Neuraxial blocks and anticoagulation with LMWH in obstetrics:

SAOA Fall meeting / SSAR 2010

Lausanne - November 4, 2010

case report and recommendations

Georges Savoldelli

Médecin Adjoint

Unité d’anesthésiologie gynéco-obstétricale

Service d’Anesthésiologie

Hôpitaux Universitaires de Genève, Suisse

Plan

1. Interactive presentation of a case report

2. Review of the current recommendations

3. Discussion

Before the case report:

Some preliminary questions…Some preliminary questions…

A surgical patient with a normal renal function receives

prophylactic sc LMWH (eg. Enoxaparin 40 mg/j sc).

After the last LMWH dose, what time interval do you wait

before performing a neuraxial blockade?

8% 1. 6h

2. 10h

1%

0%

86%

4% 2. 10h

3. 12h

4. 18h

5. 24h

Prophylactic LMWH

In addition to respecting this time interval, do you monitor the

anti-factor Xa activity before performing the neuraxial block ?

97%

1. Yes

Yes N

o

3%

2. No

A surgical patient with a normal renal function receives

therapeutic sc LMWH (Enoxaparin 60 mg bid or 1mg/kg bid).

After the last LMWH dose, what time interval do you wait

before performing a neuraxial blockade?

5% 1. 12h

2. 18h

3%

4%

84%

4% 2. 18h

3. 24h

4. 36h

5. 48h

Therapeutic LMWH

In addition to respecting this delay, do you monitor the

anti-factor Xa activity before performing the neuraxial block ?

86%

1. Oui

Oui

Non

14%

2. Non

In general, would you consider shorter time intervals if you

perform a spinal block instead of an epidural block ?

72%1. Yes

Yes N

o

28%

2. No

“Recommendations regarding the management of LMWH and

neuraxial blocks are identical for parturient and for the surgical

patient population”

60%1. True

Tru

e

Fals

e

Don

’t kno

w

8%

32%

1. True

2. False

3. Don’t know

Case report

• 34 y-old pregnant woman G3 P3

• Family Hx of DVT and PTE (father, sister : Factor II mutation;

and mother)

• Hx of superficial vein thrombosis in 1999 (airplane travel)

• 1999: complete thrombophilia search remain negative• 1999: complete thrombophilia search remain negative

• 2004: 1st pregnancy prophylactic LMWH, normal VD

• 2005: 2nd pregnancy ( twin), normal VD

• Present History:

– Twin pregnancy

– During the 1er trimester: rapid ↑ D-dimer

Case report (continued)

• Attitude:

– 10 weeks’ gestation: Fragmin®(Dalteparin) 5000 U q.d. sc

– 30 weeks’s gestation: Dalteparin↑7500 q.d. sc

– Anti-factor Xa activity = 0.56 U/ml, 4h after sc LMWH

(adequate for intermediate dosage for her weight) (adequate for intermediate dosage for her weight)

– @ 36 weeks’ gestation → Enoxaparin 40 mg b.i.d. sc

(intermediate dosage for her weight)

– Admitted @ 38 weeks’ gestation for induction of labor

Case report (continued)

• Last sc dose of Enoxaparin 40mg was given on the evening

(8:00 pm) the day before induction of labor

• 8:00 am: admitted in L&D room for induction• 8:00 am: admitted in L&D room for induction

• 8:30 am: Receives misoprostol

• 8:45 am: Early epidural analgesia is requested by the OB…

Before performing an epidural block in this patient, what time

interval would you wait after the last sc dose

of Enoxaparin 40 mg?

(she usually takes 40mg bid = intermediate dosage)

3%

1% 1. 6h

2. 8h

32%

17%

47% 3. 12h

4. 18h

5. 24h

In addition to respecting this time interval, would you monitor

the anti-factor Xa activity before performing the epidural ?

69%1. Yes

Yes N

o

31%

2. No

Case report (continued)

• 8:45 am: Staff anesthesiologist ask for dosage of anti-factor

Xa (i.e. 13h after the last LMWH dose)

• Results arrive at 11:00 am: 0.75 UI/ml (= therapeutic • Results arrive at 11:00 am: 0.75 UI/ml (= therapeutic

concentration) !

• Meanwhile:

– the patient has received some misoprostol

– modification of her cervix has begun

– rupture of membranes has occurred…

Therapeutic range of anti-factor Xa activity for sc

enoxaparin treatment

Once daily

prophylactic

Twice daily

therapeutic

Once daily

Therapeutic

Anti-Xa UI/ml draw

4 hrs after injection

0.2 - 0.4 0.5 - 1.0 1.0 - 2.0

What would you do?

(more than one possible answer)

18%

3% 1. Put the epidural in

2. Wait 12 hours and put the epidural in

10%

45%

25% 3. Re-dose the anti-factor Xa activity

4. Call the hematologists

5. Give some protamine

Case report (continued)

• Induction of labor was stopped

• Heamatologist was called

• 2nd dosage of anti-factor Xa activity @ 1:05 pm (17h after

last dose of sc LMWH)

• Results: 0.49 UI/ml (still therapeutic !)

The patient is not in active labor but the membranes

are ruptured. What would you do?

(one possible answer)

17% 1. The hematologist decides

2. Follow the anti-factor Xa activity

3%

10%

19%

51% 2. Follow the anti-factor Xa activity

3. Cesarean section under GA

4. Transfer the patient to the CHUV

5. I quit this job…

Anti-Xa

0.5

0.6

0.7

0.8

Evolution the anti-factor Xa activity before

vaginal delivery

Anti-factor Xa activity detectable X

a ac

tivity

0

0.1

0.2

0.3

0.4

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75

↑

EpiduralBlock

↑↑Last dose of

Enoxaparin 40mg sc

activity detectable 55h post injection !

Vaginal delivery

Ant

i-fac

tor

–Xa

activ

ity

(hours)

Expected Kinetic

Case report (continued)

• Vaginal delivery occurred 49h after the last dose of sc LMWH

• No complications, no PPH

• Epidural catheter was withdrawn 2 hours after delivery

• 6 hours after delivery, anti-factor Xa activity was 0.1 UI/ml !

In general after performing a neuraxial block, what time

interval do you wait before administering the first dose of sc

prophylactic LMWH?

40%

16% 1. 2h

2. 4h

1%

10%

33%

40% 2. 4h

3. 6h

4. 12h

5. >12h

After vaginal delivery in this patient at risk, what time

interval will you wait before administering the first

dose of sc LMWH?

41%

33% 1. 4h

2. 6h

11%

3%

13%

41% 2. 6h

3. 8h

4. 10h

5. 12h

For the postpartum period, what regimen of

thromboprophylaxis would you use in this patient?

20%

17% 1. Enoxaparin 40 mg b.i.d

2. Enoxaparin 40 mg q.d.

8%

45%

9%

20% 2. Enoxaparin 40 mg q.d.

3. UFH 5000 U t.i.d

4. Exoxaparin titrated according to anti-Xa

5. Other regimen

Anti-Xa

0.50

0.60

0.70

0.80

Evolution the anti-factor Xa activity after deliveryX

a ac

tivity

↑Enoxaparin 40mg sc

0.00

0.10

0.20

0.30

0.40

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77

Ant

i-fac

tor

–Xa

activ

ity

(hours)

Pharmacokinetics properties of Enoxaparin

• Elimination half-life is linear and independent of the dose:

= 4.36 h (SD± 1.07h) for single daily injection

= 7h for repeated in case of repeated injections

• Anti factor-Xa activity half-life = 4.1 h

• In pregnancy:

– LMWH do not cross the placenta in any trimester

– Elimination is usually increased (due to ↑GFR)

Anti-Xa

0.5

0.6

0.7

0.8

Evolution the anti-factor Xa activity before

vaginal delivery

Anti-factor Xa activity detectable X

a ac

tivity

0

0.1

0.2

0.3

0.4

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75

↑

EpiduralBlock

↑↑Last dose of

Enoxaparin 40mg sc

activity detectable 55h post injection !

Vaginal delivery

Ant

i-fac

tor

–Xa

activ

ity

(hours)

Expected Kinetic

Typical anti-Xa kinetics profile after sc enoxaparin

40mg relative to pregnancy and gestational age

Our patient @ immediate post partum !Higher peak effect

Clinical Pharmacology & Therapeutics (2008); 84, 3, 370–377

Higher residual concentration

after 24 h

Attempted explanations for this unusual

kinetics of the Enoxaparin

• GFR was normal

• Error of administration: excluded

• Drug conditioning error (concentration): excluded

• Literature review: no such case reported (extensive revue by

us, pharmacologists and hematologists)us, pharmacologists and hematologists)

• Hypotheses:

– Possible modification of metabolism during 3rd trim (however in

general ↓ half-life due to ↑GFR)

– Tissue accumulation ? (known for UFH) →

– Biphasic elimination (non-linear) at the end of pregnancy?

– Linked to this patient? Linked to the pregnant state ?

Review of the current

recommendationsrecommendations

And some more questions …

Spinal Hematoma in the Obstetric Patient:

some facts and uncertainties

• The frequency of spinal hematomas in the OB population is unknown

• OB patients have a significantly lower incidence of complications than

their elderly counterparts

• Estimated risk of spinal hematoma after OB epidural blockade:

1/100’000 - 1/200’0001/100’000 - 1/200’000

• Bleeding in OB patients may occur in the absence of a neuraxial block (at least 9 cases reported in the literature)

• To date, only one published case of spontaneous spinal hematoma in a

parturient anticoagulated with LMWH

(factor V Leiden + anticardiolipin, @ 27 Week gestation without NB block)

Reg Anesth Pain Med 2010;35: 64-101

American Society of Regional Anesthesia and Pain Medicine

Evidence-Based Guidelines (Third Edition)

(Reg Anesth Pain Med 2010;35: 64-101)

Among the published case reports of parturients who have experienced a spinal

hematoma after neuraxial blockade, a significant proportion of patients had

altered coagulation at the time of block placement or epidural catheter removal

(Table 12).

To date, there have been no published cases of spinal hematoma in a parturient

associated with antithrombotic therapy (with or without neuraxial block)!

Is there any special recommendation for the

management of the anticoagulated parturient

compared to the surgical patients population ?

10.1 “In the absence of a large series of neuraxial techniques in

the pregnant population receiving prophylaxis or treatment of

venous thromboembolism, we suggest that the ASRA venous thromboembolism, we suggest that the ASRA

guidelines (derived from mainly from surgical patients) be

applied to parturients (Grade 2C).”

Reg Anesth Pain Med 2010;35: 102-105

What is the recommended time interval before

initiating a neuraxial block after a single daily dose of

prophylactic sc enoxaparin 40 mg?

ASRA SFAR GSA Austria Belgium NetherlandsASRA

2010

SFAR

2006

GSA

2007

Austria

2005

Belgium

2005

Netherlands

2003

10-12 hrs* 10-12 hrs 10-12 hrs 12 hrs 12 hrs 10 hrs

*USA: if sc Enoxaparin 30 mg bid is used, interval = 24h

What is the recommended time interval before

initiating a neuraxial block after therapeutic sc LMWH

(eg. enoxaparin 60mg bid or 1mg/kg bid)

ASRA SFAR GSA Austria Belgium NetherlandsASRA

2010

SFAR

2006

GSA

2007

Austria

2005

Belgium

2005

Netherlands

2003

at least 24 h(Contra-

indicated in

2005)

24 hrs 24 hrs 24 hrs 24 hrs 24 hrs

After a neuraxial block, what is the recommended

time interval before initiating a single daily dose of

prophylactic sc enoxaparin 40 mg?

ASRA SFAR GSA Austria Belgium NetherlandsASRA

2010

SFAR

2006

GSA

2007

Austria

2005

Belgium

2005

Netherlands

2003

6-8 hrs 4-12 hrs 4 hrs 4 hrs 4 hrs 2 hrs

Is it safe to provide postoperative analgesia via an

indwelling neuraxial catheter if the patient is receiving

single daily dose of prophylactic sc enoxaparin 40 mg ?

ASRA SFAR GSA Austria Belgium NetherlandsASRA

2010

SFAR

2006

GSA

2007

Austria

2005

Belgium

2005

Netherlands

2003

YESbut no

additional

hemostasis-

altering

medications

(including

NSAID)

YES YES

but if on

NSAID

hold

LMWH

YES YES YES

• 4.2 Antiplatelet or oral anticoagulant medications

administered in combination with LMWH increase the risk of administered in combination with LMWH increase the risk of

spinal hematoma. Education of the entire patient care team is

necessary to avoid potentiation of the anticoagulant effects.

We recommend against concomitant administration of

medications affecting hemostasis, such as antiplatelet drugs,

standard heparin, or dextran, regardless of LMWH dosing

regimen (Grade 1A).

Before removing an epidural catheter, what time interval do

you wait after the last dose of sc prophylactic LMWH?

10%

6% 1. 4h

2. 6h

0%

84%

0%

10% 2. 6h

3. 10h

4. 12h

5. >12h

After removing an epidural catheter, what time interval do you

wait before administering the first dose of sc prophylactic

LMWH?

44%

9% 1. 2h

2. 4h

2%

17%

29%

44% 2. 4h

3. 6h

4. 12h

5. >12h

Current recommendations for LMWH

• Recommended time intervals for the time

– before neuraxial blockade or catheter withdrawal are

identical (i.e.: 12h)

– after neuraxial blockade or catheter withdrawal are

identical (i.e.: 4h)

• With very few exceptions …

– “Administration of LMWH should be delayed for 2 hrs after catheter

removal” ASRA 2010.

For the thromboprophylaxis after a C-section under spinal

anesthesia, what sc LMWH daily dose thromboprophylaxis do

you use for a 75 kg low risk patient ?

25%25%

1. Enoxaparin (Clexane ®) 2’000 UI anti-Xa/0,2 ml or

Dalteparin (Fragmin®) 2’500 UI anti-Xa/0,2 ml or

Nadroparin (Fraxparine®) 2’850 U.I. anti-Xa/0.3 ml

25%25%

1 2 3 4

2. Enoxaparin (Clexane ®) 4’000 UI anti-Xa/0,4 ml or

Dalteparin (Fragmin®) 5’000 UI anti-Xa/0,2 ml or

Nadroparin(Fraxparine®) 3’800 U.I. anti-Xa/0.4 ml

3. Other dosage of LMWH or UFH

4. No LMWH, but stockings or pneumatic compression

devices and/or early ambulation

Similarrecommendations

Switzerland:LMWH prophylaxis

is systematic after CS

After a Cesarean delivery under spinal anesthesia, what time

interval do you wait before administering the first dose of sc

prophylactic LMWH (once daily dosage)?

18%

29% 1. 4 hrs after the spinal block

2. 4 hrs after the end of C-section

3. 6 hrs after the spinal block

2%

2%

2%

39%

9% 3. 6 hrs after the spinal block

4. 6 hrs after the end of C-section

5. 8 hrs after the spinal block

6. 8 hrs after the end of C-section

7. other

Are the ASRA 2010 Guidelines and the ASRA 2010

executive summary in contradiction with each other

regarding post-operative administration of LMWH ?

10.1 “In the absence of a large series of neuraxial techniques in the pregnant

population receiving prophylaxis or treatment of venous thromboembolism,

we suggest that the ASRA guidelines (derived from mainly from surgical

patients) be applied to parturients (Grade 2C).”

Executive summary; Reg Anesth Pain Med 2010;35: 102-105

Are the ASRA 2010 Guidelines and the ASRA 2010

executive summary in contradiction with each other

regarding post-operative administration of LMWH ?

Full ASRA 2010 guidelines

Surgical patients Obstetric section

Post-op time interval at least 12 hrs after Post-op time interval

before single daily dose of

prophylactic LMWH

6-8 hrs

at least 12 hrs after

abdominal delivery, or

epidural removal,

whichever is later

Cesarean delivery by extrapolation 6-8 hrs at least 24 hrs

How long should we wait after a C-section ? Confusi ng no ?At the HUG, we do wait at least 6h after the end of the C-section

Vaginal ?

You have performed a spinal anesthesia for a C-section and you

have noticed blood during first needle placement but the

second attempt was successful and CSF was clear.

Do you postpone the first post-op dose of sc prophylactic

LMWH (once daily dosage)?

1. YES

0%

85%

15% 1. YES

2. NO

3. Don’t know

Recommended time interval before the initiation of

LMWH in case of blood during needle and/or catheter

placement during neuraxial block

ASRA

2010

SFAR

20062010 2006

24 hthis consideration be discussed with the

surgeon

24 h

In addition to these delays, is it recommended to

monitor the anti Xa activity before performing a

neuraxial block ?

4.1 “The anti-Xa level is not predictive of the risk of bleeding. We

recommend against the routine use of monitoring of the anti-Xa level

(Grade 1A).”

Reg Anesth Pain Med 2010;35: 102-105Reg Anesth Pain Med 2010;35: 102-105

• Most current guidelines do not recommend the use of anti-Xa activity

monitoring excepted in the presence of renal impairment.

Summary of recommendations

• Prophylactic LMWH: delay NB or KT removal for at least 12h.

• Therapeutic LMWH or twice daily dosage: delay NB for at least 24h.

• After NB or KT removal: delay prophylactic LMWH for at least 4 h

• After NB or KT removal: delay therapeutic LMWH for at least 24h

• Maintaining an indwelling neuraxial catheter with twice-daily dose

and/or therapeutic LMWH are not recommended.

• Indwelling catheter and single-daily dose of prophylactic LMWH are

acceptable but some recommend withholding NSAIDs in this situation

Summary of recommendations

• After C-section, delay the first postoperative dose of prophylactic LMWH

for at least 6-8 hrs (Risk of PPH is of bigger concern than spinal

hematoma)

• In case of blood during needle and/or catheter placement during

neuraxial block, delay LMWH for at least 24 h neuraxial block, delay LMWH for at least 24 h

• Monitoring the anti-factor Xa activity before NB or KT removal is

currently not recommended if GFR is normal

Attitude at the HUG after this unusual case

@ ≈ 37 SAanti-Xa activity

12h after sc LMWH

Pregnant ♀ andProphylactic LMWH

< 0.1 UI/ml ≥ 0.1 UI/mlNo dosageavailable

Time interval before NB = 12hØ anti-Xa dosage

If interval ≥ 24h↓

NB OK

If interval < 24h↓

Dosage of anti-XaDosage of anti-Xa

after 16 hand consult

Haematologists

Discussion

Thank you for your attention !!

• The peripartum management of the anticoagulated parturient represents a

significant clinical challenge to both the obstetrician and the anesthesiologist.

• There is a paucity of data regarding the efficacy of anticoagulants in pregnancy.

Recommendations are based largely on small case series and case reports.

• From the neuraxial anesthetic standpoint, there is even less information regarding

American Society of Regional Anesthesia and Pain Medicine

Evidence-Based Guidelines (Third Edition)

(Reg Anesth Pain Med 2010;35: 64-101)

• From the neuraxial anesthetic standpoint, there is even less information regarding

safety or risk.

• In addition, the lack of a suitable alternative to labor analgesia, as well as the

desire for women to participate in the birth during cesarean delivery further

complicates management decisions.

• Finally, the administration of LMWH (which is preferred over UFH) during

pregnancy is an off-label application.

• Without manufacturer-specified dosing guidelines, the management may

markedly vary even within an institution, further complicating patient care.