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Ist Transfusion out?

PD Dr. Andreas Buser Blutspendezentrum SRK beider Basel

Hämatologie, USB

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Übersicht

•  Blutprodukte, Entwicklung in der Schweiz

•  Sind Transfusionen schlecht?

•  Patient Blood Management

•  Ausblick

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Fallbeispiel

•  82 jähriger Mann •  Hospitalisiert wegen infektexacerbierter COPD •  Art. Hypertonie, schlecht eingestellt •  Bekannte KHK •  60 py •  Rezidivierende Gicht

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Befunde

•  Hb 78 g/l •  MCV 90 fl •  MCHC 325 g/l •  Thrombozyten 178 G/l •  Ferritin 60 ng/ml

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13 Swiss Red Cross Regional Blood Transfusion Centres

Population: 8 million

Transfusions performed in ~200 hospitals

3 centres for allogeneic stem cell transplantation

Reporting to Swissmedic Haemovigilance mandatory since 2002

Transfusions in 2013 ~ 280‘000 RBC units ~ 4‘000 plasma units

~ 35‘000 platelet concentrates

The Swiss Blood Transfusion Service

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Konzentrat von roten Blutkörperchen, leukozytendepletiert

Plasma Konzentrat von Blutplättchen

leukozytendepletiert pathogeninaktiviert

Die labilen Blutprodukte

4C° 49 Tage 217 CHF

22 C° 5 Tage

1050 CHF

-30 C° 2 Jahre

150 CHF

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Total of transfused blood units 2003 - 2013

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Transfusionsreaktionen

•  Febrile nicht-hämolytische Transfusionsreaktionen

•  Allergische und anaphylaktische Reaktionen

•  Volumenüberladung

•  Hypotonie •  Hämolytische

Transfusionsreaktionen (früh oder verzögert)

•  Transfusionsassoziierte Infektionen

•  TRALI (transfusion-related acute lung injury)

•  Transfusions-assoziierte Graft-versus-Host Disease

•  Posttransfusionelle Purpura

•  Mortalität?

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ity over a restrictive transfusion strategy (use of lowerhemoglobin thresholds). Thus, restrictive transfusion ispreferable if reliable evidence demonstrates either noninfe-riority or superiority to liberal transfusion.

Many small trials have addressed the question of opti-mal use of RBC transfusions. Two reviews of the Cochranedatabase, including an update in 2010 that included allavailable trials published through August 2009, have sum-marized those data (29, 30). Recently, 2 additional trialswere published that expanded by 30% the number of pa-

tients included in the evidence base of transfusion trials(31, 32). Thus, it is timely to reexamine the data andprovide guidance to the medical community.

GUIDELINE FOCUS

These guidelines focus on hemoglobin concentrationthresholds and other clinical variables that might triggerRBC transfusion. Practice guidelines are not intended asstandards or absolute requirements and do not apply to all

Figure. Adverse effects of RBC transfusion contrasted with other risks.

HIV

HCV

HBV

TRALI TACO

Fever

Life-threatening reaction

Fatal hemolysis

Motor vehicle fatalities

Firearm homicide

Death from medical errorAirplane fatalities

Lightning fatalities

Fall fatalities

Risk

1 in100 million

1 in10 million

1 in1 million

1 in100 000

1 in10 000

1 in1000

1 in100

1 in10

1 in 1

Risk is depicted on a logarithmic scale. Shaded bars represent the risk per RBC unit transfused, and unshaded bars represent the risk for fatality per personper year for various life events. During 2007 through 2008, HIV incidence in blood donors was 3.1 per 100 000 person-years. Residual risk was estimatedas 1:1 467 000 transfused blood components or 6.8 per 10 million transfused components (10). During 2007 through 2008, HCV incidence in blooddonors was 5.1 per 100 000 person-years with residual risk estimate of 0.87 per million transfused blood components (1:1 149 000) or 8.7 per 10 milliontransfused components (10). For 2006 to 2008, HBV incidence in blood donors was 3.41 to 3.43 per 100 000 person-years. The estimated residual riskfor HBV was 1 in 282 000 to 1 in 357 000 transfused blood components (11) or 2.8 per million to 3.6 per million transfused blood components. In arecently published, large, prospective study with active recipient surveillance, the rate of TRALI occurrence in 2009 was 0.81 (95% CI, 0.44 to 1.49) per10 000 transfused blood components or 8.1 per 100 000 transfused blood components (12). Although the literature has a wide range of TRALI riskestimates (1, 13–16), we have selected the rate reported in this recent prospective study. Three studies of TACO have produced similar results. In a studyof 901 intensive care unit patients, 6% of patients who received transfusions developed TACO. Median units transfused were 2 RBCs and 3 overall(including plasma and platelets) (17). The rate per transfused RBC unit was 2 to 3 per 100. In 382 patients undergoing hip and knee replacement, 1%developed TACO after surgery (18). In a study of patients having total hip and knee arthroplasty, 8% developed fluid overload necessitating diuretic useand 4% of patients who did not receive transfusions developed fluid overload, leading to a TACO estimate of 4% (19). In published studies from thelate 1990s, the risk for fatal hemolysis was estimated to range from 1.3 to 1.7 per million (5.9 to 7.7 per 10 million) transfused RBC units in one report(20) and 1 per 1 800 000 or 8.5 per 10 million in a second report (21). More recently, transfusion-related fatalities due to hemolysis reported to the U.S.Food and Drug Administration averaged 12.5 deaths per year from 2005 to 2010 (22). With 15 million RBC units transfused per year, the estimatedrisk for death due to hemolysis is 1:1 250 000 or 8 per 10 million RBC units. Fever (febrile nonhemolytic transfusion reactions) was estimated to be 1.1%with prestorage leukoreduction and 2.15% with poststorage leukoreduction (23). Death from medical error as reported by the Institute of Medicine was1.3 to 2.9 per 1000 hospital admissions (24). Life-threatening transfusion reactions, defined as reactions requiring major medical intervention (forexample, vasopressors, intubation, or transfer to an intensive care unit), occurred in 1:139 908 transfusions or 7.1 per million transfusions (1). Fatalmotor vehicle accidents were estimated at 13.1 per 100 000 persons in 2008 or 1.3 per 10 000 persons (25). The rate of firearm homicide (which excludessuicide) was 4 per 100 000 persons in 2008 (25). Fatal falls were estimated at 8.2 deaths per 100 000 persons in 2008 (25). Lightning fatalities rangedfrom 0.02 per million (2 per 100 million) persons in California and Massachusetts to 2.0 per million persons in Wyoming (0 risk in Hawaii, RhodeIsland, and Alaska) (26). The odds of being killed on a single airline flight on the 30 airlines with the best accident rates were 1 per 29.4 million. Amongthe 25 airlines with the worst accident records, rates were 1.7 per million per flight (27). Modified from Dzik (2002) (28). HBV ! hepatitis B virus;HCV ! hepatitis C virus; RBC ! red blood cell; TACO ! transfusion-associated circulatory overload; TRALI ! transfusion-related acute lung injury.

Clinical Guideline Clinical Practice Guideline on Red Blood Cell Transfusion

50 3 July 2012 Annals of Internal Medicine Volume 157 • Number 1 www.annals.org

Carson JL, Ann Intern Med 2012

Risks of Transfusion and other risks

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“RBC storage laesions” Changes in RBC during storage

•  Shape ∆ •  Membrane flexibility ↓ •  2,3 DPG ↓ •  ATP •  Potassium (K+) •  pH •  Lactate •  pO2 •  Hb SO2 •  Free Hb •  Hb-NO •  CD40L • Microparticles •  ……

Relevance ?

Reversibility

Clinical trials

Good enough ?

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The problem of studies on transfusion outcome

Common mistakes •  No correction for RBC transfused (even comparison with non transfused pat.) •  No correction for confounders •  And many more

medArt basel ̀ 14N Engl J Med 2008;358: 1229-1239

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Data un-adjusted for differences in patient groups shown in Table 1 !

Newer blood

Older blood

Comparison of very different patient groups gives different results !

apples

oranges

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Storage time in non-transfused patients

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Currently running or finnished RCTs

1.  NCT00326924 “ARIPI” (Canada, D. Fergusson)

<7d vs St.; Composite endpoint in premature infants

2.  ISRCTN44878718 “ABLE” (Canada, J. Lacroix)

<8d vs St.; 90 day mortality in high risk ICU patients

3. NCT00751322 “TRALI2” (US, O. Gajic)

<6d vs St.; Pulmonal function and immune activation in mechanically ventilated ICU patients

4. NCT00991341 (01274390) Recess (RECAP) (US, NHLBI)

<11d vs >20d; MODS (O2 saturation) compl.cardiac surgery

5. NCT00458783 (US, C. Koch)

<14d vs >20d; Morbid outcomes < 30d, in cardiac surgery

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Patient Blood Management

•  Frühe Detektion und Behandlung einer ggf. vorhandenen Anämie vor elektiven Eingriffen mit hohem Transfusionsrisiko –  EINE ANÄMIE IST NIE NORMAL!

•  Rationaler Einsatz von Blutkonserven

•  Minimierung des Blutverlustes und vermehrte Nutzung fremdblutsparender Maßnahmen

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Bei erwartetem (chirugischem) Blutverlust

•  Präoperative Massnahmen –  Wahl des Chirurgen und der Operationsmethode –  Anamnese (Blutungsneigung?) selber oder familiär –  Vermindern der Blutungsneigung (NSAID!!)

–  Epo –  Substrate: Eisen, Vit B12, Folsäure

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Bei erwartetem (chirurgischem) Blutverlust

Perioperative Massnahmen •  Normovolämie und Normothermie •  Chirurgische Blutstillung •  Topische Massnahmen (Fibrinkleber etc.) •  Eigenblutspende •  Korrektur Gerinnungssystem, evtl. Fibrinolysehemmung •  Akute normovoläme Hamodilution •  Cell-Saver

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Korrektur des Gerinnungssystems

•  Hemmung der Fibrinolyse

•  Vitamin K Substitution

•  Stop von Thrombozytenaggreagtionshemmern

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Generelly accepted triggers RBC

Wegen möglichen Komorbiditäten: elderly patients (>65 )y: Hb 90 bis 100g/l

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Transfusionstrigger Erythrozytenkonzentrate USB

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Papst Innozent VIII • Der Legende nach Blut von drei 10 jährigen Buben transfundiert (oder getrunken) als Jungbrunnen

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Wachstum der Bevölkerung

Gesamtbevölkerung Potentielle Spenderbevölkerung

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Trendmodell Blutspende und Blutbedarf BS/BL

Thomas Volken, Manuscript in preparation

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Artificial Blood - the future?

shRNA:  small  hairpin  RNA  

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Schlussfolgerungen

•  Transfusion is not dead, but some people think it smells funny

•  Transfusionen so viel wie nötig, aber so wenig wie möglich

•  Patient blood management

•  Voraussichtlich steigender Bedarf in Zukunft

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Literatur •  van de Watering L

Pitfalls in the current published observational literature on the effects of red blood cell storage. Transfusion. 2011 Aug;51(8):1847-54.

•  Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013 May 25;381(9880):1845-54

•  Williamson LM, Devine DV. Challenges in the management of the blood supply. Lancet. 2013 May 25;381(9880):1866-75.

•  Butler C, Doree C, Estcourt LJ, Trivella M, Hopewell S, Brunskill SJ, Stanworth S, Murphy MF. Pathogen-reduced platelets for the prevention of bleeding. Cochrane Database Syst Rev. 2013 Mar 28;3:

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Fallbeispiel

•  82 jähriger Mann •  Hospitalisiert wegen infektexacerbierter COPD •  Art. Hypertonie, schlecht eingestellt •  Bekannte KHK •  60 py •  Rezidivierende Gicht

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Befunde

•  Hb 78 g/l •  MCV 90 fl •  MCHC 325 g/l •  Thrombozyten 178 G/l •  Ferritin 60 ng/ml

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Wie weiter?

•  A) Transfusion von 2 EC •  B) Ferinject 100mg i.v •  C) Epo 40‘000 E s.c •  D) keine Behandlung der Anämie nötig

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Anämie

•  Verminderte Produktion? -  Substratmangel: Fe, Vit B12, Folsäure -  Ineffektivität: MDS, Hämoglobinopathie

•  Vermehrter Verlust? -  Blutungsquellen: gastrointestial, urogenital, pulmonal, iatrogen -  Hämolyse?

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Transfusionstrigger Thrombozytenkonzentrate

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1818: First Man-to-man transfusion

1900: Discovery of AB0 Blood Group

1918: Citrate for anticoagulation and storage

1943: Plastic Bags and Additive solutions

1960: Thromboycte Transfusions

70er Jahre: Hepatitis B Tests

1980: HIV Tests

1907: pretransfusion Blood Tests

90er Jahre: universal Leukodepletion (Europe)

2010: Pathogen Reduction

Transfusionsmedicine Highlights

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The continental divide

•  Studies (if you ignore the flaws in them) from US and Canada are not comparable to those of Europe

•  Product factors are completely neglected

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Transfusionstrigger Erythrozytenkonzentrate