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EARL WYNANDS LECTURE
Transfusion – Time for a shift
John Freedman, MD, FRCPC, St Michael’s Hospital, Toronto
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Patients think transfusion is special & beneficial, but have difficulty accepting small risks they can’t control.
Blood Donors believe their contribution is a gift to the community that will be used appropriately and safely.
Clinicians think blood is ordinary, take transfusion for granted, benefit is assumed & risks regarded as minimal.
Governments view blood as a commodity and transfusion medicine as an expensive support service which
should be regulated and funded in a cost-effective manner.
(James Isbister)
The past is prologue. Reviewing the history of transfusion tells us how far we have come, but also where we
need to go. The past has been filled with innovation and important discoveries, but is also fraught with
stumbling blocks and unintended side effects. Although much has been achieved and transfusion is safer today
than ever, we are nonetheless recognizing new potential concerns with transfusion and we are undergoing a
paradigm shift in our attitudes, approach and patient management in regard to blood transfusion.
Historical review
The Bible tells us that ‘the life/soul of the flesh is in the blood’ (Leviticus 17:11). Pliny described drinking
blood of gladiators to cure epilepsy, while Galen advised drinking blood of a weasel for rabies and ancient
Norwegians drank seal and whale blood for epilepsy & scurvy.1 Of the drinking of blood, Pietro di Abano in
C13th said: ‘He who drinks of menstrual blood or that of a leper will be seen to be distracted and lunatic,
evil-minded and forgetful, and his cure is to drink of daisies powdered and mixed with water of honey, and to
bathe in tepid water & to copulate with girls according to the law natural, and to play with pretty girls &
young boys; and … to eat serpents whose heads & tails have been cut off with the edge of a palm frond’.1
Often stated as the first transfusion, in 1492, the aging Pope Innocent VIII is said to have received a
transfusion of the blood of three young boys.2-4 The Pope died, the donors died, and the physician fled the
country. There followed a 150-year near-complete hiatus in transfusion work. In the C17th, many infusion
experiments performed e.g. intravenous wine, beer, opium, emetics, water, nitric acid and sulfuric acid but
Richard Lower, in Oxford, is credited with performing, in 1665, the first authentic blood transfusion (animal
to animal). Lower was important in that he was the first to define the appropriateness of transfusional
replacement of blood in severe hemorrhage (in marked contrast to the standard cure-all treatment of the day,
phlebotomization). The first human transfusion was by Jean-Baptiste Denis in Paris in 1667,5 who said he
preferred to use animal (rather than human) blood, as he believed it less likely ‘to be rendered impure by
passion or vice’. Denis’ 4th transfusion recipient suffered from syphilitic madness and it was thought that the
tranquil blood of an animal might alleviate his symptoms. After a symptom-free transfusion of calf blood, he
was again transfused, giving rise to the first description of a hemolytic transfusion reaction: ‘As soon as the
blood began to enter into his veins, he felt ... heat along his arm and under his arm-pits … His pulse rose …
we observed a plentiful sweat over all his face … he complained of a great pain in his kidneys, and that he
was not well in the stomach, and that he was ready to choke … he vomited of bacon and fat … found himself
urged to urine and asked to go to stool … When he awakened … a general lassitude he felt in all his limbs …
made a great glass full of urine, of a color as black as if mixed with soot of chimney…bled at the nose very
plentifully…his urine cleared up and …resumed little by little its natural color’. He improved, however, so
another transfusion was done, which proved fatal. This incident led to prohibition of blood transfusions: in
1678 by the French Parliament and by the British Royal Society and in 1679 by the Vatican, and, again, a 150year near-complete hiatus in transfusion work followed. In the C18th transfusions were done only sporadically;
generally animal to human. They were thought of as a cure for mental aberration or as a youth potion for the
aged, rather than treatment for blood loss. Reciprocal transfusions between husband & wife were suggested as
a cure for marital discord and blood was thought to carry characteristics of the donor to the recipient e.g.
sheep blood would make a dog grow wool, hooves and horns; and cat blood would make a girl feline.1
In 1818, James Blundell (obstetrician, Guy’s Hospital, London) attempted human-to-human transfusion.
He preferred human donors, because ‘What is to be done in an emergency? A dog might come when you
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whistled, but the animal is small; a calf might have appeared better suited for the purpose, but it has not been
taught to walk properly up the stairs’. Between 1825 and 1830 he performed 10 transfusions and stated: ‘The
fact that life may be saved by transfusion of blood into the veins will be beneficial a thousand years hence as it
is on this day’.6 And blood could indeed be ‘good stuff’. Following transfusion of a woman with post-partum
hemorrhage with her husband’s blood, the woman, previously semicomatose, suddenly exclaimed ‘By Jesus, I
feel as strong as a bull’.7 However, it was not without danger and in an 1849 review of reported transfusion
patients to that date there were 48 cases, of which 18 had had a fatal outcome, which was an estimated
mortality ‘rather less than that of hernia, or about the same as the average amputation’.8 Transfusions in the
1800s were plagued by complications. It became recognized that same species transfusions were more
efficacious than interspecies transfusions, but animal to human transfusions were performed as late as 1890.
However, gradually it was recognized that ‘Human blood only should be employed…When lamb’s blood is
used, an invariable result seems to be the escape, through the kidneys, of haemoglobin’.9 One problem was
that when removed from the donor, blood tended to clot. Defibrinated blood, sodium bicarbonate and
phosphate were proposed, but transfusion was generally done by either artery-to-vein cannulation or using
paraffin-coated tubes. Saline was first used as blood substitute in 1884 and was observed to be safer than, and
frequently as effective as, blood transfusion and milk infusion was advocated, as it was thought that the ‘white
corpuscles of milk were capable of being transformed into red blood corpuscles’.
Transfusion entered the scientific age when Karl Landsteiner, in 1900, described the ABO blood groups.
This was as a footnote in an article on bacterial fermentation, but for which he received a Nobel prize in 1930.
World War I led to the universal adoption of blood typing to select blood donors. During the first World War,
an important advance was the use of sodium citrate as anticoagulant. H. Lilienthal, who performed the first
transfusion on a human using Lewisohn's citrate method, wrote: ‘The ease and simplicity of this transfusion
was most amazing to me, who had so often suffered more than the patient in performing this life-saving
operation’. In 1943 Mollison described the use of acid-citrate-dextrose (ACD) as anticoagulant: this allowed
blood to be stored for 21 days and became the basis for all subsequent anticoagulant/preservative solutions: 28
days storage in CPD (1957), 35 d in CPD-adenine (1965), and currently >42 d (added glucose, mannitol). The
first functional blood bank was in Barcelona, 1936, and first transfusion service in the field during the Spanish
Civil War. Before 1939 there were only 3 blood group systems (ABO, MN, P), 3 known plasma proteins,
there was no Coombs test. In 1939, there was just whole blood and plasma. Blood component therapy may be
regarded as one of the great advances in transfusion medicine. Blood was collected into reusable glass bottles
in the first half of the C20th, but pyrogenic reactions due to incomplete cleaning were frequent, as was air
embolism due to the vacuum systems with glass bottles. In 1949 Walter conducted trials of plastic bags; these
were disposable and because of their flexibility allowed safe separation of blood components, allowing
development of component therapy. Other major advances in the C20th include the antiglobulin test (Coombs,
Mourant & Race, 1945), Blood Banks; AABB (1947), platelet concentrates (1961; decreased mortality in
cancer), AHF and cryoprecipitate for hemophiliacs (1960s), Rh immune globulin for hemolytic disease of the
newborn (1967), infectious disease testing: transfusion-transmitted hepatitis (1943), HBsAg (1971), high-risk
donor screening (1985), HIV screening (1987), anti-HBc (2002), NAT/PCR.
What will the 21st century bring? An arbitrary list might include:
* A paradigm shift in approach to transfusion: blood conservation/patient blood management (PBM)
* Error/adverse event prevention (including infections)
* Supply and demand issues
* Proteomics/genomics/molecular techniques; pharmacologics; stem cells; ‘artificial’ blood products
* Understanding the immunopathophysiology of transfusion
Current issues for transfusion
An important question remains: What is the benefit of red cell transfusion: What can we conclude?
Evidence of benefit from RBC transfusion is hard to find. No prospective randomized trials have ever been
done to establish the life-saving benefit of RBC transfusion. Most benefit is assumed and not scientifically
proven. Certainly some patients will benefit, but we need to be better able to identify who they are. We have
learned that giving more blood is not necessarily better (e.g. the TRICC study,(10) and that many transfusions
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are probably unnecessary. So, as with all areas of medicine, we need to consider the risks versus the benefits
and known risks should outweigh perceived benefits every time. Increasing evidence suggests that
transfusions are associated with poorer short and long term outcomes. Considerable literature shows the
negative effect of RBC transfusion on postoperative infection and on mortality,11,12 probably secondary to
transfusion-induced immunomodulation (TRIM). Furthermore, noteworthy is the large number of events of
incorrect blood transfusion and that the majority of these occur because of errors at the clinical unit level.13,14
In addition, while in Canada we tend to think of blood as “free”, there is a significant economic impact of
both anemia and allogeneic transfusion. We know that 30–70% of patients come to surgery anemic and that
anemia increases the cost of delivering health care by over 50%.15 Blood transfusions also cost, and any
strategy that reduces the use of blood transfusion reduces cost and Health Care Workers in ALL disciplines of
medicine can assist in reducing unnecessary and inappropriate transfusion. What is the cost of transfusion?
Direct and indirect costs include product (tubing, supplies, labor, transport, laboratory testing), as well as
hospital Blood Bank (crossmatching, etc), clerical, nursing. The cost of producing a unit of red cells for
Ontario has been estimated to be about $450. But there is further resource use in increased ICU and hospital
length-of-stay (LOS), treatment of complications, etc, with a large multicentre observational study showing
that transfusion can increase hospitalization costs by 40% and estimated the total cost at ≈$12-1400/unit.16,17
There may be issues of supply versus demand. As Boomers age, potential demand grows exponentially: it
is reported that patients < 40 years of age use 5 units RBC/1000 population, those aged 40-70 use 40 units
RBC, but those >70 years old use 200 units RBC/1000 population. An aging population may reduce the
number of eligible donors. An international survey in 2007 (bbt_7537_steve-morgan[1].pdf) indicated that
Canada overall has a relatively low red cell use at 31.8 units RBC/1000 population (versus France 32.6,
England 36.4, Australia 37.4, Finland 47.7, USA 49.4, Germany 50.8).
In summary then, it is clear that (1) the demand for blood may outweigh the supply, (2) there are real risks
associated with blood transfusion, and (3) blood is not ‘free’.
Why then do we transfuse? A large study18 examined the documented reasons for initiating a blood
transfusion in 4892 critically ill patients from 284 medical, surgical, or medical-surgical ICUs. Patients were
more frequently transfused to correct low hemoglobin (Hb) levels (i.e. laboratory-diagnosed anemia) than to
replace hemorrhagic blood loss (i.e. symptoms). Despite a plethora of guidelines (the great number suggesting
that the true answer remains unknown), probably all we have learned is that we should (a) limit transfusion to
appropriate need, (b) transfuse unit by unit, and (c) there is probably no single Hb value optimal for all
patients. For each transfusion many factors need to be considered e.g. patient symptoms, cardiac output,
hypotension, heart rate, stroke volume, contractility, peripheral vascular resistance, O2 release from red cell,
decreased blood viscosity, dilution, presence of cardiovascular, cerebrovascular disease, etc. While several
studies document a general lack of compliance with appropriate transfusion guidelines, as well as tremendous
variation in transfusion practice between different institutions and even among individual physicians within
the same institution, many hospitals are steering towards a hemoglobin trigger for transfusion of 7 g/dL
regardless of comorbidities. Some institutions use 7 g/dL for healthy patients and 8 g/dL for patients with
cardiorespiratory problems. The main point is to avoid transfusing healthy patients based on hemoglobin
alone. Meta-analyses show convincingly that a restrictive transfusion approach is beneficial.19 Nonetheless, it
is well-recognized that considerable inter-institutional variability exists e.g. a recent study of 80,000 on-pump
CABG patients in 408 hospitals found that the RBC transfusion rate ranged from 7.8 - 98.8%.20
Patient Blood Management (PBM) Programs
PBM is the timely multidisciplinary application of evidence-based medical and surgical concepts designed
to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve
patient outcome. In the presence of clinical uncertainty, the default position has been to administer a blood
transfusion; this is not usually the case with other therapies. Blood transfusion is inherently hazardous and
costly and should only be prescribed when there is evidence that patient benefit would outweigh the potential
for harm. In 1997, the Krever Commission Report in Canada stated that “blood components and blood
products will never be without risk. The best way to reduce that risk is to reduce their use”. Despite important
advances to reduce transfusion risks, this statement remains true today.
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Why Blood Conservation? In addition to frequent patient preference for avoiding allogeneic blood
transfusion, reasons include (a) improving patient outcomes: evidence is unequivocal that patient outcomes
are better when transfusion policies are restricted and several hundred articles show improved outcomes when
transfusion is restricted. In particular, several major trials21,22 have shown lower infection rates, lower
mortality and shorter LOS, with reduced transfusion, (b) conserving a limited resource: the supply of blood is
an increasing challenge. While about 40% of the population is eligible to donate blood, only ~4% do so and
changing demographics results in fewer donors and more usage. On the other hand, it has been suggested that
40-60% of transfusions are administered to stable non-bleeding patients,23 and (c) lowering costs: previous
cost analyses of transfusion generally failed to capture all the multiple activities involved in the complex
process of transfusion. The recent Cost of Blood Consensus Conference of international experts put the
average cost of delivering a unit of red blood cells as ~$1200/unit.16,17 Patients may receive many units.
Hospitals with established PBM programs may have a 50-75% reduction in blood use in orthopedic and heart
surgery and LaPar et al24 have recently shown that PBM in CABG is also cost-saving.
Likely the most effective strategy to decrease allogeneic transfusion is not to focus solely on any
particular intervention but to use a combination of initiatives in a comprehensive, multidisciplinary,
multimodal PBM program. The aims of PBM are basically two-fold: (a) to avoid allogeneic transfusion
whenever possible, and (b) when needing to transfuse, use the minimal amount possible. At its core is (1)
correcting preoperative anemia, (2) minimizing perioperative RBC loss, and (3) using minimal Hb-based
transfusion triggers. There is abundant literature over the past decade on the approaches and benefits of
PBM/Blood Conservation, e.g. the comprehensive STS/SCA Guidelines for Blood Conservation and
Transfusion in Cardiac Surgery25,26 and others e.g.27 Potential options for implementing PBM include (a)
hemoglobin enhancement (e.g. erythropoietin, oral or parenteral iron), (b) autologous blood (e.g. PAD, ANH,
cell salvage), and (c) prevention of bleeding intra-operatively (e.g. antifibrinolytics, topical hemostatics: fibrin
glues, sealants, topical thrombins, and mechanical maneuvers such as harmonic scalpels, controlled
hypotension, regional anaesthesia, etc, although most important is good surgical technique). As recently
shown28, these techniques are effective also in valve surgery. Off-pump and minimally-invasive procedures
tend to use less blood and guidelines for PBM in such cases have recently been developed.29
As noted by Kickler,30 this approach is not easy. One must work at it. It requires ‘coordination of services
across a variety of departments…. cooperation between outpatient scheduling, surgical and anesthesia
physicians and their clinic personnel, operating room scheduling, intensivists and hematologists to get the
patient prepared, … billing office…. This is in contrast to a transfusion, which can usually be accomplished
with one phone call…. A plethora of new techniques and therapies are available …and their relative merits,
alone and in combination, still needs to be investigated, but it is becoming standard of practice’.
Factors to consider in the surgical transfusion decision include clinical history (e.g. cardiopulmonary
disease, existing coagulopathy, anemia, trauma classification), medications (antiplatelet drugs,
anticoagulants), clinical symptoms (dyspnea on exertion, angina), Hb level, O2 delivery/consumption, surgical
procedure (elective versus emergency, laparoscopic versus open), estimated blood loss, Jehovah’s Witness.
Pre-operative factors predictive for transfusion include red cell mass, type and urgency of surgery, serum
creatinine >1.3 mg/dL, prothrombin time. Hence while the overall aims in PBM are (a) to start with more, (b)
lose less, and (c) save/give back what you can, preoperative anemia is one of the universal predictors of
transfusion risk and usage.31 Anemia is more common than generally recognized and has been estimated to be
present preoperatively in 40-60% of surgical patients and to increase cost of health care delivery by 50%.
Anemia is associated with increased morbidity, hospital length of stay, mortality and risk of blood transfusion,
but it remains under-recognized, poorly, inappropriately and haphazardly treated, with resultant transfusion
overuse. A preoperative anemia workup32 should begin at least 3 - 4 weeks pre-operatively and include a
routine CBC and the red cell indices. The work-up should be started by primary care physician, surgeon,
anesthesiologist, cardiologist – anyone who is involved in preoperative planning.
The ONTraC program
In 2002 the Ontario Ministry of Health funded the Ontario Transfusion Coordinators (ONTraC) program
of a network of coordinators in 25 independent hospitals throughout Ontario, a province with a population of
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almost 13 million people and 1,076,000 km² in area. This includes teaching and community hospitals and
accounts for ≈70% of the blood used in the province (≈400,000 units red cells annually). The basic intent is to
enhance transfusion practice outside of the Blood Bank, with the coordinators acting as a ‘clinical bridge’
between the Transfusion Service and the rest of the hospital. The coordinators interact with physicians, nurses
and patients to promote blood conservation and alternatives to allogeneic transfusion. Their focused role is (1)
management of a blood conservation program (50% of time), (2) patient, family, staff education (25%), (3)
data management (20%), and (4) other local activities (5%). Each hospital is provided with coordinator salary,
a computer, and a small amount for sundries. The coordinators receive initial extensive training, and there is
an annual formal contract and instructions for each hospital. Progress is monitored by an oversight committee
and there are annual site visits by the program management. In general, the coordinators assess the patients
preoperatively, usually at the pre-admission clinic visit (3-5 weeks before surgery), identify patients at risk of
transfusion ahead of surgery, discuss informed consent and transfusion alternatives, investigate, diagnose and
treat anemia through the family doctor, surgeon, anesthetist, or hematologist, and facilitate erythropoietin
and/or iron, antifibrinolytics, cell salvage, etc. Further details on the program may be found elsewhere.33,34
Our targeted procedures are knee & hip arthroplasty, CABG, and radical prostatectomy, but patients for
many other procedures are also seen by the coordinators. The proportion of patients transfused in the province
has decreased markedly e.g. in knee surgery 24.5% at onset in 2002 versus 3.2% in 2013, and in primary
CABG 60.2% in 2002 versus 21.5% in 2013. The number of units per transfused patient also decreased (in
CABG 3.3 versus 1.96 units/transfused patient). The marked inter-institutional variability seen initially has
lessened significantly (p=0.0105) with no differences between teaching and community hospitals. There has
been change in blood conservation measures employed. Whereas initially 10-15% of patients underwent PAD,
in 2013 only 0.2% of knee surgery and 0% of CABG had PAD and few of these actually received the
autologous blood. On the other hand, whereas only 1.5% and 0% of primary CABG patients received
erythropoietin or IV iron respectively in 2002, in 2013 this increased to 5-7% and was 11% in valve surgery
patients. For patients receiving erythropoietin, the mean dose was 90,000 IU and mean Hb increment was 1.47
g/dl (maximum 5.3 g/dl); there was no increase in venothromboembolic events in patients on erythropoietin
(0.2%) versus those not so treated.
In CABG patients the reduction in transfusion rate when a blood conservation measure was employed (vs.
not used) ranged from 27–41% for erythropoietin, intravenous iron, antifibrinolytics, cell salvage, topical
hemostatics, controlled hypotension, ANH. Reduction in transfusion rates was markedly enhanced when
multimodal blood conservation was employed:when no blood conservation measure was employed the
transfusion rate was 29%, when one measure was used 22%, two measures used 18%, and when > 3 used
13%. Type of surgery influences transfusion rates: 21% for 1-3 vessels, 25% for > 3 vessels, 50% for re-do
surgery, but 15.8% for minimally invasive surgery.
Preoperative Hb level is a critical parameter for subsequent transfusion. The lower Hb levels in females is
reflected in higher transfusion rates (and in number of units transfused) in women. Our data shows that when
preoperative Hb is less than 13 g/dl, transfusion rates are markedly higher and regression analysis
demonstrated that if a preoperative Hb of 13 g/dl has an odds ratio of 1 for receiving an allogeneic transfusion,
then a preoperative Hb of 10 g/dl confers a 7-fold higher odds ratio of receiving an allogeneic transfusion.
Therefore we attempt to achieve a preoperative Hb of at least 13 g/dl. It is important to have a long lead time
to optimize preoperative treatment of anemia e.g in hip arthroplasty patients seen <7 days prior to surgery,
transfusion rate was 11.5%; if seen 7-14 days prior the rate was 10.2%, 15-21 days 9.6%, and >21 days 4.8%.
However, there has been a recent emphasis on shortening wait times for cardiac surgery and only 27% of
CABG in 2013 had a lead time >14 days. Mean nadir Hb (‘transfusion trigger’) level for transfused CABG
patients was 7.4±0.6 g/dl. It has been suggested that a Hb level at discharge greater than 10 g/dl, or even 9
g/dl, in a transfused patient serves as a surrogate for excessive transfusion”.35 We found that 17% of transfused CABG patients had discharge Hb >10 g/dl, most of these targeting a Hb between 10 to 11 g/dl.
In addition to viral transmission, allergic and hemolytic transfusion reactions, TRALI, transfusionassociated cardiac overload, and errors in the transfusion process, there has been increasing recognition of
TRIM. Transfusion has been correlated with increased time to extubation, LOS, postoperative morbidity and
mortality, infection rates and decreased long-term survival. One older review found an increased odds ratio for
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bacterial infection of 3.5 (range 1.4-15.2) in transfused patients.36 A link of transfusion with increased cancer
recurrence is more tenuous. A large prospective study identified red cell transfusion as the strongest
independent predictor of all-cause morbidity and mortality after isolated CABG and each unit transfused
posed an additive risk.21 The ONTraC data shows that patients who were transfused had ≈30% longer LOS
(and infection rates) than those who were not transfused and this increased progressively with increasing
number of units of RBC transfused; in multivariate analysis transfusion was an independent predictor of LOS.
Cost savings in 2013 vis-à-vis baseline for RBC (at $450/unit) and for the entire transfusion episode (at
$1200) for the 4 targeted procedures only were $15,038,550 for red cell purchase alone, or $46,786,900 in
savings to the health care system overall (>$23 million for the ≈90,000 CABGs in the province). The cost of
the program was $3,257,000. Considering the many other patients seen, the program provides savings well
beyond the 4 procedures above. Hence, in addition to catering to many patients’ preferences, improving
quality of care and patient safety, the program has proven to be cost-efficient and cost-effective.
It has been said that pathways supporting blood conservation are simple in design, labor costs relatively
low, capital investments small, quality and outcomes gains high, savings for the organization large, and the
greater public good is served. It may be asked then why adoption of these techniques been so slow? In large
measure this is because of the traditional concept that blood products are an effective and safe therapeutic
intervention; this needs to be replaced by the concept that transfusion of blood represents an undesirable
outcome. To change practice needs data on current transfusion rates and practices – ‘buy-in’ is obtained by
sharing comparative data. No-one likes to be worse. It is sometimes difficult but essential to keep the focus on
PBM and prevent co-opting of the coordinator to other tasks. The position is not a research one and they are
not safety officers. Difficulties and pitfalls encountered in the program include governmental emphasis on
shorter wait times for surgery (sometimes precluding appropriate anemia treatment), changing scientific
evidence (e.g. in regard to erythropoietin, aprotinin, PAD, intravenous iron), costs and accessibility to some
blood conservation measures, turnover of coordinators, physicians or administrators, resulting in reversal of
gains, and sometimes difficulty in recruiting physician and administrative champions. Nonetheless, despite
difficulties, a focused PBM coordinator and a focused program dedicated to the concept can result in more
appropriate blood use.
To conclude with the famous statement of Dr Beal: “Blood transfusion is a lot like marriage. It should
not be entered into lightly, unadvisedly or wantonly, or more often than is absolutely necessary”.37
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“Our mistrust of the future makes it hard to give up the past” (Chuck Palahniuk)
“Those who cannot change their minds cannot change anything” (George Bernard Shaw)
References:
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4. Gottlieb AM: History of the first blood transfusion but a fable agreed upon: the transfusion of blood to a pope.
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5. Tucker H: Blood Work: A Tale of Medicine and Murder in the Scientific Revolution. W.W. Norton & Co, New
York, ISBN 978-0-393-07055-2, 2011.
6. Blundell J: Observations on the transfusion of blood by Dr Blundell, with a description of his gravitator. Lancet ii:
1828; 321–324.
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9. Fagge CH, Pye-Smith PH: Textbook of the Principles and Practice of Medicine, J & A Churchill, London, 1891.
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13. Serious Hazards of Transfusion Annual Report 2005. http://www.shotuk.org/SHOT%20report%202005.pdf.
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Acknowledgements: The author would like to thank the Ontario Ministry of Health and Long Term Care for
funding and supporting the ONTraC program and also express appreciation to the Program Manager, K Luke,
RN, and all participating coordinators, without whose dedication this project would not have been possible.