“Transfusional Medicine: the Quest

to prevent Blood Transfusions”

Moises Auron, FAAP, FACP, SFHM

Associate Professor of Medicine and Pediatrics

Disclosure of Financial Relationships

• Dr. Auron has no relationships with entities

producing, marketing, re-selling, or

distributing health care goods or services

consumed by, or used on, patients.

Animal – Human Transfusion

• 1667 – Jean Baptiste Denis

- first documented

transfusion of animal blood

into humans

• Used to treat psychiatric

diseases

• Patient outcomes?

- Death!!!

Human – Human Transfusion

• James Blundell – 1818

• First successful human

transfusion

• Husband to wife

• 5 out of 10 patients lived

Outline

• Anemia Physiology

• Current evidence for transfusion medicine

• Adverse effects of blood utilization

• Current protocols for Anemia optimization

• Quality improvement implementation

It is right to say……

• The safest transfusion is the one that is

avoided

• The best transfusion is the one that is avoided

• What is the evidence?

• What is the comparison?

Physiology

Pre-load

After-load Stroke volume (SV)

Contractility

SV x Heart rate = Cardiac output (CO)

•CaO2 = SaO2 x 1.34 x Hb + [PaO2 x 0.003]

•DO2 = CO x CaO2

•O2ER = VO2/DO2 (~20-30%)

•DO2crit = < 7.3 ml O2/kg/min

Madjdpour C, et al. Crit Care Med 2006; 34[Suppl.]:S102–S108.

Physiology

Acute response to Anemia

Central

– ↑ CO

Regional

– Redistribution

Microcirculation

– Capillary recruitment

http://www.frca.co.uk/article.aspx?articleid=100345

Shander A, et al. Brit J Anaesth 2011;107 (S1): i41–i59.

DeLoughery TG. N Engl J Med 2014;371:1324-31.

Outline

• Anemia Physiology

• Current evidence for transfusion medicine

• Adverse effects of blood utilization

• Current protocols for Anemia optimization

• Quality improvement implementation

Anemia tolerance: what is the

ideal hemoglobin level?

• Cardiovascular effect

- Coronary artery disease

- Valvular disease

- Elderly patient

• CNS effects

• Effects on splachnic and renal perfusion

What is my cut-off Hemoglobin

value to transfuse?

• 10/30?

- Based in “experience”

- Not supported by evidence

• Indiscriminate use of blood

- USA: 15 million pRBC/year

- Global: 85 million pRBC/year

Carson JL, et al. Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB. Ann Int Med 2012.

Anesth Analg 1996;82:687-94.

Hb 12.6±0.2 to 9.9 ±0.2 g/dl

N = 90 (60 hemodilution)

Crit Care Med. 2005 Mar;33(3):591-7.

- Hemoglobin 13±1.3 to 9.3±1 g/dl

- No LV dysfunction or hemodynamic instability.

- Maintain adequate filling pressures!

N = 20

Age +/- S.E.M. = 76 y/o (66-85)

Excluded: Hx of CAD, valvular cardiomyopathy, non-sinus rhythm, LBBB, beta-

blocker use, Hb < 10 g/dL.

Isovolumetric hemodilution was well tolerated in elderly down to 8.8 +/- 0.3 g/dL

Anesth Analg 1996;82:681-6.

Acute Anemia Physiology

Weiskopf et al., JAMA. 1998;279(3):217-221.

Acute isovolemic reduction of Hb concentration to 50 g/L in conscious healthy

resting humans does not produce evidence of inadequate systemic tissue

oxygenation

Anesthesiology. 2000;92:1646-52.

Memoria inmediata

Memoria tardía

Sumas horizontales

Sustitución numérica

There is no difference between time of

reaction (speed and precision of

processing information) or in immediate

and delayed memory between

Hemoglobin of 7 g/dL vs. 14 g/dL.

Anesthesiology 2002; 96:871–7.

N = 31 healthy volunteers (28 y/o +/- 4)

Tests: verbal and standard memory; computerized neuropsychological

Basal hemoglobin 12.7 g/dL hemodilution to 5.7 g/dL

There is no difference in reaction time in

patients with Hemoglobin of 5.7 g/dL who

used supplemental O2 (PaO2 > 350 mm Hg

equals to increase Hb ~ 2-3 g/dL reverse

effects of acute anemia

Hemodilution shows that the

body can tolerate low Hb levels

down to 7-8 g/dL. What is the

comparison in real life patients?

18% vs. 23%

NEJM 1999;340(6):409-17.

TRICC Study

N = 838

Hb < 9.0 g/dL

Euvolemic

Restrictive – Hb < 7 g/dL

(N = 418)

Liberal – Hb < 10 g/dL

(N = 420)

8.7% vs. 16.1%

5.7% vs. 13%

NEJM 2011;365:2453-62.

Patients > 50 y/o10 g/dL 8 g/dL

JAMA. 2014;311(13):1317-1326

Serious infections

R - 11.8%(95%CI, 7.0%-16.7%)

L - 16.9%(95%CI, 8.9%-25.4%)

RR (95%CI) 0.94 (0.78–1.09)

NEJM. Published online Oct 1, 2014.

Shander A, Transfusion 2014;54:2688-2695.

n = 293,

2003-2012

n = 293

1981-1994

Mortality for each gram decrease in nadir postop Hb level

- 1.79 (95% CI, 1.24-2.57; p = 0.002)

No deaths in those with postop Hb levels between 7-8 g/dl

Transfusion restriction and mortality

Carson JL, et al. Transfus Med Rev. 2002;16(3):187-99.

Clinical Outcomes of Allogeneic RBC

transfusions

Cardiovascular surgeriesHigher risk of post-operative stroke, respiratory failure, ARDS, longer intubation time, reintubation, composite morbidity, in-hospital mortality, systemic sepsis, postoperative LOS and pulmonary complications

Malignancies

Independent predictor of recurrence, survival, and increased risk of lymphoplasmacytic and marginal zone lymphomas

Vascular, orthopedic and other surgeries

Higher risk of death, thromboembolic events, AKI, mortality, composite morbidity, return to OT, systemic sepsis, and pulmonary complications

GI bleed/ STEMI / sepsis with ICU admissions

Increased risk of rebleed, mortality and secondary infections

Shander A et al. Br J Anaesth. 2011; 107(S1):i41-i59.

• Transfusion restrictive strategy

• Critical patients – consider transfusion if Hb

< 7 g/dL

• Post-op surgical patients - consider

transfusion if Hb < 8 g/dL or if symptomatic

(angina; orthostatic hypotension; tachycardia

refractory to IVF resuscitation, CHF)

Carson JL, et al. Ann Int Med 2012 Jul 3;157(1):49-58.

But….what if the patient is

bleeding?

N = 921 (severe acute UGIB)

- 461 - restrictive strategy (transfusion if Hb < 7 g/dL) – 51% transfusion free

- 6 weeks survival - 95% (R) vs. 91% (L) - HR 0.55; 95% [CI], 0.33 to 0.92; P 0.02.

- Further bleeding - 10% (R) vs. 16% (L)

- Adverse events - 40% (R) vs. 48% (L); P 0.02

- PUD (HR 0.70; 95% CI, 0.26 to 1.25)

- Cirrhosis (Child–Pugh A/B) (HR 0.30; 95% CI, 0.11 to 0.85),

Rebleeding

Length of

Hospitalization

Amount of blood

transfused

Mortality

Wang J. W J Gastroenterol. 2013;19(40): 6919-27

4 articles

N = 492

Outline

• Anemia Physiology

• Current evidence for transfusion medicine

• Adverse effects of blood utilization

• Current protocols for Anemia optimization

• Quality improvement implementation

If blood is transfused - what is the

impact of the number of units used?

17.1%

22.8%

Vincent JL. JAMA. 2002;288(12):1499-1507.

N = 3534 pts.

Europe ICU’s

J Surg Research. 2002; 102:237–244.

What are the risks of blood

transfusions?

ComplicationBlood

> 14 d (%)

Blood

< 14 d (%)P

In-hospital

Deaths2.8% 1.7% 0.004

Death at 1 yr 11% 7% 0.001

Prolonged

intubation

(>72h)

9.7% 5.6% 0.001

Renal failure 2.7% 1.6% 0.003

Sepsis 4.0% 2.8% 0.01

N Engl J Med 2008;358:1229-39.

Changes in aging blood

• RBC age rapidly in refrigeration – 75%

viable at 24hs

• Decreased ATP and 2,3 DPG

• Loss of membrane phospholipids

• Progressive structural rigidity

echynocytes at 14-21 days

Poor tissue

delivery of O2

Holme S. Transfus Apher Sci 2005;33:55–61.

Hovav T, et al. Transfusion 1999; 39(3):277-81.

N Engl J Med 2015;372:1419-29.

Blood transfusion: Risks

Carson JL, et al. Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB. Ann Int Med 2012.

*Pathology Lab Medicine- acquisition/supply cost

Supply chain/Business Intelligence- patient blood testing, administration & monitoring, processing & storage

Direct Costs

2013 RBC Acquisition Cost $215.64

Blood Bank Supply $17.16

Patient Blood Testing $174.25

Administering & Monitoring $280.22

Processing & Storage $269.00

Total Cost per RBC Unit $957.27

Cost of RBC (leukoreduced) Transfusion

Outline

• Anemia Physiology

• Current evidence for transfusion medicine

• Adverse effects of blood utilization

• Current protocols for Anemia optimization

• Quality improvement implementation

Protocols for Intravenous Iron and

Erythropoietin

Poor oral iron bioavailability

• Bacterial overgrowth

• H. pylori

• GI bleeding

- Platelet dysfunction

- Anti-platelets

• Frequent phlebotomy

• Proteinuria

• ↑ Fe utilization (ESA)

• Celiac disease

• Zinc/copper deficiency

MacDougall IC. Curr Med Res & Opin. 2010; 26(2):473–482.

Liu K, Kaffes AJ. Eur J Gastroenterol Hepatol. 2012; 24:109–116.

Lazarchick J. Curr Opin Hematol 2012, 19:58–60.

• ↓ Dietary source

- Anorexia

- Low protein diet

• ↓ GI absorption

- Hepcidin

- PO4 binders, Ca2+

- Achlorydria

- Antacids

- Atrophic gastritis

Degree of Iron deficiency

Iron deficiency

Ferritin < 100 μg/L

Transferrin saturation < 20%

Camaschella C. N Engl J Med 2015;372:1832-43.

Ganzoni’s formula

• Total Fe deficit (mg) = [Wt (kg) x (14 - actual Hb) x 0.24] + 500 (iron depot)

- Blood volume 70 ml/kg of BW ~7% of body weight

- Fe content of Hb 0.34%

- Factor 0.24 = 0.0034 x 0.07 x 1000 (g to mg).

• 70 kg; Hb 9 g/dL ~ deficit of 1400 mg.

• Underestimation of iron depot in males

- ~ 700-900 mg.

Muñoz M, et al. World J Gastroenterol 2009; 15(37): 4666-4674.

Ganzoni AM. Schweiz Med Wochenschr. 1970;100: 301–303.

On average a patient with

anemia with hemoglobin of

10 to 11 g/dL have an iron

deficit of at least 1 gram.

Parenteral Iron

DeLoughery TG. N Engl J Med 2014;371:1324-31.

Munoz M. World J Gastroenterol 2014;20(8): 1972-85.

Camaschella C. N Engl J Med 2015;372:1832-43.

Name Molecular Anaphylaxis Test dose [Fe] Max

Weight (kD) required (mg/ml) Dose

Dextran

- HMW (Dexferrum®) 265 Y Y 50 1g

- LMW (Infed®) 165 Y Y 50 1g

Fe gluconate (Ferrlecit®) < 50 N N 12.5 125mg

Fe sucrose (Venofer®) 30-100 N N 20 300mg

Iron isomaltoside 150 N N 100 1g

Ferric carboxymaltose 150 N N 50 1g

Ferumoxytol 750 ? N 30 500mg

• FDA (2001 – 2003)

- 30 million doses

- 11 deaths

- 1141 total ADE’s

• Iron sucrose - 0.6 per million doses

• Ferric gluconate - 0.9 per million doses

• LMWD - 3.3 per million doses

• HMWD - 11.3 per million doses

Chertow GM. Nephrol Dial Transplant. 2006;21(2):378-82.

Safety of iron preparations

• NATA (Network for Advancement of Transfusion Alternatives)

• Preoperative Fe therapy ↓ 2/3 Blood Transfusion

• IV Iron: Ferritin < 100, Tsat < 20%, EBL > 1500 ml

• Avoid IV Iron if Ferritin > 300 ng/ml and Tsat > 50%.

- Acute infection.

• Quality of Evidence is weak

• Recommend large RCT

Beris P. Br J Anaesth 2008; 100: 599–604.

Goodnough LT. Br J Anaesth 2011;106 (1): 13-22.

Munoz M. World J Gastroenterol 2014;20(8): 1972-85.

Intravenous iron

• 1 gram dose

- ↑ Hb ~ 2 g/dL

- ↓ intraop / postop transfusion ~ 40-60%

• ↓ cost, morbidity, infection rate

- Bypass impaired enteral iron bioavailability

• Rapid effect ideal in preoperative setting

CCF Blood Management

Erythropoiesis Stimulating Agents

• Indicated to reduce the need for allogeneic

RBC transfusions among patients with

perioperative Hb > 10 to ≤ 13 g/dL who are

at high risk for perioperative blood loss from

elective, non-cardiac, non-vascular surgery.

• Dose 600 u/kg/wk or 40,000 u/wk

• Not indicated for preoperative autologous

blood donation.

• Coverage for Epoetin alfa exclusively

• Orthopedic surgery:

- Knee and Hip arthroplasty

• Jehovah’s witness

• Perisurgery: Epoetin alfa increased the rate of deep

venous thrombosis in patients not receiving

prophylactic anticoagulation. Consider deep

venous thrombosis prophylaxis.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126481.htm

B l a c k B o x

CCF Blood Management

Outline

• Anemia Physiology

• Current evidence for transfusion medicine

• Adverse effects of blood utilization

• Current protocols for Anemia optimization

• Quality improvement implementation

Principles of Bloodless Medicine

Manage / Prevent /Stop

Blood Loss

Stimulating

Hematopoiesis

Minimize Diagnostic

Wastage

Morton J, et al. Am J Med Qual. 2010; 25(4) 289-296.

Red Blood Cell Trigger/Target

Benchmarking

Frank et al. Transfusion. 2013; 53: 3052-3059.

Pre-operative Assessment

Cleveland Clinic Blood Management

Pre-surgical Optimization Workflow

Single Unit Order Default

• Launched August 30th 2013

• Consistent increase in single unit orders

• Estimated cost savings - $250K

All Blood Product Units per Patient

Day (Main Campus)

Year-Quarter Ratio Length Of Stay Total Units Utilization Change

2011 0.2226 85635 19053

2012-Q1 0.2110 89930 18974 5.53%

2012-Q2 0.2304 88602 20413 3.09%

2012-Q3 0.2215 89350 19791 0.45%

2012-Q4 0.2037 91048 18548 8.90%

2013-Q1 0.2108 88146 18580 5.53%

2013-Q2 0.1936 89110 17252 13.91%

2013-Q3 0.1895 91018 17244 15.98%

2013-Q4 0.1800 88827 15988 21.34%

2014-Q1 0.1844 83778 15445 19.16%

Increase in Blood Utilization from Baseline

Decrease in Blood Utilization from Baseline

*Baseline Average 2011

Source: Haemonetics Impact Online

Minimizing diagnostic wastage

• Pediatric tubes

- ↓ 1/3 phlebotomized blood

• Increased awareness among providers to

minimize blood draws.

- No daily tests

Optimizing Anemia and

coagulopathy

Minimizing iatrogenic blood lossElimination of unnecessary phlebotomy

Reduction of test sample volume

Maintaining blood volume Plasma expanders: Crystalloids, Colloids

Hemostatic agents

Anti-fibrinolytics: Tranexamic ac., aminocaproic ac.

Aprotinin

Correction of coagulopathies: rVII, VIII, IX

Desmopressin, Vasopressin, Somatostatin,

Octreotide

Conjugated estrogen

Erythropoiesis stimulating

agents

Recombinant Human Erythropoietin (rHuEPO)

Vitamin B12, Folate, Iron

Thrombopoietic agents Romiplostim, Eltrombopag, IVIG/ steroids

Oxygen delivery techniquesHemoglobin Based Oxygen Carriers (HBOC)

Perfluorocarbons (PFC)-Fluosol DA 20% (FDA-20)

- Nine trials, N = 763

• ↓ blood loss = 591 ml (95% CI 536 to 647, p < 0.001)

- Current evidence does not support an increased risk of

deep-vein thrombosis (13 trials, 801 patients) or

pulmonary embolism (18 trials, 971 pts)

Alshryda S. J Bone Joint Surg Br. 2011;93-B:1577–85.

Principles of Bloodless Medicine

Manage / Prevent /Stop

Blood Loss

Stimulating

Hematopoiesis

Minimize Diagnostic

Wastage

Orthopedic Surgeons Receiving

IOL Date: Before/After Transfusion

Rate

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

30,00%

35,00%

40,00%

45,00%

02950 08288 03714 02216 01440 01390 00920

May-Aug TX Rate

Sept-Dec TX Rate

Source: Haemonetics Impact Online

Main Campus Orthopedic

Transfusion Rate

0,00

0,05

0,10

0,15

0,20

0,25

0,30

0,35

Q1/2013 Q2/2013 Q3/2013 Q4/2013 Q1/2014

Source: Business Intelligence

Primary, Revision, Bilateral, Partial LE Reconstruction

Education

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