Zin en onzin van transfusies

Sacha Zeerleder

Belangenverklaring In overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ)

Naam: Sacha Zeerleder

Organisatie: Academisch Medisch Centrum Amsterdam/Sanquin

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Type van verstrengeling / financieel belang Naam van commercieel bedrijf

Ontvangst van subsidie(s)/research ondersteuning: Viropharma

Ontvangst van honoraria of adviseursfee: Viropharma, Alexion

Lid van een commercieel gesponsord ‘speakersbureau’:

Financiële belangen in een bedrijf (aandelen of opties):

Andere ondersteuning (gelieve te specificeren):

Wetenschappelijke adviesraad:

Ik heb geen 'potentiële' belangenverstrengeling

Ik heb de volgende mogelijke belangenverstrengelingen:

Separate whole blood into:

• Erytrocytes

• Plasma

• Buffycoat = “white dust” above the erythocytes

Whole blood

Preparation blood products

• Centrifugation whole blood (4400 g)

Separation whole blood

Plasma

“ Buffy coat”: leukocytes en thrombocytes

Erythrocytes

After centrifugation

Temp. Storage Prize

Erythrocytes 2-6 C 35 days € 200

Thrombocytes 20 C 5-7 days (shaker)

€ 485 (5 E)

Plasma - 30C 1 year € 172

Storage blood products

Eythrocyte (red blood cell) transfusion

• 1665: transfusion dog dog

• 1667:Denis: calf human

• 1827: Blundell: human human

• 1901: Landsteiner: ABO system

• 1930: first blood bank

• 1940: Rhesus system

Transfusion history

• Het verwijderen van een groot deel van de leukocyten door product over een filter te brengen.

Erythrocytes

• 270 mL (Ht 0.57 L/L) • <20 mL plasma • < 1 x 106 leukocytes • Shelf life 35 days at 2-6ºC • Contains 250 mg iron

Radiation 25 Gy Shelf live • 14 days • product >14 days old: 24 hrs after radiation

12

Erythrocyte consumption Dutch UMCs 2005-2014

Ee

nh

ed

en

Role of oxygen delivery

Oxygen delivery (DO2)

= cardiac output x arterial oxygen content

Oxygen delivery (DO2)

cardiac output x

arterial oxygen content

• heart rate • stroke volume

Erythropoietin hemoglobin synthesis Rightward shift of oxyhemoglobin dissociation curve → increased O2 delivery

• ABO mismatch

– incidence

– mortality

• Delayed hemolysis

• Alloimmunisation

– Ery’s

– Trombo/Leuko

• Allergic reaction

• Fever

• Volume “overload”

• TRALI

1 op 6.000-20.000

1 op 100.000-500.000

1 op 2.500

1%

10%

1-4%

0,1-1%

10-40%

1 op 5.000-10.000

Transfusion complications

To transfuse or not transfuse, that’s the question

Female, 25 years old Sportive (Polo) • progressive endometriosis • Autoimmune gastritis Fatigue, “heavy legs” when doing sports

Male, 83 years old Used to be sportive (Army, polo) • Coronary artery disease, 2 MI • Prostatic cancer- stable • Diabetes mellitus • Chronic gastritis Fatigue, shortness of breath, angina pectoris when climbing stairs

Hb = 4.9 mmol/L

Transfusion?

Rational Impact of anemia on morbidity and mortality

Association between anemia and increased mortality

Hemoglobin level (postoperative) 30 day in-hospital mortality

Hb 4.4 to 4.9 mmol/L (n = 99) 0 %

Hb 3.2 to 4.3 mmol/L (n = 110) 9 %

Hb 1.9 to 3.1 mmol/L (n = 60) 30 %

Hb ≤1.8 mmol/L (n = 31) 64 %

Carson et al. Transfusion. 2002

Retrospective studies: 310,311 veterans >65 years of age undergoing non-cardiac surgery Inverse correlation death/cardiac events with hematocrit mild anemia (HCT 36.0 to 38.9): 10 % increase in events severe anemia (HCT 18.0 to 20.9): 52% increase in events

Wu et al. JAMA. 2007

1958 patients who declined blood transfusion for religious reasons inverse correlation of death and hemoglobin Higher mortality risk in patients with cardiovascular disease

Carsonet al. Lancet. 1996

Rational for transfusion

association between anemia and increased mortality

Correction of anemia

What is the optimal hemoglobin threshold to correct anemia? Does transfuison improve mortality?

Optimal threshold?

Optimal threshold to correct anemia?

• American Society of Anaesthesiology • British Committee for Standards in Hematologic Australian and New

Zealand Society of Blood Transfusion • Eastern Association for Surgery of Trauma (EAST) and the American College

of Critical Care Medicine of the Society of Critical Care Medicine (SCCM) • European Society of Cardiology (ESC) • Society of Thoracic Surgeons and the Society of Cardiovascular

Anaesthesiologists • Transylvanian Blood Banking Association (Dracula) • AABB (formerly the American Association of Blood Banks) • American College of Physicians • Dutch CBO richtlijn bloedtransfusie

Hb > 6 mmol/L Transfusion not necessarily beneficial

Hb 4-6 mmol/L Beneficial effect dependent on patient’s condition

Hb < 4 mmol/L Transfusion most probably beneficial

Wang et al. Vox Sang 2010; Perioperative red blood cell transfusion. JAMA 1988; Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; Murphy et al Br J Haematol 2001; Clinical Practice Guidelines: Appropriate Use of Red Blood Cells. 2001; Napolitano et al. Crit Care Med 2009; Hamm et al. Eur Heart J 2011; Ferraris et al. Ann Thorac Surg 2011; Carson et al. Ann Intern Med 2012; 157:49.

Patient condition matters

• Can the patient compensate the anemia (cardiopulmonary condition)?

• Is there evidence of acute and ongoing blood loss?

• Is there evidence for increased oxygen consumption (sepsis, fever)

• Are there any signs of atherosclerosis (heart, brain, kidney)

Dutch 4-5-6 rule

• Hb < 4 mmol/l • Acute blood loss in a healthy individual (<60 yrs)

• Hb < 5 mmol/L • Acute blood loss in a healthy individual (>60 yrs) • Acute blood loss in polytrauma • Preoperative (<60 yrs) with an expected blood loss

>500ml • Fever • Postoperative (e.g. Open heart surgery) • Mild/severe systemic disease

• Hb < 6 mmol/L • Life-threatening severe systemic disease • Inability to increase cardiac output • Septic/toxic patients • Severe long disease • Cerebrovascular diasease

Hb < 3.6 mmol/L (6 g/dL)

Transfusion recommended except in exceptional circumstances

Hb 3.6 mmol/L- 4.3 mmol/L (6 - 7 g/dL)

Transfusion generally likely to be indicated

Hb 4,3 mmol/L – 5 mmol/L (7 to 8 g/dL)

Transfusion should be considered in postoperative surgical patients, including those with stable cardiovascular disease, after evaluating the patient’s clinical status

Hb 5 mmol/L - 6.2 mmol/L (8 to 10 g/dL)

Transfusion generally not indicated, but should be considered for some populations (eg, those with symptomatic anemia, ongoing bleeding, acute coronary syndrome with ischemia)

Hb > 6.2 mmol/L (>10 g/dL)

Transfusion generally not indicated except in exceptional circumstances

AABB guideline

Is correction of anemia beneficial?

• 19 randomized clinical trials comparing • higher (liberal) versus lower (restrictive) transfusion threshold • 6264 medical and surgical patients (adults and children) • Most trials: Hb 4.3 – 6.2 mmol/L (7 and 10 g/dL)

Cochrane review: are transfusions beneficial in anemia

30 day mortality (n=4975 patients included in 11 of 19 trials)

Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012;4:CD002042. doi:10.1002/14651858.CD002042.pub3.

Cochrane review: are transfusions beneficial in anemia

39 percent decrease in the probability of receiving a transfusion (46 versus 84

percent; relative risk 0.61; 95% CI 0.52-0.72)

Fewer units (1.19) transfused per patient

trend towards a lower 30-day mortality (relative risk = 0.85; 95% CI 0.70-1.03)

trend towards a lower overall infection rate (relative risk = 0.81; 95% CI 0.66-

1.00); however, there was no difference seen with pneumonia.

No difference in functional recovery, or hospital or intensive care length of stay

No increased risk of myocardial infarction (MI) when all trials were included

(relative risk = 0.88; 95% CI 0.38-2.04) Carson et al. Cochrane Database Syst Rev. 2012;4:CD002042.

Cochrane review: are transfusions beneficial in anemia

39 percent decrease in the probability of receiving a transfusion (46 versus 84

percent; relative risk 0.61; 95% CI 0.52-0.72)

Fewer units (1.19) transfused per patient

trend towards a lower 30-day mortality (relative risk = 0.85; 95% CI 0.70-1.03)

trend towards a lower overall infection rate (relative risk = 0.81; 95% CI 0.66-

1.00); however, there was no difference seen with pneumonia.

No difference in functional recovery, or hospital or intensive care length of stay

No increased risk of myocardial infarction (MI) when all trials were included

(relative risk = 0.88; 95% CI 0.38-2.04) Carson et al. Cochrane Database Syst Rev. 2012;4:CD002042.

Transfusion Requirements In Critical Care (TRICC) trial (adult ICU)

restrictive transfusion strategy lower risk of MI (0.7 vs 2.9 %; RR= 0.25;

95% CI 0.07-0.88)

Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip

Fracture Repair (FOCUS) trial

restrictive transfusion strategy: higher risk of MI (3.8 vs 2.3 %; RR= 1.65; 95%

CI 0.99-2.75, ns). Mortality was not adversely affected Hébert et al. N Engl J Med. 1999; Carson et al. N Engl J Med. 2011

Potential approach in anemic patients

Asymptomatic hospitalized patient: hemodynamically stable medical/surgical patients Transfusion: Hb of 4.3 – 5 mmol/L (7 to 8 g/dL) Cardiovascular disease • asymptomatic medical patients with stable CAD: Transfusion <5 mmol/L (8 g/dL)

• symptomatic patients with coronary artery disease is guided by the symptoms and clinical judgment

• Acute coronary syndrome : nobody really knows… consider transfusion when the Hb is between 5 – 6.2 mmol/L (8 and 10 g/dL)

Oncology patient • Curative treatment: similar to medical patients • Palliative care: subjective responses to transfusion 31-70% But: Unnecessary transfusion keep patients in hospital

Carson et al. Ann Intern Med 2012; Kansagara et al. Ann Intern Med 2013; Gleeson et al. Palliat Med 1995; Sciortino et al. J Palliat Care 1993; ; Hébert et al. N Engl J Med. 1999; Carson et al. N Engl J Med. 2011

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liberal restrictive

“old” rule (liberal): Hb<6.0 mmol/L: transfusion 3 EC-concentraten “new” rule (restrictive): Hb < 5.0 mmol/L: consider transfusion Hb <6.0 mmol/L with comorbidities (cardial) consider transfusion

Introduction restrictive transfusion strategy dep. Hematology AMC

Reduction of 30% ~420 products ~ 91 kEuro

To transfuse or not transfuse, that’s the question

Female, 25 years old Sportive (Polo) • progressive endometriosis • Autoimmune gastritis Fatigue, “heavy legs” when doing sports

Male, 83 years old Used to be sportive (Army, polo) • Coronary artery disease, 2 MI • Prostatic cancer- stable • Diabetes mellitus • Chronic gastritis Fatigue, shortness of breath, angina pectoris when climbing stairs

Hb = 4.9 mmol/L

Platelet transfusion

5 buffy coats pooled

• 340 mL

• 390 x 109 plts

• < 1 x 106 leucocytes

• < 5 x 109 erythrocytes

• In plasma (or PAS II)

Platelets

Apharesis platelets

• 320 mL

• 360 x109 plts

• HPA/HLA matched

platelets

removal

• Major bleeding

• Acute DIC, MAHA, TTP-HUS, HELLP

• Chronic DIC (aneurysms, malignancy, hemagiomas)

• Infection (Malaria)

• Extensive thrombosis/pulmonary embolism

• Extracorporal-/intravascular device

increased consumption

destruction • severe infection (sepsis, dengue etc) • HIT •AITP • PTP (active and passive) • drugs

sequestration •hypersplenism •hypothermia

hemodilution • fluid resuscitation • blood products

circulation

Pseudothrombocytopenia

• Clotting sample • EdTA ex-vivo aggregation • Rosette formation (leucocytes) • GpIIb/IIIa inhibitor induced clumping • Macrothrombocytes

production

• toxic/radiation • MDS/leukemia • myelophtysis • chronic liver disease • infection

Decreased production

Tc pool

Etiology of thrombocytopenia?

To transfuse or not transfuse, that’s the question

Female, 25 years old Acute myeloid leukemia

Tc = <10x109/L

Female, 25 years old polytrauma with massive bleeding

Female, 25 yrs old TTP

Tc = <10x109/L Tc = 30x109/L

Transfusion?

Endothelial cell activation/damage

Primary haemostasis fully dependent on platelets

Slichter 2004

Platelet count and efficacy primary hemostasis

Harker&Slichter, N Engl J Med 1972

Critical threshold

~10x109/L

Bleeding risk- platelet threshold?

Holler et al. 2009

Gmur et al. 1991

Platelet transfusion in clinical practice

Clinical situation/intervention Platelet trigger (x109/L)

Thrombocytopenia without bleeding 10

Thrombocytopenia plus additional factors (e.g. Fever) 20

Surgery, bleeding (WHO3) 50

Neurosurgery (incl. Opthalomological interventions), bleeding WHO4

100

Platelet transfusion: No indication or only in case of life threating conditions:

Idiopathic thrombcytopenic purpura (ITP)

Thrombotic thrombocytopenic purpura (TTP)

Disseminated intravascular coagulation (DIC)

Prophylactic vs therapeutic platelet transfusion strategy

Data not entirely clear – however, prophylactic treatment seems still reasonable

To transfuse or not transfuse, that’s the question

Female, 25 years old Acute myeloid leukemia

Tc = <10x109/L

Female, 25 years old Polytrauma with massive bleeding

Female, 25 yrs old TTP

Tc = <10x109/L Tc = 30x109/L

Transfusion?

Summary

We have some idea on when to transfuse….

There are triggers - however, patient condition matters

Erythrocyte transfusion:

• < 4 mmol/L (transfusion) and >6 mmol/L (no transfusion)

• 4-6 mmol/L? dependent on comorbidities and clinical situation

• Restrictive transfusion strategy: might be beneficial

Platelet transfusion:

Trigger for prophylactic transfusion : 10 x 109/L (20 in case of fever)