Strategies to Limit Blood TransfusionDr O.E. Nnodu, FWACP (Lab Med)

Department of Haematology & Blood Transfusion

University of Abuja Teaching Hospital

Dr O.E. Nnodu 2

Introduction

• The ability to transfuse blood and its components is one of the major achievements of modern medicine which has made possible the development of many surgical procedures and medical therapies including stem cell transplantation.

Dr O.E. Nnodu 3

Introduction

• A new era in transfusion medicine was ushered in from the early 1980ies when it became increasingly clear that various pathogens especially the HIV virus, can be transmitted via blood transfusion.

• In recent years, there has been a global concern about the safety and inventory of homologous blood with 15-25% of HIV infection in sub Saharan Africa attributable to blood transfusion.

Dr O.E. Nnodu 4

Introduction

• Only 39% of the world’s blood supply is donated in developing countries although they have 82% of the global population (WHO). Inadequate blood supplies are a major contributory factor in preventable deaths especially among women and children in these countries.

• The shortfall in blood supply for developing countries is estimated to be 40 million units per year.

Dr O.E. Nnodu 5

WHO Recommendations

• To improve blood supply and safety, the World Health Organization recommends four key elements to frame a national transfusion policy.

• A nationally coordinated blood transfusion service,

• Collection of blood only from voluntary nonremunerated blood donors from low-risk populations,

• Testing of all donated blood, including screening for transfusion-transmissible infections (TTI), blood grouping and compatibility testing and

Dr O.E. Nnodu 6

Introduction

• Reduction in unnecessary transfusions through the effective clinical use of blood, including the use of simple alternatives to transfusion (crystalloids and colloids) wherever possible.

• Although this recommendation has been promoted for over 30 years since the World Health Assembly of 1975, the majority of the poorest countries have been unable or unwilling to implement such a policy.

• Majority of blood donated in our blood banks are from family replacement or commercial donors with voluntary blood donation accounting for < 5% of blood donated annually

• Infection rates for HIV in transfused children range from 1.4% in Zaria to 4.5% in Ile Ife.

• Also involved are hepatitis B and C infections with positive correlation between number of transfusions and HCV positivity.

• Exposure to malaria parasite is as high as 40.9%.

How safe is our “gift of life?”

• Blood typing for additional antigens such as C, E, Kell Kidd, (JK), S and Duffy (Fy) for prevention of alloimmunisation in poly transfused patients are not available.

• The incidence of blood transfusion reactions at a centre in Nigeria was reported to be 8.7% of which 65% are due to febrile non-haemolytic transfusion reaction.

• Adverse effects of blood transfusion correlated with a positive history of multiple transfusions (p < 0.01) (Arewa et al., 2009)  

How safe is our “gift of life?”

• 1) It is an offence for a person:-

 

(a) who has donated tissue, blood or a blood product to receive any form of financial or other reward for such donation, except for the reimbursement of reasonable costs incurred by him or her to provide such donation; and

 

(b) to sell or trade in tissue, blood or blood products, except as provided for in this Bill.

 

(2) Any person found guilty of an offence under subsection (1) is liable on conviction to a fine of N100,000 (one hundred thousand naira) or to imprisonment for a period not exceeding one year or to both fine and imprisonment.

 Section 54- Payment in Connection with the Importation,

Acquisition or Supply of Tissue, Blood or Blood Product

Dr O.E. Nnodu 10

Blood Storage & Preservation

• Whole blood is refrigerated as soon as possible after collection at

temperatures of 2-80C. The shelf of blood depends on the

anticoagulant used.

CPD 21days CPDA 1-35 days

One unit of whole blood contains-

63ml of anticoagulant and 450ml of blood. The usual anticoagulant

CPDA – I, contains citrate for Ca+ binding, phosphate substrates, to

maintain red cell 2,3, DPG levels, Dextrose, Adenine as substrates for

metabolic process of the red cell.

Dr O.E. Nnodu 11

Changes in Blood on Storage at 4C

• Within hours of collection platelets and leucocytes become non-functional.

• Gradual decrease in red cell viability depending on length of storage.

• At the end of shelf-life, about 70%

• Rise in plasma K+ and increase in H + leading to fall in PH.

• Levels of coagulation factors V and VIII decrease

• Free haemoglobin from in bag haemolysis which scavenge NO

• Asymetric dimethylarginine

• Increase in advanced glycated end products (AGE). AGE intereferes with receptors for AGE (RAGE) leading to altered immune activation and inflammatory functions.

Dr O.E. Nnodu 12

Blood Safety

• Blood donor

• Blood Collection process

• Blood storage

• Pre-transfusion testing

• Transport to recipient

• Blood transfusion – appropriateness of transfusion

• Effect of transfusion

• Haemo-vigilance

• This process has to be carefully controlled according to strict protocols but has been shown to differ remarkably in centralized blood collection systems and the hospital based blood banks.

Summary of Background

• Blood is useful and a great help in many clinical situations but

• We are not donating enough units for patients who need them

• There are major safety issues.

• Is it safe to ask clinicians to transfuse less?

• What is the scientific basis for that?

Rational For Strategies To Transfuse Less Blood

• Concerns about blood inventory.• The known hazards of blood transfusion.• Evidence for the excessive use of elective

red cell transfusion.• Evidence for the human tolerance of

anaemia.• The presence of alternatives to

homologous blood.• Evidence for the physiological adaptation

to anaemia.

Dr O.E. Nnodu 15

Physiological Adaptation to Anaemia

Physiological adaptations to anaemia(a) Increased oxygen release Increased oxygen extraction Shift of oxyhaemoglobin dissociation curve (decreased oxygen affinity).Increased levels of 2, 3 D PG

Dr O.E. Nnodu 16

Physiological Adaptation to Anaemia

(b) Increased cardiac outputDecreased after load• Vasodilatation• Diminished blood viscosity• Increased contractility• Tachycardia

Dr O.E. Nnodu 17

Network for the Advancement of Transfusion Alternatives(NATA)

• NATA was created by the cooperation amongst a group of anaesthetists, surgeons, blood bankers who are concerned with blood conservation techniques.

• The Jehovah’s Witness are also driving a system of safe and effective medical and surgical care that avoids the use of allogenic transfusions. This is a multidisciplinary approach making use of pharmaceuticals, technology, medical/ surgical techniques.

Blood conservation?

• The next set of slides are from RCTs attempting to answer the question of safety and transfusion thresholds in severely ill patients who need blood and in children

Lacroix J et al. N Engl J Med 2007;356:1609-1619

Transfusion Strategies for Patients in Paediatric Intensive Care Units

• This study involving stable, critically ill children showed that a restricted strategy (transfusion threshold, 7 g of hemoglobin per deciliter) was as safe as a liberal strategy (transfusion threshold, 9.5 g per deciliter)

• Rates of multiple-organ dysfunction were similar in the two study groups

• In stable, critically ill children a hemoglobin threshold of 7 g per deciliter for red-cell transfusion can decrease transfusion requirements without increasing adverse outcomes

Acute Upper Gastrointestinal Bleeding (Càndid Villanueva)

• A randomized clinical trial shows that among patients with upper GI bleeding, withholding transfusion until the hemoglobin level falls below 7 g per deciliter results in better outcomes than using 9 g per deciliter as the trigger for transfusion.

• As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding

•  Restrictive transfusion associated with a significant 45% relative-risk reduction in 45-day mortality.

Dr O.E. Nnodu 22

What About Patients in Critical Care?

• A multicentre randomized controlled trial of transfusion requirements in critical care was conducted to determine whether a restrictive strategy of red cell transfusion and a liberal strategy produced equivalent results in critically ill patents by comparing the death rate from all causes at 30 days and the severity of organ dysfunction.

Dr O.E. Nnodu 23

Hebert -CCCTG

• 838 critically ill patients were enrolled with euvolaemia with Hb levels of > 9g/dl ( Hebert et al Canadian Critical Care Trials Group)

• 418 were assigned to a restrictive transfusion strategy in which red cells were given if the Hb level fell below 7g/dl and Hb concentrations were maintained at 7-9g/dl

• 420 patients were assigned to a liberal transfusion strategy in which transfusions were given when the Hb concentration fell below 10g/dl. Hb concentrations were maintained between 10-12g/dl

Dr O.E. Nnodu 24

Evidence based care

Results:

• Similar overall 30 day mortality in both groups 18.7 % versus 23.3%, P = 0.11

• In patients who were less acutely ill, the rates were significantly lower in the restrictive strategy group 8.7% versus 16.15% P= 0.03 and

• Patients less than 55 years old (5.7% vs. 13% , P=0.02

Dr O.E. Nnodu 25

Evidence based care

But not among patients with clinically significant cardiac disease (20.5% vs. 22.9%, P= 0.69)

Conclusion A restrictive strategy of red cell transfusion is at least as effective and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.

Dr O.E. Nnodu 26

What About Patients With Myocardial Infarction?

• Wu et al (2001) also found in a large retrospective review of data from the Cooperative Cardiovascular Project that substantial number of lives may be saved when transfusions are administered to patients who present with acute myocardial infarction and a Hct of 33% or lower.

Dr O.E. Nnodu 27

What About Patients Who are Critically Ill? – CRIT Study

• On the flip side are the CRIT study ( Anaemia and blood transfusion in the critically ill) with 4892 patients. 44.1% of these patients were transfused with one or more units. With a mean Hb of 8.6g/dl (SD 1.7).

• The number of units transfused was an independent risk factor for mortality and length of hospital stay.

Dr O.E. Nnodu 28

The CRIT Study

• Transfused patients had more complications and more likely to experience complications

• A similar study ( Anaemia and Blood Transfusion in the Critically Ill)- ABC study was performed in European ICUs.

• Mortality was higher for transfused patients than non transfused patients with similar organ dysfunction as assessed by the Sequential Organ Failure Assessment Score (SOFA)

Dr O.E. Nnodu 29

SOAP, FOCUS Trials

• The weight of evidence from other studies such as the SOAP (3147 patients) and a large observational study with 8787 consecutive hip fracture patients indicate that transfusion at Hb levels > 8g/dl may not improve survival in elderly patients with high illness burden.

• A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.)

Summary of RCTs

• The summary of evidence from RCTs is that a restrictive transfusion policy at Hb level of 7g/dl is as good or better than Hb 9g/dl or higher except in elderly patients with myocardial infarction or coronary heart disease.

Blood Conservation Program

• Correction of anaemia: Iron, B12, folic acid, r HuEpo

• Restrictive transfusion protocol

• Reduction of blood loss: Tranexamic acid, sealants and glues, rFVIIa …..

• Autologous blood

• Preoperative autologous donation

• Normovalaemic haemodilution

• Perioperative cell salvage

Blood Conservat

ion Programm

e

Hb < 70-80g/lRestrictive transfusion

protocol

Reduction of Blood Loss: Tranexamic acid, sealants and glues, rFVilla

Autologous BloodPreoperative autologous donationNormovalaemic haemodilitionPerioperative cell salvage

Correction of anaemiaIron, B12, folic acid, rHuEpo

Dr O.E. Nnodu 33

Strategies to limit or avoid homologous blood use- Pharmacological agents

• Pharmacologic agents that:Stimulates erythropoeisis e.g. erythropoietin

Enhances haemostasis e.g.

• Desmopressin (an analogue of vasopressin which increases serum levels of factors VIII and VWF)

• Aprotinin. This is an anti fibrinolytic agent. In Europe the use of Aprotinin has resulted in decreased transfusion requirements in open heart surgery, urology and liver transplantation.

Dr O.E. Nnodu 34

Strategies to limit or avoid homologous blood use

• Fibrin glue. This is made from fibrinogen and thrombin and is used increasingly to decrease post-operative bleeding surrounding suture lines.

• All of these factors can be integrated to offer comprehensive care in bloodless management

• Increasingly however blood transfusion techniques are being subjected to strict randomized clinical trials to generate the evidence for the practice.

Dr O.E. Nnodu 35

Pre-operative Setting• Planning/Workup: Patient

history/assessment, review appropriate blood conservation techniques

• Improve blood count: Erythropoietin, iron, folic, vitamin B-12, nutrition, restrict phlebotomy to necessary tests, G-CSF, GM-CSF

• Improve haemostasis: Stop NSAIDS/ anticoagulants, identify and address coagulopathies. Give Vit K when necessary.

Dr O.E. Nnodu 36

Intra Operative Setting

• Meticulous attention to surgical haemostasis with surgery along avascular anatomical planes, AIVHD, intra-operative blood cell salvage, hypotensive anaesthesia, hypothermia etc.

• Use of electrocautery, electrosurgical coagulator, endoscopy, laser, non-invasive monitoring

Dr O.E. Nnodu 37

Intra Operative Setting

• Haemostatic agents; Aprotinin, Desmopressin, epsilon amino-caproic acid, (fibrinolytic inhibitor) tissue adhesives.

• Volume expanders- ringers lactate, DFS, hypertonic saline, (colloids and crystalloids).

Dr O.E. Nnodu 38

Post Operative

• Careful vigilance and prompt control of bleeding

• Optimum support of cardiac and respiratory function

• Appropriate resuscitation with colloids and crystalloids

• Enhance haemostasis. Aprotinin etc. Vit k, fibrinogen. Prevent hypertension to avoid disrupting spontaneous haemostasis.

• Improve blood count

• Postoperative blood salvage, erythropoietin, iron, folic acid, Vit B12, nutrition, restrict phlebotomy to necessary tests.

Blood Conservat

ion Programm

e

Hb < 70-80g/lRestrictive transfusion

protocolReduction of Blood Loss: Tranexamic acid, sealants and glues, rFVilla

Autologous BloodPreoperative autologous donationNormovalaemic haemodilitionPerioperative cell salvage

Correction of anaemiaIron, B12, folic acid, rHuEpo

Dr O.E. Nnodu 40

Dr O.E. Nnodu 41

Summary

• The WHO recommends that blood and blood products should be prescribed only if less hazardous therapy has proved or is likely to be ineffective and if the benefits of transfusion outweighs the risk.

• The human body has remarkable ability to adapt to and tolerate anaemia.

• By increasing blood counts reducing bleeding, using the patients blood where possible we can effectively care for patients by limiting blood transfusion.