Post on 23-Aug-2019
transcript
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.