Critical Care in

Obstetrics:

An Innovative and Integrated Model for

Learning the Essentials

Massive Blood Transfusion

Michael A. Belfort, MD, PhD Professor and Chairman

Department of Obstetrics and Gynecology

Baylor College of Medicine

Obstetrician and Gynecologist-In-Chief

Texas Children’s Hospital

Houston, TX

Understand the pathophysiology of

hemorrhage and DIC

Discuss massive transfusion protocols, and their

applicability to obstetrical bleeding

Order and interpret laboratory testing and

how often it should be repeated

Understand the blood product alternatives

Discuss likely complications with transfusion

Learning Objectives

Pathophysiology

Massive Transfusion Protocols

Laboratory Testing

Blood products

Factor concentrates

Antifibrinolytics

Hemostatic & Metabolic Complications

Transfusion Risks & Complications

Outline

Massive Blood Transfusion

Pathophysiology

Dilutional coagulopathy

Low fibrinogen

Hyperfibrinolysis

Activation of protein C

Acidosis

Hypothermia

Air embolism – Rapid infusers

Hypocalcemia

Hyperkalemia

Pathophysiology

Activation of Protein C (APC) Cascade

Activated protein C

Thrombin &

Thrombomodulin

Hypoperfusion

• Inhibition Factor Va & VIIIa

• Plasminogen Activator

Inhibitor-1 (PAI-1)

• Activated

• protein C

• thrombomodulin on

endothelial cells

PAI-1 Hyperfibrinolysis

Massive Transfusion

Protocols

Traditionally based on ATLS guidelines

Start with crystalloid followed by PRBCs

Use other products based on laboratory tests

Massive Transfusion (MT)

Replacement of > 50% of blood volume in 12-24 hours

Transfusion of > 10 U PRBC in 24 hours

MT protocols at many centers

No FFP until 4-10 U of PRBCs given

No clear guideline re: PLTs – based on waiting for laboratory data to guide therapy

Transfusion Medicine- traditional

Rapid identification

Frequent use of recombinant human VIIa

Rapid treatment of acidosis

Avoidance of hypothermia

Prompt initiation of 1:1:1 ratio

RBCs, pre-thawed universal donor AB plasma, and apheresis platelets

convert to fresh whole blood ASAP

??WHY THIS CHANGE

Military Approach to Coagulopathy

Hess, JR. Blood and coagulation support in trauma care. Hematology Am Soc Hematol Educ Program 2007;187-91.

Holcomb et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007; 62:307-

310.

246 patients US Army combat support hospital in Iraq

Combat-related trauma requiring MT

1:1 FFP:RBC ratio independently associated with improved

survival, primarily by decreasing death from hemorrhage

Lowered absolute risk of mortality by 55%

Conclusion: MT protocols should use 1:1 ratio of FFP:RBC for all

hypocoagulable patients with traumatic injuries.

Combat Casualties & MT

Borgman et al.

2 large studies:

Aggregate data 466 MT

cases at 16 centers

Prospective 7 center cohort

study 415 cases

Civilian Trauma & MT

Zink et al. & Sperry et al

Conclusion: FFP:PRBC ratio > 1:1.5 associated with

lower mortality but higher ARDS

Predominance of penetrating trauma (No)

Higher rate of blast injuries (No)

Longer transport times (Maybe)

Different resuscitative practices:

Thawed FFP (Unlikely)

Fresh whole blood (No)

Recombinant activated Factor VII (Maybe)

Cryoprecipitate (Yes)

Is the Military approach appropriate for Obstetrics?

(1) Do patients unnecessarily receive

excessive plasma?

(2) Does the additional plasma lead to

fluid overload (ie, edema, abdominal

compartment syndrome, respiratory

compromise and ARDS)

1:1 Ratio – 2 Big Questions

Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336.

C. Inaba et al. J Am Coll Surg. 2010;210(6):957-965.

Lowered absolute risk of mortality in Iraq

uncontrolled area, no immediate lab access

Some data in trauma here supports

More recent reviews --

Insufficient evidence to support fixed ratios in

MT trauma patients

Transfusion - RBC:FFP 1:1? - PRO

*Borgman, et al. J Trauma. 2007;63:805-813.

**Rajasekhar, et al. Crit Care Med. 2011;39:1507-1513.

High volume plasma transfusion in non-MT trauma:

12-fold increase acute respiratory distress syndrome (ARDS)

6-fold increase in multiple organ dysfunction

4-fold increase in pneumonia and sepsis

1:1 strategies did not show any improvement in survival

Best evidence:

Stop aggressive MT of components (FFP, platelets,

and cryoprecipitate) once hemostasis achieved

Additional products add risk (eg, fluid overload and

transfusion complications) without benefit

Transfusion - RBC:FFP 1:1? - CON

Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336.

C. Inaba et al. J Am Coll Surg. 2010;210(6):957-965.

Massive Transfusion Protocols

Pacheco et al AJOG 2011

Laboratory Testing

Labs should be monitored q20-30 mins

When you get the results, it’s time to send another set

Repeat MTP Panel

Hgb/Hct, platelets (purple top)

DIC Panel (blue top)

PT/INR, PTT, Fibrinogen, D-dimer, platelet count

? TEG/ROTEM

ABG with metabolites (iCa, K, Glu)

Single draw:

AGB in heparin syringe with LAB SPAN

whole blood metabolic panel

Laboratory Analysis in MTP

Assesses extrinsic cascade

Influenced by factors I, II, V, VII, X

Ca2+ & TF added to platelet poor plasma

Normal value:

10-12 seconds

Most sensitive to factors:

II, VII, IX, X

(Vitamin K dependent)

Prothrombin Time (PT)

Assesses the intrinsic cascade

Influenced by factors I, II, V, VIII, IX, X, XI & XII

Ca2+, kaolin, and partial thromboplastin added

Normal value:

25-35 seconds

Most sensitive to

factors VIII & XI

Activated Partial Thromboplastin Time (aPTT)

Blood Gases (pH, Hgb)

Electrolytes (K, iCa)

Chemistries

Coagulation (PT)

Hematology (Hgb & Hct)

Glucose

Cardiac markers

Handheld Analyzers

i-STAT® 1 System

Abbott Point of Care Inc, Princeton, NJ

http://www.abbottpointofcare.com/ISTAT

Follow MTP

Request lab testing every 20-30 min

Interpret the lab results critically

Transfused according to the labs

Principles:

Volume repeletement

Clotting factors

Electrolyte stability

How to use lab testing in massive hemorrhage

If INR > 1.5

Give 2 units FFP

If platelet count < 100K

Give 1 apheresis platelet unit

(=5 pack)

If fibrinogen < 200 mg/dL

Give 2 jumbo cryoprecipitates

(= 10 units)

Lab Results & Action

Blood products

RBC: 250-350 mL, Hct 55-65%.

FFP: well balanced all coagulation factors and

coagulation inhibitors

Cryoprecipitate:

Contains fibrinogen, Factors VIII, XIII, von

Willebrand factor, and fibronectin.

1 jumbo cryoprecipitate contains 5 units

2 jumbo cryoprecipitate units (= 10 U) may be

given at a time

Platelets: One pheresis platelet unit at a time.

Blood Components

Blood Component Therapy

WHOLE BLOOD (500 mL)

Packed Red Cells (1U = 200-250 mL)

1U increases Hematocrit 3%

Platelets (1U = 50 mL)

6 pooled U increases platelet count 30K/uL

* Plateletpheresis (1U = 6-8 pooled singles = 250 mL)

Fresh Frozen Plasma (1U = 200-300 mL)

1U increases fibrinogen 7-10 mg/dL

Cryoprecipitate (1U = 20 mL)

Factor I, VIII, XIII, vWF, fibronectin

10 pooled U increases fibrinogen 70 mg/dL

Temp (C)

of

product

1 to 6o

20 to 24o

-18o

-18o

Factor

concentrates

Fibrinogen Concentrate (RiaSTAP):

heat-treated, lyophilized fibrinogen (Factor I) powder made

from pooled human plasma.

Each vial contains 900 to 1300 mg fibrinogen, 400 to 700

mg human albumin

Used in combination with cryoprecipitate

Prothrombin Complex Concentrate (Kcentra)

Factors II, VII, IX, X, protein C and S (plasma derived)

Used instead of FFP - reduced risk of volume overload.

Kcentra does not require thawing, blood group typing, and

has a reduced risk for TRALI and allergic reactions

Pharmacy cost: ~ $2500 or more per dose

New Products - ?Value

Originally developed for treatment of

Hemophilia A or B & Inhibitors to Factor VIII or IX

Promotes thrombin generation

Significant concerns raised about lack of efficacy

and potential for harm

Administration

Dose 60 ug/kg IV bolus

Pharmacy cost ~ $1,000 per dose

Recombinant Activated Factor VIIa

Efficacy of rFVIIa depends on:

levels of other coagulation factors present

patient temperature

pH (acidosis)

Maximal effectiveness:

platelet count (>50,000/mm3)

fibrinogen level (>50 to 100 mg/dL)

near normal temperature, pH, and calcium levels

Major sources of bleeding should be controlled and

major deficiencies corrected before rFVIIa given

Activated Factor VIIa usage

Rossaint et al. Crit Care 2010; 14:R52.

Prothrombin complex concentrate (Kcentra™):

Factors II, VII, IX, and X.

Coagulopathy while waiting for FFP

25-50 units/kg

Fibrinogen concentrate (RiaSTAP™)

Low fibrinogen <150-200 mg while waiting for cryoppt

70 mg/kg or [250-current fibrinogen]/1.7 = mg/kg

Factor VIIa (Novoseven™)

Truly last option d/t possible thrombotic complications*

Fibrinogen has to be >200 mg/dL in order to work.

30-50 mg/kg (1 mg/vial)

Factor Concentrates Off-Label Use - Summary

*Callum and Rizoli. Hematology 2012, ASH

Antifibrinolytics

Synthetic derivatives of amino acid lysine

Competitively inhibits the activation of plasminogen to

plasmin

Prevents the formation of plasmin which prevents the

degradation of fibrin and the formation of FDPs

Dosing:

Adults: 5 g over 30-60 min, 1-1.25 g/hour until

bleeding stops

No more than 30 g per day

Half life 2 hours, decrease dose in renal dysfunction.

Antifibrinolytics- Amicar (E-aminocaproic acid)

Antifibrinolytics

Brands: Cyklokapron, Transamin

Newer molecule than Amicar

8x the anti-fibrinolytic activity

Elective CS, EBL reduction (unlabeled use):

I.V.: 1-2 g over 5-15 minutes at least 10 min prior to skin incision

1 mg/kg/hour during surgery (? Use in percreta)

Half life 3 hours

Cleared in urine

Antifibrinolytics- Tranexamic acid (TXA)

(Gungorduk, 2011)

Study of PPH > 800cc after vaginal delivery

RCT, open label, 72 in each group

4g over 1 hr, then 1g/hr for 6 hours

Slight improvement in EBL, decreased procoagulants

NO SAFETY DATA

Theoretical thrombosis risk

There is evidence that TXA reduces blood loss at C-section

Ongoing RTC World Maternal Antifibrinolytic (WOMAN)

Multicenter, RCT - 15,000 sample size – TXA vs. placebo.

Antifibrinolytics- Amicar or Tranexamic Acid (TXA)

*Shakur, et al. Trials. 2010;11:40.

**Roberts and Ker. Int J Gynaecol Obstet. 2011;11:220-221.

Shakur et al. The WOMAN Trial. Trials. 2010;11:40.

Roberts I,et al. Int J Gynaecol Obstet. 2011;115(3):220-221.

Ducloy-Bouthors et al Crit Care. 2011;15(2):R117.

Anti-fibrinolytic derived from bovine lung

Inhibits trypsin, chymotrypsin, kallikrein + plasmin

Action on kallikrein inhibits formation of Factor XIIa

Blocks both intrinsic coagulation + fibrinolytic pathways

Action of plasmin slows fibrinolysis

Major safety concerns and drug withdrawn:

Myocardial infarction

Stroke

Renal failure

Anaphylaxis (1:200)

DO NOT USE IN PPH

Antifibrinolytics- Aprotinin (Trasylol)

Hemostatic &

Metabolic

Complications

Rapid changes in volume status

Maintenance of tissue oxygen

Control of bleeding at the source

Coagulation factors – which?

Ionized calcium & potassium

Acid-base balance

Hemostatic & Metabolic Complications

Normal range: 3.5-5.0 mEq/L

>10 U PRBC’s MUST assume increased K+

Arrhythmias when K+>6.5 mEq/L

Ventricular fib when K+>7.5 mEq/L

K+ goes up more after rapid transfusion

Acidosis contributes to hyperkalemia

Hyperkalemia in Massive Transfusion

K+ in supernatant increases linearly from 2 to 45

mEq/l) over 2 to 42 days of RBC unit storage

Irradiation causes a rapid increase in K+

Sufficient K+ in RBC packs to lead to hyperkalemia

with large volumes

~5mEq per 300cc PRBC’s

Usually transient due redistribution of the K+ load

Hyperkalemic cardiac arrests are reported

Hyperkalemia in Massive Transfusion

MT patients should be

kept on EKG

monitoring for:

Peaked T wave (tall

tented T wave)

Decreased P wave

ECG Changes in Hyperkalemia

16 transfusion-associated hyper K+ cardiac arrests

Cancer, major vascular, and trauma

Mean K+ was 7.2 +/- 1.4 mEq/L (5.9-9.2 mEq/L)

Nearly all patients were acidotic, hyperglycemic, hypocalcemic,

hypothermic at the time of arrest

Transfusion factors:

Number of RBC units before cardiac arrest: 1-54

Fourteen (87.5%) received RBC via CVP line

Commercial rapid infusion devices (pumps) used in 73%

RBC units were rapidly administered (pressure bags, syringe

pumped) in all patients.

The in-hospital survival was 12.5%

Hyperkalemia: Cardiac Arrest

Smith et al. Anesth Analg 2008

Prevention:

RBC washing, in-line K+ filter

Treatment for hyperkalemia > 5 mEq/L

Remove K from circulation:

D10 (glucose) 500 mL + regular insulin 10 U

over 60 min.

OR bolus of regular insulin 10 U

Block of the affects of K

Calcium infusion -1g CaCl2 slow IV infusion

Correct acidosis by bicarbonate

Hyperkalemia Treatment

Watch for hypokalemia in the hours

after massive transfusion

Once citrate is metabolized:

Increase in HCO3 leading to alkalosis

which leads to loss of K+

MT and HYPOkalemia

Citrate in blood components chelates both calcium

and magnesium

Monitor EKG for the QT interval

Prolonged QT low calcium and magnesium

Hypomagnesemia can cause Torsades de Pointes

No easy way to measure ionized Mg+2

Monitor ionized calcium at baseline and q15 min.

during MT

Prophylaxis: 10% Ca gluconate (1g/10ml) - 1-2 g

over 2-3 minutes IV for every 4 U PRBC’s

Hypocalcemia and Hypomagnesemia

Hypomagnesemia - Torsades de Pointes

Normal calcium 1.1 – 1.3 mmol/l

Hypocalcemia of <0.77 mmol/l has linear;

concentration-dependent relationship with mortality

More important than lowest fibrinogen concentration,

acidosis and lowest platelet count in predicting

mortality

OR = 1.25 per 0.1 mmol/l decrement, CI: 1.04 to 1.52; P =

0.02

Aggressively treat any ionized calcium < 1 (normal) –

high risk of cardiac arrest

10% CaCl -1g (1g/10ml vial CaCl2 in 100cc saline

over 2 - 5 minutes via central line)

Hypocalcemia and Cardiac Arrest

Elmer et al 2013; Ho and Lenard. 2011

Transfusion Risks &

Complications

Avoid dilutional coagulopathy !!!!!!

check Hct/plts/PT/PTT/fib/ABG q 15 min

Use cryoprecipitate/Fibrinogen concentrate/PCC if

coagulopathic

FFP is not enough to normalize very low

fibrinogen!

Transfuse FFP/cryoprecipitate/platelets early in

heavy bleeding

Avoid acidosis, hypocalcemia, hyperkalemia

Consider Factor VIIa (last resort & only if criteria met)

Intra Operative Blood Loss Treatment

Avoid hypothermia

Warmed products & IV fluids

Beir hugger, room warming, warm irrigation

Stop & wait for reversal of coagulopathy if

possible

Pelvic pressure, aortic occlusion, pack

Do not hesitate to use staged procedure with

pressure pack placement

Intra Operative Blood Loss treatment

More questions than answers regarding use in

obstetrics

What is the optimum flow rate ?

Vascular damage from rates >700cc/min

Hemodynamic response to MT?

Rapid Transfusion Devices

OK… Now we are really transfusing!

The Belmont Rapid Infuser

High flow rates (up to 1000 ml/min

Pressure restricted (300mmHg)

Warms fluid

Detects air

Rapid Transfusion devices

Pressure from bowel edema, ascites, ileus, blood

products leads to:

Decreased venous return, lower CO, lower BP

Decreased renal perfusion and oliguria

Diaphragm dysfunction with atelectasis, AV shunting,

higher pressures and hypoxemia

Bladder pressure >20 mmHg = ACS

25 ml in NaCl in bladder, clamped, measure mmHg

Abdominal hypertension > 12 mmHg

Normal = 0 – 10 mmHg (non-pregnant)

Abdominal Compartment Syndrome (ACS)

Summary

PPH is a major cause of maternal mortality

Most deaths due to PPH are preventable

Many preventable deaths are due to inadequate blood component therapy

“Lethal Triad”- coagulopathy, hypothermia, & acidosis

MT protocols are rapidly evolving after recent observational reports from military & civilian trauma centers

This experience may be applicable to the L&D setting in MT for PPH

This topic remains highly debated and RCTs are much needed

Massive Blood Transfusion…Conclusions

Evidence

Borgman et al. The ratio of blood products transfused affects

mortality in patients receiving massive transfusions at a combat

support hospital. J Trauma 2007;63(4):805-13.

Zink et al. A high ratio of plasma and platelets to packed red

blood cells in the first 6 hours of massive transfusion improves

outcomes in a large multicenter study. Am J Surg

2009;197(5):565-70.

Pacheco et al AJOG 2011

Rajasekhar, et al. Crit Care Med. 2011;39:1507-1513

Sperry et al & Inflammation the Host Response to Injury

Investigators. An FFP:PRBC transfusion ratio >/=1:1.5 is

associated with a lower risk of mortality after massive transfusion.

J Trauma 2008 Nov;65(5):986-93.

Evidence

Hess, JR. Blood and coagulation support in trauma care.

Hematology Am Soc Hematol Educ Program 2007;187-91.

Holcomb et al. Damage control resuscitation: directly addressing

the early coagulopathy of trauma. J Trauma 2007; 62:307-310.

Burtelow et al. How we treat: management of life-threatening

primary postpartum hemorrhage with a standardized massive

transfusion protocol. Transfusion 2007;47:1564-72.

Hematol Oncol Clin North Am. 1998:12;1141-66.

Rossaint et al. Crit Care 2010; 14:R52.

Callum and Rizoli. Hematology 2012, ASH

Shakur et al. The WOMAN Trial. Trials. 2010;11:40.

Roberts I,et al. Int J Gynaecol Obstet. 2011;115(3):220-221.

Evidence

Ducloy-Bouthors et al Crit Care. 2011;15(2):R117.

Sambasivan et al. J Trauma. 2011;71(2 suppl 3):S329-S336.

C. Inaba et al. J Am Coll Surg. 2010;210(6):957-965.

Smith et al. Anesth Analg 2008

Ho and Lenard. 2011

Elmer et al 2013

Evidence

Thank You for Your Attention!

Planning Committee

Mike Foley, Director Shad Deering, co-Director

Helen Feltovich, co-Director Bill Goodnight, co-Director

Loralei Thornburg, Content co-Chair Deirdre Lyell, Content co-Chair

Suneet Chauhan, Testing Chair Mary d’Alton

Daniel O’Keeffe Andrew Satin

Supplemental

Protein C and Protein S Systems

Hematol Oncol Clin North Am. 1998:12;1141-66.

Monitoring of coagulation:

Thromboelastogram (TEG)

A = reaction time

B = clotting time

a = alpha angle

(A, B and a reflect clotting factor function)

C = max. amplitude (reflects platelet function)

D = Rate of decay of clot (reflects fibrinolysis)

Obstetric hemorrhage has enhanced fibrinolysis when

compared with other types of hemorrhage

May indicate need for EACA or tranexamic acid

Intra Operative Blood Loss Mix

Pacheco et al. AJOG 2011

Principle of ROTEM

Massive Transfusion Postpartum Hemorrhage

Stanford Univ Med Ctr Blood products

6 U PRBC 4 U FFP or LP 1 U aPLT

Lab assessment CBC & PLT PT / PTT / Fibrinogen

Recombinant Factor VIIa

Burtelow et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive

transfusion protocol. Transfusion 2007;47:1564-72.

FII

(units/mL)

FVII

(units/mL)

FIX

(units/mL)

FX

(units/mL)

Cost

20-48 10-25 20-31 22-60 $1.26/uni

t

$630/vial

Kcentra™

INR 2-4 4-6 >6

Units/kg 25 35 50

Max

dose

2500 3500 5000

Dosing Guidelines

TEMogram aka TEM®