James P. Isbister

Appropriateness of allogeneic red blood cell transfusion: the international consensus conference on transfusion outcomes.

An international multidisciplinary panel of 15 experts reviewed 494 published articles and used the RAND/UCLA Appropriateness Method to determine the appropriateness of allogeneic red blood cell (RBC) transfusion based on its expected impact on outcomes of stable nonbleeding patients in 450 typical inpatient medical, surgical, or trauma scenarios. Panelists rated allogeneic RBC transfusion as appropriate in 53 of the scenarios (11.8%), inappropriate in 267 (59.3%), and uncertain in 130 (28.9%). Red blood cell transfusion was most often rated appropriate (81%) in scenarios featuring patients with hemoglobin (Hb) level 7.9 g/dL or less, associated comorbidities, and age older than 65 years. Red blood cell transfusion was rated inappropriate in all scenarios featuring patients with Hb level 10 g/dL or more and in 71.3% of scenarios featuring patients with Hb level 8 to 9.9 g/dL. Conversely, no scenario with patients Hb level of 8 g/dL or more was rated as appropriate. Nearly one third of all scenarios were rated uncertain, indicating the need for more research. The observation that allogeneic RBC transfusions were rated as either inappropriate or uncertain in most scenarios in this study supports a more judicious transfusion strategy. In addition, the large number of scenarios in which RBC transfusions were rated as uncertain can serve as a road map to identify areas in need of further investigation.

Patient Blood Management : The Pragmatic Solution for the Problems with Blood Transfusions

ALLOGENEIC erythrocyte transfusions are associated with increased mortality, major adverse cardiac and noncardiac outcome, and low output failure in cardiac surgery. Transfusion of allogeneic erythrocyte transfusions has also been found to be an independent factor increasing mortality in trauma, including traumatic brain injury, burns, liver transplantation, intensive care medicine, and the treatment of acute coronary syndrome. In addition, allogeneic erythrocyte, fresh frozen plasma, and platelet transfusions result in a several-fold increase in postoperative and nosocomial infections. Furthermore, allogeneic erythrocyte, fresh frozen plasma, and platelet transfusions frequently cause transfusion-related acute lung injury, which in itself again increases mortality, morbidity, and costs. Last but not least, costs of erythrocyte transfusions have been significantly underestimated, even when excluding the cost of treatment of these adverse outcomes or the prolonged intensive care and hospital stay related to erythrocyte transfusion. In the current issue of the Journal, Atzil et al. alert us of another, potentially harmful effect of erythrocyte transfusions, namely the potential to promote tumor growth. In an established rat model of tumor growth, Atzil et al. demonstrate that transfusion of (the equivalent of) autologous and allogeneic erythrocytes increases lung retention of tumor cells several-fold. Interestingly, they could show that this effect is directly linked to the transfused erythrocytes and not related to the coadministration of leukocytes or soluble factors of the supernatant. The magnitude of tumor growth promotion was found to be dependent on storage duration, with erythrocytes stored for more than 9 days having a significantly more pronounced deleterious effect. The reason for cancer progression after blood transfusion is unclear, and the article by Atzil et al. did not precisely elucidate the mechanisms involved. The perioperative period is characterized by numerous processes that can induce abrupt elevation of risk factors for the outbreak of preexisting micrometastases and the seeding of new metastases. Here, deterioration of erythrocytes as a result of storage is demonstrated as a major cause for the cancer-promoting effect. Atzil et al. mainly discuss the role of cellular immunity, particularly T cells and natural killer cells in controlling minimal residual tumor disease. It is hypothesized that transfused erythrocytes become targets to host immunocytes. These deteriorated erythrocytes will outnumber circulating tumor cells, and host immunocytes after erythrocyte transfusion may have a dramatically reduced chance to interact with residual tumor cells and eliminate them. Nonimmune mechanisms may play an additional role in promoting cancer progression due to erythrocyte transfusion. Importantly, acute and chronic hypoxia might be the cause (anemia due to tumor-related blood loss) or consequence (quality of erythrocytes) of blood transfusion and may lead to different biology within a tumor. Therefore, blood transfusion may have a promoting effect on cancer progression, given many hypoxiainduced signaling responses, including transcription factor hypoxia-inducible factor 1 for angiogenesis, cell invasion, cell metabolism, and cell survival. Interestingly, Tsai et al. have recently shown that exchange transfusion with stored erythrocytes in their hamster window model reduced microvascular flow and functional capillary density by more than 50% of the level achieved with fresh erythrocytes. Moreover, tissue oxygen levels were 3.5 and 14.4 mmHg for stored and fresh erythrocytes, respectively. It is thus conceivable that the transfusion of stored erythrocytes may induce tissue hypoxia also in tumor tissue and, by consequence, result in tumor growth progression via the above nonimmune signaling pathways triggered by tissue hypoxia. Further research is urgently needed to understand these mechanisms better and to improve patient treatment in the future. The clinical epidemiologic and randomized trial evidence relating to transfusion being implicated in tumor recurrence remains controversial, but no reports suggest that transfusions are beneficial in this respect. Animal data as presented by Atzil et al., although not directly transferable to humans, further support a precautionary approach to blood transfusion. This Editorial View accompanies the following article: Atzil S, Arad M, Glasner A, Abiri N, Avraham R, Greenfeld K, Rosenne E, Beilin B, Ben-Eliyahu S: Blood transfusion promotes cancer progression: A critical role for aged erythrocytes. ANESTHESIOLOGY 2008; 109:989 –97.

Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register

Background:  There has been increasing off‐label use of recombinant activated factor VII (rFVIIa/NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) for patients with critical bleeding. Given the lack of high‐level evidence, the clinical indications, observed response and adverse events are important to capture.

Patient blood management – a new paradigm for transfusion medicine?

The saving of many lives in history has been duly credited to blood transfusions. What is frequently overlooked is the fact that, in light of a wealth of evidence as well as other management options, a therapy deemed suitable yesterday may no longer be the first choice today. Use of blood has not been based upon scientific evaluation of benefits, but mostly on anecdotal experience and a variety of factors are challenging current practice. Blood is a precious resource with an ever limiting supply due to the aging population. Costs have also continually increased due to advances (and complexities) in collection, testing, processing and administration of transfusion, which could make up 5% of the total health service budget. Risks of transfusions remain a major concern, with advances in blood screening and processing shifting the profile from infectious to non‐infectious risks. Most worrying though, is the accumulating literature demonstrating a strong (often dose‐dependent) association between transfusion and adverse outcomes. These include increased length of stay, postoperative infection, morbidity and mortality. To this end, a recent international consensus conference on transfusion outcomes (ICCTO) concluded that there was little evidence to corroborate that blood would improve patients’ outcomes in the vast majority of clinical scenarios in which transfusions are currently routinely considered; more appropriate clinical management options should be adopted and transfusion avoided wherever possible. On the other hand, there are patients for whom the perceived benefits of transfusion are likely to outweigh the potential risks. Consensus guidelines for blood component therapy have been developed to assist clinicians in identifying these patients and most of these guidelines have long advocated more conservative ‘triggers’ for transfusion. However, significant variation in practice and inappropriate transfusions are still prevalent. The ‘blood must always be good philosophy’ continues to permeate clinical practice. An alternative approach, however, is being adopted in an increasing number of centres. Experience in managing Jehovah’s Witness patients has shown that complex care without transfusion is possible and results are comparable with, if not better than those of transfused patients. These experiences and rising awareness of downsides of transfusion helped create what has become known as ‘patient blood management’. Principles of this approach include optimizing erythropoiesis, reducing surgical blood loss and harnessing the patient’s physiological tolerance of anaemia. Treatment is tailored to the individual patient, using a multidisciplinary team approach and employing a combination of modalities. Results have demonstrated reduction of transfusion, improved patient outcomes and patient satisfaction. Significant healthcare cost savings have also followed. Despite the success of patient blood management programmes and calls for practice change, the potential and actual harm to patients caused through inappropriate transfusion is still not sufficiently tangible for the public and many clinicians. This has to change. The medical, ethical, legal and economic evidence cannot be ignored. Patient blood management needs to be implemented as the standard of care for all patients.

Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion

The type and clinical characteristics of patients identified with commonly used definitions of massive transfusion (MT) are largely unknown. The objective of this study was to define the clinical characteristics of patients meeting different definitions of MT for the purpose of patient recruitment in observational studies.

The Heparin Induced Thrombosis—Thrombocytopenia Syndrome (H.I.T.T.S.): A Review

&NA; Thrombocytopenia and thrombosis occurring as a direct consequence of heparin therapy are being recognized with increasing frequency in recent years. Current conceptions of the pathophysiology of this syndrome are explained, together with the mechanisms leading to the clinical features. The clinical spectrum of H.I.T.T.S. is widening, but there are diagnostic problems arising from a lack of awarenes of the syndrome by some practising clinicians. Many laboratory methods for detecting H.I.T.T.S. have been used, but particular attention should be given to the method of platelet aggregometry. Finally, problems encountered in diagnosis and management of this condition are discussed.

Patient blood management: the global view.

F ew medical procedures rival the status of blood transfusion as one of the most widely used and emotion-laden medical treatments. Empirically applied in the 1800s to reduce or eliminate postpartum hemorrhage-related deaths, its use witnessed exponential growth as the world was engulfed in wars of the 20th century. Evidence of certain harmful consequences surfaced over the years, but the linkage between transfusions and disease transmission is what ultimately caused concern in both the public and the medical community. In response, the blood industry, with the aid of science, has been working to restore the lost confidence in blood by increased surveillance and has stated that blood is “the safest it has ever been.” However, randomized controlled and population studies have continued to link transfusions to negative clinical outcomes. Blood transfusions may be administered to treat acute severe anemia, which is a precipitous decrease in the patient’s red blood cells (RBCs) or hemoglobin (Hb) and threatens oxygen delivery to organs. Acute severe anemia initiates the body’s adaptive responses, such as increased cardiac output, reduction in systemic vascular resistance with vasodilation of the vessels to the major organs, and an increase in tissue extraction, all to fail at different stages of progression. Risk of tissue ischemia and injury can become unavoidable because of inadequate tissue oxygen delivery, which leads to tissue hypoxia, multiple organ failure, and death. Appropriate timing and dosing of RBC transfusions became an enigma after the emergence of restrictive versus liberal transfusion studies and still remains a fundamental question lacking a clear answer. The ensuing confusion led many in the transfusion world to question this practice in light both of the shifting risk–benefit ratio of transfusion and of emerging new agents to treat anemia. Some have remained focused on the indications of transfusion—when and for whom it is appropriate. Others have ventured looking beyond the blood components, asking what else can be done beside or even in lieu of transfusion. Barring the relatively small number of patients who need transfusion due to acute hemorrhage (e.g., trauma), for the vast majority of the recipients of allogeneic blood components, transfusion is the result of ongoing and chronic processes developing over a long period of time. Clearly for a chronic kidney failure patient on dialysis, sepsis patient admitted to the critical care unit, or an iron-deficient elderly individual who is scheduled for hip replacement surgery in 2 weeks, indication of transfusion is not something that is imminent. Late in the 1990s and beginning of the 2000s, movements were founded in Europe, Australia, and United States that examined transfusion practice, the underlying reasons for transfusion, and competing therapeutic modalities for those reasons. These efforts identified an initial unmet need: the detection, diagnosis, and proper management of anemia. Paralleling these movements was the accumulating knowledge and experience gained from successful treatment of patients for whom blood was not an option. Their survival with Hb levels considered incompatible with life opened new doors into the physiology and biology of anemia and resuscitation of the hematopoietic system. This added knowledge has vastly expanded our scope of attention from the simple physics of the human circulation (mostly flow related) to the intricate interactions of several other players, namely, the contribution of the endothelium and the role of gene expression. Oxygen delivery and

Decision making in perioperative transfusion.

Clinical decision making in transfusion medicine has received greater attention in recent years driven by concern about the potential hazards, especially since the recognition that HIV can be transmitted by homologous blood transfusion. These concerns about the risks of homologous transfusion has precipitated interest in the appropriateness of many transfusions and in the decision making processes in transfusion medicine. There has been increasing expenditure on the blood supply side to address the real or perceived potential infectious hazards. This has at times been to the detriment of the patient demand side of the homologous donor blood chain. This imbalance is now being addressed with the development of evidence based clinical guidelines for individual blood components, transfusion monitoring systems and quality assurance programmes. In this review of the process of clinical decision making in transfusion medicine and the factors involved in the ensuring a patient receives a safe and effect transfusion are addressed. The responsibilities of the patients clinical carers are emphasised.

Risk management in transfusion medicine

ISK/BENEFIT analysis is increasingly becoming an integral part of medical practice. As with the rest of society, there is an increasing desire to measure processes and outcomes. The jargon terms of risk/benefit analysis, (bench marking, total quality assurance, quality control, and economic rationalism) are concepts we must accept and live with on a day-to-day basis. However, in the context of this obsession with process and outcomes, we must not lose sight of the fact that clinicians are trying to achieve the best possible results for their patients ever in the context of a capped or reduced economic health environment and increased accountability for services over which they have less and less control. The simplistic view of the economic rationalists concludes that by analyzing and quantifying every part of the process it can be fully understood, and by so doing it is possible to accurately predict and achieve perfect outcomes. This naive approach denies the fact that the whole is greater than the sum of the parts. Many substantial benefits for patients are only achieved where significant risk is involved, often when unpredictable and unmeasurable factors are present. If risk is reduced to a negligible level, the likelihood is that benefit will be jeopardized. However, this is not to say that clinicians must not carefully balance and communicate the risk/benetit equation to their individual patients. Despite extensive understanding of the dangers of homologous (allogeneic) transfusion dating back to the early days of transfusion medicine, it was not until the recognition that human immunodeficiency virus (HIV) can be transmitted by blood transfusion that there has been overwhelming arousal of interest and concern about its hazards. In large measure, consumer pressure and media hype have fueled the controversy. Clinicians are rapidly learning to balance the risk/benefit equation for transfusion therapy for their patients. The days of not carefully considering the indications for blood component therapy are rapidly passing. It is now widely accepted that there must be clearly identified and valid reasons for every transfusion together with a careful appraisal of the potential hazards, informed consent, and appropriate administration and monitoring.

Effects of taipan (Oxyuranus scutellatus) venom on erythrocyte morphology and blood viscosity in a human victim in vivo and in vitro

The case of a snake handler with envenoming due to Australian taipan (Oxyuranus scutellatus) showing marked morphological changes in his red blood cells is presented. The red cells underwent sphero-echinocytic transformation and in subsequent experiments in vitro the effects of taipan venom on red cells were further characterized. Taipan venom induced sphero-echinocytic transformation at nanogram/ml concentrations and led to a marked increase in whole blood viscosity. These changes have not been featured in previous reports of taipan envenomation and are reported to highlight the diagnostic value of blood film examination in cases of suspected envenomation. The significance of the hyperviscosity, and consequent reduction in blood fluidity, is unknown and requires further investigation.