Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Schmerber v. California wikipedia , lookup
Hemolytic-uremic syndrome wikipedia , lookup
Autotransfusion wikipedia , lookup
Hemorheology wikipedia , lookup
Blood donation wikipedia , lookup
Plateletpheresis wikipedia , lookup
Men who have sex with men blood donor controversy wikipedia , lookup
Blood transfusion wikipedia , lookup
Jehovah's Witnesses and blood transfusions wikipedia , lookup
8 March 2013 No. 9 Perioperative Transfusion Triggers P Slabber Commentator: V Ramson Moderator: C Evans Department of Anaesthetics CONTENTS INTRODUCTION...........................................................................3 HISTORY OF BLOOD TRANSFUSION........................................3 PHYSIOLOGICAL PRINCIPLES..................................................4 MEASUREMENT OF TISSUE HYPOXIA.....................................7 WEIGHING UP THE RISKS: HAZARDS OF ANAEMIA………..9 WEIGHING UP THE RISKS: HAZARDS OF BLOOD ADMINISTRATION......................................................................10 WEIGHING UP THE RISKS: CONCLUSION..............................11 EVIDENCE BASED MEDICINE: A STEP CLOSER...................12 CURRENT GUIDELINES............................................................14 METHODS TO DECREASE ALLOGENEIC BLOOD USAGE PERIOPERATIVELY...................................................................15 CONCLUSION.............................................................................16 Page 2 of 21 PERIOPERATIVE TRANSFUSION TRIGGERS INTRODUCTION Many red blood cell transfusions take place in the perioperative period and as anaesthetists we are intricately involved in this decision making process. With the rising cost of blood products, critical shortages in blood supplies and increasing awareness of the complications of blood transfusion, this decision making process deserves more attention than it is currently receiving. Appropriately used blood transfusions can be life saving, but unfortunately many allogeneic blood transfusions administered to our patients are unnecessary or even harmful.(1) On a daily basis anaesthetists have to weigh up the risks of transfusion against the risks of anaemia in their decision to transfuse or not.(2) Evidence is often contradictory or extrapolated from a different patient group to the one you are faced with. Guidelines can be vague which leaves the decision up to the discretion of the often uninformed physician. This booklet aims to shed some light on these issues faced by anaesthetists, often on a daily basis. HISTORY OF BLOOD TRANSFUSION Since the 16th century physicians have shown an interest in blood transfusions. Jean Denis was the first to transfuse sheep’s blood to a young boy age 15 years in 1667. The boy survived, but this practise was outlawed in 1678 due to a very high mortality. Philip Physick was the first known to transfuse human blood to his patients, but did not publish his work. James Blundell, an obstetrician, described and published the first successful transfusion of human blood to a patient after post partum haemorrhage in 1818. He used the husband’s blood to accomplish this feat.(3,4) His mortality rate was around 50%. Since then significant advances has been made in blood transfusion practices with resultant improved mortality rates. Historically a transfusion trigger of 10g/dl was proposed as early as 1942.(5) This number was used for normal, healthy perioperative patients by the majority of physicians for the next 4 to 5 decades. This so called “10/30” rule (10g/dl haemoglobin or hematocrit of 30%) was the generally accepted Page 3 of 21 minimum level of haemoglobin, particularly in the surgical setting.(6) This led to unnecessary transfusion of patients and probably to a significant transfusion related infection rate (10% of HIV infection worldwide is thought to be transfusion related) as donated blood has only been screened for HIV since 1985 in US.(7) The “10/30” rule was challenged in 1988 during the national institutes of health consensus development conference. It led to a new era in blood administration practice and it was proposed that otherwise healthy patients with a haemoglobin of more than 10g/dl rarely require transfusion and patients with acute anaemia with a haemoglobin less than 7g/dl will frequently require transfusion.(8) This was a step in the right direction and sparked new interest in blood transfusion therapy which led to significant effort being placed on research. The hunt for the universal transfusion trigger was on. With this, guidelines was being developed and published on a frequent basis.(9) Despite all this, transfusion practices today still vary significantly worldwide.(10) Today around 85 million units are transfused annually worldwide.(11) We are seeing far fewer transfusions in the 10g/dl range. Unfortunately most transfusion decisions are still being based on a specific haemoglobin level, rather than on a combination of physiological signs due to tissue hypoxia.(12) The reasons for this are multifactorial, but one reason may be the poor understanding of the physiological principles of oxygen delivery in the body and the fact that there is currently no simple universally accepted test to detect regional tissue hypoxia in any given area in the body. PHYSIOLOGICAL PRINCIPLES The reason for red blood cell transfusion is simple. It is to improve oxygen delivery to cells. Aerobic metabolism and the prevention of hypoxia is dependent on the continuous delivery of oxygen to tissue. The oxygen flux equation is a well known physiological principle that describes all the factors involved in oxygen delivery.(9) DO2 = CO x CaO2 CO = heart rate x stroke volume CaO2 = (Hb x 1.34 x SaO2) + (PaO2 x 0.031) Page 4 of 21 From the above equation we can see that oxygen delivery (DO2) is determined by the product of cardiac output (CO) and arterial oxygen content (CaO2). Cardiac output is determined by the product of heart rate and ventricular stroke volume. Arterial oxygen content is determined by 3 factors: haemoglobin concentration, haemoglobin saturation with oxygen (SaO2) and arterial oxygen tension (PaO2). Global oxygen consumption (VO2) describes the amount of oxygen consumed by the whole body and is usually around 250mls oxygen/min at rest. Global oxygen delivery (DO2) as described by the above equation is usually around 1000mls oxygen/min at rest. The relationship between VO2 and DO2 (VO2/DO2) is known as the oxygen extraction ratio (O2ER) which is usually around 25% at rest.(18) The relationship is illustrated in figure 1.(19) Figure 1: The relationship in a healthy adult between VO2 and DO2(19) It is possible to see from this graph that a normal VO2 can be maintained for a wide range of DO2 as long as the DO2 is above the critical DO2 point, therefore the VO2 will be DO2 independent. But at a specific point termed the critical DO2 (DO2 CRIT) the VO2 starts to decrease (VO2 will be DO2 dependent) in relation to the decrease in DO2 leading to tissue hypoxia, anaerobic metabolism and lactate formation. With the above concept in mind we can now look at the body’s compensatory mechanisms in response to acute anaemia. Acute anaemia Page 5 of 21 can lead to decreased DO2. These compensatory mechanisms are aimed at keeping the DO2 above the DO2CRIT to maintain VO2 and therefore adequate tissue oxygenation. First there is a change in blood flow dynamics caused by the decreased viscosity seen in anaemic blood. This will lead to improved flow characteristics resulting in increased venous return and decreased systemic vascular resistance, both leading to increased CO and therefore DO2. Secondly, the anaemia leads to sympathetic nervous system activation causing increased CO. Third, the O2ER can be increased leading to increased VO2 for the same DO2. It must be remembered that this compensatory mechanism is sufficient to maintain VO2 only as long as the DO2 is above the DO2CRIT and that once the DO2 falls below the DO2CRIT an increase in O2ER will not be sufficient to compensate and prevent tissue hypoxia.(18) Of all the determining factors for oxygen delivery, the most important physiological adaptation during acute normovolaemic anaemia is the increase in cardiac output and increased oxygen extraction ratio.(2) Due to these compensatory mechanisms by the body we see healthy patients able to tolerate haemoglobin levels at 5g/dl by increasing their CO.(13) Reports on Jehovas Witness patients with haemoglobin levels of 5g/dl or less showed inconsistent mortality rates related to severe anaemia, demonstrating adequate compensation is possible.(14) One of the most extreme examples of anaemia tolerance is that of a 53 year old man that suffered multiple stab wounds leading to axillary artery injury and significant bleeding. He’s lowest haemoglobin was 0.7g/dl and he never showed any signs of myocardial ischemia and survived without any sequelae.(15) As mentioned before, one of the most important compensatory mechanisms during acute anaemia is an increase in cardiac output. This can only occur if there is adequate coronary perfusion to supply the increased metabolic demands of the myocardium during this stressful period. With this in mind, it would be obvious that myocardial oxygen supply is one of the factors involved in determining the physiological limits to acute anaemia. Therefore adequate coronary perfusion is believed to be an important limiting factor in the tolerance to acute anaemia.(2,16) This is probably illustrated in the observation that patients with cardiovascular disease and perioperative anaemia are more likely to have a worse clinical outcome.(17) This might also be the reason that a higher transfusion trigger is often chosen for patients with coronary artery disease. Page 6 of 21 The simplest way to support a patient’s DO2 perioperatively is by increasing the inspired oxygen fraction (FiO2). It has been argued that by increasing the FiO2, the DO2 doesn’t increase significantly due to the fact that at an arterial oxygen tension (PaO2) of 70mmHg the haemoglobin saturation is 90% (deduced from the oxy-haemoglobin dissociation curve).(20) Although during acute normovoleamic anaemia there is an expansion of the plasma compartment containing dissolved oxygen. So by hyperoxic ventilation (FiO2 = 60%) it is possible to saturate this compartment fully causing an increased gradient for oxygen between plasma and cells and therefore improving tissue oxygenation.(18) This is partly proven by a study where healthy volunteers were haemodiluted from 12.7g/dl to 5.7g/dl causing cognitive and memory impairment which was completely reversed after breathing oxygen which increased PaO2 levels to approximately 400mmHg.(21) It is obvious now that there are multiple physiological factors playing a role in tissue oxygenation. In clinical practice it would be a daunting task to try and determine which variable is responsible for the tissue hypoxia and where exactly in the body tissue hypoxia is taking place. It would be of great value if there was a simple test available to measure the degree of tissue hypoxia both on a global and regional level. Mixed venous oxygen saturation has been proposed. MEASUREMENT OF TISSUE HYPOXIA In the quest to move away from arbitrary haemoglobin based transfusion triggers, the concept of physiological transfusion triggers emerged.(22) Physiological transfusion triggers potentially reflect a reversible limitation of oxygen delivery to peripheral tissues. The reversal of a physiological transfusion trigger by a blood transfusion can be seen as an indicator of transfusion effectiveness. Of course there are prerequisites for the correct interpretation of these physiological transfusion triggers like normovolaemia and appropriate depth of anaesthesia.(19) The limitation of tissue oxygenation can be measured in a variety of regions in the body. Physiological transfusion triggers for both global (lactate, mixed venous oxygen saturation, tachycardia, increased catecholamine Page 7 of 21 demand) and regional (ST segment changes, compromised ventricular contractility seen on echo, P300 latency test) tissue oxygenation were proposed to assist in guiding red blood cell transfusion practice.(19) All the above physiological transfusion triggers have got shortfalls in their application and will require a fair amount of knowledge for their correct interpretation. I will only look at the concepts and possible short falls behind using mixed venous oxygen saturation as a physiological transfusion trigger. Mixed venous oxygen saturation (SvO2) is a clinical tool which integrates the relationship between global VO2 and DO2. It is strictly speaking the oxygen saturation of haemoglobin taken from the pulmonary artery and is usually in the range of 70% in healthy adults.(23) Because placing a pulmonary artery catheter often leads to iatrogeneic complications, a surrogate for this measurement, the central venous oxygen saturation (ScvO2) which is taken from the right atrium via a central venous catheter was suggested. It has been proposed that there is good correlation between these two measurements with ScvO2 being on average 5% higher than SvO2.(24) This is due to deoxygenated blood draining into the right ventricle from the coronary sinus and thebesian veins. There are 4 main determinants of SvO2 namely haemoglobin, CO, SaO2 (previous 3 factors determine DO2) and VO2. When haemoglobin levels decrease during anaemia, there is a decrease in DO2 if CO and SaO2 stay constant, which will lead to a decrease in SvO2 if VO2 stays the same or increases. This might be seen as a warning sign and prompt sometimes inappropriate action to increase DO2 by increasing haemoglobin (by giving blood) or increasing CO (by giving inotropes) to ensure tissue oxygenation. We assume tissue hypoxia if SvO2 decreases, but this might not be the case as an increase on O2ER (physiological compensatory mechanism) can compensate for the decreased DO2 and prevent tissue hypoxia.(23) When DO2 decreases below DO2CRIT, there is a state of VO2-DO2 dependency, also known as tissue dysoxia. This indicates tissue hypoxia and increasing lactate (a physiological transfusion trigger) formation. Dysoxia is usually present in humans when the SvO2 is below 50%. It has been proposed that measures to increase DO2 (e.g. blood transfusion) should be followed to increase SvO2 levels above 70% to ensure tissue oxygenation.(25) Although using SvO2 to guide interventions that increase Page 8 of 21 DO2 to ensure adequate tissue oxygenation can be falsely reassuring. This is because in some pathological states where there is low O2ER the SvO2 will seem adequate but the patient is really in a state of hypoxia. This is where regional oxygenation measurement might be more useful. Recently there has been a trend towards using physiological transfusion triggers to guide blood administration.(22) The shortfalls of SvO2 measurement, as explained above, has to be remembered especially in the perioperative period when there are many factors influencing the VO2-DO2 relationship.(23) The maintenance of adequate tissue oxygenation in the perioperative period is central to our practice, although there are no universally accepted guidelines or physiological transfusion trigger to monitor oxygen delivery and tissue oxygenation.(2) This leaves the physician to weigh up the risks of anaemia against the risks of blood administration while deciding whether or not to transfuse the patient. WEIGHING UP THE RISKS: HAZARDS OF ANAEMIA In healthy patients, mortality significantly increases once their haemoglobin levels drop below 3.5g/dl.(4) In the perioperative setting it was demonstrated that there was a correlation between preoperative anaemia and mortality. This study by Carson in 1988, “Severity of anaemia and operative mortality and morbidity”, showed a mortality of 7.1% when haemoglobin was above 10g/dl compared to a mortality of 61% when haemoglobin dropped below 6g/dl.(26) In patients with cardiovascular disease (including coronary artery disease) the presence of a haemoglobin less than 6g/dl let to a significant increase in 30 day mortality rate compared to those with a haemoglobin above 12g/dl.(27) In patients with chronic renal disease the presence of anaemia led to a higher annual mortality.(28) In elderly patients (>65yrs) even a mild degree of preoperative anaemia led to increased 30 day mortality rate.(29) From the above we can deduct that there is sufficient data identifying anaemia as an independent risk factor for perioperative morbidity and mortality.(2) The degree of anaemia also seem to correlate with severity of outcomes. It is also safe to say that in patients with cardiovascular comorbidities the effect of anaemia on morbidity and mortality is augmented. Page 9 of 21 WEIGHING UP THE RISKS: HAZARDS OF BLOOD ADMINISTRATION The complications associated with blood administration are numerous and often serious, contributing to patient morbidity and mortality.(34) As outlined below it can be classified into immunological and non immunological. Blood transfusion complications Non immunological Infection Viral Bacterial Immunological TACO Parasite TRALI Prion TRIM Febrile reaction Non hemolytic Anaphylactic Post transfusion purpura Hemolytic Graft vs Host disease ABO incompatibility Infection has originally been the most feared side effect of blood transfusion.(2) Costly measures has been implemented to minimise this risk and today especially in first world countries, receiving a unit of blood has been quoted as being very safe.(4) Although the risk is never zero. Cyto megalo virus is the most commonly transmitted virus with an incidence of around 1 in 20. Luckily disseminated infection seems to only develop in immuno-suppressed patients eg very low birth weight neonates. In South Africa every unit is routinely tested for HIV 1 and 2, hepatitis B and C virus and syphilis using tests like hepatitis B surface antigen, hepatitis C antibody, HIV 1 and 2 antibodies and nucleic acid amplification testing (for HIV, HBV and HCV).(30) These screening tools adds significantly to the cost of a unit of packed red blood cells is South Africa so that in 2012 you would pay R1369.00 in state sector. The incidence of adverse effects to red blood cell transfusion is well illustrated and compared to other fatal occurences on a logarithmic scale in figure 2. Page 10 of 21 Figure 2: Adverse effects of RBC transfusion contrasted with other risks on a logarithmic scale. (12) Physicians are less aware of the immunological complications of blood transfusion. Currently one of the most dangerous hazards of blood transfusion is TRALI (transfusion related acute lung injury).(31) By definition it is a new acute lung injury occurring within 6 hours of transfusion in patients without risk factors for acute lung injury.(2) It is manifested by dyspnoea, fever and hypotension and treatment is supportative, often requiring intubation and ventilation. One of the differentials for TRALI would be TACO (transfusion associated circulatory overload). TACO occurs often in the elderly and is treated with diuretics.(32) It also adds significantly to length of hospital stay. TRIM (transfusion related immunomodulation) results in a general increase in post transfusion infection rates. It is probably one of the reasons for seeing increased postoperative bacterial infection and cancer recurrence rates in patients receiving allogeneic blood transfusions.(33) WEIGHING UP THE RISKS: CONCLUSION We can now see that both anaemia and blood transfusion hold significant risks for our patients. As physicians we know that patients presenting with preoperative anaemia, are at higher risk for worse outcomes than those Page 11 of 21 without anaemia. But we also know that if you transfuse these anaemic patients in the perioperative period the outcomes are often worse. Therefore the ideal would be to have all patients presenting to theatre with normal haemoglobin levels. This might not be a viable option as patients would have to be seen months in advance, with frequent follow up, to monitor the treatment effects to anaemia. Therefore in our daily practice a trade-off between the effects of anaemia and those of red blood cell administration has to be made while calculating our decision whether to transfuse or not.(2) Having an approach to this problem, that is easy to follow, would make decisions regarding perioperative blood administration easier. Not surprisingly, there is no universally accepted approach to this complicated dilemma. EVIDENCE BASED MEDICINE: A STEP CLOSER Because it is a complicated process to weigh up the risks of anaemia against the risks of blood transfusion in our every day decision making process, maybe there is a better approach to this issue. By comparing patient outcomes through reliable evidence in specific patient groups, randomized to a restrictive (7-9 g/dl) and liberal (>9 g/dl) transfusion groups we might find a simpler approach to our practice. If the outcomes are the same, the restrictive group will not be harmed by infectious and noninfectious complications of unnecessary blood transfusions and a significant cost saving will incur as less blood units will be administered.(12) There have been multiple studies investigating the above research hypothesis. Some of them were small retrospective studies in burns patients with various flaws in study design.(35) Others were adequately powered randomised controlled trials of specific patient groups e.g. the TRACS (transfusion requirements after cardiac surgery) trial.(36) Although, to get the best overall view of the literature, systematic reviews that incorporate randomized controlled trials with specific exclusion criteria should be looked at. Two such reviews have been published by the Cochrane database, one in 2002 and the other in 2010.(37,38) The similarity in certain outcomes between these two reviews were striking: Page 12 of 21 40% decreased risk of receiving RBC in the restrictive group vs liberal group 30-day mortality and rate of cardiac events unaffected in restrictive group vs liberal group Length of hospital/ICU stay unaffected in restrictive group vs liberal group Subsequent to these reviews the FOCUS (Liberal or restrictive transfusion in high risk patients after hip surgery) trial was published.(39) They enrolled 2016 patients of age 50 yrs or older who either had a history of cardiovascular disease or had risk factors for it. After randomization, results similar to the above reviews were found: An average of 2 units more transfused in the liberal group Death or inability to walk across a room unassisted after 60 days, no difference between liberal and restrictive groups Rate of in hospital acute coronary syndrome 4.3% in liberal and 5.2% in restrictive groups (no statistically significant difference) The most recent systematic review of the literature was published in 2012 by the AABB (American association of blood banks).(12) Like the systematic reviews in the Cochrane database they used specific criteria for selection of trials from the 1950s until 2011. Based on high quality evidence they made very specific recommendations: 1. In hospitalized haemodynamically stable adult and paediatric patients only consider transfusion when Haemoglobin is <7g/dl. 2. In hospitalized heamodynamically stable postoperative surgical patients or patients with pre-existing cardiovascular disease consider transfusion when Haemoglobin is <8g/dl Or when they are symptomatic (angina, hypotension, tachycardia). Page 13 of 21 CURRENT GUIDELINES There are multiple recommendations and practice guidelines in the literature with regards to blood transfusion practices. For us as anaesthetists, the most practical and relevant guidelines was published in 2006 by the American Society of Anaesthesiologists Task Force.(40) These are most likely the guidelines that will be referred to in a court case if negligence with regards to transfusion practice is suspected. For simplicity I will summarise only what is relevant to us. ASA Practice guidelines for perioperative blood transfusion: 1. Monitor for inadequate perfusion and oxygenation of vital organs: Conventional methods - Blood pressure - Heart rate - Oxygen saturation of blood - Urine output - Electrocardiography Special methods - Echocardiography - Mixed venous oxygen saturation - Blood gasses (? lactate levels) Note: In the guideline it states that the literature is insufficient to evaluate the efficacy of these special methods for detecting inadequate perfusion/oxygenation of tissue or organs. 2. Monitor for transfusion indications: Hb < 6 g/dl (especially in acute anaemia) Hb between 6 – 10 g/dl the decision should be based on: - Ongoing indications of organ ischemia - Potential or actual ongoing bleeding (rate and magnitude) - Assessment of intravascular volume status - Risk factors for inadequate oxygenation (eg patients with cardiorespiratory disease or high oxygen consumption) Page 14 of 21 METHODS TO DECREASE ALLOGENEIC BLOOD USAGE PERIOPERATIVELY Considerable research has been done on methods to decrease allogeneic blood usage worldwide. Not all these options (like erythropoietin) are practical in the South African setting for various reasons like cost and time factor. Below I will shortly mention the most appropriate methods for anaesthetists to decrease allogeneic blood usage in the perioperative period. 1. Decreased “transfusion triggers” Decrease your transfusion trigger in stable healthy patients to 7 g/dl, being vigilant in observing for signs of tissue hypoxia. Restrictive transfusion strategies have been shown by Carless et al in a systematic review, “Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion”, to reduce the risk of receiving a red blood cell transfusion by a relative 37%.(38) This equates to an average absolute risk reduction of 33% (95% CI 21%45%).(38) It is probably the most effective and safest method to decrease allogeneic blood usage. There is no additional costs involved and in only requires a change in mindset. 2. Cell salvage Usage of this technique has become more popular with advances in technology. It is considered a viable option in specific settings. Relative contra-indications and indications have to be considered to be able to benefit maximally from this technique.(41) If the mean transfusion requirement for the specific procedure exceeds 1 unit it should be considered. 3. Acute normovolemic haemodilution The literature supports the efficacy in reducing the number of allogeneic units transfused per patient. But there is controversy with regards to the efficacy to reduce the number of patients receiving allogeneic blood.(42) It does seem to be safe and effective in centres that make routine use of this technique.(4) Page 15 of 21 4. Pharmacological interventions The use of antifibrinolytics (tranexamic acid and aprotinin) have been shown to decrease perioperative blood loss and allogeneic blood requirements in certain surgical procedures such as major orthopaedic surgery.(43) Tranexamic acid seems to be associated with less adverse events than aprotinin. 5. Induced hypotensive anaesthesia This has been shown to be effective in decreasing blood loss and requirements of allogeneic blood especially in orthognathic surgery(44), although it has been associated with it’s own side effects. Patient selection and appropriate monitoring is vital. CONCLUSION Around 700 000 units are transfused annually in South Africa.(30) As perioperative physicians we are faced with making decisions regarding blood administration almost on a daily basis. Blood should only be administered if it improves patient outcome. This is easier said than done as there are so many variables to consider. As each of our patients physiological limits to anaemia differ (depending on their state of health) the idea of a universal transfusion trigger has been correctly scrutinized in the literature as being too a simplistic approach. Although the use of physiological transfusion triggers e.g. mixed venous oxygen saturation has been suggested to guide management, they are not without limitations which need to be taken into consideration when used. Evidence based medicine has been invaluable in guiding our practice. The use of a liberal transfusion trigger (>9 g/dl) doesn’t have a better outcome for the majority of patients compared to a restrictive transfusion trigger (7-9 g/dl).(38) In specific high risk patient groups like those with acute coronary syndrome, the literature is insufficient to make recommendations with regards to transfusion guidelines.(12) In these groups vigilance with regards to monitoring for signs of tissue hypoxia is imperative to guide our decision. Page 16 of 21 The resistance to change in blood transfusion practice by doctors is affecting patient’s lives. I suggest following the ASA guidelines of 2006(40) as these are the most applicable to us as anaesthetists. I would encourage you to not only remember a specific number, but to use wisely all methods available to you and to take into consideration all variables known by you, to ensure tissue oxygenation and improve patient outcome. So before you administer the next bag of blood to your patient, ask yourself this: If this was me, would I want to receive this blood?? Page 17 of 21 REFERENCES 1. Le Manach Y, Syed S. Erythrocyte Transfusion: Remedy or Poison? Anesthesiology. 2012;117(6):1153-5 10.097/ALN.0b013e318271608b. 2. Meier J, Müller MM, Lauscher P, Sireis W, Seifried E, Zacharowski K. Perioperative red blood cell transfusion: Harmful or beneficial to the patient? Transfus Med Hemother. 2012;39(2):98–103. 3. Schmidt PJ. Transfusion in America in the eighteenth and nineteenth centuries. The New England journal of medicine. 1968 Dec 12;279(24):1319-20. PubMed PMID: 4880439. Epub 1968/12/12. eng. 4. Kaplan LJ. Transfusion and Autotransfusion. 2012. 5. Adams RC, Lundy JS. Anesthesia in Cases of Poor Surgical Risk: Some Suggestions for Decreasing the Risk. Anesthesiology. 1942;3(5):603-7. 6. Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, et al. The CRIT Study: Anemia and blood transfusion in the critically ill-current clinical practice in the United States. Critical care medicine. 2004 Jan;32(1):39-52. PubMed PMID: 14707558. Epub 2004/01/07. eng. 7. Ward JW, Holmberg SD, Allen JR, Cohn DL, Critchley SE, Kleinman SH, et al. Transmission of human immunodeficiency virus (HIV) by blood transfusions screened as negative for HIV antibody. The New England journal of medicine. 1988 02/;318(8):473-8. 8. Thurer RL. Evaluating transfusion triggers. JAMA. 1998;279(3):238-9. 9. Practice Guidelines for Blood Component Therapy: A Report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology. 1996;84(3):732-47. 10. Stover PE, Siegel LC, Parks R, Levin J, Body SC, Maddi R, et al. Variability in Transfusion Practice for Coronary Artery Bypass Surgery Persists Despite National Consensus Guidelines: A 24‐Institution Study. Anesthesiology. 1998;88(2):327-33. 11. Takei T, Amin NA, Schmid G, Dhingra-Kumar N, Rugg D. Progress in global blood safety for HIV. J Acquir Immune Defic Syndr. 2009;52:Suppl 2S127-31. 12. Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Annals of internal medicine. 2012 Jul 3;157(1):49-58. PubMed PMID: 22751760. Epub 2012/07/04. eng. Page 18 of 21 13. Weiskopf RB, Feiner J, Hopf HW, Viele MK, Watson JJ, Lieberman J, Kelley S, Toy P. Heart rate increases linearly in response to acute isovolemic anaemia. Transfusion. 2003;43:235–240. 14. Viele MK, Weiskopf RB: What can we learn about the need for transfusion from patients who refuse blood?: The experience with Jehovah's Witnesses. Transfusion 1994; 34:396-401. 15. Dai J, Tu W, Yang Z, Lin R. Case report: intraoperative management of extreme hemodilution in a patient with a severed axillary artery. Anesthesia and analgesia. 2010 Nov;111(5):1204-6. PubMed PMID: 20581160. Epub 2010/06/29. eng. 16. Tircoveanu R, van der Linden P. Hemodilution and anaemia in patients with cardiac disease: what is the safe limit? Curr Opin Anaesthesiol. 2008;21:66–70. 17. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996 Oct 19;348(9034):1055-60. PubMed PMID: 8874456. Epub 1996/10/19. eng. 18. Madjdpour C, Spahn DR. Allogeneic red blood cell transfusion: Physiology of oxygen transport. Best Practice & Research Clinical Anaesthesiology. 2007 6//;21(2):163-71. 19. Pape A, Stein P, Horn O, Habler O. Clinical evidence of blood transfusion effectiveness. Blood Transfus. 2009;7:250–258. 20. Shepherd SJ, Pearse RM. Role of Central and Mixed Venous Oxygen Saturation Measurement in Perioperative Care. Anesthesiology. 2009;111(3):649-56 10.1097/ALN.0b013e3181af59aa. 21. Weiskopf RB, Feiner J, Hopf HW, Viele MK, Watson JJ, Kramer JH, et al. Oxygen Reverses Deficits of Cognitive Function and Memory and Increased Heart Rate Induced by Acute Severe Isovolemic Anemia. Anesthesiology. 2002;96(4):871-7. 22. Vallet B, Adamczyk S, Barreau O, Lebuffe G. Physiologic transfusion triggers. Best Pract Res Clin Anaesthesiol. 2007;21:173–181. doi: 10.1016/j.bpa.2007.02.003. 23. Vallet B, Robin E, Lebuffe G. Venous oxygen saturation as a physiologic transfusion trigger. Crit Care. 2010;14:213. doi: 10.1186/cc8854. 24. Dueck MH, Klimek M, Appenrodt S, Weigand C, Boerner U. Trends but not individual values of central venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions. Anesthesiology. 2005;103:249–257. Page 19 of 21 25. Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–1377. doi: 10.1056/NEJMoa010307. 26. Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet. 1988;1:727–729. 27. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996;348:1055–1060. 28. Herzog CA, Muster HA, Li S, Collins AJ. Impact of congestive heart failure, chronic kidney disease, and anaemia on survival in the Medicare population. J Card Fail. 2004;10:467–472. 29. Wu W, Schifftner TL, Henderson WG, Eaton CB, Poses RM, Uttley G, Sharma SC, Vezeridis M, Khuri SF, Friedmann PD. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA. 2007;297:2481–2488. 30. Medical Directors of the South African Blood Transfusion Service. Clinical guidelines for the use of blood products in South Africa. 4th ed. South Africa. 2008 31. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113:3406–3417. 32. Popovsky MA, Audet AM, Andrzejewski CJ. Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematology. 1996;12:87–89. 33. Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma. 2003;54:908–914. 34. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Critical care medicine. 2008 Sep;36(9):2667-74. PubMed PMID: 18679112. Epub 2008/08/06. eng. 35. Kwan P, Gomez M, Cartotto R. Safe and successful restriction of transfusion in burn patients. Journal of burn care & research : official publication of the American Burn Association. 2006 NovDec;27(6):826-34. PubMed PMID: 17091078. Epub 2006/11/09. eng. 36. Hajjar LA, Vincent J, Galas FG, et al. Transfusion Requirements After Cardiac Surgery: The TRACS Randomized Controlled Trial. JAMA. 2010;304(14):1559-1567. doi:10.1001/jama.2010.1446 Page 20 of 21 37. Hill SR, Carless PA, Henry DA, Carson JL, Hebert PC, McClelland DB, et al.. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2002;CD002042. 38. 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;CD002042. 39. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, Nemo G, Dragert K, Beaupre L, Hildebrand K, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453–2462. 40. Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies: An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105(1):198-208. 41. Esper SA, Waters JH. Intra-operative cell salvage: a fresh look at the indications and contraindications. Blood transfusion = Trasfusione del sangue. 2011 Apr;9(2):139-47. PubMed PMID: 21251468. Pubmed Central PMCID: PMC3096856. Epub 2011/01/22. eng. 42. Segal JB, Blasco-Colmenares E, Norris EJ, Guallar E. Preoperative acute normovolemic hemodilution: a meta-analysis. Transfusion. 2004 May;44(5):632-44. PubMed PMID: 15104642. Epub 2004/04/24. eng. 43. Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, et al. Do Antifibrinolytics Reduce Allogeneic Blood Transfusion in Orthopedic Surgery? Anesthesiology. 2006;105(5):1034-46. 44. Ervens J, Marks C, Hechler M, Plath T, Hansen D, Hoffmeister B. Effect of induced hypotensive anaesthesia vs isovolaemic haemodilution on blood loss and transfusion requirements in orthognathic surgery: a prospective, single-blinded, randomized, controlled clinical study. International journal of oral and maxillofacial surgery. 2010 Dec;39(12):1168-74. PubMed PMID: 20961738. Epub 2010/10/22. eng. Page 21 of 21