ManagementOfMassiveBleedingAndCoagulopathy-01.pdf

7/29/2019 ManagementOfMassiveBleedingAndCoagulopathy-01.pdf

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Management of massive bleeding & coagulopathy

Main Author(s): Dr Jasmeet Soar, Dr Janet Birchall,Alastair Whi teway, David Mi tchel l

Date of Issue: November 2006

Ratified at Clinical Effectiveness Committee: October 2006

Date of Review: October 2008


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Management of massive bleeding and coagulopathy

This guideline is relevant to all medical and surgical teams where massive bleedingis suspected.

1. Defini tion of massive bleeding

No universal definition. Definitions include:

Loss of 50% circulating volume in 3 hours

Loss of greater than 150 ml min-1

Loss of whole blood volume within 24 hours

2. Treatment see flow diagram

1. Identify patients with uncontrolled bleeding and coagulopathy early.

2. Contact key personnel- clinician in charge, critical care team, blood bank

and haematologist.

3. Use an ABCDE (Airway, Breathing, Circulation, Disability, Exposure)

approach to recognise and treat the patient.

4. Fluid resuscitation should aim to maintain vital organ perfusion whilst

awaiting definitive control of bleeding. Once bleeding has been stopped

circulating volume should be corrected.

5. Request laboratory investigations - FBC, clotting screen, crossmatch

(ensure correct patient identification) and biochemistry.

6. Request suitable red cells. Use a blood warmer.

7. Arrest bleeding. Methods include direct pressure, surgery (plus cell

salvage), endoscopic control, reduction and fixation of fractures and

interventional radiology techniques.

8. Correct reversible causes of coagulopathy including hypothermia,

acidosis, warfarin and heparin.

9. If more than one blood volume is likely to be/has been lost prior to clotting

screen results or there is evidence of a coagulopathy request 15 ml kg-1 of

fresh frozen plasma (FFP) and one adult therapeutic dose of platelets.

10. Monitor the response to treatment.

11. Avoid unnecessary movement of bleeding patients. This will disrupt clot

formation.

Management of Patients with Massive Bleeding and Coagulopathy Nov 06 2


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12. In exceptional circumstances the use of recombinant activated factor VIIa

may be considered discuss with a haematologist.

3. Specific points

3.1 Request sui table red cells

1. Give uncrossmatched group O Rh negative if extremely urgent (no more

than 2 units). Ascertain the patients blood group and give group specific or

fully crossmatched blood as soon as possible.

2. Crossmatched blood should be used if it is available, if time allows or the

patient has abnormal antibodies.

3. A full crossmatch is not needed in acute circumstances after 10 units have

been transfused in less than 24 hours.

4. Rh D positive blood can be used in RhD negative males and post

menopausal females if stocks of RhD negative blood are restricted.

5. Use red cell salvage (cell saver), whenever possible in all cases of

massive bleeding. Tumour surgery is not a contra-indication, but frank

contamination with bowel contents is a contra-indication.

3.2 Fresh Frozen Plasma (FFP), Platelets and Cryoprecipitate

1. It is reasonable to request one therapeutic dose of FFP and one adult

therapeutic dose of platelets (haemostatic pack) in cases of massive blood

loss before the blood results are available or if there is evidence of a

coagulopathy.

2. One therapeutic dose of FFP is 15 ml kg-1(usually 3-4 units)

3. Aim for PT and APTT of less than or equal to 1.5 times the control.

4. A therapeutic dose of platelets is one bag.

5. Aim for a platelet count of greater than 50 x 109 l-1 (100 x 109 l-1 in multiple

or central nervous system trauma) or higher if platelet function is abnormal.

6. Give cryoprecipitate to maintain fibrinogen level above 1 g l-1. The usual

dose is 1 to 1.5 packs per 10kg body weight.

7. Assess response - repeat doses may be needed based on blood results.



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8. Group compatible units will be used once the patients blood group is

known.

3.3. Aprotinin, Tranexamic acid, Protamine, Vitamin K, Desmopressin

1. Consider a single loading dose of aprotinin 1 million international units iv

and/or tranexamic acid 1 to.2g iv.

2. Correct any heparin effect with protamine. 1 mg iv will neutralise 100 units of

heparin calculated to be still present. Maximum dose 50 mg iv.

3. Give 10 mg iv vitamin K for patients on warfarin therapy or with liver

disease.

4. Consider desmopressin 0.3 micrograms kg-1 in 50 mls normal saline iv over

30 minutes for patients with Von Willebrands disease or renal failure.

4. Recombinant activated factor VIIa (rFVIIa)

This should be considered if:

1. Bleeding does not respond to conventional therapy as described above.

2. Bleeding remains at more than 3-4 units red cells transfused per hour.

The initial dose of rFVIIa is 90 micrograms kg-1 iv. The drug is available in 1.2 and

2.4 mg vials. Round up dose to the nearest whole vial. Maximum single dose 7.2

mg iv. The drug is stored in the blood bank.

Check a coagulation screen before and 15 minutes after giving rFVIIa to monitor its

effect.

Consider one further dose of rFVIIa if bleeding persists.

Request must be made by a consultant and authorised by consul tant

haematologist.

Each use of rFVIIa to be audited and reviewed by the Trust Transfusion

Committee.



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North Bristo l NHS Trust Use of rFV11a Review Form

Date: .. Requesting Consultant: ...Admitting Consultant .

Patient Name:

DOB: Hospital No.

Diagnosis / reason for bleed:

Please identify interventions prior to request for rFVIIa:Surgery YES / NOAngiographic embolisation YES / NO

Correction of hypothermia YES / NOCorrection of acidosis YES / NOCorrection of coagulopathy YES / NOHeparin reversal YES / NOWarfarin reversal YES / NOUse of antifibrinolytic agents YES / NOOther, please specify YES / NO

Blood Products Used: Type Amount Time Given

Results prior to requestHb: Platelet Count:Fibrinogen: PT / INR:Ph Temperature

Outcome:

Signed: ..Please return completed form to the Transfusion Laboratory marked for the

attention of Dr Janet Birchall



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North Bristol NHS Trust Use of rFV11a Review Form, cont inued

Comments of Consultant Haematologist involved:

Signed: ... Date:

Print Name: .



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Management of patients withMassive Bleeding and Coagulopathy


rFVIIa is advised by some guidelines when all other measures have failed to stop l ifethreatening bleeding - evidence that it is effective is inconclusive. It must on ly be used

if agreed by the consultant managing the patient and a consultant haematologist.Please complete and return the form provided for Transfusion Committee review

N.B. fibrinogen MUST be > 0.5g/L bleeding MUST be > 3-4units RBCs/hr

Transfusion support

Fluid resuscitation

Request laboratory tests

Order blood products

Consider haemostaticpack

(4 uni ts FFP, 1 unit

platelets)

Contact key personnel ABCDE approach

Identi fy and arrest bleeding(e.g. surgery, angiographic embolisation)

AppropriateMedical interventions

prevent and reverse hypothermia

prevent and reverse acidosis correct coagulopathy heparin reversal warfarin reversal consider antifibrinolytic agents,

e.g. tranexamic acid / aprotinin

Laboratory Tests

Monitor response to treatmentD/W haematologist

PT, APTT > 1.5 X control 4 units FFPFibrinogen < 1g/L 1-1.5 packs of

cryoprecipitate / 10 kg


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Abstract

This guideline is relevant only to patients with massive bleeding. There is no

universal definition however loss of 50% circulating volume in 3 hours, loss of

greater than 150 ml min-

or loss of a whole blood volume within 24 hours havebeen used. This document aims to provide a simple algorithm to manage these

patients and identifies essential steps in a timely order. The need to correct

hypovolaemia and identify and stop the source of bleeding are obvious. There is

evidence that both hypothermia and acidisis affect coagulation and platelet

function. Although there is little evidence base for the use of coagulation factors in

this setting suggested use complies with national guidelines. Recombinant factor

VIIa (RFVIIa) has been used to treat massive bleeding with variable success andwe propose it should only be used in exceptional circumstances when conventional

management has failed and life threatening bleeding continues.

Background for management of massive haemorrhage(including literature review)

1. ABCDE approach

The Airway, Breathing, Disability, Exposure approach to recognition and treatment

of life threatening emergencies is the mainstay of resuscitation and taught on all

the major life support courses:

Advanced trauma life support. American college of surgeons. 2005.

Advanced life support. Resuscitation Council UK. 2006.

Advanced paediatric life support. The practical approach. Advanced life support

group. 2005.

There have been no formal studies in comparing this approach with others. There

is a commonly held view however that a systematic approach to the sick patients

improves detection of life threatening problems and appropriate treatment.

In clinical practice resuscitation requires a team approach so several interventions

would be ongoing in parallel. The guidelines empahasise a team approach to treat



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massive bleeding. Senior clinicians must be involved as the precise treatment will

need to be based on a case by case basis.

2. Massive bleeding

The patient with massive bleeding requires bleeding to be stopped and restoration

of circulating volume. There is controversy over whether aggressive fluid

resuscitation should occur before or after bleeding is stopped.

Fluid replacement therapy (intravenous infusion of fluid) attempts to reverse the

effects of hypovolaemia by increasing circulatory blood volume and blood pressure

back towards normal, in order to maintain the perfusion of vital organs

and to reduce the risk of death from multiple organ failure. Delaying fluid

replacement is believed to reduce the risk of re-bleeding caused by the

mechanical disruption of blood clots and the dilution of clotting factors, which can

occur, particularly when large volumes of IV fluid are administered.

With this in mind our guidance states that fluid resuscitation should aim to maintain

vital organ perfusion whilst attempts are being made at stopping the bleeding.

3. Use of component therapy

This guidance is based on the most recent national guidance on blood transfusion

and component therapy

References

Blood transfusion and the anesthetist. Blood component therapy. Association of

Anaesthetists of Great Britain & Ireland. 2005.

British Committee for Standards in Haematology, Guidelines for the use of fresh

frozen plasma, cryoprecipitate and cryosupernatant. British J ournal of

Haematology, 2004; 126: 11-28

British Committee for Standards in Haematology, Guidelines for the use of platelet

transfusions. British J ournal of Haematology, 2003;122: 10-23



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Handbook of Transfusion Medicine, Third Edition 2001, The Stationary Office

Summary

The evidence base for many of the interventions in massive haemorrhgae is based

on the conventional wisdom that blood components that promote coagulation will

be helping in bleeding when there is a coagulopathy. There are few or no high level

studies as I doubt they would get ethical approval.

Dr J asmeet Soar

Consultant ICU

J [email protected]

Evidence for the use of recombinant factor VIIa (RFVIIa)

No randomised controlled trials comparing rFVIIa with alternative therapy for the

management of haemorrhage have been published.

Up until the end of 2005 5 randomised controlled trials, comparing recombinant

FVIIa with placebo, to treat severe bleeding have been published (Pihusch,

Chuansumrit, Boffard, Bosch and Mayer). There is significant heterogeneity

between the tials because of the diversity of the clinical settings, dose of rFVIIaused and schedule of prescription. Pihusch looked at patients post haemopoietic

stem cell transplant and used doses up to 160g/kg with a total of 7 doses per

patient. Chuansumrit considered children with Dengue haemorrhagic fever grade II

or III and used 1 to 2 doses of 100g/kg. Boffard studied severe trauma patients,

divided them into blunt or penetrating trauma, and used an intial dose of 200g/kg

then 2 further doses of 100g/kg. Bosch looked at acute upper gastrointestinal

bleeding in patients with cirrhosis and used 8 doses of 100g/kg. Mayerconsidered patients with intracranial haemorrhage and used one dose of up to

160g/kg. All of these trials allowed the use of standard, alternative haemostatic

agents/interventions. In 4 trials the primary end point was related to measuring a

change in bleeding (Pihusch, Chuansumrit, Bosch and Mayer). Boffard used blood

transfusion requirement. Sample size calculations, when performed, were based

on the expectation that a large change would be achieved by rFVIIa. 3 trials

reported on adequate methods of randomisation (Pihusch, Bosch and Mayer) and

mailto:[email protected]:[email protected]


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some attempts at blinding were made. All trials were supported by Novo Nordisk

the manufacturers of rFVIIa.

The main results are shown in the tables below

Mortality (patient numbers)Study

Pihusch 40g/kg 80g/kg 160g/kg placebo

8 deaths/20 7 deaths/26 9 deaths/31 7 deaths/23

Chuansumrit None of the patients died. No follow up period stated.

Boffard blunt rFVIIa placebo

17 deaths / 69 22 deaths / 74

Boffard

penetrating

rFVIIa placebo

17 deaths/ 70 18 deaths/ 64

Bosch rFVIIa placebo16 deaths/116 11 death/120

Mayer 40g/kg 80g/kg 160g/kg placebo

19 deaths/108 17 deaths/92 20 deaths/103 28 deaths/ 96

Control of bleeding

Study

Pihusch 40g/kg 80g/kg 160g/kg placebo

stopped 6/20 14/26 4/30 5/22

decreased 4/20 7/26 9/30 8/22

Same/worse 10/20 5/26 17/30 9/22

Chuansumrit rFVIIa placebo

Stopped 2hrs

Stopped 24hrs

12/16

11/16

4/9

6/9

Decreased 2hs

Decreased 24hrs

3/16

4/16

1/9

3/9

Same/worse 2hrs

Same/worse 24hrs

1/16

1/16

4/9

0/9

Boffard blunt No data on control of bleeding/ blood loss

Boffard - penetrating No data on control of bleeding/ blood loss

Bosch RFVIIa placeboFailure to control bleeding 5 d 16/118 19/119

No bleed control < 24hrs 6/120 10/119

Rebleed within 5 days 9/116 10/116


% change in vol (mls) of ICH at

1 end point - mean (98.3% CI)

16 (4-28) 14 (2-27) 11 (0-23) 29 (16-44)



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Total red cell transfusion requirements (total/allogeneic; units or mls)

Study

Pihusch data provided

Chuansumrit rFVIIa placebo

Volume of RBC in thosetransfused/24 hrs median

mls/kg. (inter quartile range)

15.5(5.2-45.8)

10(5.4-10)


1end point - patients who died

assigned worst outcome

median RBC unit (range)

7.8 (0-48) 7.2 (0-35)

Boffard penetrating rFVIIa placebo

1end point - patients who died

assigned worst outcome

median RBC unit (range)

4 (0-37) 4.8 (0-41)

Bosch rFVIIa placebo

RBC units within 24hrs

RBC units within 5 days

Mean +/- SD

0.9 +/- 1.8

1.5 +/ 3.7

0.7 +/- 1.2

1.3 +/- 1.9


No transfusion requirement

Adverse events/number of patients total thromboembolic (TE), including

cardiovascular (MI) or stroke (CI) if seperately described

StudyPihusch 40g/kg 80g/kg 160g/kg placebo

1/20 TE

1/20 CI

1/26 MI

1/26 CI

3/31 TE

1/31 MI

0/23 TE

Chuansumrit N TE disease identified


2/69 TE 3/74 TE

Boffard

penetrating

rFVIIa placebo

3/70 TE

1/70 CI

2/64 TE

1/64 CIBosch rFVIIa placebo

5/121 TE

2/121 CI

7/121 TE


VenousTE 1/108 2/92 2/103 2/ 96

Either MI or

CI

6/108 2/92 8/103 0/96

In Mayer treatment group 7 MI and 9 CI.



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2 trials, Mayer and Chuansumrit, identified significant reduced bleeding with rFVIIa

compared with placebo according to the initial study primary end point. However in

the study by Chuansumrit the numbers were small, no platelets for transfusion

were initially avaliable and by 24 hours post study drug the effect was lost. In the

Mayer trial the exclusion criteria were wide and amended half way through the

study to exclude all patients with previous thromboembolic disease. Boffard found

a significant difference between rFVIIa in the group with blunt trauma at 48 hours

post study drug in an ad hoc analysis considering only those patients alive at

48hours rather than all patients at 48 hours. Similarly Pihusch and Bosch noted

significant differences between the treatment and control groups when ad hoc

analysis were performed for the 80/kg dose and grade of cirrhosis respectively. In

the Pihusch study it is difficult to see how a dose of 80/kg can reduce bleeding but

not a dose of 160/kg and differences in the poulation characteristics between

groups is likely.

Pihusch and Mayer reported an increased incidence of thromboembolic events,

including MI and cerebral infarct however according to their own study criteria none

of these differences reached statistical significance.

Summary

The use of rFVIIa compared to placebo in controlling bleeding in non haemophiliac

patients has been disappointing. There was a trend towards an increased

incidence of thromboembolic disease in 2 studies. The exact circumstances in

which rFVIIa is of value and its safety profile therefore remain to be defined and at

present it should only be used after all other standard treatments have been tried.



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ReferencesPihusch M, Bacigalupo A, Szer J , Von Depka Prondzinksi M, Gaspar-Blaudschun

B, Hyveled L, Brenner B. Recombinant activated factor VII in treatment of bleeding

complications following hematopoietic stem cell transplantation. J ournal of

Thrombosis and Haemostasis 2005;3:1935-1944.

Chuansumrit A, Wangruangsatid S, Lektrakul Y, Ng Chua M, Capeding MRZ, Bech

OM, the Dengue Study Group. Control of bleeding in children with Dengue

hemorrhagic fever using recombinant activated factor VII: a randomized double-

blind, placebo-controlled study. Blood Coagulation and Fibrinolysis 2005;16(8):

549-555.

Boffard KD, Riou B, Warren B, Choong PIT, Rizoli S, Rossaint R, Axelsen M,

Kluger Y. Recombinant Factor VIIa as adjunctive therapy for bleeding control in

severely injured trauma patients: Two parallel randomized, placebo-controlled,

double-blind clinical trials. The J ournal of Trauma Injury, Infection and Critical

Care 2005; 59: 8-18.

Bosch J , Thabut D, Bendtsen F, DAmico G, Albillos A, Abraldes J G, Fabricius S,Erhardtsen E, De Franchis R. Recombinant factor VIIa for upper gastrointestinal

bleeding in patients with cirrhosis: A randomized, double-blind trial.

Gastroenterology 2004;127:1123-1130.

Mayer SA, Brun NC, Begtrup K, Broderick J , Davis S, Diringer MN, Skolnick BE,

Steiner T. Recombinant activated factor VII for acute intracerebral hemorrhage.

The New England J ournal of Medicine 2005:352:777-785.

Dr J anet Birchall

Consultant in Transfusion Medicine

J [email protected]


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