15th Annual NATA Symposium Porto, Portugal, April 10–11, 2014

Transfusion Medicine






Update on the Safety of Blood Products

Informed Consent to Transfusion

L. T. Goodnough Departments of Pathology & Medicine, Stanford University, Stanford, CA, USA

Barrister, London, UK

Blood transfusions have been decreed to be ‘unavoidably, unsafe, and inherently dangerous’ as the basis for the Blood Shield laws in the U.S. (Zuck, 1990). Thus, the perceived risks of a blood transfusion are important elements in the bedside discussion for patients’ informed consent, particularly in the management of anaemia using available alternatives other than blood transfusion (Goodnough and Shander, 2012). The 2011–12 annual report of transfusion fatalities by the FDA Center for Biologics Evaluation and Research (CBER) shows that allcause deaths related to transfusion have been declining, with only 30 deaths reported in the U.S. for 2011 (Transfusion News, 2012). For the years 2007–11, transfusion-related acute lung injury (TRALI) caused the highest percentage (43%) of reported fatalities, followed by haemolytic transfusion reactions (23%) due to non-ABO (13%) or ABO (10%) incompatibilities. Increasing evidence suggests that a far greater number of patients have adverse clinical outcomes (increased morbidity and mortality) associated with blood transfusions. The risks of blood include not only known transmissible pathogens for infectious disease, transfusion reactions, TRALI, errors in blood administration, and circulatory overload, but also potential, as yet undefined risks such as immunomodulation (e.g., perioperative infection or tumour progression), unknown risks (such as the recently-emerging pathogens of new variant Creutzfeldt-Jakob disease and West Nile virus), and risks associated with duration of storage lesions, particularly in blood transfusions to patients undergoing cardiac surgery (Wang, Sun et al., 2012). Awareness of blood risks has led to development of institution-based initiatives in blood utilization through patient blood management. Emerging strategies for changing blood inventory management await results of ongoing clinical trials of ‘fresh’ versus ‘older’ red blood cells for transfusion therapy.

REFERENCES Goodnough, L.T. and A. Shander (2012). Patient blood management. Anesthesiology 116, 1367–1376. Transfusion News (2012). FDA Report Shows Decreasing Trend of Transfusion-Related Fatalities. July 20, 2012. http://transfusionnews. com/2012/07/20/fda-report-shows-decreasing-trend-of-transfusionrelated-fatalities. Accessed February 12, 2014. Wang, D., J. Sun, et al. (2012). Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 52, 1184–1195. Zuck, T.F. (1990). Legal liability for transfusion injury in the acquired immunodeficiency syndrome era. Archives of Pathology & Laboratory Medicine 114, 309–315.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

R. Daniel The principles and legal requirements of consent are considered together with professional writings (Taylor, 1982) and a range of decided cases (Schloendorff v Society of New York Hospital, 1914; Malette v Shulman, 1990; re MB (Medical Treatment), 1997). The concepts of Competence and Capacity have been progressively refined by the court and the three stages of the decision-making process have been analysed (re C (adult: refusal of medical treatment), 1994). The Duty to Inform of Less Invasive Treatment Options: Birch v University College Hospital (2008) established a wider legal principle: Where there are alternative treatment options that are either noninvasive or less invasive, it is no longer merely ‘best practice’ to inform the patient and discuss the relative risks and benefits. There is an actual legal duty to do so and for the informed patient then to decide. Protocols: The principal professional bodies have published Protocols (The Royal College of Surgeons of England, 2002; British Orthopaedic Association, 2005; Association of Anaesthetists of Great Britain and Ireland, 2005) on non-blood management and consent together with an article (Kotz´e, Carter et al., 2012) on a patient blood management programme. Consultation and the Obtaining of Consent: Consent to non-blood alternatives in emergencies may be by written advance directive. In elective procedures the better practice is to have a pre-operative assessment clinic at least 28 days before the planned admission to address consent to the proposed procedure, various treatment options and the risks/benefits, and pre-operative anaemia. Transfusion thresholds (recommended at 7 g/dL) should be discussed. But note the findings of the Krever Commission (Krever, 1995) in Canada. Consent to Managing Obstetrics without Blood: Ante-natal anaemia and iron deficiency are often undiagnosed or untreated. Peri- and post-partum haemorrhage: The risk of a severe bleed is recognised at 6.7 per 1000 deliveries but the problem is identifying such cases in advance. Need for advance consent to non-blood management and careful preparation in anticipation of a major bleed. Financial Consequences: The financial consequences of not obtaining valid consent are considered. Also a potential change in the law to ‘opting in’ to blood rather than ‘opting out’.

REFERENCES Association of Anaesthetists of Great Britain and Ireland (2005). Management of Anaesthesia for Jehovah’s Witnesses, Association of Anaesthetists of Great Britain and Ireland. 2nd edition, London. Birch v University College Hospital NHS Trust (2008) EWHC 2237 (QB) Cranston J.

doi: 10.1111/tme.12111

2 Abstracts of the 15th Annual NATA Symposium British Orthopaedic Association (2005). Blood Conservation in Elective Orthopaedic Surgery, British Orthopaedic Association, London. Kotz´e, A., L.A. Carter, et al. (2012). Effect of a patient blood management programme on preoperative anaemia, transfusion rate, and outcome after primary hip or knee arthroplasty: a quality improvement cycle. British journal of anaesthesia 108, 943–952. Krever, H. (1995). Commission of Inquiry on the Blood System in Canada, Minister of Supply and Services Canada, Ottawa. Malette v Shulman (1990) 67 DLR (4th) 321 per Robins J. re C (adult: refusal of medical treatment) (1994) 1 All E R 819. re MB (Medical Treatment) (1997) 2 FLR 426, per Butler-Sloss LJ at 432. Schloendorff v Society of New York Hospital (1914) 105 NE 92 at p. 93. Taylor, J.L. (1982). The Doctor and the Law, Pitman, London. The Royal College of Surgeons of England (2002). Code of Practice for the Surgical Management of Jehovah’s Witnesses, The Royal College of Surgeons of England, London.

S3 Trends in Blood Utilization L. T. Goodnough Departments of Pathology & Medicine, Stanford University, Stanford, CA, USA We analysed hospital-wide red blood cell (RBC) utilization and indicators for clinical patient outcomes at Stanford Hospital and Clinics (SHC) after implementation of real-time clinical decision support (CDS) for RBC transfusions, consisting of a best practice alert (BPA) within the computerised provider order entry (CPOE) (Goodnough, Shieh et al., 2013). A clinical effectiveness team from key clinical services developed a consensus with a suggested transfusion threshold of haemoglobin (Hb) 7 g/dL, or 8 g/dL for patients with acute coronary syndromes. Implemented in July 2010, orders for RBC units triggered an interruptive BPA above an Hb threshold of 7 g/dL for patients otherwise not excluded from the guidelines (according to their problem list: acute coronary syndrome, status post cardiothoracic procedure, haemorrhage,

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or haemodynamic instability). The BPA contained the consensus guidelines, link to relevant literature, and an ‘acknowledgement’ reason if provider chose to continue transfusion. Trends in hospital-wide RBC utilization and clinical patient outcomes were analysed for all in-patients discharged from January 2008 through December 2012. RBC transfusions decreased substantially in the interval immediately after July 2010, and have continued to decrease thereafter. For 2012 compared to 2009, total RBC transfusions decreased by 24% (P < 0.05). This decrease in utilization has occurred through 2013, despite concurrent increases in patient discharge volumes, case mix complexity, and stem cell transplantation cases. Additionally, patient clinical outcomes including mortality, length of stay, and 30-day readmission rates have declined or remained stable. For a subgroup of stable inpatients, the percentage of those receiving RBC transfusions when Hb exceeded 8 g/dL decreased from 57-66% preceding the CDS to 35% thereafter (P = 0.02); for the most recent interval, only 27% of RBC transfusions occurred outside guidelines. Comparing 2009 to 2013, total RBC transfusions decreased by 7,203 units (23%). Compared to purchase costs in 2009, for 2013 the estimated net savings (at $225/unit) in purchase costs was $1,621,000. Total net savings for 2010–2013 was $5,929,300. In summary, we have substantially decreased RBC transfusions through real-time CDS, despite increasing volumes of health care delivery (patient discharges, elective surgeries, and organ transplantations) and increasing complexity of case mix index. Moreover, hospital-wide patient quality indicators have been stable (mortality, 30-day readmission rates) or are improving (length of stay). CDS can be very effective for healthcare institutions to improve quality of care by simultaneously decreasing patient exposure to unnecessary RBC transfusion and by decreasing RBC supply costs along with the substantial transfusion-related costs.

REFERENCE Goodnough, L.T., L. Shieh, et al. (2013). Improved blood utilization using real-time clinical decision support. Transfusion, doi: 10.1111/trf.12445.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Abstracts of the 15th Annual NATA Symposium 3




Age of Blood: Does It Matter?

The Safety of Intravenous Iron and Erythropoiesis-Stimulating Agents

J. L. Carson Interim Provost, Rutgers Biomedical and Health Sciences, Vice Chair, Research, Richard C Reynolds Professor of Medicine, Chief, Division of General Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA Red blood cells may be stored up to 42 days prior to transfusion in the U.S. and other countries. The standard time period that blood can be stored is based upon in vivo studies that demonstrate that 70% of red blood cells survive 24 hours after transfusion. This standard is not based upon whether the red blood cells still function normally nor whether it is safe. An important study challenging the wisdom of using stored blood was published in 2008 (Koch, Li et al., 2008). In patients undergoing cardiac surgery in a single centre, the outcomes of 2872 patients receiving blood stored for 14 days or less was compared to 3130 patients receiving blood stored for greater than 14 or more days. Overall, there was a greater mortality and more complications in patients receiving older blood. However, it is possible that the two groups were not at similar risk of complications in this observational study. However, this work prompted the performance of clinical trials. Only one clinical trial is published at this time in 377 premature verylow-birth-weight infants (Fergusson, Hebert et al., 2012). Patients were randomly allocated to receive blood stored for 7 days or less versus usual standard issue blood. There was no difference in outcomes in 377 patients enrolled in the trial. Other trials are ongoing which should further inform the medical community in the not-too-distant future (H´ebert, Chin-Yee et al., 2005; Steiner, Assmann et al., 2010; Heddle, Cook et al., 2012). At this time, the answer to the question ‘Does age of blood matter?’ is . . . we don’t know . . . yet.

REFERENCES Fergusson, D.A., P. Hebert, et al. (2012). Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. Journal of the American Medical Association 308, 1443–1451. H´ebert, P.C., I. Chin-Yee, et al. (2005). A pilot trial evaluating the clinical effects of prolonged storage of red cells. Anesthesia and Analgesia 100, 1433–1438, table of contents. Heddle, N.M., R.J. Cook, et al. (2012). The effect of blood storage duration on in-hospital mortality: a randomized controlled pilot feasibility trial. Transfusion 52, 1203–1212. Koch, C.G., L. Li, et al. (2008). Duration of red-cell storage and complications after cardiac surgery. New England Journal of Medicine 358, 1229–1239. Steiner, M.E., S.F. Assmann, et al. (2010). Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7). Transfusion and Apheresis Science 43, 107–116. © 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

I. C. Macdougall Department of Renal Medicine, King’s College Hospital, London, UK The two major therapies utilised in the management of anaemia are erythropoiesis-stimulating agents (ESAs) and intravenous iron. Both are highly efficacious, and contribute to an improvement in the haemoglobin level, but both have independent safety concerns. With respect to ESAs, there are four highly publicised clinical trials, all published in the New England Journal of Medicine, which raised concerns about deliberately targeting a haemoglobin of ≥13 g/dL with erythropoietic therapy (Besarab, Bolton et al., 1998; Dr¨ueke, Locatelli et al., 2006; Singh, Szczech et al., 2006; Pfeffer, Burdmann et al., 2009). The US Normal Hematocrit Trial (Besarab, Bolton et al., 1998) as well as the CREATE (Dr¨ueke, Locatelli et al., 2006) and CHOIR (Singh, Szczech et al., 2006) studies all showed some evidence of harm with normalisation of haemoglobin, but it was the TREAT (Pfeffer, Burdmann et al., 2009) study that provided the strongest evidence for this, showing in a doubleblind placebo-controlled study that there was a doubling of stroke risk, doubling of venous thromboembolism, and a more than ten-fold increase in cancer from the subset of patients who had a previous malignancy. With respect to intravenous iron, the evidence base for harm is not as robust, but there are laboratory studies, animal studies, and prospective observational data in humans suggesting that intravenous iron may exacerbate oxidative stress due to the release of free hydroxyl radicals, thereby increasing lipid peroxidation and atherogenesis (Fishbane, 1998; Besarab, Frinak et al., 1999; Fishbane, 2003; Besarab and Coyne, 2010; Macdougall, 2011). There is also evidence that intravenous iron might exacerbate infections, both by enhancing bacterial proliferation and by reducing neutrophil killing defence mechanisms (Deicher, Ziai et al., 2003), but observational data are conflicting, and there are few informative robust clinical trials. Finally, there are concerns about hypersensitivity reactions to intravenous iron preparations; whether these are immune-mediated or vasoactive remains unclear. Despite all these concerns about the safety of ESAs (Vinhas, Barreto et al., 2012; Biggar and Ketteler, 2013) and intravenous iron (Fishbane, 1998; Besarab, Frinak et al., 1999; Fishbane, 2003; Besarab and Coyne, 2010; Macdougall, 2011), there is little doubt that these therapies have dramatically helped patients suffering from anaemia, enhancing their quality-of-life and reducing the requirement for blood transfusions.

REFERENCES Besarab, A., W.K. Bolton, et al. (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. New England Journal of Medicine 339, 584–590. Besarab, A. and D.W. Coyne (2010). Iron supplementation to treat anemia in patients with chronic kidney disease. Nature Reviews. Nephrology 6, 699–710. Besarab, A., S. Frinak, et al. (1999). An indistinct balance: the safety and efficacy of parenteral iron therapy. Journal of the American Society of Nephrology 10, 2029–2043.

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4 Abstracts of the 15th Annual NATA Symposium Biggar, P. and M. Ketteler (2013). ESA therapy - the quest continues: anemia treatment following recent national and international recommendations 2011 and 2012. Clinical Nephrology 79, 335–350. Deicher, R., F. Ziai, et al. (2003). High-dose parenteral iron sucrose depresses neutrophil intracellular killing capacity. Kidney International 64, 728–736. Dr¨ueke, T.B., F. Locatelli, et al. (2006). Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New England Journal of Medicine 355, 2071–2084. Fishbane, S. (1998). Iron treatment: impact of safety issues. American Journal of Kidney Diseases 32, S152-156. Fishbane, S. (2003). Safety in iron management. American Journal of Kidney Diseases 41, 18–26. Macdougall, I.C. (2011). Iron supplementation in nephrology and oncology: what do we have in common? The oncologist 16 Suppl 3, 25–34. Pfeffer, M.A., E.A. Burdmann, et al. (2009). A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. New England Journal of Medicine 361, 2019–2032. Singh, A.K., L. Szczech, et al. (2006). Correction of anemia with epoetin alfa in chronic kidney disease. New England Journal of Medicine 355, 2085–2098. Vinhas, J., C. Barreto, et al. (2012). Treatment of anaemia with erythropoiesis-stimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a metaanalysis. Nephron. Clinical Practice 121, c95-101.

S6 The Safety of Antifibrinolytics and Recombinant Activated Factor VII B. J. Hunt Thrombosis and Haemostasis, King’s College and Guy’s and St Thomas, NHS Foundation Trust, London, UK It is now clearly established that antifibrinolytic agents reduce blood loss in patients with surgical and both normal and traumatic injury. A systematic review of randomised trials assessing antifibrinolytics in patients undergoing elective surgery identified 211 studies including 20,781 participants (Henry, Carless et al., 2007). Aprotinin reduced the need for blood transfusion by 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.61 to 0.71), tranexamic acid by 39% (RR, 0.61, 95% CI 0.54 to 0.69) and epsilon aminocaproic acid by 25% (RR 0.75, 95% CI 0.58 to 0.96). A more recent systematic review looking at tranexamic acid only identified 129 trials totalling 10,488 patients (Ker, Edwards et al., 2012). Tranexamic acid reduced the probability of receiving a blood transfusion by a third (risk ratio 0.62, 95% CI 0.58 to 0.65; P < 0.001). Another systematic review of randomised trials of antifibrinolytic agents given for bleeding during the post-partum period concluded that TA reduced blood loss in post-partum haemorrhage (Ferrer, Roberts et al., 2009). The largest trial to date of antifibrinolytics, the Clinical Randomisation of Antifibrinolytics in Significant Haemorrhage (CRASH-2) trial, assessed the effects of early administration of tranexamic acid in trauma patients with, or at risk for substantial bleeding (Shakur, Roberts et al., 2010). A total of 20211 trauma patients from 40 countries were randomly assigned within eight hours of injury to either tranexamic acid (1 g load, then 1 g over 8 h) or placebo. The primary outcome was in-hospital mortality within 4 weeks of injury. All-cause mortality was significantly reduced with TA (14.5% vs 16%; relative risk 0.91, 95% CI 0.85 to 0.97;

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P = 0.0035). Bleeding-related mortality was also reduced (4.9% vs 5.7%) without an increase in fatal or non-fatal vascular occlusive events. The data from CRASH-2 showed that following the second day, bleeding is not the main cause of mortality and was ascribed to head injury, multiorgan failure and vaso-occlusive events, all of which were reduced, although non-significantly, in those receiving tranexamic acid (Roberts, Shakur et al., 2011). Secondly, the CRASH-2 trial showed a reduction in death rate due to arterial but not venous thrombosis (Roberts, Perel et al., 2012). An additional hypothesis, which may account for a proportion of the reduction in death, is that tranexamic acid reduced mortality by other mechanisms, namely anti-inflammatory and/or antithrombotic. Current clinical trials of tranexamic acid will help inform this hypothesis. The WOMAN study is assessing the use of tranexamic acid versus placebo in 20,000 women with post-partum haemorrhage (Shakur, Elbourne et al., 2010). CRASH-3 is looking at tranexamic acid versus placebo in traumatic brain injury (Dewan, Komolafe et al., 2012). The HALT-IT study is looking at the benefit of tranexamic acid in gastrointestinal haemorrhage. After the BART study (Fergusson, H´ebert et al., 2008), there was a market withdrawal of aprotinin (Trasylol). However, recent decisions by Health Canada and the European Medicines Agency led them to lift its suspension – in patients undergoing isolated heart bypass surgery who are at high risk of major blood loss. Recombinant factor VIIa which has been shown to reduce red cell usage in bleeding but not to reduce mortality, needs further evaluation. Data from placebo-controlled trials show that the off-license use of recombinant factor VIIa significantly increases the risk of arterial thrombosis.

REFERENCES Dewan, Y., E.O. Komolafe, et al. (2012). CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials 13, 87. Fergusson, D.A., P.C. H´ebert, et al. (2008). A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. New England Journal of Medicine 358, 2319–2331. Ferrer, P., I. Roberts, et al. (2009). Anti-fibrinolytic agents in post partum haemorrhage: a systematic review. BMC Pregnancy and Childbirth 9, 29. Henry, D.A., P.A. Carless, et al. (2007). Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database of Systematic Reviews, CD001886. Ker, K., P. Edwards, et al. (2012). Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. British Medical Journal 344, e3054. Roberts, I., P. Perel, et al. (2012). Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 345, e5839. Roberts, I., H. Shakur, et al. (2011). The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 377, 1096–1101, 1101 e1091-1092. Shakur, H., D. Elbourne, et al. (2010). The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials 11, 40. Shakur, H., I. Roberts, et al. (2010). 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 376, 23–32.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Abstracts of the 15th Annual NATA Symposium 5


S7 Basic Principles and Safety of Cell Salvage D. Thomas Cardiac Intensive Therapy Unit, Swansea, Wales, UK The key principle of cell salvage autotransfusion is to provide a readily available supply of a patient’s own blood. A simple method; using suction to collect spilt blood, with an innovative method of anticoagulation, it allows washing, concentration and filtration of the fresh blood prior to reinfusion. The key successful logistic surrounding autotransfusion is to have a supply of the patient’s own blood when the patient is bleeding. Cell salvage autotransfusion fulfills this criterion, as it is only possible to perform during the peri-operative period and has been proven to be more cost-effective than the other two main methods of autotransfusion, namely preoperative autologous donation and acute normovolemic haemodilution. All three methods have a place in patient blood management but cell salvage has proven to be the most efficient and cost effective method. A principle of using the relatively inexpensive collection reservoir during the surgical procedure, prior to processing, means that the remainder of the processing disposable is only opened and used should sufficient blood be collected to warrant processing. During this presentation it is the aim to highlight the advantages of such a blood conservation technique, and to give hints on how it can be performed at maximum efficiency. As with all situations in clinical medicine, patient selection and consideration of risk/benefit play a key part in the clinical outcome and the overall cost-effectiveness of such interventions.

SUGGESTED READING Association of Anaesthetists of Great Britain and Ireland & Obstetric Anaesthetists’ Association (2005). OAA / AAGBI Guidelines for Obstetric Anaesthetic Services, Association of Anaesthetists of Great Britain and Ireland & Obstetric Anaesthetists’ Association, London. Better Blood Transfusion & UK Cell Salvage Action Group. www.transfusionguidelines.org. Accessed February 12, 2014. Bryson, G.L., A. Laupacis, et al. (1998). Does acute normovolemic hemodilution reduce perioperative allogeneic transfusion? A metaanalysis. The International Study of Perioperative Transfusion. Anesthesia and analgesia 86, 9–15. Carless, P., A. Moxey, et al. (2004). Autologous transfusion techniques: a systematic review of their efficacy. Transfusion medicine 14, 123–144. Carvalho, B., B.M. Ridler, et al. (2003). Myocardial ischaemia precipitated by acute normovolaemic haemodilution. Transfusion medicine 13, 165–168. Catling, S.J., S. Williams, et al. (1999). Cell salvage in obstetrics: an evaluation of the ability of cell salvage combined with leucocyte depletion filtration to remove amniotic fluid from operative blood loss at caesarean section. International journal of obstetric anesthesia 8, 79–84. Drife, J.O. (2004). Why Mothers Die 2000–2002: The Sixth Report of the Confidential Enquiries Into Maternal Deaths in the United Kingdom, Royal College of Obstetricians & Gynaecologists Press, London. Gharehbaghian, A., K.M. Haque, et al. (2004). Effect of autologous salvaged blood on postoperative natural killer cell precursor frequency. Lancet 363, 1025–1030. © 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Gross, J.B. (1983). Estimating allowable blood loss: corrected for dilution. Anesthesiology 58, 277–280. Hu¨et, C., L.R. Salmi, et al. (1999). A meta-analysis of the effectiveness of cell salvage to minimize perioperative allogeneic blood transfusion in cardiac and orthopedic surgery. International Study of Perioperative Transfusion (ISPOT) Investigators. Anesthesia and analgesia 89, 861–869. Iwama, H. (2001). Bradykinin-associated reactions in white cellreduction filter. Journal of critical care 16, 74–81. National Institute for Health and Clinical Excellence (2005). Intraoperative Blood Cell Salvage in Obstetrics (IPG144), National Institute for Health and Clinical Excellence, London. Segal, J.B., E. Blasco-Colmenares, et al. (2004). Preoperative acute normovolemic hemodilution: a meta-analysis. Transfusion 44, 632–644. Waters, J.H., C. Biscotti, et al. (2000). Amniotic fluid removal during cell salvage in the cesarean section patient. Anesthesiology 92, 1531–1536.

S8 Cell Salvage in Cancer Surgery J. H. Waters Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Intraoperative blood salvage (IBS) involves the collection of shed surgical blood, its filtration, washing, and re-administration to the patient. The technique has been demonstrated to reduce allogeneic blood transfusion in many different surgical procedures. However, there has been some apprehension in applying this technology during cancer surgery. The fear arises from the theory that cancer cells could be incorporated into the shed blood product and concentrated during the processing, and that upon re-administration these cells could lead to diffuse metastasis. The only evidence to support the notion that salvaged blood could lead to metastases came from a single case report published in 1975 where a patient received blood salvaged during a pneumonectomy. Four weeks after the surgery, the patient died from diffuse metastasis. Malignant cells were detected in the salvaged blood so it was presumed that the reinfusion of these cells contributed in some way to the patient’s demise (Yaw, Sentany et al., 1975). The theoretical concern about metastases has even warranted recommendations in the past by the American Medical Association (AMA) Council on Scientific Affairs against using blood salvage during cancer surgery (1986). Since the publication of this case report and the AMA recommendation, multiple reports of salvage use during cancer surgery have been made. A recent meta-analysis (Waters, Yazer et al., 2012) analysed 10 such studies, which included 741 patients received IBS during their cancer surgery and a control group of 1585 patients who received intra-operative RBC transfusion strategies other than IBS (Fujimoto, Okamoto et al., 1993; Connor, Morris et al., 1995; Gray, Amling et al., 2001; Davis, Sofer et al., 2003; Hirano, Yamanaka et al., 2005; Muscari, Suc et al., 2005; Nieder, Carmack et al., 2005; Stoffel, Topjian et al., 2005; MacIvor, Nelson et al., 2009; Bower, Ellis et al., 2011). The differences between studies ranged from cancer type, length of follow-up, and method of follow-up. The cancer type ranged from low metastatic potential prostate cancers to much higher risk hepatocellular cancer. Five of the 10 studies were in prostate cancer.

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6 Abstracts of the 15th Annual NATA Symposium The associated control group also varied between studies where IBS was compared to patients who received no transfusion, allogeneic transfusion, or preoperative autologous donation. In all situations, the long term outcome of cancer recurrence or the development of metastases was the same or better in the IBS group when compared to the control group. All studies were retrospective in nature so the level of evidence is not as powerful as that in a randomised control trial; however, these studies clearly do not support the assumption of risk when IBS is used during cancer therapy. The use of additional safety measures when IBS is employed in cancer surgery has been advocated. Some of these measures include the use of leukocyte depletion filters (Waters and Donnenberg, 2009) or irradiation of the IBS product before reinfusion (Hansen, Bechmann et al., 2002). Leucocyte depletion filters have been used to remove a variety of different malignant cells types which had been spiked into discarded blood (Torre, Ferrari et al., 1994; Kongsgaard, Wang et al., 1996). These studies have all concluded that leucocyte depletion filters were highly effective at removing tumour cell contamination. Hansen and colleagues (Hansen, Bechmann et al., 2002) suggested that these studies were flawed in that the cultured tumour cells used in these models might not contain the same degree of metastatic potential as would cells from a surgical wound. Thus, they advocate irradiation of the autologous blood. Of the 10 studies analysed in the aforementioned meta-analysis (Waters, Yazer et al., 2012), only one study used a leucocyte depletion filter on the returned IBS blood. No studies used irradiation, which suggests that neither modality is needed during cancer surgery.

REFERENCES American Medical Association (1986). Autologous blood transfusions. Council on Scientific Affairs. Journal of the American Medical Association 256, 2378–2380. Bower, M.R., S.F. Ellis, et al. (2011). Phase II comparison study of intraoperative autotransfusion for major oncologic procedures. Annals of surgical oncology 18, 166–173. Connor, J.P., P.C. Morris, et al. (1995). Intraoperative autologous blood collection and autotransfusion in the surgical management of early cancers of the uterine cervix. Obstetrics and gynecology 86, 373–378.

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Davis, M., M. Sofer, et al. (2003). The use of cell salvage during radical retropubic prostatectomy: does it influence cancer recurrence? BJU international 91, 474–476. Fujimoto, J., E. Okamoto, et al. (1993). Efficacy of autotransfusion in hepatectomy for hepatocellular carcinoma. Archives of surgery 128, 1065–1069. Gray, C.L., C.L. Amling, et al. (2001). Intraoperative cell salvage in radical retropubic prostatectomy. Urology 58, 740–745. Hansen, E., V. Bechmann, et al. (2002). Intraoperative blood salvage in cancer surgery: safe and effective? Transfusion and Apheresis Science 27, 153–157. Hirano, T., J. Yamanaka, et al. (2005). Long-term safety of autotransfusion during hepatectomy for hepatocellular carcinoma. Surgery today 35, 1042–1046. Kongsgaard, U.E., M.Y. Wang, et al. (1996). Leucocyte depletion filter removes cancer cells in human blood. Acta anaesthesiologica Scandinavica 40, 118–120. MacIvor, D., J. Nelson, et al. (2009). Impact of intraoperative red blood cell salvage on transfusion requirements and outcomes in radical prostatectomy. Transfusion 49, 1431–1434. Muscari, F., B. Suc, et al. (2005). Blood salvage autotransfusion during transplantation for hepatocarcinoma: does it increase the risk of neoplastic recurrence? Transplant international : official journal of the European Society for Organ Transplantation 18, 1236–1239. Nieder, A.M., A.J. Carmack, et al. (2005). Intraoperative cell salvage during radical prostatectomy is not associated with greater biochemical recurrence rate. Urology 65, 730–734. Stoffel, J.T., L. Topjian, et al. (2005). Analysis of peripheral blood for prostate cells after autologous transfusion given during radical prostatectomy. BJU international 96, 313–315. Torre, G.C., M. Ferrari, et al. (1994). A new technique for intraoperative blood recovery in the cancer patient. European Journal of Surgical Oncology 20, 565–570. Waters, J.H. and A.D. Donnenberg (2009). Blood salvage and cancer surgery: should we do it? Transfusion 49, 2016–2018. Waters, J.H., M. Yazer, et al. (2012). Blood salvage and cancer surgery: a meta-analysis of available studies. Transfusion 52, 2167–2173. Yaw, P.B., M. Sentany, et al. (1975). Tumor cells carried through autotransfusion. Contraindication to intraoperative blood recovery? Journal of the American Medical Association 231, 490–491.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Abstracts of the 15th Annual NATA Symposium 7




Transfusion Thresholds for Patients with Coronary Artery Disease

Carson, J.L., M.M. Brooks, et al. (2013). Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. American Heart Journal 165, 964–971 e961. Carson, J.L., M.L. Terrin, et al. (2011). Liberal or restrictive transfusion in high-risk patients after hip surgery. New England Journal of Medicine 365, 2453–2462. Cooper, H.A., S.V. Rao, et al. (2011). Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). American Journal of Cardiology 108, 1108–1111. H´ebert, P.C., G. Wells, et al. (1999). A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. New England Journal of Medicine 340, 409–417. Villanueva, C., A. Colomo, et al. (2013). Transfusion strategies for acute upper gastrointestinal bleeding. New England Journal of Medicine 368, 11–21.

J. L. Carson Interim Provost, Rutgers Biomedical and Health Sciences, Vice Chair, Research, Richard C Reynolds Professor of Medicine, Chief, Division of General Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA Multiple trials in recent years suggest that a restrictive transfusion strategy is safe and in some cases superior to liberal transfusion strategy (H´ebert, Wells et al., 1999; Carson, Terrin et al., 2011; Villanueva, Colomo et al., 2013). However, patients with acute coronary syndrome may be especially vulnerable to ischemia in the setting of anaemia. There has been only one small clinical trial published in patients with acute myocardial infarction (Cooper, Rao et al., 2011). We report the results of the Myocardial Ischemia and Transfusion (MINT) pilot trial, which was funded by US National Heart, Lung, Blood Institute with the primary aim to evaluate the feasibility of performing a large-scale clinical trial (Carson, Brooks et al., 2013). We enrolled 110 patients with acute coronary syndrome or stable coronary artery disease patient undergoing cardiac catheterisation during the index hospitalisation and haemoglobin concentration less than 10 g/dL from 8 centres were randomly allocated to liberal (10 g/dL) versus restrictive transfusion strategy (8 g/dL or symptoms). Overall, recruitment rates averaged 0.89 cases per centre per month. The 110 randomised patients had an average age of 70 years (range 37–92 years). The majority of patients had non-STelevation myocardial infraction (43%) and ST-elevation myocardial infarction (30%). Most patients had a major co-morbid condition such as congestive heart failure (30%), diabetes mellitus (57%), renal disease (33%), and pre-existing anaemia (41%). Three-vessel disease was present in 40%, left ventricular ejection fraction 1 litre after Caesarean section. Of the 14 million women who have PPH every year, 2% die, with an average time from start of bleeding to death of 2–4 hours. This translates in death rates of over a hundred thousand women globally dying due to exsanguinations after PPH. Such a global burden of disease prompted the WOMAN study (the World Maternal ANtifibrinolytic trial), based on the knowledge of the benefit of tranexamic acid in reducing mortality in bleeding trauma patients (the CRASH-2 study). The same clinical trials team that conducted CRASH-2 have embarked on a clinical trial aiming to enrol 20,000 women with PPH worldwide. This is a pragmatic double-blind placebo-trial where the primary outcome is the proportion of women who die or undergo hysterectomy. Secondary outcomes include any surgical procedure to control bleeding, the use of blood transfusion, thromboembolic events, cost-effectiveness, and length of stay. In those women where is uncertainty about the benefits of tranexamic acid, 1 gram of tranexamic acid or placebo is given with the option of repeating a further gram or placebo after 30 minutes if bleeding continues, or if it stops and restarts within 24 hours. So far over 10,000 women have been recruited in centres all over the world. The current interim data will be discussed. Please visit www.womantrial.Lshtm.ac.uk for more details.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Abstracts of the 15th Annual NATA Symposium 13


S19 Yes, Hydroxyethyl Starches Should Be Abandoned N. R. S. Haase Department of Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, and Department of Anaesthesiology, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark Systematic reviews conducted by independent authors show that hydroxyethyl starch (HES) impairs renal function and increase the risk of death compared with other fluids (Perel, Roberts et al., 2013; Zarychanski, Abou-Setta et al., 2013). The trials in these reviews had highly consistent results (low statistical heterogeneity) indicating toxic effects independent of type of patient, HES fluid and trial design. In line with this, a recent post-hoc analysis of a randomized clinical trial also showed consistent harm across a large number of patient subgroups (M¨uller, Haase et al., 2013). However, most clinical data originate from critically ill patients (Brunkhorst, Engel et al., 2008; Myburgh, Finfer et al., 2012; Perner, Haase et al., 2012), and whether HES provides benefit in surgical patients is still being discussed. This does not seem to be the case for several reasons. First of all, tissue storage may be the leading mechanism for the deleterious renal effects of HES. Such storage is not restricted to critically ill patients, but widespread in both healthy volunteers and surgical patients (Bellmann, Feistritzer et al., 2012; Wiedermann and Joannidis, 2014). Secondly, the occurrence of HES-induced coagulopathy is well-established (Hartog, Reuter et al., 2011) and is likely to negatively affect clinical outcome at least in certain settings (Navickis, Haynes et al., 2012; Haase, Wetterslev et al., 2013; Rasmussen, Johansson et al., 2014). Thirdly, beneficial effects with HES beyond intermediate surrogate markers, such as fluid use, have not yet been demonstrated. Rather, the fluid sparring effect of HES seems much smaller than previously thought, which reduces the likelihood of a subsequent improved patient outcome. Finally, a recent trial in cardiac surgery suggesting harm with HES underlines that there is insufficient trial data to rule out clinically important harm in surgical patients (Skhirtladze, Base et al., 2014). Consequently, since there is no documented benefit of clear clinical relevance with HES in any group of patients, but potentially widely harmful effects, the use of HES should be abandoned to ensure patient safety.

REFERENCES Bellmann, R., C. Feistritzer, et al. (2012). Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clinical Pharmacokinetics 51, 225–236. Brunkhorst, F.M., C. Engel, et al. (2008). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. New England Journal of Medicine 358, 125–139. Haase, N., J. Wetterslev, et al. (2013). Bleeding and risk of death with hydroxyethyl starch in severe sepsis: post hoc analyses of a randomized clinical trial. Intensive Care Medicine 39, 2126–2134. Hartog, C.S., D. Reuter, et al. (2011). Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review. Intensive Care Medicine 37, 1725–1737. © 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

M¨uller, R.G., N. Haase, et al. (2013). Effects of hydroxyethyl starch in subgroups of patients with severe sepsis: exploratory post-hoc analyses of a randomised trial. Intensive Care Medicine 39, 1963–1971. Myburgh, J.A., S. Finfer, et al. (2012). Hydroxyethyl starch or saline for fluid resuscitation in intensive care. New England Journal of Medicine 367, 1901–1911. Navickis, R.J., G.R. Haynes, et al. (2012). Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. Journal of Thoracic and Cardiovascular Surgery 144, 223–230. Perel, P., I. Roberts, et al. (2013). Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2, CD000567. Perner, A., N. Haase, et al. (2012). Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. New England Journal of Medicine 367, 124–134. Rasmussen, K.C., P.I. Johansson, et al. (2014). Hydroxyethyl starch reduces coagulation competence and increases blood loss during major surgery: results from a randomized controlled trial. Annals of Surgery 259, 249–254. Skhirtladze, K., E.M. Base, et al. (2014). Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate on blood loss and coagulation after cardiac surgery. British Journal of Anaesthesia 112, 255–264. Wiedermann, C.J. and M. Joannidis (2014). Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review. Intensive Care Medicine 40, 160–170. Zarychanski, R., A.M. Abou-Setta, et al. (2013). Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. Journal of the American Medical Association 309, 678–688.

S20 No, Hydroxyethyl Starches Should Not Be Abandoned D. Faraoni & P. Van der Linden Department of Anaesthesiology, CHU Brugmann – HUDERF, Free University of Brussels, Brussels, Belgium The benefit-to-risk ratio of both colloids and crystalloids when used to maintain an adequate circulating blood volume remains controversial. The volume of effect of the different available solutions has been shown to be context sensitive, leading to the observation that their use in different clinical conditions could result in different effectiveness and safety profiles. Indeed, the presence of an intact glycocalyx protecting the endothelial barrier provides the retention of colloids within the intravascular space, whereas its impairment allows for an increased capillary permeability and extravasation of colloids. This extravascular presence of colloids increases the risk of side effects. Hypervolemia, even in healthy individuals, has been recognized to trigger atrial natriuretic peptide release (Bruegger, Jacob et al., 2005), which has the power to degrade the endothelial glycocalyx leading to increased endothelial permeability (Chappell, Jacob et al., 2008). The induction of hypervolemia in adults has indeed been reported to allow extravasation of colloids (Rehm, Haller et al., 2001).

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14 Abstracts of the 15th Annual NATA Symposium Hydroxyethyl starches (HES) are widely used for intravascular volume maintenance or replacement during surgery. In this context, various preparations have been used in many clinical circumstances for several decades. Pharmacokinetic and pharmacodynamic properties of these products closely depend on starch sources and their chemical composition, which includes their degree of substitution, the molecular location of the substitution, their average molecular weight and its distribution, as well as their concentration (Westphal, James et al., 2009). Consequently, the manufacture of HES has moved from ‘‘hetastarches’’ (molar substitution ratio of 0.7) to ‘‘pentastarches’’ (molar substitution ratio of 0.5) and then to ‘‘tetrastarches’’ (molar substitution ratio of 0.4). Recently, there has been concern regarding possible adverse outcomes when tetrastarch preparations was used in critically ill patients, especially in sepsis (Myburgh, Finfer et al., 2012; Perner, Haase et al., 2012). The results of these studies have to be interpreted with caution as some methodological pitfalls could be highlighted (Ince, 2013). In addition, another recent study performed in a similar population has reported opposite results (Annane, Siami et al., 2013). Whatsoever, the effectiveness and safety of tetrastarches is likely to differ when used in relatively healthy people rather than in critically ill patients, in which the widespread impairment of glycocalyx as well as the disruption of the vascular integrity will cause extravascular accumulation of large molecules. We recently performed a formal analysis of the data obtained from prospective randomized clinical trials in which the safety of tetrastarches administered in acute surgical settings was studied after exclusion of retracted publications (Van Der Linden, James et al., 2013). Consequently, we undertook to assess the safety of tetrastarches when used in the perioperative context. We performed a formal search that yielded 59 primary full publications of studies that met ‘a priori’ inclusion criteria and randomly allocated 4529 patients, with 2139 patients treated with tetrastarches compared to 2390 patients treated with a comparator. These analysis reported that perioperative use of tetrastarch solutions was not associated with increased blood loss (38 trials, 3280 patients) or allogeneic red blood cell transfusions (20 trials, 2151 patients), and did not induce kidney dysfunction assessed by the change or the absolute concentrations of serum creatinine as well as the need for renal replacement therapy (39 trials, 3389 patients). These latter results were confirmed in a meta-analysis (Martin, Jacob et al., 2013). These two formal analyses are in accordance with the results of two prospective randomized controlled studies performed in children undergoing cardiac surgery, that reported the equivalence of tetrastarches compared to human albumin for perioperative fluid replacement, without any increase in the incidence of postoperative complications (Hanart, Khalife et al., 2009; Van der Linden, De Ville et al., 2013). In these studies, the tetrastarch was associated with a decreased fluid balance, which could have a significant impact on postoperative morbidity and mortality (Hassinger, Wald et al., 2014). These analyses also indicate that results observed in the critically

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ill population should not be extrapolated to other non-critically ill populations, such as the surgical patients. Rather, specific consideration should apply to different categories of patients (Myburgh and Mythen, 2013).

REFERENCES Annane, D., S. Siami, et al. (2013). Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. Journal of the American Medical Association 310, 1809–1817. Bruegger, D., M. Jacob, et al. (2005). Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts. American Journal of Physiology. Heart and Circulatory Physiology 289, H1993-1999. Chappell, D., M. Jacob, et al. (2008). A rational approach to perioperative fluid management. Anesthesiology 109, 723–740. Hanart, C., M. Khalife, et al. (2009). Perioperative volume replacement in children undergoing cardiac surgery: albumin versus hydroxyethyl starch 130/0.4. Critical Care Medicine 37, 696–701. Hassinger, A.B., E.L. Wald, et al. (2014). Early postoperative fluid overload precedes acute kidney injury and is associated with higher morbidity in pediatric cardiac surgery patients. Pediatric Critical Care Medicine 15, 131–138. Ince, C. (2013). The great fluid debate: when will physiology prevail? Anesthesiology 119, 248–249. Martin, C., M. Jacob, et al. (2013). Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. Anesthesiology 118, 387–394. Myburgh, J.A., S. Finfer, et al. (2012). Hydroxyethyl starch or saline for fluid resuscitation in intensive care. New England Journal of Medicine 367, 1901–1911. Myburgh, J.A. and M.G. Mythen (2013). Resuscitation fluids. New England Journal of Medicine 369, 1243–1251. Perner, A., N. Haase, et al. (2012). Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. New England Journal of Medicine 367, 124–134. Rehm, M., M. Haller, et al. (2001). Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology 95, 849–856. Van der Linden, P., A. De Ville, et al. (2013). Six percent hydroxyethyl starch 130/0.4 (Voluven(R)) versus 5% human serum albumin for volume replacement therapy during elective open-heart surgery in pediatric patients. Anesthesiology 119, 1296–1309. Van Der Linden, P., M. James, et al. (2013). Safety of modern starches used during surgery. Anesthesia and Analgesia 116, 35–48. Westphal, M., M.F. James, et al. (2009). Hydroxyethyl starches: different products--different effects. Anesthesiology 111, 187–202.

© 2014 The Authors Transfusion Medicine © 2014 British Blood Transfusion Society

Abstracts of the 15th Annual NATA Symposium, April 10-11, 2014, Porto, Portugal.

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