NYSORA - The New York School of Regional Anesthesia: Regional Anesthesia in the Anticoagulated Patient

Regional Anesthesia in the Anticoagulated Patient
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admin on 20/09/2013 19:01:00


AUTHOR: Honorio T. Benzon
Intraspinal Hematoma
The incidence of intraspinal hematoma is approximately 0.1 per 100,000 patients
per year.(1) It is more likely to occur in anticoagulated or thrombocytopenic
patients, patients with neoplastic disease, or in those with liver disease or
alcoholism.(2) The incidence of neurologic dysfunction resulting from
hemorrhagic complications associated with neuraxial blockade is estimated to be
Antiplatelet Therapy
Antiplatelet medications inhibit platelet cyclo-oxygenase and prevent the
synthesis of thromboxane A2. Thromboxane A2 is a potent vasoconstrictor and
facilitates secondary platelet aggregation and release reactions. An adequate,
although potentially fragile, clot may form.(5) Platelet function in patients
receiving antiplatelet medications should be assumed to be decreased for 1 week
after treatment with aspirin and 1 to 3 days with nonsteroidal anti-inflammatory
drugs (NSAIDs). New platelets are produced every day, and these new platelets
partly explain the relative safety of per- forming neuraxial procedures in these
patients.
Although Vandermeulen et al (6) implicated antiplatelet therapy in 3 of the 61
cases of spinal hematoma occurring after spinal or epidural anesthesia, the
results of several large studies demonstrated the relative safety of neuraxial
blockade in combination with antiplatelet therapy. The Collaborative Low-Dose
Aspirin Study in Pregnancy Group(7) included 1422 high-risk obstetric patients
who were administered 60 mg aspirin daily and underwent epidural anesthesia
without any neurologic sequelae. The studies of Horlocker et al,(8,9) of
approximately 1000 patients in each study, showed no spinal hematomas, although
blood was noted during needle or catheter placement in 22% of the patients. A
later study in patients who were on NSAIDs and underwent epidural steroid
injections did not develop the signs and symptoms of intraspinal hematoma.(10) A
review of the case reports of intraspinal hematoma in patients on aspirin and
NSAIDs showed complicating factors that in luded concomitant heparin
administration, epidural venous angioma, and technical difficulty when
performing the procedure.(11)
The thienopyridine drugs, ticlopidine and clopidogrel, prevent platelet
aggregation by inhibiting adenosine diphosphate (ADP) receptor-mediated platelet
activation. Ticlopidine is rarely used because it causes neutropenia,
thrombocytopenic purpura, and hypercholesterolemia. Clopidogrel is preferred
because of its increased safety profile and proven efficacy. The maximal
inhibition of ADP-induced platelet aggregation with clopidogrel occurs 3 to 5
days after the initiation of a standard dose (75 mg), but within 4 to 6 hours
after the administration of a large loading dose of 300 to 600 mg.(12) There is
a case report of spinal hematoma in a patient on ticlopidine(13) and a case of
quadriplegia in a patient on clopidogrel, diclofenac, and possibly aspirin.(14)
Neuraxial blocks can be safely performed on patients taking aspirin or
NSAIDs.(4) It is safe to perform neuraxial blocks on patients taking
cyclo-oxygenase (COX)-2 inhibitors. For the thienopyridine drugs, it is
recommended that clopidogrel be discontinued for 7 days and ticlopidine for 10
to 14 days before a neuraxial injection. It is possible for epidural catheters
to be removed or neuraxial injections to be performed 5 days, and not 7 days,
after clopidogrel is discontinued.(15) If a neuraxial injection is to be
performed in a patient on clopidogrel before 7 days of discontinuation, a P2Y12
assay, a new assay of residual antiplatelet activity, can be performed;
Here is a summary of current recommendations:
1. Neuraxial blocks can be performed on patients taking aspirin or NSAIDs.(4)
2. It is safe to perform neuraxial blocks on patients taking COX-2 inhibitors.
3. For the thienopyridine drugs, the ASRA recommendation is that clopidogrel be
discontinued for 7 days and     ticlopidine for 10 to 14 days before a neuraxial
injection.
4. Epidural catheters can be removed safely and neuraxial injections can be
performed 5 days (not 7 days, as once     advised) after clopidogrel is
discontinued.(15)
5. If a neuraxial injection is to be performed in a patient on clopidogrel
before 7 days of discontinuation, a P2Y12    assay, a new assay of residual
antiplatelet activity, is performed;
Oral Anticoagulants
Warfarin exerts its anticoagulant effect by interfering with the synthesis of
the vitamin K-dependent clotting factors (VII, IX, X, and thrombin).17 It also
inhibits the anticoagulants protein C and S. Factor VII and protein C have short
half-lives (6-8 hours), and the prolongation of the international normalized
ratio (INR) during the early phase of warfarin therapy is the result of the
competing effects of reduced factor VII and protein C.(18) Adequate
anticoagulation is not achieved until the levels of biologically active factors
II (half-life of 50 hours) and X are sufficiently depressed, that is, 4 to 6
days.
Few data exist regarding the risk of spinal hematoma in patients with
indwelling spinal or epidural catheters who are subsequently anticoagulated with
warfarin. Horlocker et al(19) and Wu and Perkins(20) found no neuraxial
hemorrhagic complications in patients who received postoperative epidural
analgesia in conjunction with low-dose warfarin after total knee arthroplasty.
Because intraspinal hematomas have occurred after removal of the catheter,(6)
some have recommended that the same laboratory values apply to placement and
removal of an epidural catheter.(21) The current ASRA guidelines recommends an
INR value of ≤1.4 as acceptable for the performance of neuraxial blocks.(4)
The value was based on studies that showed excellent perioperative hemostasis
when the INR value was ≤1.5. The concurrent use of other medications, such as
aspirin, NSAIDs, and heparins that affect the clotting mechanism, increases the
risk of bleeding complications without affecting the INR.
A controversy exists regarding whether or not the epidural catheter can be
removed on postoperative day 1, or 12-14 hours after warfarin is started, when
the INR is >1.4. In the absence of other risk factors for increased bleeding,
the catheter can probably be removed. The factor VII activity should be
determined if risk factors such as low platelets, advanced age, kidney failure,
or intake of other anticoagulants are present.(18)
Warfarin is metabolized primarily by the CYP2C9 enzyme of the cytochrome P450
system. Mutations in the gene coding for the cytochrome P450 2C9 hepatic
microsomal enzyme affect the elimination clearance of warfarin by impairing the
patient's ability to metabolize S-warfarin. Other genetic factors affecting the
warfarin dose-response relationship include polymorphisms of the vitamin K oxide
reductase (VKOR) enzyme. Mutations in the gene encoding for isoforms of the
protein that can lead to enzymes with varied sensitivities to warfarin is rare,
and the American College of Chest Physicians (ACCP) advises against
pharmacokinetic-based initial dosing of warfarin at this time.(17)
Intravenous Heparin
Heparin is a complex polysaccharide that exerts its anti- coagulant effect by
binding to antithrombin III. The conformational change in antithrombin
accelerates its ability to inactivate thrombin, factor Xa, and factor IXa. The
anticoagulant effect of subcutaneous heparin takes 1 to 2 hours, but the effect
of intravenous heparin is immediate. Heparin has a half-life of 1.5 to 2 hours.
The activated partial thromboplastin time (aPTT) is used to monitor the effect
of heparin; therapeutic anticoagulation is achieved with a prolongation of the
aPTT to >1.5 times the baseline value.
There were no spinal hematomas in >4000 patients who underwent lower extremity
vascular surgery under contin- uous spinal or epidural anesthesia.(22) In this
study, patients with preexisting coagulation disorders were excluded,
heparinization occurred at least 60 minutes after cath- eter placement, the
level of anticoagulation was carefully monitored, and the indwelling catheters
were removed at a time when heparin activity was low. Ruff and Dougherty (23)
noted the occurrence of spinal hematomas in patients who underwent lumbar
puncture with subsequent hepa- rinization. The presence of blood during the
procedure, concomitant aspirin therapy, and heparinization within 1 hour were
identified as risk factors for the development of a spinal hematoma.
When intraoperative anticoagulation is planned, neuraxial technique should be
avoided in patients with coexisting coagulopathies. The following considerations
are in order:
1. There should be at least a 1-hour delay between needle placement and heparin
administration.
2. The catheter should be removed 1 hour before subsequent heparin
administration and 2 to 4 hours after the last     heparin dose.(4)
3. The partial thromboplastin time or activated clotting time should be
monitored to avoid excessive heparin effect.
Subcutaneous Heparin
The anticoagulant effect of low molecular weight heparin (LMWH) is similar to
unfractionated heparin, that is, activation of antithrombin and acceleration of
its interaction with thrombin and factor Xa.(26) LMWH has a greater activity
against factor Xa; unfractionated heparin has equivalent activity against
thrombin and factor Xa. The plasma half-life of the LMWH ranges from 2 to 4
hours after an intravenous injection and 3 to 6 hours after a subcutaneous
injection. Its half-life is two to four times that of standard heparin. The
recovery of anti-factor Xa activity after a subcutaneous injection of LMWH
approaches 100%. This characteristic makes laboratory monitoring unnecessary,
except in patients with renal insufficiency or those with body weight80 kg.
The summary of recommendations for patients receiving LMWH and neuraxial
anesthesia are as follows(4):
1. The administration of other anticoagulant medications with LMWHs may
increase the risk of spinal hematoma.
2. The presence of blood during needle placement and catheter placement does
not necessitate postponement of     surgery. However, the initiation of LMWH
therapy should be delayed for 24 hours postoperatively.
3. The first dose of LMWH prophylaxis should be given no earlier than 24 hours
postoperatively and only in the     presence of adequate hemostasis.
4. In patients who are on LMWH, needle/catheter placement (or catheter removal)
should be performed at least 12     hours after the last prophylactic dose of
enoxaparin or 24 hours after higher doses of enoxaparin (1 mg/kg every 12    
hours), and 24 hours after dalteparin (120 U/kg every 12 hours or 200 U/kg every
12 hours) or tinzaparin (175 U/kg     daily).
5. The LMWH can be administered 2 hours after the epidural catheter is
removed.(4)
6. Monitoring of anti-Xa level is not recommended
Thrombolytic Therapy
Thrombolytic agents actively dissolve fibrin clots that have already formed,
secondary to the action of plasmin. Plasminogen activators, such as
streptokinase and urokinase, dissolve thrombus and affect circulating
plasminogen leading to decreased levels of both plasminogen and fibrin. Clot
lysis leads to elevation of fibrin degradation products, which have an
anticoagulant effect by inhibiting platelet aggregation. Fibrinogen and
plasminogen are maximally depressed at 5 hours after thrombolytic therapy and
remain significantly depressed at 27 hours.(4,27)
Although epidural or spinal needle and catheter placement with subsequent
heparinization appears relatively safe, the risk of spinal hematoma in patients
who receive thrombolytic therapy is less well-defined. Cases of spinal hematoma
in patients who received neuraxial injections and thrombolytic agents were
reported recently in the medical literature.
Fibrinolytic and thrombolytic agents pose a unique problem when performing
neuraxial anesthesia. The time frame for avoidance of these drugs and puncture
of noncompressible vessels is 10 days. Except in highly unusual circumstances,
patients who received fibrinolytic or thrombolytic drugs should be cautioned
against receiving spinal or epidural anesthesia.(4,27) There are no available
data to clearly determine the length of time after discontinuation of these
drugs for the safe performance of a neuraxial technique. There is no definitive
recommendation on the timing of removal of neuraxial catheters in patients who
unexpectedly receive fibrinolytic or thrombolytic therapy. Measurement of
fibrinogen levels may be helpful in guiding a decision about removal of the
catheter.
Herbal Therapy
Herbal preparations do have some effect on platelet aggregation. For example,
garlic inhibits platelet aggregation and its effect on hemostasis appears to
last 7 days. Ginkgo biloba inhibits platelet-activating factor and its effect
lasts 36 hours. These effects last 24 hours with the use of ginseng.(4) The
effects of dietary supplements on platelet function and coagulation are not well
described, and outcomes are difficult to predict.(28) In spite of these
characteristics, herbal preparations appear to present no added significant risk
in the development of spinal hematoma in patients having epidural or spinal
anesthesia. At this time, there appears to be no specific concerns as to the
timing of neuraxial block in relationship to the dosing of herbal therapy,
postoperative monitoring, or the timing of neuraxial catheter removal.(4)
Fondaparinux
Fondaparinux is a synthetic anticoagulant that produces its antithrombotic
effect through selective inhibition of factor Xa.(29) The drug exhibits
consistency in its anticoagulant effect because it is chemically synthesized and
its bioavailability is 100%. Rapidly absorbed, it reaches maximum concentration
within 1.7 hours of administration. Its half-life is 17 to 21 hours, allowing
once-daily dosing.(30) The actual risk of spinal hematoma with fondaparinux is
unknown. The daily dosing makes safe catheter removal harder to predict. The
ASRA(4) recommends against the use of fondaparinux in the presence of an
indwelling epidural catheter. These recommendations were based on the sustained
and irreversible antithrombotic effect of fondaparinux, early postoperative
dosing (6 hours after surgery), and the spinal hematoma reported during initial
clinical trials. Performance of neuraxial techniques should occur under the
conditions used in clinical trials (single needle pass, atraumatic needle
placement, and avoidance of indwelling neuraxial catheters).(4)
A 2007 study showed no complications in patients who had neuraxial injections
or deep peripheral nerve blocks.(31) In this study, the catheters were removed
36 hours after the last dose of fondaparinux and dosing was delayed for 12 hours
after the catheter was removed. In a review article, Rosencher et al(32)
recommended that catheter removal should be delayed at least 36 hours
(equivalent to two half-lives) and that the subsequent injection should be timed
to at least 7 hours after the removal of the catheter.
Thrombin Inhibitors
Recombinant hirudin derivatives, such as desirudin (Revasc), lepirudin
(Refludan), and bivalirudin (Angiomax), inhibit both free and clot-bound
thrombin.(4) Argatroban, although an L-arginine derivative, is also a thrombin
inhibitor. These drugs are used in the treatment of heparin-induced
thrombocytopenia and as an adjunct when angioplasty is performed.(33) Their
anticoagulant effect is present for 1 to 3 hours after intravenous
administration and is monitored by the aPTT. There is no pharmacologic reversal
to the effect of these drugs. Desirudin is used as thromboprophylaxis after
total hip replacement.(34) There are no published reports of spinal hematoma
related to neuraxial anesthesia in patients who have received a thrombin
inhibitor, probably because of the hesitancy of clinicians to perform neuraxial
injections in patients taking the drugs, which is probably related to their
unfamiliarity with the drugs. The most recent ASRA guidelines recommend against
the performance of neuraxial techniques in patients who received thrombin
inhibitors.
Newer Anticoagulants
Dabigatran Etexilate
Dabigatran is an oral direct thrombin inhibitor. Its bioavailability is only
5%, peak plasma levels occur at 2 hours, and its half-life is 8 hours after a
single dose but up to 17 hours after multiple doses. The drug is approved for
clinical use in Europe. Studies showed dabigatran (150 or 220 mg daily) to be
less effective than enoxaparin (30 mg twice daily) when used for
thromboprophylaxis after total joint surgery.(35,36A) 48-hour interval is
recommended before a neuraxial injection.
Rivaroxaban
Rivaroxaban is an oral factor Xa inhibitor approved for use in Europe and
Canada. It is awaiting approval by the Food and Drug Administration (FDA) in the
United States. It has an 80% bioavailability; its peak effect occurs after 1
hour; the duration of effect is 12 hours; and it has a half-life of 9 to 13
hours. Clinical studies comparing rivaroxaban, at doses of 5 to 40 mg, to
enoxaparin showed similar or superior efficacy.(37-40) There were no reports of
spinal hematoma in these studies. Apparently, a 24-hour interval (2 x half-life)
was observed between the rivaroxaban dose and epidural catheter placement or
removal; subsequent dosing of the drug was 6 hours after removal of the catheter
(personal communication with the company). The drug offers several salutary
characteristics including efficacy and simplicity with once-daily oral dosing.
Prasugrel
Prasugrel is an oral anticoagulant approved for use by the FDA in July 2009.
Its mechanism of action is similar to clopidogrel; that is, it acts as a
noncompetitive antagonist of P2Y12, inhibiting the ability of platelet ADP to
induce aggregation for the life of the platelet.(41) Prasugrel and clopidogrel
are prodrugs; however, prasugrel has a quicker onset of action, a longer
duration (the effect of 60 mg is 1-1.5 hours compared with 6 hours with 300 mg
clopidogrel); it is 10 times more potent; and less prone to drug-drug
interactions and variability in patient response than clopidogrel.(41,42) A 7-10
day interval is recommended before a neuraxial injection. Other novel
antiplatelet drugs are in development, including ticagrelor and cangrelor, which
are under study for use in patients with acute coronary syndromes.(43)
Anticoagulation and Peripheral Nerve Blocks
Spontaneous hematomas have been reported in patients who took anticoagulants.
Abdominal wall hematomas, intracranial hemorrhage, psoas hematoma, and
intrahepatic hemorrhage have occurred after LMWH.(44-47) Major hemorrhagic
complications occur in 1.9 to 6.5% of patients on enoxaparin.(48) The increased
bleeding that occurs after vascular or cardiac procedures and regional nerve
blocks in these patients can result in an expanding hematoma with resultant
ischemia of the nerve.
There has been no prospective study on peripheral nerve blocks in the presence
of anticoagulants. However, there have been several case reports of hematomas
when peripheral blocks are performed in patients who are on these drugs. The
hematomas occurred in patients with abnormal and normal coagulation status, and
in patients who were given LMWH, ticlopidine and clopidogrel, warfarin, heparin,
or a combination of the drugs.(49-55) In most cases, however, recovery of
neurologic deficits occurred within a year.
The diagnosis of bleeding after peripheral nerve block in patients on
anticoagulants include pain (flank, paravertebral, or in the groin with psoas
bleeding), tenderness in the area, fall in hemoglobin/hematocrit, fall in blood
pressure, and sensory and motor deficits. Although definite diagnosis is made by
computed tomography, ultrasound can be a diagnostic aid, and its increasing use
will make this modality a useful tool for the diagnosis and subsequent
monitoring of peripheral hematomas. Treatment of peripheral hematomas usually
includes surgical consult, blood transfusion as necessary, and watchful waiting
versus surgical drainage.
The most recent ASRA guidelines recommended that the same guidelines on
neuraxial injections apply to deep plexus or peripheral nerve blocks. Some
clinicians may find this to be too restrictive and apply the same guidelines
only to deep plexus and noncompressible blocks (e.g., lumbar plexus block, deep
cervical plexus blocks) or to blocks near vascular areas, such as celiac plexus
blocks or superior hypogastric plexus blocks. If peripheral nerve blocks are
performed in the presence of anticoagulants, the anesthesiologist must discuss
the risks and benefits of the block with the patient and the surgeon, and follow
the patient very closely after the block.
Table 1: Summary of Guidelines on Anticoagulants and Neuraxial Blocks*
Guidelines of Various Societies
Guidelines on use of regional anesthesia in the presence of anticoagulants have
been published by a number of societ- ies throughout the world to better fit
them to the realm of the local practices. By necessity, there are similarities
and differences among them. A good example is the new ASRA guidelines (56) and
the Belgian and German guidelines.(57,58) The guidelines of the three
organizations are similar with regard to antiplatelet medications,
unfractionated heparin, and throm- bolytic agents. With regard to LMWH, the ASRA
guidelines are more conservative, partly due to the differences in the dosing of
the drug. For fondaparinux, the German guidelines allow an indwelling epidural
catheter, whereas the ASRA and the Belgian guidelines recommend against it. The
Belgian and German guidelines allow neuraxial injections in patients on direct
thrombin inhibitors; the ASRA guidelines do not. Finally, some of the newer
anticoagulants have been approved for use in Europe and are awaiting approval in
the United States so the guidelines for these drugs are forthcoming.
Summary
Adherence to the discussed guidelines should lead to a lesser risk of
hemorrhagic complications after regional anesthesia, including spinal hematomas.
Likewise, implementation of the guidelines leads to improved vigilance and
better care of patients on anticoagulants in whom nerve blocks are performed or
entertained. Consensus guidelines, however, should be viewed only as
recommendations; specific decisions on nerve blocks in patients on
anticoagulants should be individualized. Adequate monitoring, follow-up, and
timely treatment should be implemented in patients on anticoagulants who are
receiving neuraxial or peripheral nerve blocks (see algorithms on the following
pages).