Dr . Azam s Notes in Anesthesiology

3

Dr Azam’s Notes in Anesthesiology 2013


Dedication

To Mohammed Shafiulla, my father, my oxygen, companion, and best friend; for being my major pillar of support and making this vision a reality. Thank you for your continual sacrifices with boundless love and limitless gratitude, for the sake of your children. I owe you a debt I can never repay.

I also would like to thank my mom (Naaz Shafi), my wife (Roohi Azam), my two lovely kids (Falaq Zohaa & Mohammed Izaan), for their support, ideas, patience, and encouragement during the many hours of writing this book.

Finally, I would like to thank my teachers (Dr.Manjunath Jajoor & team) & Dr T. A. Patil . The dream begins with a teacher who believes in you, who tugs and pushes and leads you to the next plateau, sometimes poking you with a sharp stick called "truth."

Dr. Azam

4



A NOTE TO THE READER

Anesthesiology is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications.

However, in view of the possibility of human error or changes in medical sciences, neither the author nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this publication.

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Dr Azam’s Notes in Anesthesiology 2013Contents

1. Blood & Blood Products - 62. Development of Red Blood Cells - 12 3. Blood Group system - 13 4. Blood storage System - 14 5. Recommendation of Blood transfusion - 16 6. Compatibility Testing - 17 7. Blood Component therapy & Blood substitutes - 188. Define Massive blood transfusion. Discuss the complications

associated with massive blood transfusion - 24 & 71 9. Describe Anesthetics concerns for regional anesthesia in a

patient on anticoagulants - 28 10.What is Disseminated intravascular coagulation? Enumerate its

causes and management - 30 11.Enumerate the indications of packed red cells, fresh frozen

plasma(FFP), platelets & cryoprecipitates - 33 12.Write the blood conservative strategies in a 20 year old female

scheduled for excision of angiofibroma of nose - 35 13.Autologus Blood transfusion - 37 & 63 14.Replacement therapy for coagulation factor deficiency - 41 15.Partial thromboplastin time - PTT - 42 16. Activated Clotting Time - ACT - 43 17.Prothrombin Time - PT - 44 18. Describe the coagulation factors. How do you investigate a

case of intra operative coagulopathy - 45 19. Categorization of coagulation disorders - 47 20.Describe various test used for monitoring peri-operative

coagulation - 48 21. Thromboelastography - 51 22. Assessment of blood Loss during Surgery - 53 23. Sickle Cell Anemia & Anesthesia - 55 24. Anemia & Anesthesia - 59

25. Coagulation & Anesthesia - 7926. Hemophilia - 90 27. Coagulation Factors - 96 28. Artificial BloodBlood Substitutes - 9729.What is recombinant factor VIIa? Describe the clinical usage of it - 99

6


Dr Azam’s Notes in Anesthesiology 2013 1. Blood & Blood Products.

History:• 1616 – William Harvey – circulations of blood • 1818 – James Blundell – man to man transfusion • 1874 – William Hagumore– suggested autologous blood

transfusion • 1899 – Shaltock – noticed agglutination • 1900 – LANSTEINER – described ABO grouping • 1902 – Decastello and Sturli – described AB blood group • 1916 – Rous and Turne – preservation of blood • ! Oswald Robertson first blood bank • 1936 – Levine and stetson – Rh.system Blood:• Blood consists of a fluid medium, plasma, in which are

suspended a number of circulating cells each with its own highly specialized functions.

Site of blood formation:• Production of blood cells commences in the yolk sac of the

embryo, but then shifts to the liver and to a lesser extent the spleen, so that these organs become the dominant site of production between the 2nd and 8th month of gestation.

• The liver and spleen are then supersede by the bone marrow which serves as the only important site of blood cell production after birth.

• Hematopoietic tissue fills all the cavities within the bones of the newborn, but with increasing age becomes localized in the cavities of upper shafts of the femur, humerus, the pelvis, spine, skull and bones of the thorax- this is referred to as red marrow because of its macroscopic appearance and its total volume is 1-2 liters.

• The remaining bone marrow in the more peripheral regions of the skeleton contains predominantly fat, and is termed as YELLOW MARROW. It also occupies a volume of 1-2 liters and serves as a space into which hematopoietic tissue can expand in response to an increased demand for blood cell production.

• Only in pathological situations significant hematopoietic activity occur in liver, spleen and other sites during adult life and is referred to as extramedullary hematopoesis.

Development of blood cells:• Blood cells develop from a small population of TOTIPOTENT

hematopoietic STEM CELLS which maintain their numbers by self replication and also gives rise to precursors of one or other of the various blood cells series and cells of the immune system.

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Dr Azam’s Notes in Anesthesiology 2013 Blood & Blood Products.Continuation:

White Cells:• Normal white cell count: 4-11 x 109 / lit. • White cells count in infancy and childhood tend to be greater

than in adults, with values as high as 25 x 109 / lit at birth. After 1st week of life the count drops to 14 x 109 / lit.

• The leukocyte count undergoes minor degree of diurnal variation with slight increases in the afternoon.

• Values of upto 15 x 109 / lit are common during pregnancy, following parturition the count may rise to 20 x 109 / lit returning to normal values within a week.

Normal values for the cellular elements in human blood:Cell Normal range Percentage

Total WBC 4000-11,000Granulocytes Neutrophils 3000-6000 50-70%Eosinophils 150-300 1-4%Basophils 0-100 0.4%

Lymphocytes 1500-4000 20-40%Monocytes 300-600 2-8%

Erythrocytes Females 4.8 x 106

Males 5.4 x 106

Platelets 200,000-500,000

Blood Volume:• For normal subjects can be estimated in relation to height and

weight. RBC volume:• Men: 26-33 ml/kg • Women: 22-29 ml/kg • Plasma volume: 35-45 ml/kg Total blood volume:!• 70ml/kg – adults • 80ml/kg – children • 90ml/kg – neonates • Total blood volume = plasma vol. x 100. ! ! ! 100 - Hematocrit Distribution of blood:• 60-70% venous • 15% arteries • 10% in the heart • 5% capillary Blood group and blood transfusion:Introduction:• The anesthesiologist has to frequently use blood or blood products in

treating the shocked or bleeding patient. The importance of recognizing adverse reactions associated with transfusion therapy is emphasized by the estimate that over half of all transfusions of blood products are given during anesthesia. Hence knowledge of blood groups and transfusion reactions are very important for the anesthesiologist.

Blood groups:• Human RBC contains on their surface a series of glycoproteins and

glycolipids which constitute the blood group antigens also called agglutinogen. They appear early in fetal life and remain unchanged until death. On the basis of these antigens, at least 15 well defined blood group, systems have been described. They are the ABO, MN, P, Rh, Lutheran, kell, Kidd, Lewis, Duffy, Diego, YE, Xg, Li, Dombrock and cotton systems; of these only ABO and Rh systems one of major clinical importance.

8



Blood group systems:1) ABO system:• A and B antigens are inherited as Mendelian dominants, and

individuals are divided into 4 major blood types on this basis. • Type A individuals have A ag on the RBCs• Type B individuals have B ag • Type AB individuals have both antigens • Type O individuals have neither Several subgroups of A exist; the most important being A1 and A2. • The difference between A1 and A2 appears to be quantitative.

Each A1 cell has about 1,000,000 copies of the A ag on its surface and each A2 cell has about 250,000.

• The A and B antigens are found in many tissues in addition to blood these include salivary glands, saliva, pancreas, kidney, liver, lungs, testes, semen and amniotic fluid.

• Antibodies against red cell agglutinogen are called agglutinins. • The serum of an individual contains antibodies against the Ags

lacking on the persons red cells. Thus type A individuals develop anti B antibodies; type B individuals develop anti A abs, type O individuals develop both, type AB individuals develop neither.

2) The Rh group:• The Rhesus (Rh) blood group system was first demonstrated in

humans, by the use of an antiserum prepared by immunizing rabbits with red cells from a rhesus monkey. It was found that some human red cells were agglutinated by the serum “Rh +ve cells” – while others were not – “Rh –ve cells”. This system is composed primarily of C, D and E antigens of which D is the most important antigenic component and the term “Rh positive” means that the individual has the D antigen and “rh –ve” means that the individual has no D antigen.

• Over 99% of Asians are D +ve. Unlike the antibodies of the ABO system anti-D abs do not develop without exposure of a D –ve individual to D +ve red cells by transfusion or entrance of fetal blood into the maternal circulation.

Storage of Blood:• Several different preservative solutions can be added to either whole

blood or packed RBCs to allow storage of these products. • In general preservative solutions contain additives that

a) Prevent coagulationb) Support glycolysis c) Maintain ATP generation

• The preservative determines the blood products storage on shelf life. The duration of storage is determined by the requirement that at least 70% of the transfused red blood cells remain in circulation for 24 hrs after infusion.

• A unit of whole blood generally contains 450ml (± 10%) of blood and about 60ml of preservative.

The various preservatives are:ACD (acid citrate dextrose)• Trisodium citrate = 2.2gm /dl• Citric acid = 0.8gm/dl • Dextrose = 2.5gm /dl• Water upto = 100ml • pH = 5.0-5.1• 67.5ml ACD is mixed with 420-450ml of blood duration of storage =

21 days Preservatives:• Acid citrate dextrose (ACD) -21 days• Citrate phosphate dextrose (CPD) -28 days• CPD + adenine – 35 days

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CPD (citrate phosphate dextrose) • Trisodium citrate ! ! - 2.6gm /dl• Citric acid ! ! ! - 0.327gm/dl• Sodium dihydrogen phosphate ! - 0.2gm /dl• Dextrose ! ! ! ! - 2.55gm /dl• Water ! ! ! - 100 ml• pH ! ! ! ! ! - 5.5 • 63ml of CPD with 450ml of whole blood storage duration – 28

days 1. Citrate prevents clotting by binding calcium. 2. Dextrose allows continuation of glycolysis of RBC and thus

maintains sufficient concentrations of high energy ATP to ensure continued red blood cell metabolism and subsequence viability during storage.

3. The acid of CPD (pH = 5.5) acts as a buffer and counter acts the large fall in hydrogen ions that occur when the blood is cooled.

Other preservatives 3. CPD with adenine:• The addition of small amounts of adenine (0.25-0.5mg)

increases red blood cell survival of aiding synthesis, of ATP by the RBCs to 35 days.

4. ADSOL (AS-1) – 49 days • Adenine – glucose – mannitol – sodium chloride is a preservative

for the storage of packed red blood cells. Storage time – 49 days.

5. Nutricel (AS-3)• Nutricel contains glucose; adenine; citrate; phosphate and

sodium chloride. With the addition of nutricel; the shelf life can be extended to 42 days. Saline = 140mmol/l; adenine = 1.5mmol/lʼ glucose = 50mmol/l; mannitol = 30mmol/l.

6) Frozen storage:• RBCs previously frozen to -790C in glycerol can be thawed without

damage; but it must be free from glycerol before being transfused. Storage time-- several years.

The advantages of frozen and thawed RBCs are the following:1. Blood of rare types can be stored for long periods, increasing

viability and eliminating outdating. 2. Frozen, reconstituted blood is believed to be safer in patients who

are especially susceptible to allergic reaction because the freezing and washing process reduces sites with histocompatible antigens.

3. Frozen blood, low in fibrin and leukocyte aggregates, would be safer in patients requiring massive blood transfusion.

4. Frozen washed blood may reduce risk of transfusion hepatitis. 5. Frozen RBCs may be desirable in clinical conditions requiring

prompt tissue oxygenation because normal levels of 2, 3-DPG are retained in frozen erythrocytes.

Heparin:• Whole blood stored in heparin is used in some situations for priming

the pump during cardiopulmonary bypass. • Heparinized whole blood is used in open heart surgery to prevent

cardiac abnormalities that might result from depression of ionized calcium levels by the citrate in other storage solutions.

• Heparin anticoagulant is not a RBC preservative because it lacks glucose.

• Its anticoagulant effect is also neutralized during storage by the thromboplastic substances liberated by the cellular elements of blood during storage.

• Blood stored in heparin must be used within 24 to 48 hours of collection.

10



• Changes that occur during storage of whole blood in CPD at 40CParameter Day 1 Day 7 Day 14 Day 21 Day 35↓ PH 7.2 7 6.9 6.84 6.73

↓ 2,3 DPG (μm/ml) 4.8 7.2 1 1 <1↓ P50 (mmHg) 26 23 20 17↑ K+ (mEq/l) 4 12 17 21

↑ Hb (mg/dl) in plasma 1.7 7.8 13 19 46↑ Blood PCO2 (mmHg) 48 80 110 140

↓ Platelets (%) 10 0 0 0 0↓ Viable cells 24 hrs after transfusion (%)

100 98 85 80

Parameters that decreases:• pH (7.2)• P50 (26)• 2,3 DPG (4.8)• Platelet cells % (10%)• Viable cells 24 hrs later % (100%)

Parameters that increases:• K+ (4)• PCO2• Hb in plasma

Blood transfusion:• Considerable morbidity and to a lesser extent mortality are

associated with blood transfusion therapy. Blood and blood products should be transfused only when there are clear therapeutic indications.

The recommendations of the ASA practice guidelines include:• Transfusion is rarely indicated when the Hb concentration is greater

than 10gm/dl and is almost always indicated when it is less than 6gm/dl, especially when the anemia is acute.

• The determination of whether intermediate Hb comes (6 to 10gm/dl) justifies or require red blood cell transfusion should be based on the patients risk for complications of inadequate oxygenation.

• The use of a single haemoglobin “trigger” for all patients and other approaches that fail to consider all important physiologic and surgical factors affecting oxygenation are not recommended.

• When appropriate, preoperative autologous blood donation, intraoperative and postoperative blood recovery; acute normovolemic hemodilution and measures to decrease blood loss may be beneficial.

• The indications for transfusion of autologous RBCs may be more liberal than those for allogeneic RBCs because of lower risks associated with the former.

Recommendations:• Hb > 10 not indicated, < 6g/dl acute.• 6-10 g/dl à based on patients risk for complications of inadequate

oxygenation. Administrations of one unit of packed RBCs will increase hematocrit value by 3-5 percent. Indications are 1. Blood loss > 20 percent of blood volume 2. Haemoglobin < 8gm/dl3. Haemoglobin < 10gm/dl with major d/s eg. emphysema; IHD 4. Haemoglobin 10gm/dl with autologous blood.5. Haemoglobin < 12gm/dl and ventilator dependence

11



COMPATIBILITY TESTING:• Compatibility testing are designed to demonstrate harmful

antigen, antibody interactions in vitro so that harmful in vivo antigen-antibody interactions could be prevented.

• The ABO-Rh type, cross match and antibody screen are frequently referred to as compatibility tests.

I. ABO-Rh typing:• Determination of ABO group and Rh of the recipient and donor is

the 1st step in selecting blood for transfusion therapy. ABO typing is performed by testing RBCs for the A and B antigens and the serum for the A and B antibodies before transfusion. The only additional required testing is that for the Rh (D) ag. About 85% of individuals possess the D antigen and are termed Rh(D) positive, the remaining 15 percent, who lack the D antigen, are termed Rh(D) negative.

II. Cross matching:• A cross match is essentially a “trial transfusion” within a test tube

in which donor RBCs are mixed with recipient serum to detect a potential for series transfusion reactions. The cross match can be completed in 45 to 60 mins and is done in three phases: an immediate phase; an incubation phase; and an anti-globulin phase.

a) Immediate phase:• The immediate phase is conducted at room temperature. It

detects ABO incompatibilities and those caused by naturally occurring antibodies in the MN, P and Lewis systems. This takes approx. 1 to 5 mins to complete.

b) Incubation phase:• Involves incubation of the 1st phase reaction at 370C in albumin or

low ionic strength salt solution. The addition of these 2 aids in the detection of incomplete antibodies or those antibodies that are able to attach to a specific antigen (sensitization) but unable to cause agglutination in a saline suspension of red blood cells.

• This phase primarily detects antibodies in the Rh system. The incubation of 30 to 45 mins in albumin and of 10-20 mins in low ionic strength salt solution in this phase is of sufficient duration to allow antibody uptake sensitization by the cells so that incomplete antibodies missed in this phase can be detected in the subsequent anti-globulin phase.

c) Anti-globulin phase:• Involves the addition of anti-globulin sera to the incubated test tubes

with this addition, antihuman antibodies present in the sera become attached to the antibody globulin on the red blood cells, thus causing agglutination. This phase detects most incomplete antibodies in the blood group systems including the Rh, Kell, Kidd and Duffy blood group systems.

Types of cross match:Major cross match: is done when the donorʼs erythrocytes are incubated with the plasma of the recipient. Agglutination confirms that the plasma of the recipient contains antibodies to antigens on cell membranes of donor erythrocytes. Minor cross match: is done when the plasma of the donor is incubated with the erythrocytes of the recipient. Agglutination results if the plasma of the donor contains antibodies to antigens on cell membranes of recipient erythrocytes. III. Antibody screening:• This is also carried out in 3 phases and is similar in length to the

cross match. This test is conducted on recipient serum to rule out the possibility of hemolytic transfusion reaction. It is also done on the donor serum to detect unexpected antibodies in order to prevent their introduction into the recipients serum or to prevent reactions between transfused donor units.

12


Dr Azam’s Notes in Anesthesiology 2013 2. Development of Red Blood Cells.

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DEVELOPMENT OF BLOOD CELLS:• Blood cells develop from a small population of

TOTIPOTENT hematopoietic STEM CELLS which maintain their numbers by self replication and also gives rise to precursors of one or other of the various blood cells series and cells of the immune system.

Bombay Blood group:• Extremely rare ABO group• First discovered in Bombay• Their red cell lack ABH antigen and their sera

containing Anti - A, Anti - B and Anti H.• The Anti H would not be detected in ABO group.

Other Systems other than ABO:• M & N system• Kell System• Lewis system• Kidd - Zolinger• Duffy• I = I & i antigen• P - similar to ABO• Lutheran

13


Dr Azam’s Notes in Anesthesiology 2013 3. Blood Group system.

There are two Systems: ABO & Rh.1) ABO system:• A and B antigens are inherited as Mendelian

dominants, and individuals are divided into 4 major blood types on this basis.

• Type A individuals have A ag on the RBCs• Type B individuals have B ag • Type AB individuals have both antigens • Type O individuals have neither

• Several subgroups of A exist; the most important being A1 and A2.

• The difference between A1 and A2 appears to be quantitative. Each A1 cell has about 1,000,000 copies of the A ag on its surface and each A2 cell has about 250,000.

• The A and B antigens are found in many tissues in addition to blood these include salivary glands, saliva, pancreas, kidney, liver, lungs, testes, semen and amniotic fluid.

• Antibodies against red cell agglutinogen are called agglutinins.

• The serum of an individual contains antibodies against the Ags lacking on the persons red cells. Thus type A individuals develop anti B antibodies; type B individuals develop anti A abs, type O individuals develop both, type AB individuals develop neither.

2) The Rh group:• The Rhesus (Rh) blood group system was first demonstrated in

humans, by the use of an antiserum prepared by immunizing rabbits with red cells from a rhesus monkey. It was found that some human red cells were agglutinated by the serum “Rh +ve cells” – while others were not – “Rh –ve cells”. This system is composed primarily of C, D and E antigens of which D is the most important antigenic component and the term “Rh positive” means that the individual has the D antigen and “rh –ve” means that the individual has no D antigen.

• Over 99% of Asians are D +ve. Unlike the antibodies of the ABO system anti-D abs do not develop without exposure of a D –ve individual to D +ve red cells by transfusion or entrance of fetal blood into the maternal circulation.

Bombay Blood group:• This is an extremely rare ABO group, called so because it was

first discovered among some people in Bombay (now Mumbai). Although the group is more likely to occur in East Indians, it is a very rare group even here.

• It is not restricted to East Indians but found in Caucasians, Japanese, etc.

• Their red cells lack ABH antigens and their sera contain anti-A and anti-B and anti-H.

• The anti-H would not be detected in the ABO group but would be detectable in pre-transfusion tests.

14


Dr Azam’s Notes in Anesthesiology 2013 4. Blood storage System.

1. Several different preservative solutions can be added to either whole blood or packed RBCs to allow storage of these products.

2. In general preservative solutions contain additives that a. Prevent coagulationb. Support glycolysis c. Maintain ATP generation

3. The preservative determines the blood products storage on shelf life. The duration of storage is determined by the requirement that at least 70% of the transfused red blood cells remain in circulation for 24 hrs after infusion.

4. A unit of whole blood generally contains 450ml (± 10%) of blood and about 60ml of preservative.

The various preservatives are:ACD (acid citrate dextrose) - 21 days.• Trisodium citrate = 2.2gm /dl• Citric acid = 0.8gm/dl • Dextrose = 2.5gm /dl• Water upto = 100ml • pH = 5.0-5.1• 67.5ml ACD is mixed with 420-450ml of blood

duration of storage = 21 days

Preservatives:• Acid citrate dextrose (ACD) -21 days• Citrate phosphate dextrose (CPD) -28 days• CPD + adenine – 35 days

CPD (citrate phosphate dextrose): – 28 days ! Trisodium citrate ! ! ! - 2.6gm /dl! Citric acid ! ! ! - 0.327gm/dl! Sodium di hydrogen phosphate ! - 0.2gm /dl! Dextrose ! ! ! ! - 2.55gm /dl! Water !! ! ! ! - 100 ml! pH ! ! ! ! ! - 5.5 • 63ml of CPD with 450ml of whole blood storage duration – 28 days 1. Citrate prevents clotting by binding calcium. 2. Dextrose allows continuation of glycolysis of RBC and thus maintains

sufficient concentrations of high energy ATP to ensure continued red blood cell metabolism and subsequence viability during storage.

3. The acid of CPD (pH = 5.5) acts as a buffer and counter acts the large fall in hydrogen ions that occur when the blood is cooled.

Other preservatives CPD with adenine: - 35 days• The addition of small amounts of adenine (0.25-0.5mg) increases red

blood cell survival of aiding synthesis, of ATP by the RBCs to 35 days. ADSOL (AS-1) – 49 days • Adenine – glucose – mannitol – sodium chloride is a preservative for the

storage of packed red blood cells. Storage time – 49 days.

Nutricel (AS-3): 42 days• Nutricel contains glucose; adenine; citrate; phosphate and sodium

chloride. With the addition of nutricel; the shelf life can be extended to 42 days. Saline = 140mmol/l; adenine = 1.5mmol/lʼ glucose = 50mmol/l; mannitol = 30mmol/l.

Frozen storage: 3 to 5 years• RBCs previously frozen to -790C in glycerol can be thawed without

damage; but it must be free from glycerol before being transfused. Storage time - several years.

15


Dr Azam’s Notes in Anesthesiology 2013Blood storage System.Continued

The advantages of frozen and thawed RBCs are the following:1. Blood of rare types can be stored for long periods,

increasing viability and eliminating outdating. 2. Frozen, reconstituted blood is believed to be safer in

patients who are especially susceptible to allergic reaction because the freezing and washing process reduces sites with histocompatible antigens.

3. Frozen blood, low in fibrin and leukocyte aggregates, would be safer in patients requiring massive blood transfusion.

4. Frozen washed blood may reduce risk of transfusion hepatitis.

5. Frozen RBCs may be desirable in clinical conditions requiring prompt tissue oxygenation because normal levels of 2, 3-DPG are retained in frozen erythrocytes.

Heparin:• Whole blood stored in heparin is used in some situations for

priming the pump during cardiopulmonary bypass. • Heparinized whole blood is used in open heart surgery to

prevent cardiac abnormalities that might result from depression of ionized calcium levels by the citrate in other storage solutions.

• Heparin anticoagulant is not a RBC preservative because it lacks glucose. Its anticoagulant effect is also neutralized during storage by the thromboplastic substances liberated by the cellular elements of blood during storage.

• Blood stored in heparin must be used within 24 to 48 hours of collection.

Changes that occur during storage of whole blood in CPD at 400CParameter Day 1 Day 7 Day 14 Day 21 Day 35

↓ 1) PH 7.2 7 6.9 6.84 6.73↓ 2) 2,3 DPG (μm/ml) 4.8 7.2 1 1 <1↓ 3) P50 (mmHg) 26 23 20 17↑ 4) K+ (mEq/l) 4 12 17 21↑ 5) Hb (mg/dl) in plasma 1.7 7.8 13 19 46↑ 6) Blood PCO2 (mmHg)

48 80 110 140

↓ 7) Platelets (%) 10 0 0 0 0↓ 8) Viable cells 24 hrs after transfusion (%)

100 98 85 80

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Dr Azam’s Notes in Anesthesiology 2013 5. Recommendation of Blood transfusion.

BLOOD TRANSFUSION:• Considerable morbidity and to a lesser extent mortality

are associated with blood transfusion therapy. Blood and blood products should be transfused only when there are clear therapeutic indications.

The recommendations of the ASA practice guidelines include:I. Transfusion is rarely indicated when the Hb

concentration is greater than 10gm/dl and is almost always indicated when it is less than 6gm/dl, especially when the anemia is acute.

II. The determination of whether intermediate Hb (6 to 10gm/dl) justifies or require red blood cell transfusion should be based on the patients risk for complications of inadequate oxygenation.

III. The use of a single haemoglobin “trigger” for all patients and other approaches that fail to consider all important physiologic and surgical factors affecting oxygenation are not recommended.

IV. When appropriate, preoperative autologous blood donation, intraoperative and postoperative blood salvage; acute normovolaemic hemodilution and measures to decrease blood loss may be beneficial.

V. The indications for transfusion of autologous RBCs may be more liberal than those for allogeneic RBCs because of lower risks associated with the former.

Recommendations:1. Hb > 10 not indicated, < 6g/dl acute - Always Indicated.2. 6-10 g/dl à based on patients risk for complications of

inadequate oxygenation. • Administrations of one unit of packed RBCs will increase

hematocrit value by 3-5 percent. Indications are I. Blood loss > 20 percent of blood volume II. Haemoglobin < 8gm/dlIII. Haemoglobin < 10gm/dl with major d/s e.g. emphysema; IHD IV. Haemoglobin 10gm/dl with autologous blood.V. Haemoglobin < 12gm/dl and ventilator dependence

17


Dr Azam’s Notes in Anesthesiology 2013 6. Compatibility Testing

• Compatibility testing are designed to demonstrate harmful antigen, antibody interactions in vitro so that harmful in vivo antigen-antibody interactions could be prevented.

• The ABO-Rh type, cross match and antibody screen are frequently referred to as compatibility tests.

I. ABO-Rh typing:• Determination of ABO group and Rh of the recipient and

donor is the 1st step in selecting blood for transfusion therapy. ABO typing is performed by testing RBCs for the A and B antigens and the serum for the A and B antibodies before transfusion. The only additional required testing is that for the Rh (D) ag. About 85% of individuals possess the D antigen and are termed Rh(D) positive, the remaining 15 percent, who lack the D antigen, are termed Rh(D) negative.

II. Cross matching:• A cross match is essentially a “trial transfusion” within a test

tube in which donor RBCs are mixed with recipient serum to detect a potential for series transfusion reactions. The cross match can be completed in 45 to 60 mins and is done in three phases: an immediate phase; an incubation phase; and an antiglobulin phase.

a) Immediate phase:• The immediate phase is conducted at room temperature. It

detects ABO incompatibilities and those caused by naturally occurring antibodies in the MN, P and Lewis systems. This takes approx. 1 to 5 mins to complete.

b) Incubation phase:• Involves incubation of the 1st phase reaction at 37 °C in

albumin or low ionic strength salt solution. The addition of these 2 aids in the detection of incomplete antibodies or those antibodies that are able to attach to a specific antigen (sensitization) but unable to cause agglutination in a saline suspension of red blood cells.

• This phase primarily detects antibodies in the Rh system. The incubation of 30 to 45 mins in albumin and of 10-20 mins in low ionic strength salt solution in this phase is of sufficient duration to allow antibody uptake sensitization by the cells so that incomplete antibodies missed in this phase can be detected in the subsequent antiglobulin phase.

c) Antiglobulin phase:• Involves the addition of antiglobulin sera to the incubated test tubes

with this addition, antihuman antibodies present in the sera become attached to the antibody globulin on the red blood cells, thus causing agglutination. This phase detects most incomplete antibodies in the blood group systems including the Rh, Kell, Kidd and Duffy blood group systems.

Types of cross match:• Major cross match: is done when the donorʼs erythrocytes are

incubated with the plasma of the recipient. Agglutination confirms that the plasma of the recipient contains antibodies to antigens on cell membranes of donor erythrocytes.

• Minor cross match: is done when the plasma of the donor is incubated with the erythrocytes of the recipient. Agglutination results if the plasma of the donor contains antibodies to antigens on cell membranes of recipient erythrocytes.

III. Antibody screening:• This is also carried out in 3 phases and is similar in length to the cross

match. This test is conducted on recipient serum to rule out the possibility of hemolytic transfusion reaction. It is also done on the donor serum to detect unexpected antibodies in order to prevent their introduction into the recipients serum or to prevent reactions between transfused donor units.

18


Dr Azam’s Notes in Anesthesiology 2013 7. Blood Component therapy & Blood substitutes

• Except for conditions which result in acute haemorrhage, transfusion therapy is occasioned by the need to correct or deficiency in a specific component of whole blood. The rationale for component therapy stems from the recognition that blood is a complex tissue with numerous constituents or components, both cellular and noncellular, serving disease functions. Component therapy permits the physician to deliver an effective, therapeutic dose of the deficient component with minimum risk of circulatory overload, or of adverse reactions to the administration of unnecessary blood components.

Blood components:I. Erythrocyte preparations:

1. Packed red cells 2. Leucocyte poor red cell 3. Washed red cells 4. Frozen red cells

II. Leukocytes:1. Granulocytes 2. Mononuclear cells

III. Platelets IV. Plasma fractions:

1. Fresh frozen plasma 2. Platelet rich plasma3. Cryoprecipitate 4. Fractionated plasma

o Factor VIII concentrate o Prothrombin complex concentration and factor IX

concentrate o Albumin o Immunoglobulin o Antithrombin III concentrates

Diagrammatic scheme of how whole blood is separated for component therapy:

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I. Erythrocyte preparations:i) Packed red blood cells:• The red cells from whole blood can be administered after removing

80% of the plasma. Packed red cells have a hematocrit of 60-90%. • RBCs, rather than whole blood, should be used for the treatment of all

patients who require a transfusion because of a red cell mass deficit. An absolute requirement for RBC exists, when transfusing anemic patients with actual or incipient congestive heart failure. RBCs are administered in the same fashion as whole blood.

• Packed red cells are prepared by centrifuging whole blood and is useful in RBC exchange in chronic anemiaʼs like thalassaemia.

ii) Leukocyte poor RBC:• Prepared during procuring blood or at the time of transfusion using

specially designed filters. • Other methods include sedimentation, inverted centrifugation filtration

through nylon or cotton fibres, saline batch washing; frozen and thawed red cells or blood through microaggregate filters. Major indications for using leukocyte poor red cells are:

1. To prevent non-hemolytic febrile reactions. 2. To prevent alloimmunization by HLA antigen in case of perspective

organ transplant cases. 3. To minimize or avoid transmission of CMV.4. To prevent transfusion associated graft vs host disease (TA-GVHD).

19


Dr Azam’s Notes in Anesthesiology 2013Blood Component therapy & Blood substitutes.Continuation:

iii) Washed red cells:• Usually obtained from whole blood. Packed red cells

obtained by centrifugation can be washed with saline using either manual batch centrifugation or continuous flow separator. Washed red cells should be used with in 24 hours after processing because of the risk of bacterial contamination (during processing). Washed red cells are also prepared from blood salvaged during surgery.

Indications for washed red cells areI. In patients who are hypersensitive to plasma. II. Who develop allergic or febrile reactions following whole

blood transfusion. III. Multiple transfusion patients IV. Saline washed red cells are also indicated in case of

neonatal transfusions to reduce the quantity of metabolic breakdown products, extra-cellular potassium and the risk of CMV infusion.

V. To avoid TA-GVHDFrozen red cells:• After addition of a cryoprotective agent, RBC may be stored

continually below freezing temperatures. Freezing retards or arrests the deleterious biochemical changes which occur during liquid storage. Red blood cells can be frozen at -800C or below using 10% glycol as a preservative, and stored for 3-5 years or even more. They are leukocyte poor and relatively plasma free.

• Other advantages include availability of an inventory of rare blood; promotion of component therapy; reduction in the incidence of non hemolytic reactions; a ready supply of metabolically superior red cells; reduction in sensitization to histocompatibility antigens for potential transplant recipient and a reduced incidence of transfusion hepatitis.

• However the technology is complicated and the whole process is expensive where one unit of frozen blood costs 3 times more than a unit of stored blood in liquid state.

II. Leukocytes:• Less than 5% of the total body neutrophils pool is in the intravascular

space. These cells have a half life of only four to ten hours in the intravascular compartment and are therefore rapidly replaced. The collection of large number of granulocytes requires the processing of between 5 to 10 liters of blood per donation.

i) Granulocytes:The indications for granulocyte transfusion are not easy to define .In general, the patient should have:

1. An absolute granulocyte count < 500/ml2. Fever 3. An unidentified microorganism 4. No decrease in fever after 48hrs of antibiotic treatment.

ii) Mononuclear cells:• Collection of blood stem cells come under this category. Stem cells are

obtained for bone marrow transplant.• Blood stem cells make up a very small part of the circulating

mononuclear cell pool, cell separator techniques facilitate processing large quantities of blood.

• Variety of substances like glucocorticoids, folinic acid, endotoxins help release of stem cells into circulation, but the best currently used substance is human growth factor.

• Therapeutic use of peripheral stem cells is best cited in marrow transplantation; in cases like AML; Hodgkinʼs disease; multiple myeloma; solid tumors like Carcinoma breast, ovarian Ca, neuroblastoma etc.

III. PLATELETS:i) Random donor platelets (RDP): 7-10 x1010 / unit• RDP is collected from routine donations of whole blood. Each platelet

bag contains 7-10 x 1010 platelets / unit. These platelets are suspended in 40-50 ml of donor plasma to be stored at 20-220C under constant agitation for 5 days. Also has leukocyte contamination.

20



ii) Single donor platelets:• Prepared from single donor and each unit measures

250-300ml. No significant WBC contamination & can be stored at 220C under constant agitation for 5 days.

• One unit platelet concentrate will increase platelet count by 5000/mm3 to 10,000/mm3.

INDICATIONS FOR PLATELET TRANSFUSION:1) Thrombocytopenia with decreased platelet production (Megakaryocyte thrombocytopenia) - Malignancy with cytoreductive therapy - Aplastic anemia - Myelodysplastic syndrome

2) Thrombocytopenia due to loss, destruction or sequestration of platelets (megakaryocytic thrombocytopenia) Platelet loss - Exsanguinations: replacement with stored blood - Cardiopulmonary bypass

a. Platelet sequestration - Splenomegaly - DIC

b. Accelerated platelet destruction - Idiopathic thrombocytopenic purpura; ITP- Hereditary thrombocytopenia - Neonatal isoimmune thrombocytopenia

3) Qualitative platelet disorders- Congenital - Acquired (myeloproliferative and myelodysplastic

syndrome)

IV. PLASMA FRACTIONS:1) Fresh Frozen plasma (FFP):• FFP is the fluid portion of one unit of whole blood that is centrifuged,

separated & frozen solid at -180C or lower, to be transfused within 6 hrs of collection.

• The initial volume of FFP transfused should be adequate to replace deficient coagulation factors.

• The average adult usually requires two to nine units of about 200ml each given over a period of a few hours. The Prothrombin time (PT) and / or partial thromboplastin time (PTT) should be determined immediately before and after transfusion.

1. Plasma not frozen within 8 hours or thawed after freezing and not used within 24 hours has decreased levels of labile coagulation factors V and factor VIII.

2. FFP contains factors IV, V, VII, VIII, IX along with naturally occurring anticoagulants like protein C, protein S and also antithrombin III, electrolytes, albumin, Immunoglobulins and complement proteins.

3. Each unit of FFP prepared from a single unit of blood will have a volume of 200-250ml and by Plasmapharesis can be upto 1 lit-1.5lit.

Indications of FFP:1. Coagulation factor deficiency [2, 5, 7, 9, 10, 11, 13]2. Reversal of warfarin effect 3. Massive blood transfusion 4. Antithrombin III replacement 5. Thrombotic thrombocytopenic purpura 6. DIC 7. Coagulopathy of liver disease 8. Protein C or S deficiency 9. Hemolytic uremic syndrome

Dose of FFP: 1 unit for every 10 kg.

21



2) Cryoprecipitate:• Cryoprecipitate is prepared by thawing FFP at 40c and

removing the supernatant. Three major classes of plasma derivatives are obtained from the cryoprecipitate ie ; coagulation factors VIII and IX; immunoglobulin and albumin preparations.

• One unit of cryoprecipitate will have a volume of approx. 10-20ml and should contain 80-120 units of factor VIII and 100-250ml of fibrinogen.

Indications:1. Factors VIII and von Willebrand factor replacement. 2. Fibrinogen replacement (a/dys/hypo-fibrinogenemia) 3. Factor XIII replacement (↓ in trauma, burns and sepsis) 4. Fibrin sealant – a combination of thrombin and

cryoprecipitate.5. Coagulum pyelotomy – a coagulum formed by the addition

of thrombin and calcium to cryoprecipitate is used to entrap calculi in the renal pelvis to facilitate pyelotomy removal.

Replacement therapy for coagulation factor deficiency:Factor Therapeutic dose Component / derivativesi) Fibrinogen 1 units / 5kg body

wtCryoprecipitate(100-250gms fibrinogen/bag)

ii) Prothrombin 10-20ml plasma /kg Plasma or prothrombin complex concentrate

iii) Factor V 20ml fresh frozen plasma/kg

Fresh frozen plasma

iv) Factor VII 10-20ml plasma/kg Plasma or prothrombin complex concentrate

v) Factor VIII 15-50 units/kg Cryoprecipitate (100 units/bag) factor VIII concentrate

vi) Factors IX 20-80 units/kg Prothrombin complex concentrate plasma (1 unit of factor IX/ml)

vii) Factor X 10-20ml plasma/kg Plasma or prothrombin complex viii) Factor XI 10-20ml plasma/kg Plasmax) Factor XIII 4-6 bags

Cryoprecipitate or 500ml plasma

Plasma or Cryoprecipitate

V. Albumin:• The source material is whole blood plasma, serum or placenta. At least

96% of the total protein in the final product is albumin. The derivative is available in 5% and 25% solutions. Plasma protein fractions containing albumin and globulins are available for use as volume expanders. They can be given without regard to ABO blood type. They are expensive and are in short supply. They should be administered within 4 hours of starting the infusion.

Indications:1. Hypoproteinemia 2. Burns 3. Peritonitis VI. Intravenous immunoglobulins:Indications:1. Viral infections: CMV 2. ITP 3. Post-transfusion purpura 4. Thrombotic thrombocytopenic purpura

22



VII. Antithrombin III concentrates:• Antithrombin III deficiency • Shock and DIC VIII. Factors VIII concentrates:• Used in treatment of hemophilia A IX. Factor IX concentrates:• Used in treatment of hemophilia B Hazards of component therapy:• All hazards of blood transfusion are applicable to transfusion

of components also:Immediate reactions:

1. Febrile reactions 2. Allergic reactions 3. Transfusion Related Acute Lung Injury - TRALI 4. Acute hemolytic transfusion reactions 5. Sensitivity to leukocytes and platelets 6. Non cardiogenic pulmonary oedema 7. Bacterial contamination 8. Bleeding syndrome 9. Circulatory overload 10.Air embolism

Delayed reactions:1. Delayed hemolytic reactions 2. Post transfusion purpura 3. TA-GVHD4. Transmission of diseases like hepatitis B, hepatitis C,

HIV, CMV, HTLV-3 etc.

Blood substitutes:• Some functions such as maintaining circulatory volume and oncotic

pressure can be replaced with various crystalloids and colloid macromolecules such as Dextrans and Hydroxyethyl starch.

Substitute Half life Reaction MechanismDextran mol. wt 75,000 6 hrs Mild Allergic Mol. wt 40,000 2 hrs Severe Anti-dextran antibodies Gelatin 35,000 2-3hrs Immediate Histamine releaseStarch 4,50,000 6 hrs Immediate Complement activation

These, however do not provide for oxygen transport. Red cell substitutes:2 main indications:• Severe haemorrhage • Chronic symptomatic anemia for which no specific therapy exists.• In both circumstances, the aim of red cell transfusion is to improve the

O2 supply to the tissues by raising the O2 content of blood according to the equation.

O2 delivery = cardiac output x arterial O2 content Arterial O2 content = Hb conc. x % saturation x 1.34 Oxygen Flux = Cardiac output x Hb x % saturation x 1.34 ! (variables are CO, Hb, saturation)Perfluorocompounds:• Perfluorochemical are large organic compounds in which all the

hydrogen atoms are replaced by fluorine. A unit volume of perfluorochemical carries almost three times the oxygen carried by a similar volume of blood. They are chemically inert and not metabolized, but require emulsification with surfactants to be miscible with blood.

i) Fluosol-DA:• A 20% emulsion of 2 different Perfluorocompounds described as

FLUOSOL-DA which has O2 carrying capacity at 370C of about 40% of that of red cells.

Dose: 20ml/kg Side effects: • Pulmonary reactions; cytotoxicity; complement activation; retention of

the product in the liver and spleen and vulnerability to oxygen toxicity.

23



ii) Polyfluoro-octobromide (Perflubron):• It is a newer Perfluorocompounds (radiopaque) • Has 2 advantages • Higher concentration of the compound can be administered

because 100% emulsion with a phospholipids has a sufficiently low viscosity to be infused without dilution.

• O2 is more soluble in perflubron • It can carry as much O2 as a Hb solution at a conc. of 7gm/dl.

Conclusion:• Red cell substitutes under trial have too short a survival time in

circulation to be substitutes for red cell in treatment of chronic anemia.

• They can be used in short term procedures, such as immediate resuscitation and in intra operative haemodilution, red cell has to be transfused within next 24 hrs.

24

8. Define Massive blood transfusion. Discuss the complications associated with massive blood transfusion.



Definition:• Massive blood transfusion may be defined either as the acute administration of more than 1.5

times the patients total blood volume by homologous blood in less than 24 hours.Also defined as: • Transfusion of one pint of blood with in 5 minutes; • Transfusion of 5 units within 1 hr • Transfusion of 10 units within 6hrs, • Transfusion of >10% of blood volume within 10 minutes.

Complications of Massive Blood transfusion:

Early Late

• Hemolytic reactions! Immediate! Delayed• Non-hemolytic febrile reactions• Allergic reactions to proteins, IgA • Transfusion-related acute lung injury • Reactions secondary to bacterial contamination Circulatory

overload • Air embolism • Thrombophlebitis• Hyperkalaemia • Citrate toxicity • Hypothermia • Clotting abnormalities (after massive transfusion)

• Transmission of infection ! Viral (hepatitis A, B, C, HIV, CMV)! Bacterial (Salmonella), Parasites (Malaria, Toxoplasma)• Graft-vs-host disease• TRIM - Transfusion related immunomodulation• Iron overload (after chronic transfusions)• Immune sensitization (Rhesus D antigen)

25

The most serious complications of blood transfusion result from interactions between antibodies in the recipientʼs plasma and surface antigens on donor RBCs. - Incompatible blood

Complications of Massive Blood transfusion:

Early

• Hemolytic reactions- Immediate- Delayed

Signs and symptoms of hemolytic transfusion reaction:• Fever and chills • Chest pain• Hypotension• Nausea • Flushing • Dyspnoea • Hemoglobinuria

Treatment of Hemolytic reaction:I. Stop the transfusion II. Maintain the urine output at a minimum of 75-100ml/hr III. Alkalinize the urine1. Send patient blood and urine sample to blood bank for examination. 2. Prevent hypotension to ensure adequate renal blood flow. 3. Maintain IV line, O2 therapy; resuscitative measures. 4. Antihistamine – diphenhydramine 0.5-1mg/kg IV. 5. Steroid – hydrocortisone – 2-4mg/kg IV.6. Antibiotics



• Clotting abnormalities (after massive transfusion)

A massive transfusion of red blood cells (RBCs) may lead to a • Dilutional Coagulopathy,• Consumptive coagulopathy,• Thrombocytopenia.

• Administration of platelets and FFP• Dose: 1 Unit of FFP for every 10 kg• 2 unit FFP for each 10unit of blood transfused • 6 unit Platelet concentration for every 20u of

blood transfused • Basic screening tests for bleeding after surgery--

Platelet count; prothrombin time; APTT; plasma fibrinogen concentration and fibrinogen degradation products when indicated.

Treatment

• Citrate toxicity:↓ in ionized calcium

Citrate binds calcium, thus lowering the ionized plasma calcium concentration. This is usually prevented by rapid hepatic metabolism unless the patient is hypothermic

Treatment

• Calcium gluconate 10ml 10% over 10 min • is less effective than calcium chloride

because it must be metabolized to be effective.

• 13.4% calcium chloride containing calcium 0.192 mmol/ml is more effective than the weaker 10% calcium gluconate solution which contains only 0.22mmol/ml of calcium.

• Massive transfusion with PRBC alone causes a dilutional coagulopathy.

• Massive hemorrhage causes consumptive coagulopathy.

26

Complications of Massive Blood transfusion: Continuation

Early

• Hyperkalemia:

The potassium concentration of blood increases during storage, by as much as 5–10mmol. After transfusion, the RBC membrane Na+–K+ ATPase pumping mechanism is re-established and cellular potassium re-uptake occurs rapidly.

• Acid-base disturbances:

• Hypothermia:

RBCs are stored at 4 °C. Rapid transfusion at this temperature will quickly lower the recipientʼs core temperature and further impair haemostasis. Hypothermia reduces the metabolism of citrate and lactate and increases the likelihood of hypocalcaemia, metabolic acidosis and cardiac arrhythmias, Peripheral coagulopathy, vasoconstriction, Infection.

Treatment:• This reduction in temperature can

be minimized by warming all IV • Fluids and by the use of forced air

convection warming blankets to reduce radiant heat loss.

• Reduction in coagulation factors for each 1 °C, drop in temperature.

• CT is prolonged below 33 °C.• Increase room temperature.• Surface waring the patient with

heating blanket, heating lamps.• Heated & humidified inspiration

gases.• Using blood and fluid warmer.

Each unit of RBCs contains 1–2mmol of acid. This is generated from the citric acid of the anticoagulant and from the lactic acid produced during storage; metabolism of this acid is usually very rapid.

Treatment:• Adequate fluid

resuscitation • At times may

require Bicarbonate therapy

• Transfusion-related acute lung injury

• Occurs during or within 6 hours of transfusion.

• Two different mechanisms for the pathogenesis of TRALI :

• Immune (Antibody mediated) • Non-immune.

• Immune TRALI results from the presence of leucocyte antibodies in the plasma of donor blood, directed against human leucocyte antigens (HLA) and human neutrophil alloantigens (HNA) in the recipient.

• Transfusion of > 7 units of PRBCs, associated with independently increases potassium.



Note:• 10% reduction in

coagulation for 1 °C drop in temperature.

27

Complications of Massive Blood transfusion: Continuation

Late:

•Transfusion-related infections

BacterialBacterial contamination of blood components is an infrequent complication of transfusion.• Brucella • Pseudomonas • Salmonella • Shigella ViralThe incidence of transfusion-related viral infection has greatly reduced• Cytomegalovirus (Incidence 1:10 to 1:30)• Hepatitis • HIV (Incidence 1:50000)• Epstein barr virus • Herpes simplex • Measles Parasites:• Malaria • Toxoplasmosis

• Transfusion-associated graft-vs-host disease: • Immunomodulation

Transfusion-associated graft-vs-host disease (GvHD) is a very rare complication of blood transfusion

The potential to modulate the immune system of transfusion recipients remains an exciting but controversial area of transfusion medicine.



• Non-haemolytic febrile reactionsThese reactions are very common and are usually not life-threatening. Reactions result from donor leucocyte antigens reacting to antibodies present in the recipient’s plasma.• Allergic reactionsAllergic reactions are common and usually mild. The majority are due to the presence of foreign proteins in donor plasma and are IgE-mediated. Pruritus and urticaria, with or without fever, are the most common features. The transfusion should be stopped and antihistamines administered.Treatment is he same as for anaphylaxis from other causes, with IV fluid resuscitation, epinephrine administration (to reestablish vasomotor tone and reverse bronchospasm), antihistamines, corticosteroids and respiratory support. If subsequent transfusions are required in such patients, washed RBCs should be used (residual plasma and therefore IgA is removed).Incidence:

• HCV = 1:30,000 to 40000• EBV = 1:200

28



9. Describe Anesthetics concerns for regional anesthesia in a patient on anticoagulants.

• Guidelines based on literature, case studies, and consensus statements . • The morbidity of spinal hematomas can be greatly reduced with early diagnosis and intervention. • Neurological monitoring at least every 2hrs should be considered in high-risk situations. • Consider using neuraxial infusions with low doses of local anesthetic in higher risk situations. • This will enhance early detection of spinal hematoma • Combined therapies, which attack unique components of the coagulation cascade, may increase the risk of bleeding complications. (e.g. Heparin AND coumadin) • Approach new agents affecting coagulation with caution.(e.g.Fondaparinux)

Regional anesthesia in a patient on anticoagulants - ASRA

• Consider avoiding neuraxial blocks, except in extreme circumstances. Time block at least 10 days after, and 10 days before thrombolytics given.

• If thrombolytics are given around the time of neuraxial puncture, monitor patients at least Q2hrs, and use solutions with weak local anesthetic.

• No recommendation for timing of catheter removal after unexpected thrombolytics use.

• Use caution and consider checking fibrinogen levels.

E.g: • Alteplase• Reteplase• Streptokinase• Urokinase

• Thrombolytics• Heparin- Unfractionated

Subcutaneous Heparin • No contraindication for neuraxial techniques

with mini-dose SQ heparin • Time insertion of needle or removal of

catheters 4 hours after last dose, and 2-4 hours before subsequent dose.

• Consider checking a platelet count in patients receiving SQ heparin for greater than 4 days, to rule out heparin-induced thrombocytopenia (HIT.)

Low dose intra-operative heparin• Delay heparin dose for 1 hr after needle

placement. Remove catheter 1 hr before any subsequent dose, or 2-4 hrs after last dose.

• Consider postoperative monitoring (q2hr neuro checks) and using weak local anesthetic concentrations.

Prolonged therapeutic heparinization• Neuraxial blocks should be avoided in this

situation

• Low Molecular Weight Heparin (LMWH)

High Dose-BID LMWH(e.g. enoxaprin 1mg/kg q12hr, or 1.5mg/kgQD) !• First dose should be given >24hrs after

the block, and 2 hrs after catheter removal

• Indwelling catheters should be removed prior to initiating therapy

LowDose-QDLMWH(EuropeanRegimen) • Indwelling neuraxial catheters can be

safely maintained. • First dose of LMWH should be given 6-8

hrs after block. • Catheter should be removed >10-12 hrs

after the last dose. o!Subsequent dose of LMWH given >2 hrs after removal of catheter.

29



Regional anesthesia in a patient on anticoagulants

• Coumadin/Warfarin:

• Chronic oral anticoagulation should be stopped 4-5 days prior to block, and PT/INR checked before procedure performed.

• If initial dose given >24 hrs prior to procedure,or if 2 or more doses given, check PT/INR before block.

• Catheters can be safely maintained on low dose (5mg) warfarin therapy CheckPT/INR QD for indwelling catheter in pts on warfarin

• If INR > 3, with hold or reduce coumadin dose.

• Catheters can be removed when INR < 1.5.

• Minimize local anesthetic concentration; monitor neuro status during therapy and for 24hrs after catheter removal

• Anti-platelet Medications

• Includes NSAIDS (motrin,naproxen),thienopyridines(ticlopidine and clopidogrel), glycoprotein IIb/IIa antagonists (abciximab, tirofiban)

• Bleeding time not a reliable test. Risk for bleeding increased in females, elderly, and those with a history of easy bruising/excessive bleeding.

• NSAIDS-no added risk or timing concerns for neuraxial techniques when used alone.

Ticlopidine,clopidogrel, and platelet GP antagonist may represent significant risk:• Ticlopidine- discontinue 14 days prior to

block Clopidogrel- discontinue 7 days prior to block

• Abciximab- discontinue 2 days prior • Eptifibatide and tirofiban- discontinue 8hrs

prior to block (GPIIb/IIIa)Cox-2selective inhibitors(rofecoxib, celecoxib, valdecoxib) • Minimal effect of platelet function. • Consider in patients requiring anti-

inflammatory peri-operatively.

• Fondaparinux

• Anti-thrombotic effect through factor Xa inhibition, actual risk unknown.

• Consensus recommendations based on the sustained and irreversible anti thrombotic effect, early postoperative dosing, and report of spinal hematoma reported during initial clinical trials.

• Recommend single needle pass, atraumatic needle placement, and avoidance of indwelling neuraxial catheters

Herbal Preparations: Of concern to the anesthesia provider is the side effect of bleeding in the patient who consumes herbal preparations.Mechanism of action: varies with the preparation. • Garlic, ginger, feverfew: inhibit platelet

aggregation • Ginseng: antiplatelet components • Alfalfa, chamomile, horse chestnut, ginseng:

contain a coumadin component • Vitamin E: reduces platelet thromboxane

production • Ginko: inhibits platelet activating factor The risk for epidural/spinal hematoma is unknown. Surgical patients should be advised to stop herbal products 5-7 days before surgery. One of the crucial aspects of preoperative assessment is the concomitant use medications that alter coagulation. In addition, the patient should be screened for bleeding tendencies

30



10. What is Disseminated intravascular coagulation? Enumerate its causes and management.

Disseminated intravascular coagulation (DIC), also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation (blood clotting) mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood vessels throughout the body

Pathophysiology of DIC:

StimulusTissue destruction Endothelial Injury

Tissue factor

Extrinsic pathway Factor XII activation (Intrinsic pathway)

Thrombin generation

Intravascular fibrin depositionPlatelet consumption

Thrombocytopenia

Thrombosis

RBCʼs Damaged

Tissue Ischemia

Hemolytic anemia

Plasminogen activation

Plasmin generation

Fibrinolysis

Fibrin degradation products (inhibit thrombin & platelet aggregation)

Clotting factor degradation

Bleeding

Decreased circulating blood

Decrease O2 transport

Tissue Hypoxia

ORGAN FAILURE

http://en.wikipedia.org/wiki/Coagulation


31Dr Azam’s Notes in Anesthesiology 2013

Dr Azam’s Notes in Anesthesiology 2013Enumerate its causes and management. Continuation:

Causes for DIC

Infection:• Septicemia • Viremia • Fungaemia• Protozal

Obstetric:• Pre-Eclampsia• Placental abruption• Amniotic fluid embolism• Retained products of

conception• Placenta praevia

Malignancy:• Acute promyelocytic

leukemia• Metastatic carcinoma

Traumatic:• Polytrauma with shock• Burns• Fat embolism• Neurosurgery

Intravascular Hemolysis:• Snake Venom• ABO transfusion reaction

Clinical Features: S/S• Bleeding or bruising - from GI Tract,

genitourinary tract, ecchymosis,petechiae, purpura.

• Laboratory findings: Thrombocytopenia, anemia, prolonged PT aPTT & FDP, Deranged D-DIMER.

Investigation: Abnormalities of Lab DIC:• Increase PT, aPTT• Decrease platelets• Smear = Schitocytes• Decrease in Fibrinogen• Decrease in Factor V• Decrease in Factor VIII• Increase in D-DIMER

Treatment & Management of DIC:• Treat the underlying cause• Provide supportive management of complications• Support organ function• Stop abnormal coagulation and control bleeding by replacement of depleted blood and

clotting components (FFP,Platelets,PRBC)• Medications can be used and choice depends on the patientʼs condition (Heparin,

Antithrombin III (ATIII), Fibrinolytic inhibitors)Plasma therapyIndications• Active bleeding• Patient requiring invasive procedures• Patient at high risk for bleeding complicationsFresh frozen plasma(FFP):• Provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.• Usual dose is 10-15 ml/kgPlatelet Therapy:Indications• Active bleeding• Patient requiring invasive procedures• Patient at high risk for bleeding complications• Platelets• approximate dose 1 unit/10kg• Cryoprecipitate = 1U/10 kg• Fibrinogen concentrate = 2 - 3 gms

32



Treatment & Management of DIC:Blood Therapy:• Replaced as needed to maintain adequate oxygen delivery.• Blood loss due to bleeding• RBC destruction (hemolysis)Coagulation Therapy:• Antithrombin III• Protein C concentrate• Tissue Factor Pathway Inhibitor (TFPI)• HeparinAntithrombin III:• The major inhibitor of the coagulation cascade• Levels are decreased in DIC.• Anticoagulant and anti-inflammatory properties• Therapeutic goal is to achieve supranormal levels of ATIII

(>125-150%).Recombinant Protein C:• Inhibits Factor Va, VIIa and PAI-1 in conjunction with

thrombomodulin.• Protein S is a cofactor

Enumerate its causes and management of DIC. Continuation:

Preoperative preparation:• Antibiotics for infection• Hypovolemia to be corrected• Warm fluids & Blood products• Evacuation of retained products of conception• Blood product to given based on the laboratory

investigations• Coagulopathy corrected with FFP & platelets• If fibrinogen level < 1gms/liter - Cryoprecipitate to be

transfused• Adequate blood & blood products to be available before

surgery• Recombinant protein C - in severe sepsis• Intra-muscular injections to be avoided

Peri-operative Anesthetic implications & Management:• Coagulopathy - CI for regional anesthesia• General anesthesia is preferred • Invasive cardiovascular monitoring required - ABP,CVP• Large bore IV lines for rapid transfusion• Naso-tracheal intubation to be avoided• Blood, platelet concentrate,FFP & Cryoprecipitate should

be transfused promptly, bleeding parameters needs to be measured regularly

Post-operative management:• Patients to be managed in ICU• May require mechanical ventilation• Hypothermia to be avoided• Antibiotics to be continued• Frequent measurement of PT,PTT & INR to be done.Note:• Epsilon Amino Caproic Acid and fibrinogen should not be

administered in presence of continuing intravascular coagulation. EACA would inhibit secondary fibrinolysis which is an intrinsic protective mechanism in patients with persistent DIC.

33



11. Enumerate the indications of packed red cells, fresh frozen plasma(FFP), platelets & cryoprecipitates.

A. Packed Red Cells:Indications of Packed red cell:• Deficient oxygen caring capacity or tissue hypoxia, due to

inadequate circulating red cell mass• Exchange transfusion in hemolytic disease of new born or

in Sickle cell anemia• Hypovolemia secondary to hemorrhagic shock.

Description of Packed red cells:• 150 to 200 ml red cells from which most of the plasma has

been removed• Hemoglobin approximately 20 g/100 ml ( not less that 45 g/

unit)• Hematocrit 55 to 75%.

B. Fresh Frozen Plasma:Indications of FFPʼs:• Congenital factor deficiency

• Invasive procedure or trauma ( e.g. factor XI deficiency)• Emergency warfarin reversal • Acquired bleeding disorders with active bleeding or prior to

an invasive procedure. (liver disease; vitamin K deficiency; disseminated intravascular coagulation; dilutional coagulopathy).

• Microvascular bleeding & elevated PT/PTT• Loss of more that one blood volume & no lab values then

give empirically.• FFP is indicated in massive transfusion with demonstrated

deficiency of factor VIII & V• Exchange transfusion in neonates.

FFPʼs Continued:Product• Anticoagulated plasma in frozen state

CharacteristicsVolume: 200-250 ml (= 1 unit) Contains all plasma proteinsPharmacological EffectIncrease plasma clotting factors and prevent or stop bleeding

Dose of FFP:10 - 15 ml/Kg

C. Cryoprecipitate:Defini&on: IT IS THE INSOLUBLE PORTION OF PLASMA REMAINING AFTER THE FRESH FROZEN PLASMA HAS BEEN THAWED BETWEEN 4°C TO 6°C. Increase plasma levels of high molecular weight clotting factors

Indications of Cryoprecipitate:• Hemophilia A• Von Willebrandʼs disease• Congenital or acquired fibrinogen deficiency• DIC • Massive transfusion with dilutional hypofibrinogenemia• Hypofibrinogenemia: Fibrinogen < 100 mg/dL with active bleeding or fibrinogen

< 200 mg/dL in a postoperative patient with excessive bleeding.• Uremia or hereditary platelet disorder • Factor XIII DeficiencyComposition:• Volume: 5 - 15 ml (= 1 Unit; 1 BAG) • Contains high molecular weight glycoproteins such as fibrinogen (300 mg/unit);

Factor VIII (80-100 U/unit); von Willebrand factor; factor XIIIDose:• 1 unit/10 Kg wt; Frequently 10 BAGS

34



Enumerate the indications of packed red cells, fresh frozen plasma(FFP), platelets & cryoprecipitates. Continuation:

D. Platelets:

Indications of Platelets:• Thrombocytopenia • Platelet function defect• Microvascular bleeding in surgical or obstetric patients• Dengue fever• Massive blood transfusion

Characteristics:Whole Blood Donation

Apheresis Donation

Potency 5-8x 1010 40 x 1010

Volume (ml) 35 - 60 180 - 400

Labeling Platelets Platelets, pheresis

Common Usage Random Donor Units

Single Donor Unit

Platelets increased by 5000 - 7000 60,000 to 70,000

Doses of Platelets:• 1 unit/10 Kg weight; 4 units/m2 Surface Area• 1 Platelets, Apheresis

35



12. Write the blood conservative strategies in a 20 year old female scheduled for excision of angiofibroma of nose?

Blood conservative strategies are getting great clinical relevance due to the concern in transfusion allogenic blood. This is done to avoid potential risk associated with blood transfusion.

Methods of reducing blood transfusion/Method for blood conservation strategies are:

1. Optimization of the preoperative hemoglobin:• Preoperative Hb is best predictor of the need for allogenic transfusion• If Anemia due to Iron deficiency - oral iron is prescribed. If it is not

effective intravenous administration of iron-sucrose can be done.• If anemia not due to iron or Vit B12 deficiency or absence of chronic

blood loss then Hb & HCT will improve with administration of erythropoietin combined with iron supplement.

• Erythropoietin Regimen:• 300U/kg for 15 days beginning 10 days before surgery or• Weekly administration of 600 U/kg starting 3 weeks before surgery• Erythropoietin should always be combined with iron

supplementation.

2. Strategies to decrease perioperative blood loss / Reduction of blood loss:

• Any congenital or acquired bleeding disorders should be detected• Aspirin & NSAIDS to be stopped 1 week before surgery• Patients of LMWH, Vit K antagonist & aspirin should be stopped

before surgery.• Position of the patient affects intraoperative bleeding:

• Lateral position in THR decreases blood loss• Elevation of lower limbs after TKR reduces post operative blood

loss• Controlled hypotensive spinal or epidural anesthesia using adjuvants

like clonidine neuraxially decreases blood loss• Maintaining normothermia decreases bleeding.• Preoperative arterial embolization for complex pelvic fractures or

highly vascular tumors

• Surgical hemostasis is done using bone wax & surgicel• Local hemostatic agents such as: fibrin spray, application of

platelet gel before wound closure, topical use of Tranexemic acid.

• Systemic hemostatic agents Tranexemic acid, desmopressin,aprotinin

• Tranexemic acid ( synthetic fibrinolytic inhibitor) reduces bleeding

• Initial bolus dose 10 mg/kg Max of 30 mg/kg/day• Pneumatic tourniquet

3. Lowering the transfusion trigger:• The transfusion trigger of 10gm/dl & HCT of 30% can be safely

be lowered in most patients without any cardia or respiratory co-morbidities.

• 8 gm/dl in older without any co-morbidity & 7 gm/dl in younger healthy patients

4. Strategies in optimization of use of patients own blood: Can be done by

• Acute isovolemic hemodilution: blood has low HCT which reduces RBC loss. It enhances microcirculation.

• Autologus blood donation & transfusion: It should be targeted to men with Hb of 11 to 14 gm/dl & to women with level of 13 to 14 gm/dl, whose blood loss is close to 1000 ml.

• Perioperative blood salvage:• Re-infusion of blood drained within 6 hours after operation

using cell salvage. • It is generally accepted that no more than 1000 ml of

drained blood be re-infused & not more than 6 hours after end of surgery should not be transfused.

• Contraindicated in patients with infection & malignancy.

36



Write the blood conservative strategies in a 20 year old female scheduled for excision of angiofibroma of nose? Continuation:

Use of Blood Substitutes: Two types of blood substitutes are available:

Perflurocarbons: • They are biologically inert volatile fluids

with high dissolving capacity for o2 & CO2• They transport & deliver O2 by simple

physical dissolution• Not water soluble• their O2 carrying capacity depends on the

concentration of perflurocarbons which varies between products.

• H+ atoms are replaced by fluorines• One unit of perflurocarbons carry 3

times O2 carried by similar volume of blood

• Fluosol - DA : 20 % emulsion of 2 different compounds. Dose = 20ml/kg

• Polyfluro-octobromide: O2 solubility is more

Hb based o2 carriers:• These are based on natural or

recombinant human Hb or bovine Hb• produced by purification, encapsulation in

synthetic phospholid. • Side effect:

• Increased Blood pressure due to increased systemic vasoconstriction due to scavenging of nitric oxide & oxidation which generated Meth Hb.

• Short intravascular half life• hence used in emergency situation.

37


Dr Azam’s Notes in Anesthesiology 2013 13. Autologus Blood transfusion.

Definition: Autologous blood transfusion is one in which both donor as well as recipient are the same.

Types of autologous blood transfusion:I. Preoperative blood donation II. Intraoperative blood salvage III. Postoperative blood salvage IV. Isovolemic hemodilution

I. PREOPERATIVE BLOOD DONATION:Criteria:• The haemoglobin > 11gm/dl • The haemoglobin never below 10gm/dl.

Contraindications:• Active bacterial infection • Cardiac disease • Loss of consciousness • Impaired placental blood flow – HTN, PET, DM • COPD - Emphysema

Method:• 450ml of blood at weekly intervals.• Last donation 4 days before surgery • Preferably 1 week prior to surgery.• Should commence oral iron prior to their first

donation and continue until the day of surgery.

II. INTRAOPERATIVE BLOOD SALVAGE:• Pre-deposit donation is limited by the time that the blood can be

stored and by the ability of patients to donate at frequent intervals.The main steps of this technique are 1. Salvaging the blood from the operative site. 2. Anticoagulating the whole blood – prior to surgery and during

suction. 3. Re-infusing whole blood as such after filtering or re-infusing the

red cells after washing. There are three basic methods for IBS:1. Semi continuous flow centrifugation 2. Canister collection 3. Single use disposable reservoirs

1. Semi continuous flow centrifugation: • Blood is aspirated, using a double lumen sucker, into a reservoir. • The blood is washed, with saline prior to being re-infused. • Two varieties of equipment available, the so called

• slow flow machines which produce one unit every 7-10 mins • Fast flow system which produce a unit in less than 3 mins.

2) Canister collection: • Aspirated, via a double lumen sucker • Allows anticoagulant to be mixed at the sucker tip, through a

170μm filter into a rigid reservoir containing a disposable liner.

38


Dr Azam’s Notes in Anesthesiology 2013Autologus Blood transfusion. Continuation:

1) Single use Disposable reservoirs: • Blood is aspirated using a vacuum pressure of less than

150mm Hg • Anticoagulated prior to surgery, • Anticoagulated using citrate. • Re-infused by gravity using microaggregate filter, • stored until room temperature, until required. Advantage – cheap and requiring no specialized equipment or specially trained personnel. Disadvantage – slow, small volumes, unwashed and has a low hematocrit.

Precautions:Avoid hemolysis: • The sucker should have a plastic tip with multiple holes• Turbulence to be avoided• pressure to be below 150-‐200 mmHg.

Anticoagulants: • Citrate in a ratio of 1:5 to 1:1, or heparin at a concentration of 30,000 units per lt of saline, with 15ml of heparin / saline being added to each 100 ml of blood (ratio heparin to blood, 1:7).

Wash solution:• The volume of saline wash solution should be three to four times that of the volume of the blood, although for orthopedic cases this may be increased to six to seven times with a minimum volume of 150ml.

INDICATIONS FOR INTRAOPERATIVE CELL SALVAGE:• Cardiovascular:• Vascular surgery:- Aortic aneurysm - Aortic rupture

• Orthopedic: Hip and spinal surgery • Liver transplantation • Neurosurgery • Trauma • Plastic surgery • Jehovahʼs witnesses • Serological antibodies:

Contraindications:• Infections, sepsis, bacteremia• Blood containing significant amounts of amniotic fluid

should not be auto transfused. • Blood containing:

• wound irrigants Betadine; • methylmethacrylate, • antibiotics

39



COMPLICATIONS FOR INTRAOPERATIVE CELL SALVAGE:1) Air embolism 2) Re-infusion of hemolyzed red cells:! If the vacuum pressure on the sucker is too high or excess turbulence has been caused by improper aspiration technique, hemolyzed red cells can be re-infused into the patient. 3) Coagulation disorders 4) Thrombocytopenia 5) Hypocalcaemia 7) Toxic antibiotic effects 8) Microfibrillar collagen haemostatic material

III. Post operative blood Salvage:Used in:• CTVS• Joint replacement• Trauma - chest wall & abdomen• Vacuum pressure = 0 - 40 mm of Hg• Time between start of collection & re-infusion should be

< 4 hours. Product has:• No clotting factors• HCT 15 - 20 %• Free Hb

Complication:• Products of clot lysis Volume > 800 ml of unwashed

blood are re-infused.• Upper airway oedema requiring intubation• Non-cardiogenic pulmonary oedema

IV. ACUTE NORMOVOLAEMIC HEMODILUTION/Isovolemic:• Definition: It indicates dilution of the blood while keeping the circulating

blood volume constant.• HCT is usedContraindications to acute normovolaemic hemodilution:1. Hematocrit less than 24%.2. Valvular heart disease and intra or extra cardiac shunting. 3. Respiratory insufficiency needing mechanical ventilation. 4. Haemostatic defects. Compensatory mechanisms during hemodilution:• Blood Rheology: Decreased viscosity & decreased oxygen carrying

capacity• Utilization of O2:

• Increased blood flow to the tissue • Increased oxygen extraction

• Autonomic effectsEffect on organ systems:i) Cardiac: Increased CO, Increased Coronary blood flow, Coronary Vasodilation.ii) Cerebral: Increased Cerebral blood flow iii) Hepatic and gastrointestinal: Increased Hepatic blood flow,

Increased oxygen extraction iv) Renal: Decreases renal blood flowv) Pulmonary: Hemodilution does not alter pulmonary function vi) Pregnancy: Hemodilution should be used with caution in pregnant patients, may result inadequate oxygen content in the blood perfusing the placenta.

Autologus Blood transfusion. Continuation:

40


Dr Azam’s Notes in Anesthesiology 2013Autologus Blood transfusion. Continuation:

Methods:• Crystalloids: 3:1 crystalloids to blood ratio.• Colloids: 1: 1 Colloid to blood ratio.

• Albumin• Dextran• Hetastarch• Gelatin

Technique:• Draw blood either

• Under anesthesia • Prior to induction

• Blood withdrawal rate must parallel the administration of appropriate diluent volumes to assure normovolaemic and circulatory stability.

• Serial HCT• Collections in bags & bottles• Monitoring

Methods:• Ferraric Method:• Preoperatively collect:

• 1 - 3 U of RBC suspended in saline together with an average of 1.6 x 10 platelets & 460 ml of plasma collected preoperatively.

Takaonʼs Method:• If Blood loss > 400 ml, 500 ml of RL is

given, after which 600 ml of blood is withdrawn, which is replaced by 600 ml of dextran 70.

• If Blood loss > 1L 600 ml of blood is taken & is replaced with equal volumes of 600 ml dextran 70.

41


Dr Azam’s Notes in Anesthesiology 2013 14. Replacement therapy for coagulation factor deficiency

Factor Therapeutic dose Component / derivatives

i) Fibrinogen 1 units / 5kg body wt Cryoprecipitate(100-250gms fibrinogen/bag)ii) Prothrombin 10-20ml plasma /kg Plasma or prothrombin complex concentrate iii) Factor V 20ml fresh frozen plasma/kg Fresh frozen plasma

iv) Factor VII 10-20ml plasma/kg Plasma or prothrombin complex concentratev) Factor VIII 15-50 units/kg Cryoprecipitate (100 units/bag) factor VIII concentrate

vi) Factors IX 20-80 units/kg Prothrombin complex concentrate plasma (1 unit of factor IX/ml)

vii) Factor X 10-20ml plasma/kg Plasma or prothrombin complex viii) Factor XI 10-20ml plasma/kg Plasmax) Factor XIII 4-6 bags Cryoprecipitate or 500ml plasma Plasma or Cryoprecipitate

42


Dr Azam’s Notes in Anesthesiology 2013 15. Partial thromboplastin time - PTT

Partial thromboplastin time:• PTT measures the intrinsic pathway i.e. factor

I,II,V,VIII,IX,X,XI,XII. • Specimen: citrate anticoagulated whole blood to be kept

refrigerated and transported as soon as possible.• Procedure: Performed with addition of contact activator (celite,

kaolin, micro silicate, ellagic acid).• Plasma sample is added to activator and incubated at 370C for 5

minutes. Thromboplastin preparation is added, mixed with addition CaCl2 and the timer is started.

Normal range: 25-‐39 seconds • Healthy premature babies have prolonged PT, PTT, TT which

returns to normal at 6 months. • Panic range:> 70 seconds Use:• Evaluation of intrinsic pathway, Heparin therapy, Screening for

hemophilia A and B (factor VIII) , dysfibrinogenemias, DIC, - liver failure, Vitamin K deficiency

Contraindications:• Specimen obtained less than 3 hrs after heparin doses. • About 30% of normal concentration of factor V, VIII, IX, X, XI and

XII will maintain a rate of thrombin formation sufficient to produce normal PTT. Prolongation occurs when any of the above single clotting factor falls below this level.

• Heparin à active serine protease

Control of heparin therapy • Heparin is an acid mucopolysaccharides found in Mast cells and

Basophils, which inhibits all the active serine proteases like IIa, IXa, Xa, XIa and XIIa.

• Response to heparin can be measured by whole blood PTT, APTT whole blood clotting time and PTT with comparable responses.

Administration of heparin:1. Heparin can be given subcutaneously / IV.2. IV can be intermittent or continuous infusion.3. Usually in dose of 400-500 units / kg / day divided into 6th hrly

dosage.4. 3 levels of heparin therapy.5. Low dose (10,000 – 20,000 units/day) mainly used as prophylaxis

against venous thrombosis (DVT), measurable changes in APTT usually does not occurs.

6. Moderate dose (20,000 to 60,000 units/day) used in patient without active thrombo embolic disease.

7. APTT is adjusted to 1½ to 2 times the control. 8. High dose (60,000 to 1,00,000 units / day) used in patient with

active thrombo embolic disease.9. This high dose is usually used for first 24-48 hrs and then

reversed back to a dose of 30,000-45,000 units/day.

43


Dr Azam’s Notes in Anesthesiology 2013 16. Activated Clotting Time - ACT

Synonymous à Activated clotting time ground gloss clotting time is a screening time for coagulation deficiencies and is of special application to the monitoring of heparin effect. Specimen: Fresh whole blood that is free of venepuncture derived thromboplastin.Procedure: manually mixing of whole blood with an activator substance such as celite / kaolin. • Contact of the activator with the blood initiates the

activation of the clotting cascade.• Commercially available timing systems are uses clinically

to measure the activated clotting time. These devices detect the onset of clot formation.

• Tubes of freshly drawn blood are incubated at 370C and tilted at 300 second intervals until the flow of blood stops.

• Tilting and recording can be made manually or by automated machines.

Normal range à 9-120 seconds (Millerʼs text 107± 13 seconds)Limitations à Relatively insensitive to lower concentration of heparin • Insensitive to factor VII deficiency • Hypothermia and haemodilution à prolongs ACT• It assays over all coagulation activity and during

monitoring for heparin therapy, prolonged values may not be exclusively due to heparin therapy.

• Abnormal values due to platelet abnormality.

Uses:• Monitoring of heparin therapy.• A baseline value of ACT is determined - Before IV administration of heparin - Approximately 3 mins after administration - 30 mins intervals thereafter.

• Use to monitor anticoagulation when large doses of heparin are used as during cordial surgical procedure.

• During CPB the anticoagulant effect of heparin is often is considered as adequate if the ACT is more than 300 seconds, questionable with ACT between 300-180 sec and inadequate with ACT < 180 sec.

• In patients receiving antifibrinolytic agent aprotinin, kaolin should be used to measure ACT, because it will bind the aprotinin and remove it from the plasma.

During CPB:• ACT = 300 - Adequate• ACT = 300 - 1800 Questionable• ACT = < 180 in adequate.

44


Dr Azam’s Notes in Anesthesiology 2013 17. Prothrombin Time - PT

• P T, measures the extrinsic pathway (I, II, V, VII, X) of coagulation and common pathway.

Specimen à sodium Citrated anticoagulated whole blood. Procedure à clotting time of Citrated anticoagulated plasma is determined after the addition of optimum concentration of calcium and an excess of thromboplastin. Clot detection is either normal or by an automated device.• The final result depends on the concentration and source of

thromboplastin, calcium concentration and the method used to detect clot formation. Therefore results may vary a great deal from laboratory to laboratory.

• Normal range – 10-14 seconds. • Premature, new born have normally prolonged PT, TT,

APTT which comes to normal range by 6 months. • Panic range à> 20 secs à non anticoagulated • 3 times control à anticoagulated

Use:• Useful in screening for deficiency of prothrombin,

dysfibrinogenemias, afibrinogenemia, liver failure, DIC, heparin effects, coumarin / warfarin effects, screening of vitamin K deficiency, and factor V, VII, & X (5, 7, 10)

• Prolongation of the PT usually reflects severe liver decrease unless vitamin K deficiency is present because only 20-30% of normal factor activity is required.

• Failure of the PT to correct, following parenteral administration of vitamin K implies severe liver disease, correction normally requires 24 hrs.

• Limitations – PT drawn less than 2 hrs after heparin administration is prolonged( minimum duration is more than 6 hrs).

INR (INTERNATIONAL NORMALIZED RATIO)• The INR was established as a mean of standardizing the PT for oral

anticoagulant therapy. Calculated as INR = PT of patient (sec) Mean of normal PT(ISI) • INR rate is used in monitoring patient in oral anticoagulant therapy

and it is recommended to monitor. INR of 1.3-1.5 (15-18 seconds) but slightly higher range of 1.5-2.0 is recommended for patients with prosthetic valves and recurrent embolism.

•• INR of 1.5 to 2.0 in prosthetic valve and recurrent embolism.

45


Dr Azam’s Notes in Anesthesiology 201318. Describe the coagulation factors. How do you investigate a case of intra operative coagulopathy?

• Coagulation, often referred to as secondary hemostasis involves formation of a fibrin clot, which usually binds and strengthens a platelet plug.

• Fibrin can be formed via one of the 2 pathways that involve activation of soluble coagulation precursor proteins in blood.

Coagulation factors:I! FibrinogenII! ProthrombinIII! Tissue thromboplastinIV ! Calcium/Labile FactorV! ProaccelerinVII! Proconvertin VIII! Antihemophilic factorIX! Christmas factor X! Straut power factor XI! Plasma thromboplastin antecedents (PTAXII! Hageman factor XIII! Fibrin stabilizing factor (Laki-Lorand factor)

Factors contributing to excessive bleeding during and following surgery:• Hemostasis following trauma and surgery is dependent on 3

major processes. A defect in any of the following leads to bleeding diathesis and increased blood loss.

Seconds:1. Vascular spasm2. Formation of platelet plug – primary hemostasis

Minutes:• Coagulation of blood – secondary hemostasis • Vascular spasm: result of release of humoral factors and local

myogenic reflexes.• Sympathetic mediated vasoconstriction in medium – sized

vessels.

Primary hemostasis: Platelet plug formation

3 stages 1. Adhesion – circulating platelets adhere to subendothelial collagen via

specific glycoprotein receptor. Stabilized by circulating glycoprotein called vWf which forms additional bridges via GPIb.

2. Release of platelet granules: collagen (as well as epinephrine and thrombin) activates platelet membrane bound

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)/01#%(23%&'"())

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3. Aggregation: These factors attract and activate additional platelets – resulting in platelet plug.

4. Coagulation cascade: Fibrin can be formed via one of the 2 pathways.

• The extrinsic pathway – triggered by the release of tissue lipoprotein (thromboplastin) from injured cells.

• More important pathway in humans.• Factors involved – 1, 2, 5, 7 and 10.• Test prothrombin time.

46


Dr Azam’s Notes in Anesthesiology 2013Describe the coagulation factors. How do you investigate a case of intra operative coagulopathy?Continuation:

Intrinsic pathway:• Triggered by interaction between sub-endothelial collagen with circulating factor XII,

HMWK and prekallikrein.• Factors involved – 1, 2, 5, 8, 9, 10, 11,12, • Test – PTT• Regardless of pathway activated, the coagulation cascade is ends in the conversion

of fibrinogen to fibrin.• Thrombin plays a central role in coagulation.• Thrombin then converts fibrinogen to soluble fibrin monomers that polymerize on

the platelet plug.

Tests for coagulation:Test Normal value Measured1) Bleeding time 3-10 minutes Platelet function vascular integrity2) Platelet count 150,000 to 400,000 cells/

mm3

3) Prothrombin time 10-12 seconds Factors 1, 2, 5, 7, 104) PTT 25-35 secs Factors 1, 2, 5, 7, 9,10, 11,125) Activated clotting time 90-120 secs same as above6) Thrombin time 9 -11 seconds Factors 1, 27) Fibrinogen 150-250 mg/dl8) Fibrin degradation product

< 4 mg/ml

47


Dr Azam’s Notes in Anesthesiology 2013 19. Categorization of coagulation disorders:

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!"#$%&'(')*+*),-*.*/$,*0'(("12),-*-'3")3"*+4'12$,$5',"#')**6)78$2*/*-"4**6)78$2*/999*-"4*:2$8"',"*-"4*+,8'8&2$#1',*999*-"4*

./0!1"#%23"#'&%4"-'5&%*2'6,7'&%25!/5&#'-23"#'&%4"-*2'6,7'&%25-!- ;'(<8'$,)(*8&2$#1$7=8"*

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AB:.C*.2)',*82)<#)C*$28&$%"-'7C*$138"82'7D*

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• FFP – 1 u/ml of factor VIII• Cryoprecipitate– 5 -10 u/ml factor VIII• Factor VIII concentration – 40 u/ml factor VIII• DDAV - ↑ 2 to 3 times.

48



20. Describe various test used for monitoring peri-operative coagulation.

Traditionally, perioperative coagulation monitoring has focused on:

(1) preoperative testing to identify patients at increased risk for perioperative bleeding (2) intraoperative monitoring of heparin therapy during cardiac and vascular surgery.

Test for Monitoring Perioperative Coagulation.

Partial thromboplastin time:• PTT measures the intrinsic pathway i.e. factor

I,II,V,VIII,IX,X,XI,XII. • Normal range: 25-39 seconds • Healthy premature babies have prolonged PT,

PTT, TT which returns to normal at 6 months. • Panic range:> 70 seconds• Use:• Evaluation of intrinsic pathway, Heparin therapy,

Screening for hemophilia A and B (factor VIII) , dysfibrinogenemias, DIC, - liver failure, Vitamin K deficiency

• Control of heparin therapy • Heparin is an acid mucopolysaccharides found in

Mast cells and Basophils, which inhibits all the active serine proteases like IIa, IXa, Xa, Xia and XIIa.

• Response to heparin can be measured by whole blood PTT, APTT whole blood clotting time and PTT with comparable responses.

PROTHROMBIN TIME:• P T, measures the extrinsic pathway (I, II, V, VII, X) of

coagulation and common pathway. • Normal range – 10-14 seconds. • Premature, new born have normally prolonged PT, TT,

APTT which comes to normal range by 6 months. • Panic range à> 20 sec à non anticoagulated • 3 times control à anticoagulatedUse:• Useful in screening for deficiency of prothrombin,

dysfibrinogenemias, afibrinogenemia, liver failure, DIC, heparin effects, coumarin / warfarin effects, screening of vitamin K deficiency, and factor V< VII, & X (5, 7, 10)

• Prolongation of the PT usually reflects severe liver decrease unless vitamin K deficiency is present because only 20-30% of normal factor activity is required.

• Failure of the PT to correct, following parenteral administration of vitamin K implies severe liver disease, correction normally requires 24 hrs.

• Limitations – PT drawn less than 2 hrs after heparin administration is prolonged( minimum duration is more than 6 hrs).

INR (INTERNATIONAL NORMALIZED RATIO):• The INR was established as a

mean of standardizing the PT for oral anticoagulant therapy.

• Calculated as INR = PT of patient (sec)/ Mean of normal range

• INR rate is used in monitoring patient in oral anticoagulant therapy and it is recommended to monitor. INR of 1.3-1.5 (15-18 seconds) but slightly higher range of 1.5-2.0 is recommended for patients with prosthetic valves and recurrent embolism.

•• INR of 1.5 to 2.0 in prosthetic valve

and recurrent embolism.

49



ACTIVATED COAGULATION TIME (ACT):• Activated clotting time ground gloss clotting time is a

screening time for coagulation deficiencies and is of special application to the monitoring of heparin effect.

• Normal range à 9-120 seconds (Millerʼs text 107± 13 seconds)

Uses:• Monitoring of heparin therapy.• A baseline value of ACT is determined

i. Before IV administration of heparin ii. Approximately 3 mins after administration iii. 30 mins intervals thereafter.

• Use to monitor anticoagulation when large doses of heparin are used as during cordial surgical procedure.

• During CPB the anticoagulant effect of heparin is often is considered as adequate if the ACT is more than 300 seconds, questionable with ACT between 300-180 sec and inadequate with ACT < 180 sec.

In patients receiving antifibrinolytics agent aprotinin, kaolin should be used to measure ACT, because it will bind the aprotinin and remove it from the plasma.

Describe various test used for monitoring peri-operative coagulation.Continuation:

Test for Monitoring Perioperative Coagulation.

THROMBOELASTOGRAPHY:

• It is a viscous elastic technique which measures entire spectrum of clot formation from early fibrin strands to clot retraction and eventual fibrinolysis. This test evaluate clot formation as a dynamic process unlike standard coagulation tests which measure isolated endpoints.

R—Reaction time for initial fibrin formation! N à 6-8 mins! ↑ in deficiency of a coagulation factors. R + K à coagulation time ! ! N à 10-12 mins.α0à clot formation rate! N à> 500↓ in coagulation disorder. MA à Maximum Amplitude A60à Amplitude 60 min other MAF à Whole blood clot lysis time ! N à> 300 min

Uses:• Coagulation monitoring during • Liver transplantation • Obstetric anesthesia • Trauma anesthesia (massive

transfusion) • Diagnosis pre-coagulant defect. - Platelet dysfunction - Fibrinolysis - Hyper-coagulation state

• Real time detection of clotting abnormalities in liver transplantation CPB

• Differentiates surgical bleeding from coagulopathy in cardiac surgery.

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50



Describe various test used for monitoring peri-operative coagulation.Continuation:

Normal Hemophilic Thrombocytopenia Fibrinolysis Hypercoagulability 1) Prolonged R 1) Prolonged R 1) ↓ MA 1) Shortened R

2) ↓α0 2) ↓α0 2) ↓α0 2) ↑ MA3) ↓ MA 3) ↓ MA 3) ↓ F 4) Prolonged F

THROMBOELASTOGRAPHY: Continuation:

Treatment for the TEG:

TEG Parameters Treatment

R 11 - 14 min 2 x FFP or 10 ml/kg

R > 14 min 4 x FFP or 20 ml/kg

MA 46 - 50 mm 1 Platelet concentrates

MA < 46 mm 2 platelet concentrates

Angle < 52° 2 x FFP or cryoprecipitate

Ly 30 > 8% Antifibrinolytics

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Dr Azam’s Notes in Anesthesiology 2013 21. Thromboelastography

Definition:• It is a viscous elastic technique which measures entire spectrum of

clot formation from early fibrin strands to clot retraction and eventual fibrinolysis. This test evaluate clot formation as a dynamic process unlike standard coagulation tests which measure isolated endpoints.

Method of recording:• 0.35 ml of blood placed in a disposable curette within the instrument.

The curette continuously rotates around an axis of 50.• A metal piston attached by a tissue wire to an electronic needle

recorder is lowered into the blood in the curette. A clot formation occurs, the piston become with in the clot & the solution of curette is then transfused to piston and to the electronic recorder.

• Hyper coagulated within 30 min of obtaining the sample.

• It aids in the diagnosis of a procoagulation deficiency (hemophilia), platelet dysfunction, fibrinolysis, DIC.

R—Reaction time for initial fibrin formation! N à 6-8 mins! ↑ in deficiency of a coagulation factors. R + K à coagulation time ! ! N à 10-12 mins.α0à clot formation rate! N à> 500↓ in coagulation disorder. MA à Maximum Amplitude A60à Amplitude 60 min other MAF à Whole blood clot lysis time ! N à> 300 min

Uses:• Coagulation monitoring during • Liver transplantation • Obstetric anesthesia • Trauma anesthesia (massive transfusion)

Uses:Diagnosis pre-coagulant defect. - Platelet dysfunction - Fibrinolysis - Hyper-coagulation state

Real time detection of clotting abnormalities in liver transplantation CPBDifferentiates surgical bleeding from coagulopathy in cardiac surgery. Disadvantages:Lack of specificity associated with abnormal findings Qualitative assessment is not possible Schematic depiction of coagulopathy as selected by the Thromboelastography compared with normal one

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52


Dr Azam’s Notes in Anesthesiology 2013Thromboelastography

Normal Hemophilic Thrombocytopenia Fibrinolysis Hypercoagulability 1) Prolonged R 1) Prolonged R 1) ↓ MA 1) Shortened R 2) ↓α0 2) ↓α0 2) ↓α0 2) ↑ MA

3) ↓ MA 3) ↓ MA 3) ↓ F 4) Prolonged F

Treatment for the TEG:

TEG Parameters Treatment

R 11 - 14 min 2 x FFP or 10 ml/kg

R > 14 min 4 x FFP or 20 ml/kg

MA 46 - 50 mm 1 Platelet concentrates

MA < 46 mm 2 platelet concentrates

Angle < 52° 2 x FFP or cryoprecipitate

Ly 30 > 8% Antifibrinolytics

• R - Reaction time fibrin formation• K - Time & Kinetics for fibrin cross linkage.• α (Alpha) - Strength of the clot & clot formation

ratio.• MA - Maximum Amplitude for fibrin & platelet

interaction.• Ly 30 - Measures lysis time after MA.

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Dr Azam’s Notes in Anesthesiology 2013 22. Assessment of blood Loss during Surgery

• Normal blood volume in an adult is 70ml/kg for 17.7% of body weight. Total blood volume can be measured as the sum of the red cell volume and plasma volume or from formulae depending on height and weight.

• One of the most important tasks of anesthesiologist is to continuously monitor and estimates blood loss. Unless estimates are complicated by occult bleeding into wound or under surgical drapes, accuracy is importance to guide fluid therapy transfusion.

• Most commonly used method for estimating blood loss is measurement of blood in surgical container and visually estimating blood on surgical sponges and laparotomy pads.

• A fully soaked sponge (4x4) said to hold 10 ml of blood; where as soaked lap holds 100-150 ml.

• More accurate estimates are obtained if sponges and laps are weighed before & after use.

• Serial hematocrit / hemoglobin concentration reflect ratio of blood loss to plasma, not necessarily blood loss. Hematocrits may be useful during long procedure or when estimates are difficult.

Measurement of blood loss:1) Visual observation of degree of bleeding 2) Clinical signs: give indirect information concerning blood loss. These include fall in B.P., fall in C.V.P., tachycardia, sweating and pallor of skin. It is advantageous to replace blood loss before these signs become evident. These methods give a reasonable estimate in the case of minimal blood loss. Errors are likely to be cumulative if blood loss continues over a prolonged period. 3) Gravimetric method – simplest, most common employed blood loss estimate by measurements of gain in weight of swabs and towels, together with measurement of contents of suction bottle. 1ml of blood weighs 1g.Weighing of swabs underestimates blood loss by 25%.4) Dilutional methods:! a) colorimetric method b) use of radioactive tracer a. Calorimetric method – swab + towel mixed thoroughly with large known volume

of fluid which is then estimate calorimetrically. Error may occur due to incomplete extraction or contamination with bile. patient hemoglobin must be known.

Blood loss = Calorimeter reading X Volume of Solution/200 X % of Pt HbIn operations involving complex exchanges of blood (extracorporeal circulation). It may be useful to weigh whole patient before and after operation. b) Use of radioactive tracer dilution methods:When measuring the volume of anybody compartment by this method, it is important that the tracer used remain within that compartment. In the case of blood volume, either the patientʼs own red blood cells (labelled with Cr51 following incubation with the isotope or pooled human albumin (labelled with I125 or I131) are used. All 3 isotopes are gamma emitters, but I125 is the isotope of choice because it emits less energy. The activity of the tracer is first measured and then injected intravenously.

54


Dr Azam’s Notes in Anesthesiology 2013 Assessment of blood Loss during Surgery

• The activity remaining in the empty syringe is measured and deducted from the amount of the isotope injected. After 10-15 minutes, a sample of blood is withdrawn from the opposite arm. This is to ensure there is no contamination of the sample from any isotope remaining at the injection site. The activity of this sample is then measured and the dilution volume calculated from the result. Repeated measurements can be made to estimate the change in blood volume with allowance made for residual radio activity from the previous measurements.

• In a shocked patient, the time taken for mixing throughout the total blood volume may be in excess of the 10-15 minutes usually allowed. So the measurement is a better indication of the effective circulating volume than it is of the total blood volume errors may also arise from loss of the injected isotope by vigorous hemorrhage before mixing is complete.

Average blood volume. Neonates: Premature 95 ml/kg, Full term 85 ml/kg, Infants 80 ml/kgAdults: Men 75 ml/kg Women 65 ml/kgReplacing blood loss:• Ideally blood loss should replace with crystalloid or colloid to

maintain intravascular volume (normovolemia) until danger of anemia outweighs risks of transfusion.

• At that point further blood loss is replaced with transfusion of RBCs to maintain Hb concentration or hematocrit at that level for most patients it corresponds to Hb between 7-8 g/dl.

• Hb < 7gm/ dl à cardiac output ↑ to maintain O2 delivery.• Hb – 10gm/dl à for patients with cardiac / pulmonary disease /

elderly.Replace:• 1 ml of Blood = 3 ml crystalloid• 1 ml of Blood = 1 ml colloid• Patients with normal hematocrit should generally be transfused

only after losses greater than 10-20% of their blood volume.

Exact point is based on patientʼs medical condition & surgical procedure. 1. Estimate blood volume. 2. Estimate RBC volume at pre operative hematocrit. 3. Estimate RBC volume at hematocrit 30% assuming

normal blood volume is maintained. 4. Calculate red cell volume lost when Hematocrit is 30%.5. RBC volume lost =RBC preoperative – RBC volume 30%.6. Allowable blood loss = RBC volume (lost) x 3

Hemorrhagic Shock:Class I Class II Class III Class IV

Blood loss 750 750-1500 1500-2000 ≥ 2000% or volume 15% 15-30% 30-40% ≥40%Pulse rate < 100 > 100 > 120 ≥ 140BP Normal Normal Decreased DecreasedPulse pressure

Normal / increase

Decrease Decrease Decrease

Capillary refilling (3 -4 seconds)

Normal Positive Positive Positive

Respiration rates

14-20 20-30 30-40 > 35

Urine output ( ml)

≥30 20-30 5-15 Negligible

CNS mental status

slightly anxious Mild anxious Anxious &confused

Confused& lethargic

Fluid replacement

Crystalloid Crystalloid Crystalloid & blood

Crystalloid & blood

55


Dr Azam’s Notes in Anesthesiology 2013 23. Sickle Cell Anemia & Anesthesia

• Sickle cell anemia was first noted clinically by J.B. Herrick in 1904. in 1927 Hah and Gellespie induced hypoxia and acidotic sickling and incriminated haemoglobin as the cause, by demonstrating them in ghost erythrocyte

• Sickle cell disease is a hereditary hemoglobinopathy in which the red cells contain Hb-S instead of Hb-A. Hb-S differs from normal adult Hb-A by the substitution of valine for glutamic acid at β-6 of Hb molecule.

Types - Two Types • Sickle cell trait (heterozygous)• Sickle cell anemia (homozygous)• Sickle cell trait – asymptomatic carrier state for

Hb-S • Incidence in American blacks – 8-10%• RBC have Hb-S concentration < 50%

[38-45%]• Sickle cell anemia – incidence in American

blacks – 0.2% • RBC have Hb-S concentration 70-98%

• Characterized by– Chronic hemolysis – Acute episodic vaso-occlusive crisis • Sickle cell crisis–Life threatening complication

in contrast to anemia

Pathophysiology: Low PaO2

↓Deoxygenation of Hb-S

↓Sickle shaped RBC

↓Sickled Hb-S has 2 reactive sites

↓Hb-S molecules bind with each other

↓Long aggregates / tactoids (rigid, less soluble)

↓Increased viscosity of blood

↓Stasis of blood flow

↓Localized / generalized vascular occlusion

↓Infarction crisis

Vaso-occlusion common in liver and kidney where portal circulation PO2 is usually low.

Aplastic crisis – Characterized by bone marrow depression – cessation of erythropoesis

↓Rapidly declining hematocrit Often associated with viral infection

Sequestration crisis –Is due to depletion of circulating RBC by virtue of pooling of these cells in liver and spleen. Mainly affects children and infants – may need immediate transfusion. Diagnosis -1) Hb – 6-9g/dl • Peripheral smear – normocytic normochromic anemia 2) Sickle test – Precipitation reaction 3) Sickle test 4) Haemoglobin electrophoresis – definitive test

56


Dr Azam’s Notes in Anesthesiology 2013Sickle Cell Anemia & Anesthesia. Continuation:

Treatment:Principles of Treatment of sickle cell crisis • To keep the patient warm • To alleviate pain • To rehydrate • To treat infection, hypoxia, acidosis • Pain – Treatment with an opioid• The use of epidural analgesia using local anesthetic / opioid may be

useful if pain is in lower extremities. • Partial exchange transfusion – with fresh normal RBC Containing Hb-A-

leads to decreased HbS concentration Goals:• To ↑ HbA conc. To close to 50%• To keep hematocrit below 35% • Oral bicarbonate (up to 20 g/day) to produce mild Alkalization

Management of anesthesia • Pt with sickle cell trait – Not at increased risk during perioperative period • Pt with sickle cell anemia – Increased risk • Orthopedic conditions are frequent in these patients. • Ex. Necrosis of head of femur, Leg ulcers, Gall stones, Priapism

FACTORS CAUSING SICKLING1) Low PO2! In sickle cell anemia PaO2< 40 mm Hg ! In sickle cell trait PaO2< 20 mm Hg 2) pH ! Decreased pH – Acidosis – Favors sickling ! Sickling – greater in veins than in arteries 3) Decreased body temperature

Exposure to cold – Vasoconstriction↓

Stasis of blood Clow↓

Sickling4)Dehydration – increases viscosity – stasis – sickling

Clinical manifestations:1. Those due to infarctive events due to occlusion of

blood vessels with sickle cells. 2. Those due to chronic hemolytic anemia (Hb 6-8 gm/dl).

Infarctive events are responsible for wide spread organ damage. Cardiovascular system: Cor-pulmonale due to repeated pulmonary emboli, and also, secondary to high output failure. Central nervous system: Cerebrovascular accidents are common especially in children. Stroke is significantly reduced by transfusion programme of 2 units every fortnight. Stroke may be induced by hyperventilation, severe anemia, infection, sickle cell crisis. Respiratory system: Total Lung Capacity (TLC) and vital capacity (VC) are frequently decreased. Pulmonary embolism and respiratory infection are common in post operative period. Genitourinary system: Renal abnormalities are established by the age of five to either years. The hypertonic medulla concentrates Hb and with its low oxygen partial pressure promotes sickling. This produce papillary necrosis, hematuria and inability to concentrate urine and renal failure. Priapism is a common occurrence. Hepatic and splenic infracts: May be focal or diffuse. Sever liver dysfunction can result in pseudo-cholinesterase deficiency.Skeletal system: Aseptic necrosis of femoral head and salmonella infection of small bones of the hand.

57



Chronic hemolysis of erythrocytes is reflected by:1. Elevated levels of plasma bilirubin leading to cholelithiasis and

cholecystitis. 2. Periodic transfusion increases risk of viral hepatitis. 3. Hemochromatosis ensues with iron overload following repeated

transfusions. It leads to cirrhosis of liver and left ventricular dysfunction also.

4. White cell function is depressed with increased susceptibility to infection.

Infarctive crisis:! This is triggered off by infection, trauma or associated elevations in temperature. It is characterized by acute onset of pain usually abdominal with fever and vomiting.

Treatment:1. Adequate hydration.2. Partial alkalization of blood3. Partial exchange transfusion with erythrocyte containing

haemoglobin A.4. Antibiotics. In infants – splenomegaly children (6 yrs) – autosplenectomy.

Pre operative assessment and preparation:1. Existing organ dysfunction should be assessed.2. Aggressive pre-operative hydration is essential. 3. Prophylactic antibiotic cover. 4. Systemic preoperative alkalization which on one hand confers

an anti-sickling effect and on the other hand shifts the oxy-Haemoglobin curve to left.

Correction of co-existing infection. Preoperative transfusion – Depend on severity of anemia and magnitude of planned surgery

Goals of preoperative RBC transfusion1. To increase HbA conc. Close to 50% 2. To achieve hematocrit of 35%

Premedication:• Avoid drugs that causes respiratory depression. • Pre-oxygenate well; induction with thiopentone sodium and

succinylcholine followed by tracheal intubation and controlled moderate hyperventilation with nitrous oxide and oxygen. 30% oxygen is adequate and judicious doses of halothane to promote vasodilatation

Intraoperative management• Avoidance of acidosis due to hypoventilation • Maintenance of optimal oxygenation • Prevention of circulatory stasis due to! - Improper body positioning ! - Use of tourniquets • Maintenance of normal body temperature • Pre-oxygenate with high inspired O2 tension • Because to maintain normal to increased PaO2

Regional anesthesia preferred to G.A.• Administration of supplemental O2• Epidural / spinal – Produce compensatory vasoconstriction

and decreased PaO2 in non blocked areas – sites of infraction. There may be decrease in number of circulatory sickle cells during and immediately after G.A.

Prevention of circulatory status requires.- Maintenance of cardiovascular stability by adjustment

of depth of anesthesia. - Anticipation and Rapid correction of hypotension. - Maintenance of I.V. fluid volume by crystalloids

58



Post operative management: Post operative period:• Continue oxygenation up to 8 hrs.• Early mobilization of patient.• Chest physiotherapy.• Adequate antibiotic cover to control chest infection.• Careful watch for infarction crisis; bone pain usually heralds bone

infarcts. Heparin and Magnesium Sulfate should be given immediately.• Maintenance of intravascular volume.

59


Dr Azam’s Notes in Anesthesiology 2013 24. Anemia & Anesthesia.

Definition:Anemia is a condition in which there, is decreased oxygen carrying capacity of the blood, because of reduced concentration of haemoglobin in the presence of a normal or near normal blood volume for the age and sex of the individual. It is not a primary disease but a manifestation of some other underlying disease.

Normal haemoglobin levels: • Men = 13 – 18 g/dl• Women = 11.5 – 16.5 g/dl• Full term infant = 13.5 – 19.5 g/dl• Children = 11-14 g/dl• In India, usually Hb concentration of less

than 10 g/dl is taken is anemia.

Etiology and classification of anemia:Classification:• Pathophysiological • Etiological

! ! ! Pathophysiological Classification!

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! ! ! Morphological classification!

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60


Dr Azam’s Notes in Anesthesiology 2013Anemia & Anesthesia.Continuation:

Compensatory mechanisms in anemia:I. Increased blood flow to the tissues (Decreased Viscosity, increased Cardiac output & redistribution of tissue blood Flow):

Decreased blood viscosity↓

Fall in peripheral vascular resistance↓

Increased blood flow in microcirculation↓

Increased venous return↓

Increased cardiac output

II. O2 transport capacity is 100% at hematocrit of 40% but physiological supply of O2 to tissues is optimum at hematocrit of 30%III. Redistribution of tissue blood flow in metabolically active tissue à +Brought about by 1. Auto-regulation 2. By input from autonomic nervous system 3. Increased cardiac output 4. Increased tissue oxygen extraction

Effect of anemia on myocardial O2 consumption:At a Hematocrit of 20-25%.

↓Tachycardia and increased contractility

↓• Increased cardiovascular work and increased O2 demand by the heart: • Heart: ↑ O2 extraction normal 65-70% in heart,↑ coronary blood flow• In anemia O2 extraction quickly reaches maximum. C.O doubled (2

times),CBF trebled (3 times)• In healthy persons – if Hb decreases by 50%

Clinical features of anemiaMild Moderate SevereAsymptomaticTirednessWeaknessEasy fatigabilityLassitude

Dyspnoea on exertion Palpitations GiddinessTinnitus !Spots before eye anorexia Lack of concentration

Dyspnoea at restAngina pectoris in older patients murmurs Cardiomegaly Congestive cardiac Failure JVPEdema High output state(Collapsing pulse) clouding of conscious koilonychias

1. Haemoglobin à decreased2. RBC count à decreased (N à 4.5 – 5.5 million / mm)3. Total WBC count à increased if infection 4. Differential count 5. Peripheral smear:

I.D.A Megaloblastic AplasticMicrocytic hypochromic Anisocytosis Poikilocytosis

Macrocytic RBCHypersegmentedNeutrophils

Normocytic Normochromic Leucopenia Thrombocytopenia

61



6. Red cell indices:• MCV = PCV/RBC Count

• Normal 75 to 100 femtoliters (fl)• ↑megaloblastic • ↓ in IDA

• MCH = total Hb/RBC count• Normal 24 – 33 pg • ↓IDA

• MCHC = Total Hb/PCV• Normal 30 -‐36 g/dl

Blood Indices

Normal Fe Def. Folate / B12 Def

MCV (fl) 75 - 100 < 75 140/110

MCH (pg) 24 - 33 < 25 33/40

MCHC(%) 30 - 36 < 30 32/38• Biochemical INV ! Megaloblastic IDA

Serum iron !! Serum vitamin B12 assay T.I.B.C.! ! Serum folate assay S. ferritin ! ! Schilling test

VI) Anesthetic management:Preoperative evaluation: 1) To search for cause and correction of anemia 2) To assess the nature and degree of compensation/ 3) To evaluate the amount of reserve available for intraoperative compensation. • History à weakness / dyspnoea / palpitation / chronic blood loss / jaundice /

parasthesia / smoking / pain abdomen.• Examination à Build, nourishment, pallor, icterus, GPE oedema, clubbing,

lymphadenopathy.• Pulse, B.P. UVP, Shift of apex beat.• CVS à Tachycardia, apex beat, auscultate for murmur in L+ 2nd ICs,

cardiomegaly, carotid bruit • R.S. à Breath sounds infections.• P.A à Organomegaly à Liver, spleen • LAB INV à Hb%, TC, D.C, peripheral smear.• B/U, S.Creatinine, S/Bilirubin, ECG, CXR, urine – routine

• Elective surgery: Major surgeries postponed and treated with iron, vitamin B12, folic acid if Hb < 7 g/dl.

• Blood transfusion considered it should be completed 48 hrs prior to surgery.• Packed RBC preferred to whole blood. • Transfusion of RBC à to ↑O2 carrying capacity, not for volume expansion. • Fresh blood preferred to stored blood (2, 3 DPG less) transfusion of 1 unit

whole blood à increases Hb by 1 g/dl/ Hct by 3%. • Packed RBC produce twice increase in Hb compared to whole blood basis for

decision for preoperative transfusion à duration and etiology of anemia intravascular fluid volume urgency of surgery.

• Likely blood loss co-existing diseases à myocardial ischemia, lung disease, cerebrovascular disease.

• Emergency surgery: No time to correct anemia patient scheduled for surgery without delay.

• Premedication à Benzodiazepines – Ex: Diazepam 0.01-0.2 mg/kg. • Narcotic drugs low dose (because Respiratory depression) avoid atropine.

62



Aim: To minimize significant changes which interfere with O2 delivery. To tissues. 1. Inspired O2 tension à adequate à for full saturation 2. Avoid all drugs which induce fall in cardiac output 3. Avoid a shift to left of ODC à Eg. Hyperventilation4. Careful positioning à avoid peripheral pooling5. Quick blood transfusion6. Slow and smooth induction 7. Use of tourniquet à to ↓ operative blood loss 8. Avoid hypothermia, acidosis, hypoxia and dehydration

Monitoring: • Pulse, • B.P. • pulse oximetry • ECG, • ABG, • CVP, • urine output.

Regional anesthesia :• Spinal if patient is normovolaemic & has no tachycardia,

precaution during preloading, epidural anesthesia preferred to spinal, local blocks preferred for limb surgery supplement with O2 and adequate sedation.

• Avoid regional blocks if Hb < 8 gm/dl• Avoid regional anesthesia in megaloblastic anemia with

neurological changes.

General anesthesia:Preoxygenation:• Using high FIO2 (100%).• To optimize PaO2Induction: • If normovolemic à propofol à 1.5 – 2.5 mg/kg , thiopentone 3-5 mg/kg

for intubation à scoline 1-2 mg/kg midazolam à 0.1 – 0.3 mg/kg.• Maintenance à with very low levels of inhalational anesthetic s (because

depression of myocardial). Less soluble in plasma of anemic patient (↓ lipid rich RBC).

Nitrous oxide avoided in megaloblastic and aplastic anemia:• Oxygen à FiO2 – 50% • Controlled ventilation with non depolarizing relaxant.• Vecuronium à cardiostable avoid drug causing tachycardia like

pancuronium• Extubation à after complete reversal and fully awake patient

glycopyrrolate preferred to atropine.

Postoperative management:• Avoidance of hypoxemia à O2 given in first 24 hr with FiO2 30-50%• Avoidance of hypovolemia à correct with blood transfusion,

crystalloids 3:1, colloids 1:1• Avoidance of hypothermia, hyperthermia, convulsion. • Affect O2 supply / demand ratio. Patient kept warm. • To avoid shivering • Avoidance of pain, as pain à tachycardia à increased O2 demand à

adequate postoperative analgesia. • N2O inhibits the activity of methionine synthetase by oxidizing the

cobalt atom of vitamin B12 from an active to inactive state.• Even relatively short exposures to N2O may produce megaloblastic

changes methionine synthetase is needed for cell division.

63


Dr Azam’s Notes in Anesthesiology 2013 24. Autologous Blood transfusion.

• Autologous blood transfusion is one in which both donor as well as recipient are the same.

• There are 4 types of autologous transfusion. The advantages and disadvantages, applications and complications vary with the techniques being used. It is often appropriate to employ more than one technique for patients undergoing surgical procedures associated with significant blood loss.

Types of autologous blood transfusion:I. Preoperative blood donation II. Intraoperative blood salvage III. Postoperative blood salvage IV. Isovolumic haemodilution I. PREOPERATIVE BLOOD DONATION:• In suitable cases, approx. 70% of patients can have their

total surgical blood requirement satisfied using pre-deposited donation.

i) Patient selection:• The criteria for pre-deposited donations are less strict than

those for normal homologous blood donors. The haemoglobin concentration should normally be greater than 11gm/dl and never below 10gm/dl.

ii)Contraindications: ! !"#$%&'()"#&*$)+'$,-&"#$.,''

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Active bacterial infection: • Patients who have active infections septic, if such blood is

drawn, the bacteria may proliferate during storage, leading to fatal reactions.

Patients with cardiac disease:1. Absolute contraindications to pre-deposited are 2. Significant aortic stenosis 3. prolonged and / or frequent unstable angina 4. Significant narrowing of the left main coronary artery. 5. Cyanotic heart disease 6. Uncontrolled hypotension Loss of consciousness:• Patients who have previously been blood donors and have had a

prolonged fainting attack should not be accepted. Impaired placental blood flow:• Pregnant patients should not pre-donate if they are suffering from a

disease, such as hypertension; pre-eclamptic toxemia or diabetes mellitus, which is associated with impaired placental flow and / or intrauterine growth retardation.

Method:• Patients can donate 450ml of blood at weekly intervals; the last

donation being at-least 4 days and preferably 1 week prior to surgery. • They should commence oral iron prior to their first donation and

continue until the day of surgery. Adults weighing less than 50kg and pediatric patients require special consideration.

• The volume withdrawn at any one time should not exceed 12 percent of the Pts estimated blood volume.

• They should have blood drawn into pedipack containing 35ml of anticoagulant and which are suitable for collection of up to 250ml of blood.

• The physiological response in patients taking β-blockers and / or ACE inhibitors is compromised by their treatment, they should therefore be given isovolumic crystalloid replacement to minimize the hazardous sequelae, which may follow a sudden reduction in blood volume, when donating late in pregnancy; patients should be in the lateral position because of the weight of the uterus impedes the venous return when the patients is lying on her back.

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Dr Azam’s Notes in Anesthesiology 2013Autologous Blood transfusion.Continuation:

INTRAOPERATIVE BLOOD SALVAGE:• Pre-deposit donation is limited by the time that the blood can

be stored and by the ability of patients to donate at frequent intervals. Isovolumic hemodilution or acute normovolemic hemodilution (ANH) is limited by the patients total blood volume and by hemodynamic considerations. Postoperative salvage is limited by mechanical problems and possible bacterial contamination intraoperative cell salvage (ICS) in contrast, can be used throughout the surgical procedure and is able to replace blood in proportion to the amount lost.

Methods and equipment:• The basis of ICS is to collect shed blood from the operative

field; into a sterile container where the blood may or may not be further processed; prior to returning it to the patient. To prevent the blood clotting; either the patient has to be anticoagulated prior to the operation, or anticoagulant has to be added to the blood at the sucker tip. Anticoagulation cannot be delayed until the blood has arrived in the container because, unlike the situation in normal blood donation, the coagulation factors have been activated in the operative field.

The main steps of this technique are 1. Salvaging the blood from the operative site. 2. Anti-coagulating the whole blood – prior to surgery during

suction. 3. Re-infusing whole blood as such after filtering or re-infusing

the red cells after washing.

There are three basic methods for ICs:I. Semi continuous flow centrifugation II. Canister collection III. Single use disposable reservoirs

1) Disposable reservoirs: Shed blood is aspirated using a vacuum pressure of less than 150mm Hg into a single- use self contained disposable reservoir. Unless the patient has been anticoagulated prior to surgery, the blood should be anticoagulated using citrate. When the reservoir is full, the blood can either be immediately re-infused by gravity using a standard given set and microaggregate filter, or stored until room temperature, until required. Advantage – being cheap and requiring no specialized equipment or specially trained personnel. Disadvantage – slow, only suitable for small volumes and the product is unwashed and has a low hematocrit. 2) Canister collection: The blood is aspirated, via a double lumen sucker that allows anticoagulant to be mixed at the sucker tip, through a 170µm filter into a rigid reservoir containing a disposable liner. When the canister is full, the liner is removed and the blood re-infused through a standard transfusion set and microaggregate filter. Prior to reinfusion the blood can be washed using a standard cell washer which is usually situated in the blood bank.3) Semi continuous flow centrifugation: Blood is aspirated, using a double lumen sucker, into a reservoir. The blood is washed, with saline prior to being re-infused. There are two varieties of equipment available, the so called slow flow machines which produce one unit every 7-10 mins and the fast flow system which produce a unit in less than 3 mins.To avoid hemolysis the following precautions should be taken 1. Blood should be aspirated by placing the tip below the surface of the

blood. The surgeon must avoid skimming, as aspiration of air with the blood will lead to turbulence and hemolysis.

2. The sucker should have a plastic tip with multiple holes. This is especially important during orthopedic surgery as aspirated debris may occlude some of the holes, thereby increasing turbulence.

65



Anticoagulant:• Citrate in a ratio of 1:5 to 1:1, or heparin at a concentration of 30,000

units per lt of saline, with 15ml of heparin / saline being added to each 100 ml of blood (ratio heparin to blood, 1:7).

Wash solution:• The volume of saline wash solution should be three to four times that of

the volume of the blood, although for orthopedic cases this may be increased to six to seven times with a minimum volume of 150ml.

Re-infusion:• The blood must be re-infused using a standard blood filter with or

without a microaggregate filter. INDICATIONS FOR INTRAOPERATIVE CELL SALVAGE:1) Cardiovascular:• The canister collection method should be used when the anticipated

blood loss is less than 1500ml when greater loss is expected, a semi continuous flow centrifugal method is preferred.

2) Vascular surgery:• Both in the reconstruction of an aortic aneurysm and in the treatment of

aortic rupture there is requirement for rapid salvage and returns of blood. In these cases, fast flow instruments are usually best.

3) Orthopedic: Hip and spinal surgery • In hip and spinal surgery, the use of ICS, especially when combined

with pre-deposit elevation can usually avoid the need for homologous blood.

4) Liver transplantation 5) Neurosurgery – AVM: ICS is used during the refashioning of

arteriovenous malformations.

66



6) Trauma 7) Ectopic pregnancy:• Thorough washing of the blood is required to prevent the

reinfusion of amniotic fluid leading to emboli and DIC. 8) Plastic surgery 9) Jehovahʼs witnesses 10) Serological antibodies:• Patients with rare and / or multiple serological antibodies

and / or other cross-match problems can be candidates for ICS.

Contraindications:1. Retrieval of blood from infective sites and from abdomen

with fecal soiling is to be avoided. This should be done only as a last resort as it carries a high risk of bacteremia and septicemia. This can be minimized to a certain extent by prophylactic antibiotics.

2. Blood containing significant amounts of amniotic fluid should not be auto transfused.

3. Blood containing wound irrigants such as Betadine; methylmethacrylate, antibiotics not meant for parenteral use and topical haemostatic agents should not be salvaged.

Product:• The product is immediately available at body temperature.

Blood collected by ICS has a high 2, 3 DPG content so that the haemoglobin can easily offload oxygen. The ODC is normal or even slightly right shifted, in contrast to that of homologous banked blood which is markedly left shifted and normal oxygen release is not achieved for 6-12 hours post transfusion. ICS red cells have increased osmotic resistance with an excellent 24-hour post transfusion survival, and a normal cell life (T ½ - 24 days). This may be because only the younger and fitter cells survive the collection and washing procedure.

Washed saline suspended red cells:• Typically 10% of the red cells are hemolyzed and lost in the washing

procedure. The level of free Hb in the salvaged blood will be between 200 and 500mg/dl although washing removes 50-70% of this. The MCV, MCH, MCHC are normal and the majority of the cells are morphologically normal. The hematocrit to re-infused product is between 45 and 65%. Platelet numbers are reduced and their function is grossly impaired, probably due to the release of β-thromboglobulin. Washing removes all the plasma proteins, including most of the clotting factors as well as most of the anticoagulant. Although complement activation occurs during cell salvage the washed product is complement free.

Unprocessed salvaged blood:• As this blood is not concentrated, the Hb level is between 7 and 9g/dl

and is sometimes as low as 4g/dl. The plasma Hb is normally in the range of 60-250 mg/dl but may be upto 2000 mg/dl. There is marked increase in fibrin degradation products and D-dimers. Anticoagulant is added to the shed blood as it is aspirated from the operative field and this is not removed during processing. Concentrations of heparin of 3 iu/ml and higher have been found in the re-infused blood.

COMPLICATIONS:1) Air embolism 2) Reinfusion of hemolyzed red cells:• If the vacuum pressure on the sucker is too high or excess turbulence

has been caused by improper aspiration technique, hemolyzed red cells can be re-infused into the patient.

3) Coagulation disorders 4) Thrombocytopenia 5) Hypocalcaemia 7) Toxic antibiotic effects 8) Microfibrillar collagen haemostatic material These products promote platelet adherence and aggregation leading to local hemostasis.

67



POST OPERATIVE BLOOD SALVAGE:• This method is mainly used after cardiothoracic surgery and

sometimes after joint replacements. The suction drain is connected either to a disposable collection device or to a cardiotomy reservoir. Anticoagulation is seldom required as the blood is defibrinated within the mediastinum, but if the bleeding is brisk, citrate should be added to the container. The vacuum pressure should be between 0 and 40 mm Hg. Because of the dangers of bacterial contamination the time between the start of collection and reinfusion should be less than 6 hours. The product contains no clotting factors, including fibrinogen, has a hematocrit of 15-20% and contains considerable free haemoglobin and products of clot lysis when volumes greater than 800ml of unwashed blood are re-infused. It has been shown that platelet function is deranged and the patient develops a mild coagulopathy. Others complications include prolongation of thrombin time; upper airway oedema requiring intubation; non-cardiogenic pulmonary oedema due to platelet and complement activation leading to the capillary leak phenomenon.

POST TRAUMATIC SALVAGE:• Following chest or abdominal trauma, blood collected in

aerosal cavities is devoid of fibrinogen and hence does not clot. This can be salvaged and auto transfused and maybe a life saving procedure in many situation.

ACUTE NORMOVOLAEMIC HEMODILUTION:• Haemodilution is defined as a dilution of all blood constituents resulting

from a limited exchange of the patientʼs whole blood for cell free plasma like fluid.

• The phrase “isovolemic hemodilution” indicates dilution of the blood while keeping the circulating blood volume constant. Hematocrit is the parameter used to define the degree of haemodilution.

• Limited or moderate preop haemodilution means an intentional reduction of the Hct from its normal value of 0.30-0.25 immediately prior to surgery and is used to minimize the loss of autologous red cells and plasma components during surgery.

Contraindications to acute normovolaemic hemodilution:1. Hematocrit less than 24%.2. Patients with limited ability to increase cardiac output such as valvular

heart disease and intra or extra cardiac shunting. 3. Patients with respiratory insufficiency needing mechanical ventilation. 4. Patients with haemostatic defects. Compensatory mechanisms during hemodilution:a) Blood Rheology:• According to the Poiseuilleʼs-Hagen law, the resistance to laminar flow

of a fluid is inversely proportional to the fourth power of the radius but directly proportional to the viscosity of the fluid and length of the tube.

• According to the Poiseuilleʼs-Hagen law, the resistance to laminar flow of a fluid is inversely proportional to the fourth power of the radius but directly proportional to the viscosity of the fluid and length of the tube. Q = (P1 - P2) X π r4 / 8 nl

• Q = flow; (P1 – P2) = pressure drop across the tube; l = length of the tube; r = radius of the tube ; η = viscosity of the fluid. However this law deals only with laminar flow in a straight rigid tube.

68



• Initial losses of energy may be considerable when flow is constantly changing and these losses do increase with extensive hemodilution which leads to an increased bulk flow and an augmented kinetic energy of the blood. Turbulence is more likely to occur if the linear flow rate is increased and viscosity of blood is lowered; both of which are changes initiated by hemodilution.

• In hemodilution, there is a decreased red cell aggregation and dilution of proteins like fibrinogen, hence the viscosity is reduced.

• In summary, haemodilution decreases the oxygen carrying capacity of blood and decreases the resistance to flow. An optimal hematocrit for tissue oxygen delivery has been found to be around 30%. !

b) Utilization of oxygen:• Aerobic metabolism is maintained in a tissue despite a

decrease in the circulating red cell mass as a result of two compensatory mechanisms.

1. Increased blood flow to the tissue 2. Increased oxygen extraction c) Autonomic effects:• During hemodilution, there is peripheral to central

redistribution of blood mediated by alpha adrenergic mechanism. This is basically a capacitance vessel response. Contradictory results have been obtained regarding cardiac autonomic function in haemodilution. Hence this technique should be performed in caution in patients treated with autonomic blocking agents and in patients under spinal or epidural anesthesia.

Effect on organ systems:i) Cardiac: The heart must increase its output as this is the main adaptive mechanism of hemodilution compensation is achieved mainly by an increase in coronary flow rates. Coronary vasodilatation is also important to meet the increased demand.ii) Cerebral: Cerebral blood flow increases during hemodilution and normal oxygen delivery is maintained without cerebral vasodilatation. Hyperventilation results are hypocapnia which decreases cerebral blood flow and thus should be avoided during hemodilution. iii) Hepatic and gastrointestinal: Hepatic blood flow increases during acute isovolumic haemodilution in proportion to the cardiac output. As the liver receives some of its blood supply, as desaturated blood, it compensates for this by an increased oxygen extraction. If intestinal blood flow decreases and oxygen extraction increases, hepatic oxygen supply via the portal vein decreases. Centrilobular hepatic necrosis has been reported at hematocrit value below 20%. iv) Renal: Hemodilution causes renal vasoconstriction resulting in redistribution of blood flow to the inner cortex and a reduction in the fraction of cardiac output to the kidney. The large renal arteriovenous oxygen content reserve prevents impairment of tissue oxygenation. v) Pulmonary: Hemodilution does not alter pulmonary function or ventilation / perfusion distribution. The alveolar to arterial oxygen tension difference decreases during hemodilution indicating better arterial oxygenation. vi) Pregnancy: Hemodilution should be used with caution in pregnant

patients. This is primarily due to the fact that a low maternal hematocrit can result in inadequate oxygen content in the blood perfusing the placenta.

Methods of producing isovolaemic haemodilution:The diluent chosen must 1. Maintain the circulatory volume 2. Not adversely affect the Oxygen Dissociation Curve 3. Not affect the rheological properties of blood.

69



Crystalloids:• Only a 3:1 crystalloid to blood replacement ratio is

associated with an increased cardiac output with no change in mean arterial pressure.

Colloids:

Colloid

Composition and mean mol. Wt. (Daltons)

DistributionDistribution Distribution half life (hours)

Adv. reactionsColloid

Composition and mean mol. Wt. (Daltons)

Interstitial (vol%)

Intra vascular (vol%)

Distribution half life (hours)

Adv. reactions

Albumin Albumin (69,000)

20% 80% > 24 hrs Least

Dextran 70 Polysaccharide (70,000)

0 100% 6-12 hrs Few if treated with dextran

1Dextran40 Polysaccharid

e (40,000)0 100% 2-3 hrs Few if

pretreatedHetastarch Amylopectin

(450,000)0 100% > 24 hrs Few

Gelatin (polygeline)

Polypeptide (35,000)

50% 50% 2-4 hrs Few

The amount of blood loss during isovolaemic hemodilution can be calculated from the following equation-

Blood loss =

• The estimated blood volume is generally taken as 70ml/kg in females of normal body habitus. The decrease in hematocrit is calculated as the difference between the initial hematocrit and the final hematocrit after isovolumic haemodilution. The haemoglobin concentration can be substituted for the hematocrit values in the above equation.

• The above formula is applicable when blood is lost during surgery and is substituted with an erythrocyte free fluid after the bleeding has stopped. However, in haemodilution, the blood loss is being simultaneously replaced by a cell free infusion. Hence during the constant exchange, the washout of the red cell decreases with time, this is described by the equation.

Blood loss = estimated blood volume x In (H0/H1)Where H0 is the initial hematocrit, H1 is the final hematocrit and ʻInʼ is the natural logarithm. Since this is not very practical, a reasonable accurate equation is:

Blood loss =

The average hematocrit during haemodilution is calculated as the

average of critical hematocrit and final hematocrit is . • Blood can be drawn either under anesthesia or prior to induction of

anesthesia. Blood withdrawal rate must parallel the administration of appropriate diluent volumes to assure normovolaemic and circulatory stability. Hematocrit measurement midway throughout surgery prevents over dilution. It is also measured at the end of haemodilution.

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Advantages of autologous transfusion:• Eliminates the risk of transfusion reaction. • Eliminates the risk of disease transmission. • Eliminates the risk of alloimmunization to red cells, white

cells, platelets or plasma proteins. • Eliminates the risk of transfusion transmitted graft VS host

disease. • Allows safe transfusions in patients with multiple

alloantibodies or with rare blood groups. • Pre-deposit donation “stimulates” erythropoeisis prior to

surgery. • Hemodilution improves tissue oxygen perfusion by lowering

the blood viscosity. • Provides blood cover for some Jehovahʼs witnesses. • Provides readily available blood in cases of major

hemorrhages. • Reduces the demand on homologous blood supply in remote

areas or developing countries. • Gives patients the psychological benefit of activity

participating in their treatment.

Disadvantage of autologous transfusion:• Complex logistics for collection; storage and transfusion of the correct

unit to the appropriate patient. • Only suitable for certain operative procedures. • Tendency to over transfuse. • If the surgical procedure is delayed; the blood may become outdated. • Bacterial contamination • Patient is made grossly anemic by either too frequent pre-deposit

donation or over hemodilution.• Coagulation defects • Incorrect techniques can cause red cell hemolysis. • Equipment for intraoperative blood salvage is expensive and requires

trained staff. • Tends to give a misguided impression that normal homologous

donations are unsafe.

Precautions:• Agents such as atropine and pancuronium which cause tachycardia are

best avoided. Monitoring should include ECG: urine output; temperature, central venous pressure and preferably invasive arterial pressure. Ventilation should be adjusted to prevent acidosis or a left ward shift of the ODC caused by alkalosis resulting from hyperventilation.

• Blood is drawn into standard bags containing acid citrate dextrose (ACD) solution and stored at room temperature. Reinfusion of the patientʼs blood should ideally be undertaken when operative bleeding has ceased. Units of blood which were drawn last should be transfused first. A filter should not be used in the administration set.

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Dr Azam’s Notes in Anesthesiology 2013 25. Massive Blood Transfusion.

Definition:• Massive blood transfusion may be defined either as the

acute administration of more than 1.5 times the patients total blood volume by homologous blood in less than 24 hours.

• Also defined as transfusion of one pint of blood with in 5 minutes; or transfusion of 5 units within 1 hr or transfusion of 10 units within 6hrs, or transfusion of >10% of blood volume within 10 minutes.

Precautions:• At least 2 large gauge venous cannula (12 gauge) should be

secured; solely for the purpose of blood transfusion. • If peripheral venous access is difficult, cannula may be

inserted into a large, central vein such as the subclavian, internal jugular or femoral vein. A venous cut down may also be alternatively performed in the saphenous vein at the ankle.

• In addition an arterial catheter and triple lumen central venous catheter may be useful in allowing rapid blood sampling and direct measurement of arterial and central venous pressures respectively. The triple lumen catheter also provides access for intermittent bolus administration of drugs or drug infusions.

• Alternatively (or in addition) a sheath introducer (8 French gauge) may be inserted into the central vein; providing a large cannula for transfusion and means whereby a pulmonary artery catheter can be inserted, when indicated.

• Unless contraindicated by pelvic or urethral injury; a urethral catheter should be passed and urine output measured (intermittently) hourly.

• Central and peripheral temperature should be recorded. • Pulse oximeter – for heart rate and oxygen saturation.

• Needles and sharp objects should be handled and disposed of carefully to avoid needle stick injury.

• Wearing of gloves is recommended, to prevent contamination of hands with spilled blood.

• Use of 3-way taps with or without extension tubing reduces the need to use needles for drug administration or blood sampling.

Pressure bags, blood warming and rapid infusion devices:• Major haemorrhage may require the transfusion of blood at fast flow

rates (upto 500ml/min) and at temperatures greater than 35 °C.• This can be achieved by using a constant pressure infusion device

combined with an efficient blood warmer and a purpose designed double length blood warming coil.

• Efficient counter current aluminum heat exchanges have been investigated under conditions of high flow and have been found to be effective.

• Priming or flushing blood through the system with fluids containing calcium (such as compound sodium lactate and haemacel) should be avoided, as this may result in blood clot formation in the tubing. This is due to the reversal of the anticoagulant effect of citrate by calcium ions.

• The hematinics rapid infuser device has a 3 litre reservoir into which cell saved or banked blood and FFP can be stored, warmed and infused at rates of upto 2l/min.

• If such equipment for rapid transfusion is not available the speed of transfusion can be increased by simple maneuvers for e.g. increasing height of fluid above the patient or using intermittent manual compression of the lower chamber of the giving set when full of fluid. Alternatively using a large syringe and a 3-way tap in line; fluid can be drawn rapidly into the syringe from the giving set before being administered to the patient through the 3-way tap.

• A manually operated Martinʼs rotatory pump may be used (not available now)

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Dr Azam’s Notes in Anesthesiology 2013Massive Blood Transfusion.Continuation:

Complications:1) Coagulation changes:• In situations other than those of liver transplantation and in

patients with a pre-existing coagulopathy; it is unusual for a significant reduction of plasma coagulation factors to occur solely as a result of massive transfusion of stored whole blood.

• Stored whole blood contains adequate amounts of coagulation factors I, II, VII, IX, X, XI and XII. Concentrations of factors V and VII are reduced in stored blood.

Causes of coagulopathy after massive blood transfusion;1. Preexisting defects caused by the underlying disease or

drugs used. 2. Dilution by replacement therapy. 3. Artificial plasma expanders e.g. dextran and hydroxyethyl

starch. 4. Stress 5. Tissue injury 6. Shock 7. Bacteremia • In patients with severe liver disease; the pre-existing

coagulopathy consists of a decrease in platelet count and all coagulation factors except factors I and V (because of a decrease in synthetic ability of liver). This leads to increased prothrombin time (PT) and APTT.

Treatment:• Administration of platelets and FFP• Dose: 1 Unit of FFP for every 10 kg• 2 unit FFP for each 10unit of blood transfused • 6 unit Platelet concentration for every 20u of blood

transfused • Basic screening tests for bleeding after operation-- Platelet

count; prothrombin time; APTT; plasma fibrinogen concentration and fibrinogen degradation products when indicated.

2) Citrate toxicity:↓ in ionized calcium • Each unit of blood contains approx. 3gms of citrate as an anticoagulant.

In normal circumstances the liver metabolizes this rapidly. Liver metabolism must be impaired before citrate metabolism becomes overwhelmed.

• Citrate binds to ionized calcium fraction in blood and causes a decrease in myocardial function, hypotension, small pulse pressure and increased diastolic and central venous pressures.

• Transient changes in ionized calcium concentrations causes little hemodynamic disturbance and the routine use of calcium with blood transfusion is not recommended unless hepatic function is compromised. This may be caused by a low cardiac output; hypothermia; liver d/s; or liver transplantation and in these situations, chances of developing a decreased calcium concentration and citrate toxicity is increased.

• Calcium also plays a role in both extrinsic and intrinsic coagulation pathways. A bleeding diathesis associated with hypocalcaemia is uncommon as cardiac arrest is said to occur before the plasma concentration decreases to a value that affects coagulation.

Treatment:• The adverse effects of hypocalcaemia can be treated by administration

of calcium chloride if the patients become hypotensive and is not hypovolemia; or on the basis of a measured decrease in plasma concentration of ionized calcium.

• Calcium gluconate is less effective than calcium chloride because it must be metabolized to be effective.

73



3) Potassium:• K+ in stored blood increases to almost 30mmol/l after 3

weeks of storage. After transfusion, viable RBC establishes their ionic pumping mechanism and intracellular reuptake of K+ occurs.

• Transient hyperkalemia has been observed during massive blood transfusion and correlates strongly with the rate of transfusion. Therefore ECG monitoring is advisable during massive blood transfusions.

4) Acid-base disturbances:• 3 week old stored blood (citrated) contains an acid load of

upto 30-40 mmol/l and this originates mainly from the citric acid of the anticoagulant and lactic acid generated by red cells during storage.

• Citrate is metabolized to bicarbonate and may produce a profound metabolic alkalosis after transfusion because of this it is not necessary to correct minor degrees of metabolic acidosis.

• Shocked patients more likely to develop metabolic acidosis. 5) Hypothermia:• The problems attributable to hypothermia include reduction

in citrate and lactate metabolism (thereby increasing the probability that patient will develop hypocalcaemia and metabolic acidosis during transfusion); an increase in the affinity of Hb for O2; impairment of red cell deformity; platelet dysfunction and bleeding and an increased tendency to cardiac arrhythmias.

• Therefore core temperature measurement is important during massive blood transfusion and can be measured with a temperature probe at the midpoint of the oesophagus.

• Body temperature may decrease because of administration of large volumes of cold fluids and blood (which is stored at 40C) or because of loss of radiant heat and latent heat of evaporation of body fluids from the open abdominal or thoracic cavity or skin (especially in burn patients).

Treatment:I. Placing patient on a heated “ripple” mattress II. Warming IV fluids III. Covering patient with thermally insulating drapes. IV. In small children, an overhead infra-red heater minimizes heat loss

from radiation. V. The ambient temperature of the theatre may be increased.

6) Pulmonary dysfunction: TRALI• Pulmonary dysfunction after transfusion is caused or exacerbated by

the formation and subsequent administration micro-aggregates formed in stored blood.

• They are composed largely of degenerating platelets; granulocytes; denatured proteins; fibrin strands and other debris and their rate of formation and size (10-200μm in diameter) vary according to the different types of storage solutions.

• Blood filters have been designed to remove micro-aggregates and are of 2 types.

• Depth filters: which remove particles by impaction and adsorption • Screen filters: which operate on a direct interception principle and have

an absolute poor size rating of 40µm (the standard blood administration set has a pore size of 170µm).

BLOOD TRANSFUSION REACTIONS• Major life threatening complications following blood transfusion are rare

and human error remains an important etiological factors in many. • Complications that can accompany administration of blood / blood

components include I. Transfusion reactions II. Metabolic abnormalities – H+, K+, citrate III. Transmission of diseases – hepatitis, HIV, viral, bacterial protozoal IV. Microaggregate infusion – post transfusion pulmonary dysfunction.

74



I. Transfusion reactions:Immediate reactions:

1. Febrile reactions (due to ab. to donor, leukocyte Ag) 2. Hemolytic (red cell incompatibility 3. Anaphylaxis (Ab to IgA of donor) 4. Urticaria (allergic – due to Ab to plasma proteins) 5. Non-cardiogenic pulmonary oedema (donor antibodies

to pt. leucocytes) 6. Fever with shock (bacterial)7. CCF (fluid overload)

Delayed reactions:1. Hemolysis 2. GVHD3. Purpura 4. Alloimmunization

1) Allergic reactions:• Can occur in 3% of correctly typed and cross matched blood

transfusion. Incompatible plasma proteins (Haptogens) are the probable cause. Manifestations include pruritis, erythema and urticaria often accompanied by increase in body temperature and eosinophilia. Rarely laryngospasm and bronchospasm are also present. Under anesthesia the first manifestation of allergic reactions due to blood transfusion may be the appearance of erythema along the pathway of the vein receiving the blood plus urticaria particularly on the chest, neck, face.

• Serious anaphylactic reactions are most likely to occur in patients who lack IgA. These patients have an anti IgA and can develop severe allergic reactions when they are administered serum containing IgA such patients should receive transfusion only from IgA deficient donors.

2) Febrile reactions:• Are the most common non hemolytic reaction. This is due to interaction

between Abs and Agʼs present in leucocytes and or platelets of the donor. Fever results from the release of pyrogenic substances from injured cells.

• Body temperature may increase within 4 hrs after starting the transfusion. Headache, nausea, vomiting and chest or back pain may accompany the elevation of body temperature. Treatment of mild febrile reactions is by slowing the rate of infusion of blood and by administration of paracetamol. Pethidine 25mg iv to adults, is useful for the treatment of shivering which may accompany the reactions – severe febrile reactions may require discontinuation of the blood infusion.

3) Hemolytic reactions:Hemolytic reactions are almost mainly due to ABO incompatibility. Although rare, they are a major cause of transfusion associated mortality. • The quantity of antibody in acute hemolytic reactions appear to

determine the resultant morbidity and mortality. • Group O recipients have both anti A and B in their plasma. If group O

recipient, receive type A, B or AB blood, the biological consequences of this incompatibility to the patient are greater than after a small volume of donor plasma containing antibodies directed against the recipient cells is transfused (i.e. group O to a recipient of group A, B or AB).

• The Ag-Ab interaction activates the complement cascade and this results in lysis of donor cells – intravascular hemolysis.

• Complement activation results in release of complement fragments (C3, C5) and histamine which are potent vasodilating compounds and enhance capillary permeability. This leads to hypotension.

• DIC is initiated by material released from hemolyzed erythrocytes, leading to thrombocytopenia and increased circulatory concentrations of fibrin degradation products.

• Elevation of unconjugated fractions of bilirubin in plasma are maximal 3-6 hrs after the onset of hemolytic reactions.

• Renal damage resulting in acute renal failure is a consequence of multiple factors including:

75



1. Glomerular deposition of fibrin. 2. Reduced renal blood flow, due to histamine induced

vasomotor changes. 3. Precipitation of stromal and lipid contents and erythrocytes

in distal renal tubules.4. Free Hb does not directly damage the kidneys but can

contribute to renal failure if it is precipitated in the renal tubules and blocks the tubules.

5. Acute tubular necrosis – results from Ag-Ab reactions à release of tonic substances from RBC à vasoconstriction.

In the anaesthetized patient, the immediate signs and symptoms of hemolytic reactions are masked. Hypotension and abnormal bleeding may be the only finding.

Schematic representation of what happens to hemolyzed erythrocytes as a result of the administration of incompatible blood:

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%&''!()'*+,-+./0!

1)'*+,-+./02()34+,-+./0!5+*3-'6!!

!!!!!!!!!!!!!!!7899*,:;!

</=0'>!!

!"'4/5?-+2'0=+4('-/)-!

@>@4'*!!

• As little as 50ml of incompatible blood may exceed the binding capacity of haemoglobin, which is a protein that can bind about 100mg of hemoglobin per 100ml of plasma. When hemoglobin not exceeding this amount is injected or liberated into the blood stream, the Hb circulates as a complex with the haptoglobin, which is cleared by the reticuloendothelial system. A sample of plasma that contains 2mg/dl of haemoglobin is faintly pink or light brown. When the level of Hb reaches 100mg/dl, then the plasma is red. When the plasma hemoglobin reaches 150mg/dl, hemoglobinuria occurs. In general, the quantity of free haemoglobin in the plasma is correlated with the volume of incompatible blood transfused.

Lab tests that should be performed if hemolytic transfusion reactions are suspected include • Serum haptoglobin • Plasma and urine haemoglobin • Bilirubin

• Direct antiglobulin-confirms the presence of hemolytic transfusion reaction because it shows that there is antibody attached to transfused donor red blood cells.

h) Signs and symptoms of hemolytic transfusion reaction:• Fever and chills • Chest pain• Hypotension• Nausea • Flushing • Dyspnoea • Hemoglobinuria

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The treatment of a hemolytic transfusion reaction:• Stop transfusion • Maintain the urine output at a minimum of 75-100ml/hr by the

following methods:1. Generously administer fluids intravenously and possibly

mannitol 12.5 to 50gm given over a 5 to 15 min period. 2. If intravenously administered fluids and mannitol are

ineffective then administer furosemide 20-40 mg/hr. 3. Alkalinize the urine, because bicarbonate is

preferentially excreted in the urine; only 40-70mEq/70kg of body wt. Sodium bicarbonate is usually required to raise the urine pH to 8. Where upon repeat urine pH determinations indicate the need for additional bicarbonate.

4. Assay urine and plasma Hb concentrations. 5. Determine platelet count; partial thromboplastin time

and serum fibrinogen level.6. Return unused blood to blood bank for re-cross match.7. Send patient blood and urine sample to blood bank for

examination. 8. Prevent hypotension to ensure adequate renal blood

flow. 9. Maintain IV line, O2 therapy; resuscitative measures. 10.Antihistamine – diphenhydramine 0.5-1mg/kg IV. 11.Steroid – hydrocortisone – 2-4mg/kg IV.12.Antibiotics.

II. Metabolic abnormalities:Metabolic abnormalities produced by administration of blood are related to changes that occur during storage. • Hydrogen ions: 30mmol/L after 3 weeks • Hydrogen ion content of stored blood is initially increased by the

addition of ACD (pH. 5) or CPD (pH 5.5) causing the pH of freshly drawn blood to decrease to 7-7.1. Continued metabolic function of erythrocytes results in additional production of hydrogen ions.

• Furthermore CO2 partial pressure increases between 150mmHg and 200mmHg since this gas cannot diffuse through glass or plastic containers.

• Despite these changes, metabolic acidosis is not a common, occurrence, even with the rapid infusion of large volumes of stored blood.

• Metabolic alkalosis, rather than metabolic acidosis, is a frequent accompaniment of massive blood transfusion. This alkalosis is preserved to be partly due to metabolism of infused citrate to bicarbonate, which could further be exaggerated by administration of lactated ringerʼs solution.

Potassium:• Potassium content of ACD blood reaches about 14mEq/l by 7 days of

storage and increases further to 21mEq/l to 24 mEq/l after 21 days. Potassium levels of blood stored in CPD are about 20% lower. Still, nevertheless, massive transfusions of stored blood rarely increase plasma concentration of potassium.

• The metabolic alkalosis produced by massive transfusions of whole blood favor transfer of K+ from extracellular fluid into intracellular spaces, offsetting any tendency toward hyperkalemia. However, in patients with impaired or absent renal function, transfusion of blood could produce hyperkalemia.

77



Decreased 2, 3 diphosphoglycerate:• Normal storage of blood results in progressive reductions in

concentrations of 2, 3 DPG in erythrocytes resulting in increased affinity of Hb for oxygen. This results in the shift of ODC to the left which could jeopardize tissue O2 delivery, particularly in the presence of anemia. The high pH of CPD anticoagulant, as compared to ACD anticoagulant, prevents rapid depletion of 2,3 DPG concentration in erythrocytes. The P50 of CPD preserved blood is maintained at near normal levels for 1st 2 weeks of storage.

Citrate intoxication:Hypocalcaemia:• Citrate intoxication is not caused by the citrate ion per se, but

because citrate binds calcium. • Manifestations of hypocalcaemia due to citrate intoxication

include hypotension and prolonged Q-T intervals in ECG; reflecting mobilization of Ca2+ stores in bone and the ability of liver to metabolize citrate to bicarbonate rapidly.

• The rate of whole blood transfusion in adults has exceeded 150ml/70kg/minute or 1 unit of whole blood in 5 mins before reduction in plasma ionized calcium can be documented. Therefore arbitrary administration of calcium is not indicated.

• Although hypocalcaemia due to citrate intoxication is unlikely in adults the same is not true of neonates receiving blood transfusion and supplemental calcium may be necessary.

• In the presence of hypothermia or marked liver dysfunction the ability to metabolize citrate to bicarbonate may be reduced.

• The usual dose of calcium chloride is 3-6mg/kg administered over 5-15 mins with continuous ECG monitoring.

III. Transmission of diseases:a) Hepatitis:• Remains the infection most frequently transmitted by blood and its

products. Icteric hepatitis develops 50-180 days after a blood transfusion and has a variable clinical course, ranging from being asymptomatic to being fatal.

Diagnosis by:• Observation between 14 to 180 days transfusion of 2 consecutive

elevations (minimum of 14 days apart) of recipients ALT.• Diagnosis of hepatitis B includes appearance of hepatitis B surface

antigen; the hepatitis B surface or core antibody. • The absence of serological markers indicative of acute hepatitis A or B

in the presence of liver enzymes abnormalities are taken as presumptive evidence of “non-A-non B” viral hepatitis, now called hepatitis ʻCʼ, the most common causative agent of post transfusion hepatitis. - Precautions taken to avoid hepatitis transmission are exclusion of

blood with elevated serum alanine aminotransferase (ALT) or presence of Abs to hepatitis B is antigen. !

b) Acquired immunodeficiency syndrome (AIDS):• Risk of AIDS from blood transfusion is very low, owing to the treating of

donor units for the Ab to the human immunodeficiency virus. However the infections period does occur during the 12 weeks necessary for HIV seroconversion. Some infected individuals have a much greater latency period (35 months).

78



The other infections that can be transmitted through blood transfusion are;Viral:Cytomegalovirus ! ! - Epstein barr virus Herpes simplex ! ! - Measles

Bacterial:Brucella ! ! ! - Pseudomonas Salmonella ! ! ! - Shigella

Parasitic:Microfilaria ! ! ! - Plasmodium Trypanosoma

Infectious disease testing for blood transfusions:1. Hepatitis (antibody) 2. Ab to hepatitis B core Ag3. HIV-14. HIV-25. HIV Ag (P&H Ag) 6. HTLV I/II7. Serological tests for syphilis IV. Micro-aggregate infusion • Microaggregates consisting of platelets and

leucocytes form during storage of whole blood. Accumulation of these microaggregates become significant after 2-5days and can cause post transfusion pulmonary dysfunction.

• Micropore filters have been developed to remove particles with diameter in the 10 micron to 40μ range. Micropore fitters are not necessary for whole blood < 3 days old.

CH

EST

/ 137

/ 1

/ JA

NU

AR

Y, 2

010

213

ww

w.c

hest

jour

nal.o

rg

It i

s im

port

ant

to r

ecog

nize

the

diff

eren

ces

in e

le-

men

tal

calc

ium

tha

t ca

lciu

m c

hlor

ide

and

calc

ium

gl

ucon

ate

prov

ide

( Tab

le 3

). 42 A

s ele

men

tal c

alci

um is

re

plac

ed in

trav

enou

sly, i

t is

impo

rtan

t to

cont

inue

to

mon

itor s

eria

l art

eria

l ion

ized

cal

cium

con

cent

ratio

ns.

Prol

onge

d Q

T i

nter

val

duri

ng M

T m

ay a

lso

be

rela

ted

to h

ypom

agne

sem

ia, a

nd th

eref

ore

both

blo

od

calc

ium

and

mag

nesiu

m c

once

ntra

tions

mus

t be

mon

i-to

red

durin

g M

T. L

ow l

evel

s of

mag

nesiu

m d

urin

g M

T ca

n be

due

to

the

infu

sion

of la

rge

volu

mes

of

mag

nesiu

m-p

oor fl

uid

s as w

ell a

s the

bin

ding

of m

ag-

nesiu

m to

citr

ate.

43

Aci

dosi

s and

Alk

alos

is

The

stor

age

of b

lood

in c

itrat

e ph

osph

ate

dext

rose

ad

enin

e so

lutio

n le

ads

to a

pH

of

7.0

of m

ost

fres

h PR

BC

uni

ts. B

lood

pH

dec

reas

es t

o 6.

6 to

6.8

with

st

orag

e fo

r 21

to

35 d

ays,

in

part

rel

ated

to

an

incr

ease

d C

O 2 c

once

ntra

tion.

44 A

s ci

trat

e is

met

abo-

lized

to b

icar

bona

te, i

t is

com

mon

that

pat

ient

s w

ho

requ

ire M

T fr

eque

ntly

dev

elop

a m

etab

olic

alk

alos

is.

The

refo

re t

he p

rese

nce

of a

met

abol

ic a

cido

sis

in

patie

nts

who

req

uire

MT

is

an i

ndic

ator

of

tissu

e hy

pope

rfus

ion

and

is n

ot r

elat

ed t

o bl

ood

prod

uct

adm

inis

trat

ion.

Agg

ress

ive

resu

scita

tive

mea

sure

s sh

ould

be

cont

inue

d in

thes

e pa

tient

s. T

he re

vers

al

of a

cido

sis

with

alk

alin

izin

g ag

ents

(so

dium

bic

ar-

bona

te,

trom

etha

min

e) in

the

se p

atie

nts

shou

ld b

e us

ed a

s a

tem

poriz

ing

mea

sure

in p

atie

nts

with

sev

ere

met

abol

ic a

cido

sis a

nd h

emod

ynam

ic i

nsta

bilit

y or

w

ith re

nal d

ysfu

nctio

n or

rena

l fai

lure

, and

ther

efor

e an

inab

ility

to c

ompe

nsat

e fo

r the

met

abol

ic a

cido

sis.

Res

tora

tion

of a

dequ

ate

tissu

e pe

rfus

ion

is pa

ram

ount

to

reve

rse

any

unde

rlyin

g la

ctic

aci

dosis

. A

cido

sis,

how

ever

, may

exa

cerb

ate

coag

ulop

athy

. C

lotti

ng fa

ctor

s are

enz

ymes

who

se a

ctiv

ity is

impa

ired

by a

cide

mia

; fo

r ex

ampl

e, a

dec

reas

e of

pH

fro

m

7.4

to 7

.0 re

duce

s the

act

ivity

of f

acto

r VII

a by

mor

e th

an 9

0%, f

acto

r VII

a/tis

sue

fact

or c

ompl

ex b

y 55

%,

and

the

fact

or X

a/fa

ctor

Va

(pro

thro

mbi

nase

) co

m-

plex

by

70%

. 45 T

hrom

bin

gene

ratio

n, t

he p

rim

ary

engi

ne o

f he

mos

tasi

s, is

thu

s pr

ofou

ndly

inhi

bite

d by

aci

dosi

s. 46 T

he e

ffec

t of

aci

dosi

s on

coa

gula

tion

has b

een

mea

sure

d by

thro

mbo

elas

togr

aphy

, whi

ch

reve

als

prog

ress

ive

impa

irm

ents

up

to 1

68%

of

cont

rol

leve

ls i

n th

e ra

te o

f cl

ot f

orm

atio

n an

d

poly

mer

izat

ion

with

a d

ecre

ase

in p

H f

rom

7.4

to

6.8

. 47

A n

otab

le im

pair

men

t of

hem

osta

sis

aris

es w

ith

seve

re m

etab

olic

aci

dosi

s. T

hus,

in c

ases

of s

ever

e he

mor

rhag

e, b

uffe

ring

tow

ard

phys

iolo

gic

pH v

alue

s (a

rter

ial p

H !

7.2)

is r

ecom

men

ded,

esp

ecia

lly w

ith

mas

sive

tr

ansf

usio

n of

ol

der

RB

Cs

disp

layi

ng

exha

uste

d R

BC

buf

fer

syst

ems.

5 Pat

ient

s w

ith li

ver

failu

re w

ho re

quire

mas

sive

tran

sfus

ion

may

man

ifest

a

met

abol

ic a

cido

sis th

at is

mor

e se

vere

and

diffi

cul

t to

trea

t as t

hey

do n

ot m

etab

oliz

e la

ctat

e, n

or d

o th

ey

conv

ert t

he c

itrat

e in

blo

od p

rodu

cts

to b

icar

bona

te.

The

impa

ired

liver

may

also

pro

duce

lact

ate,

thus

com

-po

undi

ng th

e pr

oble

m. 48

Blo

od T

rans

fusi

on a

nd P

osti

njur

y M

ulti

ple

Org

an F

ailu

re

Blo

od t

rans

fusio

n w

as fi

rst

ide

ntifi

ed a

s an

ind

e-pe

nden

t risk

fact

or fo

r mul

tiple

org

an fa

ilure

(MO

F)

in a

3-y

ear s

ingl

e-in

stitu

tion

stud

y (n

5 39

4) a

imed

at

findi

ng a

pre

dict

ive

mod

el f

or p

ostin

jury

MO

F. 49

Tr

aum

a pa

tient

s (n

5 39

4) w

ith a

n in

jury

sev

erity

sc

ore

(ISS

) . 15

and

surv

ival

. 24

h w

ere

exam

ined

. Th

e fo

llow

ing

varia

bles

wer

e id

entifi

ed

as e

arly

inde

-pe

nden

t pre

dict

ors o

f MO

F: a

ge .

55 y

ears

, ISS

! 25

, an

d .

6 u

nits

PR

BC

s in

the

fir

st 1

2 h

post

inju

ry.

Add

ition

ally,

a b

ase

defi c

it .

8 m

Eq/

L (

0-12

h)

and

lact

ate

. 2.

5 m

mol

/L (

12-2

4 h)

wer

e in

depe

nden

t pr

edic

tors

of M

OF.

A

subs

eque

nt p

rosp

ectiv

e st

udy

by th

is gr

oup

con-

fi rm

ed t

hat

bloo

d tr

ansf

usio

n w

as a

n in

depe

nden

t ris

k fa

ctor

of

post

inju

ry M

OF

(51

3 tr

aum

a pa

tient

s w

ith I

SS .

15

adm

itted

to

the

ICU

who

sur

vive

d .

48

h),

cont

rolli

ng f

or o

ther

ind

ices

of

shoc

k,

incl

udin

g ba

se d

efi c

it an

d la

ctat

e. 50

A d

ose-

resp

onse

re

latio

nshi

p be

twee

n ea

rly b

lood

tra

nsfu

sion

and

post

inju

ry M

OF

was

iden

tifi e

d an

d bl

ood

tran

sfus

ion

was

con

fi rm

ed a

s an

inde

pend

ent r

isk fa

ctor

for M

OF

in

mul

tiple

logi

stic

regr

essio

n an

alys

is.

Blo

od T

rans

fusi

on a

nd S

yste

mic

In

fl am

mat

ory

Res

pons

e Sy

ndro

me

Blo

od tr

ansf

usio

n in

trau

ma

was

ass

ocia

ted

with

an

incr

ease

d in

cide

nce o

f sys

tem

ic in

fl am

mat

ory r

espo

nse

synd

rom

e (S

IRS)

(de

fi ned

as

SIR

S sc

ore

! 2 51

) in

a

Tabl

e 3 —

Ele

men

tal C

alci

um C

once

ntra

tion

s in

Cal

cium

Chl

orid

e an

d C

alci

um G

luco

nate

Solu

tion

Ele

men

tal C

alci

umU

nit V

olum

eTo

tal E

lem

enta

l Cal

cium

Osm

olar

ity

10%

Cal

cium

chl

orid

e27

mg

(1.3

6 m

Eq)

/mL

10 m

L A

mpu

le27

0 m

g/ 1

0 m

L20

00 m

Osm

/L

10%

Cal

cium

glu

cona

te9

mg

(0.4

6 m

Eq)

/mL

10 m

L A

mpu

le90

mg/

10

mL

680

mO

sm/L

10

% C

alci

um c

hlor

ide

cont

inuo

us in

fusio

n2.

45 m

g/m

L5

Am

ps/5

00 m

L N

S1,

350

mg/

550

mL

200

mO

sm/L

10

% C

alci

um g

luco

nate

con

tinuo

us in

fusio

n0.

82 m

g/m

L5

Am

ps/5

00 m

L N

S45

0 m

g/ 5

50 m

L20

0 m

Osm

/L

Am

ps 5

ampu

les;

NS

5 n

orm

al sa

line.

(Ada

pted

with

per

miss

ion

from

Str

atta

et a

l. 42 )

© 2

010

Amer

ican

Col

lege

of C

hest

Phy

sici

ans

at S

t Jud

e C

hild

rens

Res

earc

h H

ospi

tal o

n Ja

nuar

y 5,

201

0ch

estjo

urna

l.che

stpu

bs.o

rgD

ownl

oade

d fro

m

79


Dr Azam’s Notes in Anesthesiology 2013 25. Coagulation & Anesthesia.

COAGULATION SYSTEM AND PATHWAY• The process of blood coagulation is of paramount

importance to survival. The blood clotting and subsequent dissolution of clot following repair of the injured tissue is termed hemostasis.

• Hemostasis has 4 major events 1. Vasoconstriction – This causes obliteration of vessel

lumen caused by serotonin and vasoconstrictors from platelets.

2. Platelet activation to form platelet plug 3. Fibrin mesh formation due to coagulation pathway

activation. 4. Clot dissolution by plasmin after tissue repair.

Platelet and Platelet activation:• Vascular injury disrupts single layer of endothelial cells lining

blood vessels exposing subendothelial proteins consisting of collagen, von Willebrand factor (vWf) and fibronectin.

• These act as sites for attachment of platelets. Glycoprotein 1b on the surface of platelets makes adhesion of platelets to vWf possible.

• Platelets are activated by collagen and thrombi. Activation of platelets causes release of arachidonic acid by Phospholipase A2. This is converted to thromboxane A2(TXA2) by Cyclooxygenase. Activated platelets also secrete ADP, TXA2 and ADP also activate platelets.

• These causes platelet to change shape to form long pseudopodia. Integrin α11β3 on the surface along with pseudopodia fibrinogen and vWf links adjacent platelets together to form platelet plug.

Inhibition of platelet aggregation• PGE2, PGI2 and Nitric oxide secreted by the vascular

endothelium inhibits platelet aggregation. • Prevention of linking of platelets by internalization of α11 to β3.

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Platelet aggregation inhibition: PGE2, PGI2 and NOCoagulation cascade:Essential features:1. Cascade system where precursor zymogen is converted to active

enzyme 2. Rapid response due to amplification of response. 3. Limited in response in terms of location and duration due to

1. Quiescent vascular endothelial cells 2. Negative feedback loops 3. Decrease in substrate

Concentration by consumption • Inhibition of coagulation enzymes after they are formed. • Coagulation pathway (Fig.2) lead to fibrin clot formation through the

intrinsic pathway or extrinsic pathway. These finally converge into common pathway.

80


Dr Azam’s Notes in Anesthesiology 2013Coagulation & Anesthesia.Continuation:

A

Coagulation 1769 56

Section IV

Anesthesia M

anagement

plasma form phospholipid-bound activation complexes with tissue factor, factor X, and calcium to promote conversion of factor X to Xa.21 Recently, the tissue factor/factor VIIa complex has been demonstrated to activate factor IX of the intrinsic pathway, further demonstrating the key role of tissue factor in initiating hemostasis.22

Intrinsic Pathway of Coagulation

Classically, the intrinsic or contact activation system was described as a parallel pathway for thrombin generation by way of factor XII. However, the rarity of bleeding disorders resulting from contact activation factor de!ciencies led to our current under-standing of the intrinsic pathway as an ampli!cation system to propagate thrombin generation initiated by the extrinsic pathway.22 Recent cell-based models of coagulation suggest that thrombin generation by way of the extrinsic pathway is limited by a natural

inhibitor, tissue factor pathway inhibitor (TFPI).23 However, small quantities of thrombin generated before neutralization of the extrinsic pathway activate factor XI and the intrinsic pathway. "e intrinsic pathway subsequently ampli!es and propagates the hemostatic response to maximize thrombin generation (Fig. 56-2). Although factor XII may be activated by foreign surfaces (i.e., cardiopulmonary bypass circuits or glass vials), the intrinsic pathway appears to play a minor role in initiation of hemostasis. Proteins of the intrinsic pathway may, however, contribute to in#ammatory processes, complement activation, !brinolysis, kinin generation, and angiogenesis.22,24

Common Pathway of Coagulation"e !nal pathway, common to both extrinsic and intrinsic coagu-lation cascades, depicts thrombin generation and subsequent !brin formation. Signal ampli!cation through both extrinsic and intrinsic pathways culminates in formation of prothrombinase complexes (phospholipid membrane bound activation complexes)

Figure 56-1 Depiction of the classic coagulation cascade incorporating extrinsic and intrinsic pathways of coagulation. (From Slaughter TF: The coagulation system and cardiac surgery. In Estafanous FG, Barash PG, Reves JG [eds]: Cardiac Anesthesia: Principles and Clinical Practice, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2001, p 320, with permission.)

Cross-linked fibrin

Intrinsic Pathway

XII

XIII

XIIIa

Fibrinogen Fibrin monomer

XIIaVascular endothelial

injury

Tissue factor/VIIa complex

“Prothrombinase complex”

XI XIa

IX IXaVIIIa

X Xa Va

II IIa

Va/VIIIa

Extrinsic Pathway

Figure 56-2 Clot formation at vascular injury site. Vascular injury exposes subendothelial tissue factor initiating plasma-mediated hemostasis via the extrinsic pathway. The intrinsic pathway further amplifies thrombin and fibrin generation. Platelets adhere to exposed collagen to undergo activation, resulting in recruitment and aggregation of additional platelets. (From Mackman N, Tilley RE, Key NS: Role of extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscleros Thromb Vasc Biol 27:1688, 2007, with permission.)

Thrombin

Binding of plateletsto collagen

TF-dependentinitiation of coagulation

Propagation Stabilization

Platelet-plateletinteraction

Fibrin deposition

Recruitment of plateletsto growing thrombus

Amplification ofcoagulation cascade

Blood

Microparticles

Platelets

TF TF TF TF TF TF TFTFEndothelium

Tissue

Fibrin

Initiation

Coagulation involves different proteins 1. Zymogens 2. Cofactors 3. Fibrinogen 4. Transglutaminase

INTRINSIC PATHWAY:• It is so called because all the necessary protein components are present in plasma. This can

occur without tissue injury (e.g. abnormal vessel wall). • The first part is called the contact phase, carried out by Factor XII, Prekallikrein and High

molecular weight kininogen (HMW Kininogen). Activation of factor XII to XIIa in vivo is by exposed collagen and negatively charged phospholipids and in vitro by negatively charged particles like kaolin, glass, dextran sulphate, etc.

• Factor XIIa a serine protease, activates factor XI to XIa and prekallikrein to kallikrein. Kallikrein in turn activates factor XII to XIIa. This is called reciprocal activation.

• Factor XIa activates factor IX to IXa which requires Ca2+, Factor IXA, Ca2+, X and factor VIIIa from a complex known as tenase complex, which converts factor X to Xa which forms the entry point into common pathway. Here factor VIIIa acts as a receptor for IX and X and is called cofactor.

81



EXTRINSIC PATHWAY:• Initiation of fibrin clot formation in response to tissue injury is

called extrinsic pathway. Tissue factor or factor VII is responsible for extrinsic pathway, so called because tissue factor (TF) is not present in plasma, but supplied by vascular endothelial cells and leukocytes. After release of tissue factor it binds with factor VII which is then activated to TF-VIIa by thrombin, XIIa, IXa. TF – VII a complex converts factor X to Xa.

FINAL COMMON PATHWAY:• Factor Xa formed by extrinsic and intrinsic pathways activate

prothrombin to thrombin. This is prothrombinase complex which consists of platelet surface complex which consists of platelet surface complex which consists of platelet surface phospholipids, Ca2+, Factor Va factor Xa and prothrombin. Thrombin a serine protease converts fibrinogen to fibrin monomer. The fibrin monomers undergo polymerization which leads to fibrin clot. Thrombin also converts factor XIII to XIIIa which cause cross linking of fibrin monomers to form stable fibrin clot.

• In the revised model of coagulation factor VIIa – TF complex is thought to initiate coagulation rather than contact phase. After an initial burst of Xa and thrombin, tissue factor pathway inhibitor dampens VIIa/TF pathway. VIIa – TF also activates factor IX to IXa. So it is now thought that VIIa – TF complex is the principal initiator of coagulation, whereas in the intrinsic pathway is necessary to sustain coagulation response. This is because, no bleeding was observed in contact factor deficiencies (factor XII, Prekallikrein, HMW kininogen) but bleeding was observed in Factor XI deficient patients.

Vitamin K dependent clotting factors:• They are factors, II, VII, IX, X. They are synthesized in the liver and

undergo post translational modification by γ carboxylation. This is carried out by vitamin K dependent γ glutamyl carboxylase. Coumarin anticoagulants block this.

Anti clotting mechanism:Two ways:1. Limiting coagulation cascade 2. Fibrinolytic system Control of coagulation cascade It is by anti coagulant proteins. These include:i) Protein C ii) Protein Siii) Antithrombin IIIiv) Thrombomodulin v) A2 macroglobulin vi) Heparin cofactor IIvii) Tissue factor pathway inhibitor • Antithrombin III (ATIII) is the important inhibitor of thrombin, factor IXa,

Xa, XIa, XIIa. It is greatly augmented by heparin and heparin sulphate present in vascular endothelium. AT III is called heparin cofactor.

• Protein C (Fig. 3) together with thrombomodulin (TM) and protein S act as an important negative feedback loop. TM is a protein present on the surface of quiescent vascular endothelial cells. TM binds with thrombin. This activates protein C. Activated protein C (APC) inactivates VIIIa and Va. Protein S potentiates protein C.

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Regulation of protein C

82



• Heparin Cofactor II- This inhibits thrombin. It is potentiated many fold by heparin.

• Tissue factor pathway inhibitor or lipoprotein associated coagulation inhibitor (LAC1) inhibits VIIA-TF.

Fibrinolytic system:• Degeneration of fibrin clot is a function of plasmin a serine

protease that circulates as a proenzyme plasminogen. Conversion of plasminogen to plasmin by plasminogen activator.

Plasminogen activation occurs through 1. Intrinsic system: Here plasminogen interacts with intrinsic

pathway of blood coagulation to generate plasmin. Accounts for 15% of fibrinolysis.

2. Extrinsic system: Consists of tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA). Endothelial cells release T-PA by the action of thrombin, histamine, bradykinin, shear stress or vasocclusion.

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Activation Function

Factor XII By binding to collagen, also to glass, kaolin, dextran.

XIIa activates factor XI and prekallikrein

Factor XI By XIIa Converts factor IX to IXa Need Ca2+

Factor X Activated on surface of activated platelets by tenase complex or by TF-VIIa in presence of Ca2+

Activates prothrombin to thrombin

Factor II Activated by Prothrombinase complex (Platelet phospholipids, Ca2+, Va & Xa)

Converts fibrinogen to fibrin

Factor VII Activated by thrombin, Xa, VIIa and IXa

Activates factors IX & x

2. Co factors Factor VIII Thrombin & Xa VIIIa is a cofactor for

activating factor X by IXa Factor V Thrombin & Xa Cofactor for the activation

of Prothrombin by factor Xa

Factor III Cofactor for factor VIIa, Ca2+ dependant

3. Fibrinogen Factor I Thrombin in presence of

Ca2+Forms Fibrin

4. Transglutamase Factor XIII Thrombin in presence of

Ca2+Stabilizes fibrin clot by convalent cross links

Table 2: Functional classification of clotting factors.Table 2: Functional classification of clotting factors.Table 2: Functional classification of clotting factors.

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NAME FUNCTIONProtein C Activated by thrombin bound to

thrombomodulin, degrades VIIIa and Va Protein S Cofactor for protein C

Thrombomodulin Protein on the surface of endothelial cells, binds thrombin which activates protein C.

vWf Present in plasma, subendothelial tissue and endothelial cells. Carrier of factor VIII and prolongs its half life, adhesive protein which binds platelet to subendothelial tissue.

HMW Kininogen Carries prekallikrein and factor XI and deliver them to anionic surfaces

Prekallikrein Activated by XIIa to Kallikrein which activates XII to XIIa

Table 3: Regulatory and other proteinsTable 3: Regulatory and other proteins

ASSESSMENT OF COAGULATION FUNCTION AND ANESTHETIC MANAGEMENT OF A PATIENT WITH COAGULATION DISORDERS:• Successful surgery depends, in part on adequate hemostatic

ability of the patient. Haemorrhage and thrombosis are two major problems which affect the outcome of surgery. Hemostasis depends on vascular integrity, platelet function and coagulation. Assessment of coagulation function prior to Surgery is of utmost importance for successful outcome of surgery. But doing all the tests of coagulation prior to surgery is not cost effective. So we have to approach every patient in a stepwise systematic manner and order appropriate tests whenever necessary.

• As with any patient, approach to a patient with possible coagulation disorder should start with a detailed history, as many a time detection of potential problems in hemostasis becomes evident in the history itself.

History:• History with regard to previous bleeding, petechiae, ecchymoses,

hemarthrosis, family history of bleeding disorders, drug history of use of aspirin, non steroidal anti-inflammatory drugs, coumarin, heparin or thrombolytic. History of uremia, liver disease, leukemia.

• A recent uneventful tooth extraction or a minor surgery will virtually rule out the possibility of coagulation disorder in the patients.

• If you get a positive history from a patient, then guidelines to your approach are as given in Table 4. !

Enquiry Action to be taken if response is positivePast or recent history of bleeding or bruising

Blood count, coagulation screen

Family history of bleeding

Blood count, coagulation screen

Drug history Warfarin

Aspirin

Non-steroidal anti-inflammatory drug

Discontinue 72h preoperatively. Use heparin if necessary. In emergency reverse with FFP + vit KDiscontinue 72h preoperatively. Give platelets if bleeding excessive Discontinue 24h preoperatively. Watch for GI haemorrhage if anticoagulants used postoperatively.

Past history or family history of thrombosis

If positive or doubtful discuss thrombophilia screening with hematology laboratory. LMW heparin should be used in all high risk situations.

Oestrogen containing contraceptive pill

Stop 4 weeks prior to elective surgery. For emergency surgery use LMW heparin prophylaxis.

Hormone replacement therapy

Adhere scrupulously to normal prophylactic measures.

Table 4 – Enquiries relevant to hemostasis to be made preoperativelyTable 4 – Enquiries relevant to hemostasis to be made preoperatively

84



Test Normal range

Abnormalities indicated by prolongation

Common causes of disorder

Thrombin time (TT)

14-16S Deficiency or abnormalities of

fibrinogen. Inhibition of thrombin by

heparin or EDPs

Heparin therapy. DIC

Prothrombin time (PT)

10-14S Deficiency or inhibition of V, VII,

X, prothrombin, fibrinogen

Warfarin therapy. Liver disease, Heparin, DIC,

Vitamin K deficiency

Partial thromboplastin

time with Kaolin (PTTK)

30-40S Deficiency or inhibition of V, VII, IX, X prothrombin,

fibrinogen

Heparin therapy, DIC, Hemophilia,

Christmas disease, von Willebrandʼs disease, liver

disease. Bleeding time 3-8 min Abnormal platelet

formation, Reduced platelet

number

Inherited disorders of platelet function. Drug induced renal

failure. Von Willebrandʼs

diseaseTable 5: Screening test for coagulation disorders Table 5: Screening test for coagulation disorders Table 5: Screening test for coagulation disorders Table 5: Screening test for coagulation disorders

Integrity of extrinsic pathway • Prothrombin time (PT) measures the integrity of the extrinsic

pathway including factors VII, the common pathway factors V, X, prothrombin and fibrinogen. It is expressed in terms of international Normalized Ratio (INR) which is a method to standardize the prothrombin time assay.

INR = ISI

• Where ISI is the international sensitivity index which is the calibration factor of the lab thromboplastin used for the test against a WHO reference preparation.

Integrity of intrinsic pathway:• Activated partial thromboplastin time (aPTT or PTT) measures the

integrity of the intrinsic pathway including factors VIII, IX, XI, XII as well as V, X prothrombin and fibrinogen.

Integrity of final common pathway:• It is measured by thrombin time. It is prolonged in functional

abnormality of fibrinogen and to inhibitors of thrombin activity including the presence of fibrin degradation products.

Integrity of vascular endothelium, platelet function and number:• Measured by doing a bleeding time. Thromboelastogram:• Even though this cannot be used as a screening test due to the costs

involved, this gives a rapid complete assessment of all pathways, factor abnormalities, platelet function and thrombolysis.

• If you find an abnormality in the screening tests, individual factor assays may indicate which factors are deficient and appropriate replacement materials can be made available before surgery.

• Even though we know how to correct the coagulation abnormality, there is no definitive answer as to when to correct the laboratory abnormalities in coagulation tests. The laboratory abnormalities should be corrected if there is potential risk of severe haemorrhage; keeping in mind that the blood products are expensive and can transmit diseases and that transfusion to correct the coagulation abnormality may end up in fluid overload.

85



• Table 6 shows which coagulation factors are present in which blood products and Fig.5 shows an outline to the approach towards a patient with a possible bleeding disorder.

Common conditions and guidelines to correct the coagulation abnormalities. 1) Liver disease • In liver disease with coagulation abnormalities, there will be

prolongation of the prothrombin time. The consensus now (to correct the coagulation abnormality) is that if platelet count is greater than 80 x 109/L (80,000/-mm3), and bleeding time is normal, administration of fresh frozen plasma (FFP) is unnecessary if the INR is < 1.6. These patients can be managed by giving 10mg Vit. K IM daily x 3 days and availability of FFP should be ensured in the per operative period.

• If the INR is greater than 1.8 or if there is thrombocytopenia or platelet dysfunction, FFP or cryoprecipitate should be given within 6 hours of the start of surgery.

Blood product Main coagulation factors

Uses Comments

Fresh frozen plasma (FFP)

Fibrinogen, prothrombin factors, V, X, XI, Some factor VIII, IX, VII

Correction of coagulation disorders in liver disease Replacement of factors in DIC or following major trauma Replacement during massive transfusion

ABO compatible only should be given (contains anti-A.B. antibodies) stored at < - 300C Potential source of HIV, hepatitis viruses should be used within 30 min of rapid thawing

Cryoprecipitate Fibrinogen (50-80g/dl) Factor VIII (2-5u/ml)

Additional source of fibrinogen and factor VIII in massively transfused patients. Source of factor VIII for mild hemophiliacs or heterozygotes at risk To correct bleeding time and permit surgery in patients with platelet storage disease

No ABO antibodies present Single donor but potential source of virus transmission. Useful addition to FFP if volume overload is a problem Stored at -200CStable for 6 months

Albumin solution No coagulation factors

Volume replacement

Small risk of virus transfusion

Platelet concentrates

Platelets In disorders of platelet production. In platelet storage diseaseIn massively transfused patients

ABO compatible should be used can transmit viruses including CMV (unless white cell depleted) Not effective in immune thrombocytopenia.

Table-6: Blood products used for hemostasisTable-6: Blood products used for hemostasisTable-6: Blood products used for hemostasisTable-6: Blood products used for hemostasis

86



Read Patient with possible bleeding disorder - Chart from old notes:2) Patients on anticoagulants • Oral anticoagulants should be stopped at least 72 hours

preoperatively and maintained on heparin during the perioperative period especially if the oral anticoagulants were started for prosthetic cardiac values or for recent thromboembolism. Ideally the therapeutic dose of heparin is adjusted to maintain aPTT at about double the normal value of 25 to 30 seconds.

3) Hemophilia • For major surgery, in a patient with hemophilia A, a target

concentration of 100% factor VIII is set, to be maintained for the first 5-7 postoperative day, whereas minor procedures may be adequately covered by concentration of 50% after the first day.

• For hemophilia B, factor IX concentrate is given to maintain a plasma concentration of 30% of normal during the perioperative period.

4) Platelet disorders • Patients with platelet counts above 50 x 104/L (50,000/mm3)

do not need prophylactic platelets. If it is less than 50 x 109/L, prophylactic platelets may be advisable, particularly if the patient requires transfusion of red cells intraoperatively – as transfusion of red blood cells lowers the platelet count probably by increasing the consumption of platelets through complement activation. If platelet count < 30 x 109/L (30,000/mm3), then it is advisable to raise the count to 30x109/L pre surgery and then to give platelets in theatre according to bleeding tendency and to maintain the count above 30 x 109/L pre surgery and then to give platelets in theatre according to bleeding tendency and to maintain the count above 30 x109 L in the postoperative period.

• For conditions due to increased destruction of platelets – like in immune thrombocytopenic purpura (ITP), intravenous immunoglobulin and steroids should be given to raise the platelet count.

• Exposure to antiplatelets drugs will increase the risk of surgical haemorrhage whatever the route of anesthesia. Aspirin should ideally be stopped one week before surgery and definitely 72 hours prior to surgery and non steroidal and inflammatory drugs two days prior to surgery. If for emergency surgery, if aspirin cannot be stopped, bleeding can be controlled by transfusing platelet rich plasma.

Disorders of Hypercoagulability:• Patients who undergo prolonged abdominal surgery or surgery to the

legs particularly if they require a period of reduced mobility postoperatively are at a high risk from venous thrombosis and embolism. The risk is increased if they have one or more risk factor given in table 7. These patients require anticoagulant measures during and / or after surgery with subcutaneous heparin.

Related to venous stasis Thrombophilic states• Immobility • Dehydration • Cardiac failure • Stroke• Pelvic obstruction • Nephrotic syndrome • Varicose veins • Hyper viscosity • Sickle cell disease • Multifactorial • Age • Obesity • Sepsis

• Hereditary • Ant. Thrombin III, • Protein C deficiency • Protein S deficiency • Acquired • Lupus anticoagulant • Paroxysmal nocturnal

hemoglobinuria • Pregnancy and Puerperium• Estrogens • Hormone replacement therapy (?)• Surgery-abdominal and hip • Malignant disease • Major trauma

Table-7 Risk factors of ThromboembolismTable-7 Risk factors of Thromboembolism

87



Points to remember before giving anesthesia • I/M medication are best avoided whenever possible. • Choice of regional anesthesia especially central neuraxial

blockade is avoided in patients with coagulation failure. • In general anesthesia, nasal intubation is avoided. • Drugs like Warfarin are highly protein bound drugs and can

displace protein bound anesthetic drugs. • Patients may have coexisting liver disease and drug

metabolism would be affected. • These patients may have received previous blood

transfusion and so universal precautions should have to be taken to avoid transmission of HIV and Hepatitis B.

With this knowledge, a patient with coagulation abnormality can be efficiently managed during the peri operative period. ANTICOAGULANTS AND REGIONAL ANESTHESIA:• Increasing number of patients now receive oral anticoagulant

therapy to reduce the risk of stroke from atrial fibrillation and other cardiac disorders. It is generally accepted that some regional anesthetic techniques will be hazardous in the presence of coagulopathies and anticoagulants. In particular during central neuraxial blockade (intrathecal, extradural, caudal anesthesia), bleeding is contained in a space restricted by bone.

Anticoagulants are used for 1. Established venous thromboembolism 2. Prophylaxis against deep vein thrombosis. 3. Patients with prosthetic heart valves 4. To prevent extension of an arterial thrombus 5. As a long term anticoagulation to prevent arterial thrombo-

embolism in patients with large left atrium or atrial fibrillation.

6. Antiplatelets therapy to reduce the incidence of fatal and non-fatal myocardial infraction in patients with unstable angina.

Property Unfractionated heparin

Low molecular weight heparin

Mean molecular weight 15 KDa 4.5KDaAnti XA / Anti IIa activity 1:1 3:1Inhibition of platelet function Yes NoBioavailability in low dose 50% 100%Elimination Hepatic and Renal Renalt1/2 of anti Xa activity Intravenous Subcutaneous

1hr2 hrs

2hrs4hrs

Thrombocytopenia High LowRisk of hemorrhage + DecreasedOsteoporosis with prolonged therapy

Yes Yes

Neutralization with protamine Full Anti lla fully neutralized. Anti Xa

partial.Table 8: Comparisons of properties of Unfractionated and low molecular

weight heparinTable 8: Comparisons of properties of Unfractionated and low molecular

weight heparinTable 8: Comparisons of properties of Unfractionated and low molecular

weight heparin

Anticoagulants commonly used are:Heparin • Un-fractionated heparin • Low molecular weight heparin Coumarins Aspirin

88



HEPARIN:• Unfractionated heparin and low molecular weight heparins

are commonly used. Their properties are given in Table 8. • Heparin is now used increasingly to - Reduce the risk of deep vein thrombosis - Reduce the risk of venous thromboembolism.

• In orthopedic surgery, without prophylaxis, deep vein thrombosis occur in 50-70% of patients undergoing total hip replacement, total knee replacement, or hip fractures.

Regional anesthesia and heparin:• Spinal bleeding following epidural catheters occurs in

approximately 1:200,000 cases, more common in elderly women (75%)

• Removal of epidural catheter is a significant risk factor of spinal bleeding. 30-60% of clinically important hematomas occurs in this circumstance.

RECOMMENDATIONS:• Smallest possible needle used for regional anesthesia.• Smallest effective dose of aspirin used preoperatively • Low molecular weight heparins should be delayed as long as

possible postoperatively, in case of neuraxial anesthesia (12 hours minimum, preferably 24 hours).

• For central blockade, avoid preoperative administration. • First dose of subcutaneous heparin is administered after

establishment of block• In post operative period, catheter removal should take place

in a period 1 hour before dose of heparin is administered to just before the administration of next dose i.e., when anticoagulant activity is at the lowest.

• One dose may be stopped after removal of catheter. • Frequent evaluation of neurological status is done. If

continuous infusions are used for postoperative analgesia, dilute solutions will be preferable as with them the motor block will be low and may not affect the neurological examination.

• In presence of blood during needle or catheter placement, heparin therapy is delayed for 24 hours.

• Single shot spinal anesthesia carries the least risk in central neuraxial blockade.

• If the patient is on a standard dose regimen of heparin, anesthesia must be delayed for 12 hours following last dose if possible.

• If on a high dose anesthesia is delayed for > 24 hours.

DICOUMAROLS• Dicoumarol are Vitamin-K antagonists and inhibit the formation of

factors II, VII, IX and X. Dicoumarol are stopped about 3-5 days before surgery and converted to heparin.

• Prothrombin time (PT) is monitored for dicoumarol activity, and activated partial thromboplastin time (aPTT) is monitored for activity of heparin.

• When PT is less than 1.5 times the normal and aPTT is about 55-70 sec. it is considered to be effective weaning from dicoumarol and effective anticoagulation by heparin.

Regional anesthesia and dicoumarol:• As all patients on dicoumarol are converted to heparin preoperatively,

all the recommendations for heparin holds true for patients on dicoumarol too.

• Postoperatively dicoumarol are started but, before starting dicoumarol, or before the drug gets effective, catheter introduced epidurally has to be removed.

ASPIRIN AND OTHER NON STERIODAL ANTI INFLAMMATORY DRUGS (NSAIDS)• Low dose aspirin therapy about 75mg daily is given for most patients

with coronary artery disease to decrease the risk of platelet aggregation and embolism.

89



• Aspirin irreversibly acetylates platelet cyclooxygenase, the enzyme that converts arachidonic acid into prostaglandin endo-peroxidases, which is needed for platelet aggregation.

• Because cyclooxygenase is not regenerated in circulation within the life span of platelet, one aspirin affects platelet function for a week.

• Other NSAIDS and drugs that inhibit platelet function e.g. Vit E, sulphinpyrazone, dipyridamole, antidepressants, phenothiazines, furosemide, steroids etc, inhibit platelet function reversibly and for about 24-48 hours.

• If emergency surgery is needed, before 8 day period of stopping aspirin or 2 day period of stopping other drugs mentioned other than aspirin, 2-5 units/70Kg of platelet concentrate will bring platelet concentration to a normal. This may also reduce the risk of hematoma formation after regional anesthesia.

• Low dose aspirin < 650 mg/day allows aspirin to be gone from the body 24 hours after administration of the last dose. Because the body makes about 70,000 platelets /ml/day, a 48 hour period is sufficient for platelet aggregation to become normal and regional anesthesia becomes safe.

• Considerable controversy exists in the area of stopping aspirin before anesthesia. Bedside platelet function test (Ivy bleeding time) may provide guidance as to safety, should be < 10 minutes. According to some workers, there are practical difficulties with standardizing and reproducibility of test and wide normal range

Manifestations of complications of regional anesthesia in anti coagulated patients• Hematoma formation and nerve compression are common

complications, which occur in these patients.• In central neuraxial blockade, hematoma is restricted by spinal canal

and permanent damage to spinal cord or nerves occurs.• Warning signs include localized back pain and signs of nerve

compression. These signs may be masked by blockade, especially if the technique is used in postoperative analgesia

90


Dr Azam’s Notes in Anesthesiology 2013 26. Hemophilia.

Bleeding Disorders:Hereditary AcquiredHemophilia A,B DICVon willebrands disease

Perioperative anticoagulation

Afibrinogenemias Dilutional thrombocytopeniaFactor V deficiency Massive blood transfusionProtein C Deficiency Drug induced hemorrhage/platelet

dysfunctionAntithrombin III deficiency

ITP, TTP

Vitamin K deficiency Type of surgery (CPB)

Clinical Features of hemophilia• Easy bruising, prolonged bleeding after trauma/surgery• Bleeding into joints and skeletal muscle hemorrhages• Bleeding into closed spaces can result in compression of peripheral nerves or vascular or airway obstruction.

• Intracranial bleed may lead to death

Diagnosis:• History of unusual bleeding• Laboratory test- Normal platelet count and PT- Prolonged activated PTT- Specifically factor VIII/IX/XI deficiency

Preoperative evaluation and preparation • Ask history of unusual bleeding• History of hemostatic responses to prior operations (tonsillectomy,

dental extractions)• History of drug ingestion (aspirin, oral anticoagulants)• On physical examination petechial which suggests thrombocytopenia/

abnormal platelet function/defects in vascular integrity • Coagulation tests to be done: BT, CT, PT, APTT, platelet count

thromboelastography, thrombin time.• History of coexisting diseases (hepatic, renal) or scheduled surgery

(CPB, liver transplantation) which may alter coagulation.

Premedication:• Ideally given orally• Im injections avoided• Anticholinergic given iv if necessary• Correct the factor level up to normal or 100% using desmopressin

0.3µg/kg iv• Factor VIII concentrates and infusion of 1U/kg which increases plasma

factor VIII level by 0.02U/ml • 0.3U/ml factor level gives minimal hemostasis. • 0.5U/ml factor level necessary for serious bleeding disorder.

Hemophilia and Coagulation Disorders:Classification:• Hemophilia: Type ʻAʼ (X linked recessive disorder) (85%) 1:5000

incidence à Factor VII deficiency• Hemophilia: Type ʻBʼ (14%) (X linked recessive pattern) à

deficient or defective factor IX• Hemophilia: Type ʻCʼ (1%) (autosomal disorder) à deficiency in

factor XI

91


Dr Azam’s Notes in Anesthesiology 2013 Hemophilia.Continuation:

• Coagulant factor VIII is a plasma protein that has two components, factor VIII; VWF and factor VIII: C each of which is under separate genetic control.

• VWF components serves to adhere platelets to collagen in the sub-endothelial lower of blood vessels during primary hemostasis and to carry the factor VIII molecule.

• In hemophilia A this factor VIII: C is deficient in quantity or quality.

• Physiologic events after endothelial interruption in the blood vessel. The small size of platelets relative to other blood components results in slower transit in the blood vessel with resultant margination the process in which the faster mving, larger components push the platelets toward the walls of the blood vessel. As a result platelets are in contact with the surface of the blood vessel and can immediately detect any break in endothelium. Any endothelial break exposes platelets to subendothelial structures including collagens and other activating proteins, which cause the glycoprotein receptors on the platelets to rapidly adhere to these substances. This adhesion begins the process of platelet activation, in which the shape of the platelet is changed and the contents of the cytoplasmic granule are released. These substances include factors such as ADP, which further stimulate platelet aggregation. The platelet plug that is formed in this process provides initial hemostasis.

• Activation of factor XIII produces cross polymerization of loose fibrin to produce firm clot.

• Localization of coagulation and control of primary hemostasis are controlled by factor thrombosis A2, PG and prostacyclins.

• TxA2 released at the site of injury and stimulates vasoconstriction ADP release and platelet aggregation.

• Prostacyclin is produced by intact endothelial cells and prevents platelet aggregation and clot formation.

• Clot localization is maintained by dilution of procoagulants flowing in the blood the removal of activated factors by the liver the action f circulating procoagulant inhibitors such as antithrombin III and protein C and release of serine protease tissue plasminogen activator (TPA). TPA digests fibrinogen as well as factors V and VIII, initiating the physiologic process of fibrinolysis and resulting in fibrin degradation (split) products, which are removed by the mononuclear phagocyte system.

Extrinsic Coagulation Pathway:!

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92


Dr Azam’s Notes in Anesthesiology 2013Hemophilia.Continuation:

The levels of factor VIII necessary for hemostasis:Clinical Presentations Factor eight concentrations

(%) of normalSpontaneous hemorrhage 1 – 3%Moderate trauma 4 – 8% Hemarthrosis and deep skeletal muscle hemorrhage

10 – 15%

Major surgery > 30%Specific components measured by different coagulation tests:Laboratory tests Normal values Components

measuredBleeding time 3 – 10 minutes Platelet count,

vascular integrity Prothrombin time 10 – 12 seconds I, II, V, VII & XPartial Thromboplastin time (PTT)

25 – 35 seconds I, II, V, VII, IX, X, XI, & XII

Thrombin time 9 – 10 seconds I, IIACT 90 – 120 seconds I, II, V, VII, IX, X,

XI & XII• PT is measured by adding tissue from thromboplastin (TP) to

a blood specimen and measuring the time until clot formation. A normal PT could occur with an abnormal fibrinogen level. Because the PT is only prolonged if the fibrinogen level <100mg/dl.

• PTT is performed when partial thromboplastin is added to a test tube of blood and time is measured until clot forms. This test can be modified by the addition of the surface activating factors XII and XI before the addition of the partial thromboplastin, creating the activated partial thromboplastin time (aPTT). The aPTT is a faster test than PTT and is a standard test used in clinical practice .

• ACT also is an accelerated version of PTT and activated by diatomaceous earth, but less sensitive than aPTT to specific factor deficiencies.

• Thrombin time measures conversion of fibrinogen to fibrin, a useful test to determine both inadequate amounts of fibrinogen as well as inadequate fibrinogen molecules.

• Thrombodiastogram measures both speed of clot formation as well as clot firmness and helpful following transfusion of large quantities of blood products.

Preoperative evaluation and preparation:1. Correct the patients coagulation status before surgery. • Factor VIII levels of 30% of normal will usually provide adequate

hemostasis. For a major orthopedic procedure, the level should be corrected to 100% of normal approximately 1 to 2 hours before procedure. A repeat dose should be given if surgical procedure lasts more than 1.5 hours or if measured factor VIII levels falls below 40% of normal.

• One unit of factor VIII: C clotting activity is defined as the amount present in 1ml of fresh normal, pooled plasma.

• A single unit of factor VIII clotting activity per kilogram of baby weight will increase plasma factor VIII levels approximately 2%.

• Factor VIII concentrates are very stable at room temperature after reconstitution and thus are appropriate for infusion use.

• But approximately 10-20% of hemophilics will develop an antibody inhibitor against factor VIII and do not achieve the anticipated response following factor VIII infusion. But some patients who do not respond well to bolus injections, a continuous infusion can be effective because appropriate level of missing factor can be achieved relatively easily by infusion, because complete inhibition of factor only occurs after 1-2 hours. If the factor is continuously infused, there will always be some that is circulating, unneutralized and hemostatically active.

93



2. Factor VIII activity is present in FFP and cryoprecipitate:FFP:• Prepared from single donor• Contains all plasma proteins and factor VIII• After blood donation, approximately 200ml of FFP are

extracted. • Factor VIII activity is between 0.7 – 0.9 units of clotting

activity per ml of FFP.• FFP may carry AIDS and hepatitis B, C etc.,

Indications for FFP• Isolated factor deficiency• Volume expands/massive blood transfusion• Reversal of antithrombin III deficiency• Selected immune deficiencies• Thrombocytopenic purpura

Cryoprecipitate:• It is fraction of plasma that precipitates when FFP is thawed.• It contains !- Factor VIII: vWF- Factor XIII, fibrinogen

• 5-12 units of factor VIII clotting activity/mlIndications:• Hemophilia, VWF disease, hypofibrinogenemia uremic

platelet dysfunction• It may sensitize the Rh –ve individuals to Rh antigens if the

donor is Rh +ve because of presence of small amounts of red cell frequents in cryoprecipitate.

• Synthetic analog of ADH is used to prepare mild and moderate hemophilias for minor surgery.

• Intravenous DDAVP will rapidly release preformed. Factor VIII complex, which leads to a two to threefold increase in circulating factor VIII within 30-60 minutes of administration.

• In addition factor VIII: C and vWF are released from endothelial cells. • The half time of this released factor is approximately 12 hours and

repeated administration of DDAVP will deplete the storage capacity in the endothelial cells.

• If DDAVP is to be used preoperatively the release of plasminogen activator by DDAVP mandates the use of EACA as well which is a antifibrinolytic.

Advantages of Factor III :Advantages Disadvantages

Cryoprecipitate • Readily available• Long shelf life• Low risk of AIDS and

hepatitis

Allergic reaction Hyperfibrinogenmias

Factor VIII concentrates • Easily stored and reconstituted long life, known potency

High risk of infection

Monoclonal purified factor VII

• Stability, biologic safety

Cost (?)

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Intraoperative Management:1. Iron injections can be safely administered if factor VIII

activity is greater than 30%2. Sedatives or anticholinergic drug should be given iv routes3. Regional anesthesia is contraindicated because of concern

of hematoma formation at the regional site. But with proper management of the coagulation status, regional techniques can be used successfully.

• But in a patient with full stomach, regional technique might be more appropriate because relative risk of aspiration

• For a completely elective procedure in hemophiliac patient GA is better.

• Manipulation of airway during intubation should not be performed until appropriate replacement factors have been administered.

• Elective laryngoscopy should only be attempted following preoperative factor correction and achievement of complete muscle relaxation.

• A smaller than predicted small well lubricated ETT well lubricated ET Tube to be used for intubation.

• Avoid nasal intubation because of increased chance of epistaxis.

• Carefully face mask is applied to avoid trauma to lips, tongue or face.

• Strict asepsis to be maintained.• Gentle face mask application and ventilation. • Coexisting liver diseases is a common complication in

hemophiliac patients because of hepatitis acquired from previous blood or factor transfusion. So, drugs which are metabolized by liver should be used with caution.

• A balanced intravenous technique is preferable to an inhaled anaesthetics because of reduced hepatic blood flow observed in inhaled technique. Halothane is avoided.

• If there is blood loss during surgery, whole fresh blood should be preferably transfused because it increased O2 carrying capacity and provides all components of coagulation and also expands the intravascular volume.

• If there is acute hemolytic transfusion reaction occurs during intra operative during blood transfusion, immediately stop transfusion and draw blood from the patient and send to blood bank for further cross matching. An additional tube of blood should be collected and allowed to sit undisturbed for 5-10 minutes allowing separation of red cells from plasma. The presence of free plasma Hb in the serum is diagnostic of a hemolytic reaction.

• If life threatening hemorrhage occurs and patient is having high titre of antibodies (IgG) against factor VIII, then massive doses of factor VIII concentrates and plasma pheresis with replacement of factor VIII should be given and it may be of temporary benefit.

• Porcine factor VIII may provide hemostasis because of its distinct antigenecity even in presence of circulating inhibitors.

• Alternatively APC activated prothrombin complex concentrates which contain vitamin K dependent enzymes as well as recombined factor VIIIa can be given. These activated coagulants enter coagulation cascade distal to level of factor VIII and bypass the effects of inhibitor thrombosis is a possible complication.

• During extubation gentle oropharyngeal suction to be done under direct vision.

Post operative Management:1. Analgesics, containing aspirin/NSAIDs avoided2. Antihistamines and antitussives can be inhibit platelet aggregation

and prolong bleeding time. So to be used continuously. 3. Narcotics paracetamol in titrated dose can be used for pain4. If regional blockade with catheter was used for anesthesia, analgesics

can be given through this route. 5. Factor VIII are supplemented for at least 2 – 4 weeks following

surgery. 6. Postoperatively some surgeries maintain factor VIII level at 80% of

normal for first 4 post operative days, whereas others feel that levels at least 40% of normal are adequate.

7. Home infusions of factor VIII concentrates can also be used.

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Correction of factor VIII level:

Single unit of factor VIII clotting activity per kilogram of body weight will increase plasma factor VIII level s approximately 2%.E.g., to correct a 70kg hemophilia patient with 5% factor VIII activity to 95% of normal will be

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Dr Azam’s Notes in Anesthesiology 2013 27. Coagulation Factors.

Table 24.1 The coagulation factors.

Factor number Descriptive name Active form

I Fibrinogen Fibrin subunit

II Prothrombin Serine protease

III Tissue factor Receptor/cofactor*

V Labile factor Cofactor

VII Proconvertin Serine protease

VIII Antihaemophilic factor Cofactor

IX Christmas factor Serine protease

X Stuart–Prower factor Serine protease

XI Plasma thromboplastin antecedent Serine protease

XII Hageman (contact) factor Serine protease

XIII Fibrin-stabilizing factor TransglutaminasePrekallikrein (Fletcher factor) Serine proteaseHMWK (Fitzgerald factor) Cofactor*

HMWK, high molecular weight kininogen.* Active without proteolytic modification.

Table 24.2 The coagulation factors.

Factor Plasma half-life (h) Plasma concentration (mg/L) Comments

II 65 100 } Prothrombin group: vitamin K needed for synthesis; require Ca2+ for activation

VII 5 0.5

IX 25 5

X 40 10

I 90 3000 } Thrombin interacts with them; increase in inflammation, pregnancy, oral contraceptives

V 15 10

VIII 10 0.1

XI 45 5

XIII 200 30

Table 24.3 Screening tests used in the diagnosis of coagulation disorders.

Screening testsAbnormalities indicated by prolongation

Most common cause of coagulation disorder

Thrombin time (TT)

Deficiency or abnormality of fibrinogen or inhibition of thrombin by heparin or FDPs

DICHeparin therapy

Prothrombin time (PT)

Deficiency or inhibition of one or more of the following coagulation factors: VII, X, V, II, fibrinogen

Liver diseaseWarfarin therapyDIC

Activated partial thromboplastin time (APTT or PTTK)

Deficiency or inhibition of one or more of the following coagulation factors: XII, XI, IX (Christmas disease), VIII (haemophilia), X, V, II, fibrinogen

Haemophilia, Christmas disease (+ conditions above)

Fibrinogen quantitation

Fibrinogen deficiency DIC, liver disease

DIC, disseminated intravascular coagulation; FDPs, fibrin degradation products.NB. Platelet count and the tests of platelet function are also used in screening patients with a bleeding disorder (p. 328).

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28. Artificial BloodBlood Substitutes Dr Azam’s Notes in Anesthesiology 2013


ARTIFICIAL BLOOD CELLS • Artificial blood or blood surrogates is a substance used to mimic

and fulfill some functions of biological blood, usually in the oxygen-carrying sense.

• The main aim is to provide an alternative to blood transfusion.• Artificial blood does not contain the plasma, red and white cells,

or platelets of human blood, but functions to transport and deliver oxygen to the body's tissues until the recipient's bone marrow has regenerated the missing red blood cells.

• Artificial blood can be produced in different ways using synthetic production, chemical isolation, or recombinant biochemical technology.

• Current blood substitutes are either haemoglobin-based oxygen carriers (HBOCs) or perfluorocarbons (PFCs).

• While HBOCs utilize haemoglobin, an actual component of red blood cells, PFCs rely solely on synthetic chemical processes.

COMPOSITION OF ARTIFICIAL BLOOD • Perfluoro-octyl bromide - 28% • FO-9982 - 12% • Yolk lecithin - 2.4% • DSPE- - 0.12%• Distilled water - 57.48%

ADVANTAGES OF PERFLUOROCARBONS (PFC) EMULSIONS• PFCs do not react with oxygen. • PFCs allow easy transportation of the oxygen to the body. • They allow increased solubility of oxygen in plasma. • PFCs minimize the effects of factors like pH and temperature in

blood circulation.

DISADVANTAGES OF PERFLUOROCARBONS (PFC) EMULSIONS• Often causes flu-like symptoms. • This is often caused by phagocytosis of the perfluorocarbons emulsion by

the recipient organism's immune system.• Unable to remain mixed as aqueous solutions – thus, they must be prepared

as emulsions for use in patients. • A decrease in blood platelet count. • PFC products cannot be used by the human body, and must be discarded.

This takes approximately 18-24 months. • PFCs absorb oxygen passively, patients must breathe at a linear rate to

ensure oxygenation of tissues.

ADVANTAGES OF HEMOGLOBIN-BASED OXYGEN CARRIERS (HBOCS)- • Available in much larger quantities. • Can be stored for long durations. • Can be administered rapidly without typing or cross-matching blood types.

Can be sterilized via pasteurization.

DISADVANTAGES OF HEMOGLOBIN-BASED OXYGEN CARRIERS (HBOCS)- • Reduced circulation half-life • Disrupts certain physiological structures, especially the gastrointestinal tract

and normal red blood cell haemoglobin. • They release free radicals into the body.

IDEAL CHARACTERISTICS OF ARTIFICIAL BLOOD1. Safe to use. 2. Compatible in human body. 3. Able to transport and release oxygen where needed. 4. Storable and durable for longer time periods. 5. Is free of pathogens and toxins which would produce an immune system

response in the human body.

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Artificial BloodBlood Substitutes Dr Azam’s Notes in Anesthesiology 2013


• Perfluorocarbons (PFC) based- Perfluorochemicals cannot mix with blood, therefore emulsions must be made by dispersing small drops of PFC in water.

• This liquid is then mixed with antibiotics, vitamins, nutrients and salts, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood.

Artificial blood Blood substitute

• The main purpose of artificial blood is to act as normal blood in the body, providing a long-term solution to blood loss or distortion. No working artificial blood has been created in the status quo.

• The main purpose of a blood substitute is to provide temporary support to the circulatory system when necessary.

• Blood substitutes generally are focused on the role of transporting oxygen for short-term cases such as blood transfusions or surgeries.

• Blood substitutes are generally simpler since they are only focused on one of the several functions of real blood. Several types of blood substitutes have been found including:

• Hemoglobin-based oxygen carriers Perfluorocarbons emulsion

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Dr Azam’s Notes in Anesthesiology 2013 29. What is recombinant factor VIIa? Describe the clinical usage of it?

• Recombinant human coagulation Factor VIIa (rFVIIa), intended for promoting hemostasis by activating the extrinsic pathway of the coagulation cascade.

• Factor VII (formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa .

• Administration approval for uncontrolled bleeding in hemophilia patients.

• It is often used unlicensed in severe uncontrollable bleeding.

Physiology:• The main role of factor VII (FVII) is to initiate the process

of coagulation in conjunction with tissue factor (TF/factor III).

• Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream. Upon vessel injury, tissue factor is exposed to the blood and circulating factor VII.

• Once bound to TF, FVII is activated to FVIIa by different proteases, among which are thrombin (factor IIa), factor Xa, IXa, XIIa, and the FVIIa-TF complex itself.

• The most important substrates for FVIIa-TF are Factor X and Factor IX.

• The action of the factor is impeded by tissue factor pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation.

• Factor VII is vitamin K dependent; it is produced in the liver.

• Use of warfarin or similar anticoagulants decreases hepatic synthesis of FVII.

A summary of the structure and properties of coagulation factor VII is as follows:I. Synthesis and localization - Synthesized in the liver and circulates in the

plasma as a zymogenII. Half-life - 3-6 hoursIII. Molecular weight - 50,000IV. Structure - Amino-terminal (light chain), carboxy-terminal (heavy chain)

catalytic domain, 2 epidermal growth factor domains V. Cofactor - Tissue factorVI. Substrate - Factor VIIa/tissue factor complex activates factors X and IX

• Replacement therapy for persons with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity.

• Spontaneous hemorrhage or mild trauma, therapeutic factor VII levels of 5-10% are sufficient to stop bleeding.

• This level may be achieved by administering plasma at a dose of 5-10 mL/kg of body weight and repeating the dose every 8-12 hours for 1-2 days or major hemorrhage or surgery, plasma may be administered in a loading dose of 15-20 mL/kg and followed by 3-6 mL/kg every 8-12 hours until the surgical wound heals.

• This may require 5-7 days of treatment.Dose: 20 - 90 µg/Kg

FDA Approved Indications of Factor VII A:• Hemophilia A/B with inhibitors - 90 µg/kg every 2 hours• Congenital factor VII deficiency - 15 0 30 µg/kg every 4 to 6 hours.• Acute Hemophilia - 70 - 90 µg/kg every 2 - 8 hours

RCTʼS:• Body trauma - 200 µg/kg then 100 µg/kg BD• Brain Trauma 40 - 100 µg/kg • CVS surgery - 50 - 160 µg/kg • ICh - 15 - 160 µg/kg • Liver transplant 100 - 200 µg/kg

http://www.rxlist.com/script/main/art.asp?articlekey=15839

http://www.rxlist.com/script/main/art.asp?articlekey=15839

http://en.wikipedia.org/wiki/Protein

http://en.wikipedia.org/wiki/Protein





http://en.wikipedia.org/wiki/Enzyme

http://en.wikipedia.org/wiki/Enzyme

http://en.wikipedia.org/wiki/Serine_protease

http://en.wikipedia.org/wiki/Serine_protease

http://en.wikipedia.org/wiki/Recombinant

http://en.wikipedia.org/wiki/Recombinant

http://en.wikipedia.org/wiki/Tissue_factor

http://en.wikipedia.org/wiki/Tissue_factor

http://en.wikipedia.org/wiki/Thrombin

http://en.wikipedia.org/wiki/Thrombin

http://en.wikipedia.org/wiki/Factor_X

http://en.wikipedia.org/wiki/Factor_X

http://en.wikipedia.org/wiki/Factor_IX

http://en.wikipedia.org/wiki/Factor_IX

http://en.wikipedia.org/wiki/Tissue_factor_pathway_inhibitor




http://en.wikipedia.org/wiki/Vitamin_K

http://en.wikipedia.org/wiki/Vitamin_K

http://en.wikipedia.org/wiki/Liver

http://en.wikipedia.org/wiki/Liver

http://en.wikipedia.org/wiki/Warfarin

http://en.wikipedia.org/wiki/Warfarin

http://en.wikipedia.org/wiki/Anticoagulant

http://en.wikipedia.org/wiki/Anticoagulant

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Dr . Azam s Notes in Anesthesiology

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