ASRA stands for the American Society for Regional Anesthesia, and they have developed evidence-based guidelines regarding neuraxial anesthesia in patients taking medications that might induce a coagulopathy. That is what we will be discussing today.
This is the anesthesia preoperative evaluation of the patient that we will be discussing today. As you can see, she has history of a partially occlusive left femoral DVT and was on heparin 10,000u TID at the time of presentation.
This brought up a question of when we could safely perform neuraxial anesthesia on this patient. So it was decided to use this opportunity today to discuss the most recent ASRA guidelines regarding neuraxial anesthesia.
This is the article we will be discussing today, published in Regional Anesthesia and Pain Medicine early this year. As you can see, the article is rather long, and filled with studies and literature that the group used to come up with their evidence-based recommendations. We will go over some of that literature today… some in more detail than others.
After each of the recommendations later in the presentation, you will see a grade consisting of a number and a letter. Before we get too far into it, I wanted to go over what these grades mean. Letters refer to the strength of evidence, while numbers refer to the general agreement. (Read the slide)
First, let’s go over the complication we are attempting to avoid…
Another study, a large study done in Sweden, found that age, presence of coagulopathy, difficult needle placement, and presence of an indwelling catheter during sustained anticoagulation are all variables contributing to the multifactorial manner in which risk of clinically significant bleeding varies.
ASA Closed Claims database shows similar data: increased motor block (83%) vs. back pain (25%). Importantly, the presence of postoperative numbness or weakness was typically attributed to local anesthetic effect, which delayed the diagnosis.
This presents an important point for us to remember: Progression of motor block should not be ignored because we are on a time limit!
So, why would parturients need to be placed on antithrombotic therapy in the first place?
This is the first guideline that we will discuss today. It is out of order (as evidenced by the number 10), but it deals with the parturient, so I felt as though I should mention it first.
This just says that the parturient is no different than the non-parturient in terms of risk for spinal hematoma with neuraxial anesthesia, and so depite the fact that the guidelines we discuss today were developed for the non-pregnant patient, they are very much relevant to us as well.
Just a quick review of heparin…
The pentasaccharide sequence is responsible for binding antithrombin, and the large tail wraps around and makes AT more effective at inactivating the very large thrombin molecule. You can see here why the larger molecule might be better at inhibiting both thrombin and Xa. We’ll talk about this a bit more when we go over the low-molecular weight heparins.
The fact that the onset time of SQ administration is 1-2 hours, means that previous recommendations to wait at least 2 hours after SQ administration to perform any neuraxial anesthesia, may actually correlate with peak effect. Clinical experience shows better outcome waiting more than two hours after, even with the prophylactic BID heparin.
You can see here the results of a similar study by Stafford-Smith. The risk of spinal hematoma dramatically increased with heparin and traumatic placement, heparin <1 hr after puncture, and heparin plus aspirin. This differs from the previous study in that the risk factor is administration of heparin AFTER puncture as opposed to the administration of heparin given before puncture.
Prophylactic regimens of 5000u BID (NOT TID) represents no contraindication to neuraxial anesthesia. Remember, it is still probably best to wait at least 2 hours after the last dose and wait at least 1 hour after needle placement to the next dose.
Guideline 3.5 refers to systemic heparinization, such as with vascular surgery. I included it in this talk because it refers to heparinization with an indwelling catheter in place.
Guideline 3.6 is specific for full anticoagulation such as that required to go on cardiopulmonary bypass and has been left out of this presentation.
From the figure here you can see why low molecular wt heparins are not as effective at neutralizing thrombin as unfractionated heparin. Xa is a much smaller molecule than thrombin.
Protamine preferentially neutralizes more anti-IIa, and less anti-Xa, so LMWH are inadequately reversed with protamine.
Anti-Xa levels do not seem to correspond directly to anticoagulant effect
To me, this says that the BID dosing that we use so often here is associated with a much higher risk of spinal hematoma than once daily dosing. But we’ll get to that in a minute.
4.4.1 These are thromboprophylactic doses, NOT treatment doses.
4.4.2 BID dosing, even if for thromboprophylaxis, carries with it an increased risk of spinal hematoma. Therefore, any BID dosing would fall under these recommendations.
The fibrinolytic system dissolved intravascular clots as a result of the action of plasmin. Plasmin is produced by the cleavage of a single peptide bond of the inactive precursor, plasminogen. The resulting compound is a nonspecific protease capable of dissolving fibrin clots. Exogenous plasminogen activators, such as streptokinase and urokinase, dissolve thrombus, but also affect circluating plasminogen as well. Endogenous tissue plasminogen activator formulations, such as Alteplase, are more fibrin-selective. Clot lysis leads to elevation of fibrin degradation products, which themselves have an anticoagulant effect. The plasma half-life of these meds is typically only hours, but it may take days for the thrombolytic effect to resolve. Fibrinogen and plasminogen are maximally depressed at 5 hours, but may remain significantly depressed at 27 hours.
Much of what we know about neuraxial anesthesia and thrombolytic therapy is based on case reports, such as this one.
So, avoid thrombolytic drugs for at least 10 days after neuraxial anesthesia, and avoid neuraxial anesthesia in patients with recent thrombolytic therapy, with no clear recommendation for length of time.
What this means is that an INR of 1.5 in the initial phase of coumadin therapy corresponds to normal hemostasis. The corollary to this is that the early recovery of factor 7, may correspond to an INR of 1.5, but factors 2 and 10 may lag behind for several days. So that is just something to keep in mind.
ASRA Guidelines for Neuraxial
Amy Powers Woods, M.D.
Department of Anesthesiology, UTSW
August 25, 2010
To summarize anesthesia preop…
• 38 yo G4P3 at 38 wks gestation
– A1 Diabetes Mellitus
– Previous C-section x3
– Hx of partially occlusive femoral DVT in LLE
• Was on Lovenox until 7/12/10
• Changed to Heparin 10,000u SQ TID
– Last dose 7/29 at 1330
– Desires permanent sterilization
– Physical exam unremarkable, VSS
– Most recent labs 7/12/10 Hct 30.1
• Presented on 7/30/2010 for repeat C-section/BTL
Third Consensus Conference on Regional Anesthesia and Anticoagulation
As published in Regional Anesthesia and Pain Medicine, Vol 35, No 1,
January-February 2010, pp 64-101
Strength and Grade of ASRA
• Strength of Evidence
– A: Randomized, clinical trials and meta-analyses
– B: Observational and epidemiologic studies
– C: Case reports and expert opinion
• Grade of Recommendation
– 1: General agreement in efficacy
– 2: Conflicting evidence or opinion on the usefulness
– 3: General agreement that procedure is not useful
(and may be harmful)
• Definition: Symptomatic bleeding within the
• Actual incidence of spinal hematoma is unknown
– Extensive literature search by M. Tryba (1993)
• 13 cases after 850,000 epidural anesthetics (<1:150,000)
• 7 cases after 650,000 spinal anesthetics (<1:220,000)
– Study was prior to routine thromboprophylaxis
• Recent epidemiologic surveys suggest the risk is higher
Risk Factors for Spinal Hematoma
• Literature review (1906 – 1994) by Vandermeulen et al
– 61 cases of spinal hematoma associated with epidural or
spinal anesthesia (60% in most recent decade)
• 42 of 61 (68%) had evidence of hemostatic abnormality
– 25 had heparin (UFH or LMWH), additional 5 PRESUMABLY had
heparin (vascular procedures, etc.)
– 12 had evidence of coagulopathy, thrombocytopenia, or were
treated with antiplatelet medications, oral anticoagulants,
thrombolytics, or dextran 70 immediately before or after neuraxial
• 15 of 61 (25%) needle or catheter placement difficult
• 15 of 61 (25%) needle or catheter placement bloody
– Overall, 53 of 61 (87%) either a clotting abnormality or
needle placement difficulty was present.
Neurologic Outcome with Spinal
• Vandermeulen’s literature
– Neurologic outcome reported
for 55 of 61 cases
• Progression of sensory or
motor block (68%)
• Bowel or bladder dysfunction
• NOT severe radicular back
– Spinal cord ischemia tended
to be reversible in pts who
within EIGHT hrs of onset of
Antithrombotic Therapy and
• Parturients 5 to 50x more likely to develop VTE
than non-pregnant counterparts
• PE continues to be one of the most common
causes of maternal death in U.S. and U.K.
• Risk factors for VTE in parturients include
increasing age, prolonged immobilization,
obesity, thrombophilia, previous VTE, and C-
• The six-week period following delivery has an
even higher rate of thrombosis and PE than
Unfractionated IV and SQ Heparin
• Heparin binds antithrombin (AT) and
accelerates its ability to inactivate thrombin
(factor IIa), factor Xa, and factor IXa
• Larger molecular wt heparins will inhibit both
IIa and Xa, while smaller wts only inhibit Xa
Unfractionated IV and SQ Heparin
• Onset of action
– IV – immediate onset of action
– SQ – 1-2 hrs delayed **
• Half-life is 60-90 minutes
• Anticoagulant effect
– Both dose- and molecular size-dependent
– Not linear, increases disproportionately with
– Monitored with aPTT (1.5-2x normal)
– Reversed with protamine (1mg to every 100u)
Risk Factors for Spinal Hematoma in
the Heparinized Patient
• Ruff and Dougherty (1981)
– 342 pts who received therapeutic heparin after
• 7 of 342 developed spinal hematomas
• 3 risk factors identified
– Less than 60-minute time interval between administration of
heparin and lumbar puncture
– Traumatic needle placement
– Concomitant use of other anticoagulants (aspirin)
• Risk factors verified in subsequent reviews of
Stafford-Smith M. Impaired haemostasis and regional
anesthesia. Can J Anaesth. 1996; 43: R129-141.
Low-Molecular Weight Heparin
• Properties different
– Inability to monitor
– Prolonged half-life (3-
– Incomplete reversal
– Prolonged therapy
Neuraxial Anesthesia in the Patient
• Bergqvist et al (1992 & 1993)
– European study
– 19 articles involving 9013 pts who received LMWH
thromboprophylaxis and neuraxial anesthesia
– ONE case of spinal hematoma was reported
– Important note: European dosing is once daily
• May 1993: U.S.A. approved dosing regimen 30mg
every 12 hours
– Nearly 60 spinal hematomas were tallied by FDA from
1993 to 1998!
Risk Factors for Spinal Hematomas
With LMWH Thromboprophylaxis
Fibrinolytic and Thrombolytic Therapy
• Plasma half-life of
these meds is only
may last days
• Max depression of
plasminogen at 5
• Contraindication to
includes surgery OR
puncture of non-
within 10 days
• An 84 yo man received an uncomplicated
epidural steroid injection in the morning. He
developed chest pain later that day, was
admitted to the hospital, diagnosed with
acute myocardial infarction, and treated with
tissue plasminogen activator and heparin. He
subsequently developed back pain and
paraplegia. MRI demonstrated an epidural
hematoma extending from T10 to the sacrum.
• Avoid thrombolytic drugs for at least 10 days
after puncture of noncompressible vessels
• Avoid neuraxial anesthesia in pts with recent
thrombolytic therapy (no clear timeline)
• Perform frequent neuro checks (no less than q
2hrs) when thrombolytic therapy is given
unexpectedly to pt with recent neuraxial
• Check a fibrinogen level prior to removal of
Oral Anticoagulants (Warfarin)
• Interferes with the synthesis of
vitamin K-dependent clotting
factors (II, VII, IX, X)
• Clinical experience suggests
40% factor necessary for
• INR of 1.5 corresponds to 40%
of Factor VII
• Warfarin should be stopped for 4-5 days AND the
INR normalized (<1.5) prior to neuraxial
• PT/INR should be checked daily if warfarin and
neuraxial catheter are used concurrently
– PT/INR should be checked before catheter removal if
the last dose were within 36 hrs
– Catheter removal may be attempted when INR is < 1.5
• If INR were >3, the next dose of warfarin may
need to be withheld for an indwelling catheter
• NSAIDs (and aspirin) represent no significant added
risk for the development of spinal hematoma.
• Avoid neuraxial techniques if NSAIDs are used
concurrently with medications that affect clotting
– COX-2 inhibitors have little effect on platelets.
• Do not perform neuraxial anesthesia within 14
days of ticlid therapy or 7 days of plavix therapy.
• Avoid neuraxial techniques until platelet function
has returned in pts receiving GP IIb/IIIa inhibitors.
– Reduces blood pressure, thrombus formation, and serum
lipid and cholesterol levels
– Inhibits in vivo platelet aggregation is dose-dependent
– Time to normal hemostasis after discontinuation – 7 days
– Cognitive disorders, peripheral vascular disease, vertigo,
tinnitus, and altitude sickness
– Inhibits platelet activating factor
– Time to normal hemostasis after discontinuation – 36 hrs
– Protects against effects of stress
– May inhibit the coagulation cascade
– Time to normal hemostasis after discontinuation – 24 hrs
• These represent no added risk for spinal hematoma
• Essentially, there is insufficient evidence to
make risk assessments. It is best to avoid
neuraxial techniques in this population.
Back to our case….
• Lovenox converted to heparin at 35/36 wks EGA
• Last heparin was given 7/29 at 1330 (>24 hrs prior
• Combined Spinal-Epidural chosen
– Uneventful, atraumatic placement
– Injection on 7/30 at 1441
• C-section and Bilateral Tubal Ligation
– Uneventful, normal EBL
• Epidural removed 7/30 at 1530
• Heparin 5000u SQ q 12h restarted 8/1 at 1600
• Converted to Lovenox 80mg q 12h on 8/2 at 1800,
to be continued for 6 wks postpartum
Obstetric Management per ASRA
• No later than 36 wks, switch to LMWH or UFH
• At least 36 hrs before induction of labor or C-
section, convert LMWH to UFH.
• Discontinue UFH 4-6 hrs before anticipated
• Postpartum, resumption of prophylaxis (5000u
UFH SQ BID) should not resume until 12 hrs after
epidural removal for SVD, or 24 hrs post C-
– If higher doses are required, prophylaxis should be
delayed for at least 24 hrs.
What to Remember
• Heparin prophylactic BID dosing is not a
contraindication to neuraxial anesthesia
• TID dosing may represent increased risk, so vigilance is
• Try to avoid neuraxial techniques for more than 1-2
after heparin SQ, as this correlates to peak drug effect
• LMWH not quite as simple
– Low dose: Wait 10-12 hrs after last dose. Restart no
sooner than 2 hrs after needle placement. Indwelling
catheters ok, just delay removal 10-12 hours after last dose
and don’t restart until 2 hrs after cath removal.
– High dose, BID dose: Wait 24 hrs after last dose. Restart
no sooner than 24 hrs postop. Indwelling catheters not as
What to Remember
• Remember BID dosing of LMWH represents an
increased risk of spinal hematoma with
• Convert to UFH at least 36 hrs prior to
• Discontinue UFH 4-6 hrs prior to planned
• Resume UFH 12 hrs post SVD, 24 hrs post C/S