical care patients, a transfusion trigger of 7 g/dl is widely accepted. Possible exceptions to the use of a restrictive strategy include patients with ischaemic heart disease where there is evidence of active myocardial ischaemia9 (consider transfusion to a haemoglobin of 9.5 g/dl) and in early severe sepsis (aim for haemoglobin >10 g/dl) to ensure central venous oxygen saturations are >70%.10
WHO grading of anaemia severity Grade
Severity
Hb range (g/dl)
0 1 2 3 4
None Mild Moderate Severe Life threatening
>11 9.5e10.9 8.0e9.4 6.5e7.9 <6.5
Table 1
altitude) have been considered. The World Health Organization (WHO) defines anaemia as a haemoglobin <13 g/dl (haematocrit <39%) for adult males and <12 g/dl (haematocrit <36%) for non-pregnant adult females.1 The WHO also grades severity of anaemia for patients with cancer using the scale detailed in Table 1. Whilst a cause for anaemia should always be considered (Box 1), there is variation in practice as to when and how anaemia should be treated. A critical value for anaemia is reached when oxygen delivery fails to provide the oxygen demand under specific clinical circumstances. For young, healthy patients, it is unclear what this critical value is e survivors of extreme anaemia (Hb < 1 g/dl) have been reported, but these are the exception.2 For the majority of patients, a complex interaction of cardiac co-morbidity, age, degree of anaemia and actual blood loss exists. The risks of complications and death increase with all these variables, but a marked increase in mortality has been seen with haemoglobin levels lower than 6 g/dl.2 For many patients, however, the risk of complications remains significant at higher haemoglobin levels. Thus, a specific trigger for transfusion will depend on individual patient assessment to a large degree. Even decades after the introduction of the arbitrary traditional 10/30 ‘rule’ (haemoglobin 10 g/dl or haematocrit 0.3), it is not possible to provide a simple answer. General recommendations are that few adult patients require a haemoglobin greater than 10 g/dl, and few should be denied transfusion with a haemoglobin below 6 g/dl.3
Established blood products available for transfusion Until the late 1970s, most blood was transfused without being processed into its constituents and was termed ‘whole blood’. While this is still common practice in some countries, in the UK almost all donations are now processed into red cells, platelets and plasma after screening for infectious agents and removing white cells (leucodepletion) (Figure 2). The donor blood is drawn into a bag containing 63 ml of an anticoagulant preservative solution, normally CPDA1 (citrate, phosphate, dextrose and adenine). The citrate binds calcium, acting as an anticoagulant while the other components support red cell metabolism. Each donation is tested to determine the ABO and RhD group of the donor’s red cells. Anti-A and anti-B antibody titres are also checked on donations from blood group O to minimize the risk of transfusion reactions.
Anaemia in the critically ill Red cells A standard unit of red cells contains approximately 20 ml of plasma with the rest replaced by 100 ml of a storage solution. This solution has been improved over time, and currently contains saline, adenine, glucose and mannitol (SAGM). The total volume ranges from 180 ml to 350 ml with a mean of 282 ml. Mean haematocrit is 57%. The red cells are stored between 2 and 6 C for up to 35 days and the product must be compatible with the recipient’s ABO (and usually RhD) type. During the storage process, RBCs undergo numerous changes which may be deleterious to their intended function of carrying oxygen in the recipient patient. These include haemolysis, decreased concentrations of 2,3 DPG, NO and ATP, intracellular acidosis and leakage of potassium. The erythrocyte consequently becomes irregular (an echinocyte) with a less deformable cell
Anaemia is a common problem in critical care patients, affecting approximately 60e70% of patients on admission, with moderate to severe anaemia (<9 g/dl) affecting around a quarter of
Causes of anaemia in surgical and critically ill patients C C C C C C C
Blood loss Haemodilution Frequent phlebotomy B12 or folate deficiency Reduced red cell survival or production Low erythropoietin levels Functional iron deficiency
Box 1
SURGERY --:-
2
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Production of blood products and plasma derivatives Education Recruitment Selection Donation
Platelet pheresis
Test for: HIV Hepatitis B Hepatitis C HTLV Syphillis ABO + RhD Other phenotypes Red cell antibodies (CMV HbS, malaria)
Process into blood components Filter to remove leucocytes
Red cells
Pooled platelets Fresh frozen plasma
Plasma (from non-UK source)
Fractionation
35 days Confirm compatibility 4˚C
5 22˚C days (Pool)
24 –30˚C months Plasma (Thaw) derivatives e.g. albumin, immunoglobulin
Patient 14 Reproduced with permission from the Handbook of Transfusion Medicine . CMV, cytomegalovirus; HIV, human immunodeficiency virus; HTLV, human T-lymphotropic virus.
Figure 2
membrane and reduced oxygen carrying capacity. This was of particular concern given that in the UK, the average age of blood administered is 14 days.11 This resulted in two major trials e RECESS12 and ABLE13 being undertaken and recently published. They both showed that age of blood did not correlate with organ dysfunction or mortality.
Platelets are either derived either from the buffy coat of whole blood pooled from four donors or by single donor aphaeresis which has the advantage of exposing the recipient to the blood of fewer donors. They are stored at 22 C with agitation to ensure function is maintained and should ideally be ABO and RhD compatible with the recipient, due to the plasma present.
Platelets Platelet transfusions are for the prevention and treatment of haemorrhage in patients with thrombocytopaenia or in those with platelet dysfunction (e.g. aspirin and clopidogrel therapy).
Fresh frozen plasma (FFP) Fresh frozen plasma is indicated for the replacement of coagulation factors in specific circumstances and for thrombotic thrombocytopaenia. It refers to plasma that has been
SURGERY --:-
3
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
centrifuged, separated and frozen at 30 C within 8 hours of collection. Each unit of FFP is obtained from a single donor. It is no longer used in haemophilia now that concentrated forms of coagulation factor are available for use. FFP should be ABO matched to avoid the risk of haemolysis from donor anti-A or anti-B but does not need to be RhD matched. It can typically be stored for up to 2 years. Once thawed, plasma can be stored at room temperature for 4 hours without loss of activity, or for 5 days at 1e6 C.
multiple other antigens, modern cross-matching to ensure minimal risk has become a much more complex process. Bacterial contamination Although rare, this is more likely to occur with platelet transfusions as they are stored at higher temperatures. The clinical features are similar to haemolytic reactions, with a rapid onset. Examination of the donor bag to confirm the diagnosis and identify the offending organism is important to guide antibiotic therapy.
Cryoprecipitate Cryoprecipitate is produced after controlled thawing of FFP to precipitate the high molecular weight proteins, namely fibrinogen, factor VIIIc and von Willebrand factor. A typical adult dose of 110e250 ml, derived from 5 units of FFP, will perhaps raise the fibrinogen level by about 1 g/l.
Transfusion-related lung injury (TRALI) Characteristically occurring six hours after transfusion, the patient develops dyspnoea, hypoxia, cough and bilateral infiltrates on chest X-ray. Treatment is supportive. Although TRALI may occur after any blood product (or similar, such as intravenous immunoglobulin), platelets and FFP are both most strongly implicated. The donors are almost always parous women with antibodies that react strongly against the recipient’s leucocytes.
Acute complications of transfusion Acute haemolytic reaction The ABO blood groups are divided into groups A, B, AB and O based on which antigen the individual’s red cells carry. IgM antibodies are produced from early childhood against either the A or B antigens depending on what the red cell expresses. Therefore if incompatible blood is administered, the transfused cells will be destroyed with resultant haemolysis and the liberation of inflammatory cytokines (TNF, IL-1, IL-8) causing vasodilation, hypotension, bleeding and organ failure. Mortality from such reactions has been quoted at 5e10%. The variation in severity is thought to be due to the different potency of antibodies produced and in particular the relative lack of potency in group A or B individuals compared to group O. The reaction is usually most severe when group A blood is transfused to a group O patient. Haemolytic reactions are usually prevented by means of the group and screen. This involves characterizing the patient’s ABO and RhD group and screening for any additional antibodies that could haemolyse donor red cells. A traditional grid of donor-recipient compatibility is shown in Table 2. However, with increased testing and recognition of
Transfusion-associated circulatory overload (TACO) This tends to occur when patients receive high volumes of blood products quickly in the setting of heart failure. It can be treated with supportive treatment and diuresis. Allergic reactions Most allergic reactions are mild and can be treated with antihistamines and steroids if necessary. Anaphylaxis is rare. Figure 3 shown below summarizes the NHS Blood and Transplantation (NHSBT) guidelines for the management of acute reactions to transfusion in the UK.
Delayed complications of transfusion Delayed haemolytic transfusion reaction (DHTR) This is a delayed reaction (more than 24 hours) after a transfusion in a patient who has previously been immunized to a red cell antigen either by transfusion or pregnancy. Rhesus antibodies and Kidd antibodies are most often implicated with typical features being jaundice, fever, falling haemoglobin concentration and even renal failure. Characteristically, there will be haemolysis on the blood film with raised LDH and a positive direct Coombs test.
A+ AB+ BAB+ ABO+ O-
A+
A-
safe
safe safe
B+
Red Cell Donor BAB+
safe safe
safe safe
safe
safe safe safe safe
AB-
O+
O-
safe
safe safe safe safe safe safe safe safe
safe safe
safe safe
safe safe
Transfusion-associated graft-versus-host disease This occurs 1e2 weeks after transfusion and is caused by donor lymphocytes damaging recipient cells carrying HLA antigens. Although rare, it is more common in patients who are immunocompromised or those receiving a transfusion from a close relative. The condition causes multi-organ failure and is associated with a high mortality. For this reason, all patients at risk of GvHD should receive irradiated blood products to inactivate donor lymphocytes.
AB+ “The universal recipient”
Recipient
Traditional blood group compatibility
O negaƟve “The universal donor”
Post-transfusion purpura This is caused by platelet-specific alloantibodies and is more common in female patients. Symptoms start to appear approximately 1 week after exposure with spontaneous bleeding
Table 2
SURGERY --:-
4
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Acute transfusion reactions Symptoms/signs of acute transfusion reaction Fever; chills; tachycardia; hyper-or hypotension; collapse; rigors; flushing; urticaria; bone, muscle, chest and/or abdominal pain; shortness of breath; nausea; generally feeling unwell; respiratory distress
Stop the transfusion and call a doctor • Measure temperature, pulse, blood pressure, respiratory rate, O2 saturation • Check the identity of the recipient with the details on the unit and compatibility label or tag
Febrile non-haemolytic transfusion reaction • If temperature rise less than 1.5°C, the observations are stable and the patient is otherwise well, give paracetamol • Restart infusion at slower rate and observe more frequently
Urticaria Mild fever
Reaction involves mild fever or urticarial rash only
Mild allergic reaction • Give chlorphenamine 10 mg slowly IV and restart the transfusion at a slower rate and observe more frequently
ABO incompatibility • • • • • • •
Stop transfusion Take down unit and giving set Return intact to blood bank Commence IV saline infusion Monitor urine output/catheterize Maintain urine output at › 100 ml/hr Give furosemide if urine output falls/ absent • Treat any DIC with appropriate blood components • Inform hospital transfusion department immediately
NO Severe allergic reaction YES Suspected ABO incompatibility
NO YES Severe allergic reaction
Haemolytic reaction/bacterial infection of unit • Stop transfusion • Take down unit and giving set • Return intact to blood bank along with all other used/unused units • Take blood cultures, repeat blood group/ cross-match/FBC, coagulation screen, biochemistry, urinalysis • Monitor urine output • Commence broad spectrum antibiotics if suspected bacterial infection • Commence oxygen and fluid support • Seek haematological and intensive care advice
Fluid overload • Give oxygen and frusemide 40–80 mg IV
NO
YES
Bronchospasm, angioedema, abdominal pain, hypotension • Stop transfusion • Take down unit and giving set • Return intact to blood bank along with all other used/unused units • Give chlorphenamine 10 mg slow IV • Commence O2 • Give salbutamol nebulizer • If severe hypotension, give adrenaline (0.5 ml of 1 in 1000 intramuscular)* • Clotted sample to transfusion laboratory • Saline wash future components (* equivalent to 0.5 mg IM)
Other haemolytic reaction/bacterial contamination NO
Acute dyspnoea/ hypotension Raised Monitor blood gases Perform CXR CVP Measure CVP/ pulmonary capillary pressure
TRALI Normal CVP
• Clinical features of acute LVF with fever and chills • Discontinue transfusion • Give 100% oxygen • Treat as ARDS – ventilate if hypoxia indicates
Reproduced with permission from the Handbook of Transfusion Medicine.14 ARDS, acute respiratory distress syndrome; CVP, central venous pressure; CXR, chest X-ray; DIC, disseminated intravascular coagulation; FBC, full blood count; IM, intramuscular; IV, intravenous; LVF, left ventricular failure; TRALI, transfusion-related lung injury.
Figure 3
SURGERY --:-
5
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
associated with severe thrombocytopenia. High dose IV immunoglobulin is the treatment of choice.
Preoperative autologous blood transfusion (PABD) This involves the patient donating their own blood for storage up to 5 weeks before their operation. Starting haemoglobin concentration should be >10 g/dl for females and >11 g/dl for males. At least 2 units, but usually 3e5, are donated and the patient is subsequently given iron therapy and erythropoietin to accelerate recovery. Whilst this strategy reduces the risk of developing red cell antibodies and acquiring viral infections, it does not reduce (and may actually increase) the risk of bacterial contamination or wrong blood errors. The optimal strategy for PABD is for patients having elective major surgery with a high predicted blood loss, but without intraoperative blood salvage.
Transfusion and cancer recurrence rates The issue of whether transfusing blood products during or after cancer surgery increases recurrence rates has been debated for over 20 years. Chung et al.15 published a meta-analysis of 100 observational studies in 1993 of patients with colorectal, head and neck, breast, gastric, lung, cervical and prostate cancer. They reported that the odds ratio of adverse clinical outcome was significant (p < 0.05) in the transfusion group for all sites except the cervix. Brand and Houbiers16 performed a further metaanalysis 6 years later for colorectal patients. They found no association between perioperative transfusion and cancer recurrence (p ¼ 0.55) or death due to cancer recurrence (p ¼ 0.19) but found a relationship between perioperative transfusion and higher overall mortality (p < 0.001). There are a number of possibilities for the above findings. Firstly, patients who require allogeneic blood transfusion are likely to have more significant disease, suffer a greater physiological insult during treatment and are therefore more likely to have an adverse outcome. Secondly, publication bias may exist which means the studies that were included into both metaanalyses may be skewed in favour of showing adverse outcomes with transfusion. Thirdly, it is possible that a transfusionrelated immunomodulatory (TRIM) effect contributed to the results. If so, since the advent of leucodepletion of blood products in many countries, this seems less likely to be a continuing issue. As yet, no adequately designed trial has demonstrated a causal relationship between cancer recurrence and allogeneic blood transfusion. Therefore, a pragmatic viewpoint should be taken and no patient who absolutely requires transfusion should have this withheld based on the risk of cancer recurrence.
Acute normovolaemic haemodilution This involves withdrawing several units of blood from the patient at induction of anaesthesia and replacing the circulatory volume with colloid or crystalloid. Total red cell mass lost during the operation is therefore reduced and the withdrawn blood from the patient can be replaced postoperatively. Acute normovolaemic haemodilution is an unproven technique and is rarely used in the UK. Cell salvage Allogeneic transfusion is a limited resource with associated risks as described and significant cost implications. As a result, autologous transfusion with intraoperative and postoperative cell salvage, when possible, should be considered as this may reduce allogeneic transfusion by around 40%.18 In this process, blood from the surgical field is collected and anticoagulant is added. It is then filtered and washed (usually by centrifugation) to remove contaminants. Red cells remain whilst plasma, platelets, heparin and inflammatory mediators are discarded to give a product with a haematocrit of 50e70%. Cell salvage should be considered for operations where the intraoperative blood loss is predicted to be >1 litre or >20% of blood volume. It should also be specifically considered in certain patient groups such as those with rare blood groups or antibodies, patients with preoperative anaemia or where there is patient refusal to receive allogeneic blood transfusion. The views of individual Jehovah’s Witnesses to allogeneic and autologous blood transfusion vary and so this should be discussed with each patient on a case by case basis. Although cell salvage for cancer surgery is not recommended by the manufacturers due to the possibility of reinfusion of cancer cells, the UK National Institute for Health and Care Excellence (NICE) has approved cell salvage for surgery involving urological malignancies following a trial in patients undergoing radical prostatectomy and cystectomy which showed no difference in recurrence rates.19 Other concerns exist with cell salvage during bowel surgery (due to potential infection risk) and obstetric haemorrhage (due to potential amniotic fluid embolization and rhesus sensitization). As a result, with bowel surgery, cell salvage should commence after decontamination of the infected area and by using broad-spectrum antibiotics. In the obstetric setting, there should be separate suctioning of amniotic fluid and blood.
Reporting adverse reactions (SHOT/SABRE) All adverse reactions or events associated with transfusion should be reported. In the UK, the Medicines Health Related Agency (MHRA) has set up a reporting system called SABRE (Serious Adverse Blood Reactions and Events) that is linked to SHOT (Serious Hazards of Transfusion), an independent haemovigilance body set up and run by professionals working within the transfusion service. Both systems are designed to analyse such incidents and respond in a positive way so that patient safety can be improved. Similar systems exist in many other countries.
Alternative strategies for managing anaemia Ferrous sulphate Ferrous sulphate can be taken orally at a dose of 200 mg three times daily when iron deficiency is proven and there is no sinister cause. Correction will be achieved at 1 month in 90% of cases but is often poorly tolerated by patients. The PREVENTT Trial17 (Preoperative Intravenous Iron to Treat Anaemia in Major Surgery) is currently recruiting patients to assess if intravenous iron reduces the need for perioperative transfusion of red cells. B12 and folate replacement can be instituted if deficiency of either is found to be the cause.
SURGERY --:-
6
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
Summary
Blood substitutes Advantages
Disadvantages
Not limited by number of donors If mass produced could be cheaper Significantly reduced infective complications Fewer ethical objections Longer storage time No need to refrigerate Allow for full immediate oxygen carrying capacity
Currently expensive Not widely available for commercial use Novel therapies that are as yet unproven Many substitutes withdrawn due to unacceptable adverse CVS and renal events
Anaemia is a common problem encountered in surgical patients. The management is not always straightforward and difficult cases should ideally be managed within a multidisciplinary approach tailored to the individual patient. Where transfusion is necessary, clear communication should ensue with the haematology team to ensure that optimal patient care is delivered and that adverse incidents are minimized. Where they do occur, reporting is mandatory. Research is active in developing alternatives strategies to blood products, but remain largely outwith standard clinical practice at present. A REFERENCES 1 Emmanuel JE, McClelland B, Page R, eds. The clinical use of blood in medicine, obstetrics, paediatrics, surgery anaesthesia, trauma & burns. World Health Organization, 1997; 337. 2 Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011; 107(S1): i41e59. 3 Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger. Vox Sang 2010; 98: 2e11. 4 Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288: 1499e507. 5 Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically illdcurrent clinical practice in the United States. Crit Care Med 2004; 32: 39e52. 6 Corwin HL, Rodriguez RM, Pearl RG, et al. Erythropoietin response in critically ill patients. Crit Care Med 1997; 25(suppl 1): A82. 7 Hebert PC, Wells G, Martin C, et al. Canadian survey of transfusion practices in critically ill patients. Transfusion Requirements in Critical Care Investigators and the Canadian Critical Care Trials Group. Crit Care Med 1998; 26: 482e7. 8 Carless PA, Henry DA, Carson JL, Hebert PP, McClelland B, Ker K. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2010. Art. No.:CD002042. 9 Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases? Crit Care Med 2001; 29: 227e34. 10 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368e77. 11 Nee PA, Bonney SC, Madden P, et al. Transfusion of red blood cells in critical illness. JICS 2010; 4: 240e4. 12 Steiner ME, Ness PM, Assman SF. Effect of red cell storage duration on patients undergoing cardiac surgery. NEJM 2015; 372: 1419e29. 13 Lacroix J, Hebert PC. Fergusson DA age of transfused blood in critically ill adults. NEJM 2015; 372: 1410e8. 14 McLelland DBL. Handbook of transfusion medicine. 4th edn. 2007. 15 Chung M, Steinmetz OK, Gordon PH. Perioperative blood transfusion and outcome after resection for colorectal carcinoma. Br J Surg 1993; 80: 427e32.
Table 3
Blood substitutes (Table 3) With an ageing population in many countries, allied to expanding surgical interventions in the elderly and a reduced number of younger donors, the availability of blood is reducing. The cost of a unit of blood varies significantly (currently around £135/unit in the UK), but has increased with the introduction of additional processing and testing (HIV, uncommon antibodies, leucodepletion, etc.). Thus, there is an ongoing requirement for a safe and reliable red cell substitute. Blood substitutes can be classified as haemoglobin-based oxygen carriers (HBOC) such as or perfluorocarbon-based oxygen carriers (PFBOC). The first such product was approved more than twenty years ago but their use is still confined to specialist areas particularly within the field of trauma in Russia and South Africa. Much work, however, continues across the world in developing such products and it is anticipated that future developments will follow. Other products to prevent intraoperative bleeding The CRASH-2 trial from 201020 was an international multicentre trial which showed a mortality benefit from the early intravenous use of the antifibrinolytic drug, tranexamic acid in the context of trauma. This has led to its widespread use in this setting. It has also largely replaced aprotinin in the context of reducing blood loss during cardiopulmonary bypass and is increasingly now used in the orthopaedic setting, particularly in joint replacements. It acts by competitively inhibiting the activation of plasminogen to plasmin, thus preventing the breakdown of fibrin clots. For life-, limb- or sight-threatening bleeding within the context of a coagulopathy (most commonly, the use of warfarin), prothrombin complex concentrate (PCC) can be considered and used after discussion with a haematologist. PCC is a combination of high doses of the clotting factors II, VII, IX, X and proteins C and S. It works quickly to reverse the coagulopathy. It should not be used, however, for the routine reversal of warfarin.
SURGERY --:-
7
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007
PERIOPERATIVE MANAGEMENT
16 Brand A, Houbiers JGA, Vamvakas EC, Blajchman MA, eds. Clinical studies of blood transfusion and cancer. Immunomodulatorys effects of blood transfusion. Bethesda, MD: AABB Press, 1999; 145e90. 17 https://clinicaltrials.gov/ct2/show/NCT01692418 Preoperative Intravenous Iron to treat Anaemia in Major Surgery (PREVENTT). 18 Carless PA, Henry DA, Moxey AJ, O’Connell DL, Brown T, Fergusson DA. Cell salvage for minimising perioperative allogeneic blood transfusion (review). Cochrane Database Syst Rev 2006. Art. No.:CD001888.
SURGERY --:-
19 Neider AM, Carmack AJK, Sved PD, Kim SS, Manoharan M, Soloway MS. Intraoperative cell salvage during radical prostatectomy is not associated with greater biochemical recurrence rate. Urol 2005; 65: 730e4. 20 Shakur H, Roberts I, Bautista R. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 23e32.
8
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Paul B, Nesbitt I, Anaemia and blood transfusion, Surgery (2016), http://dx.doi.org/10.1016/ j.mpsur.2015.11.007