Regional Anesthesia in the Anticoagulated Patient

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 <1 in 150,000 epidural procedures and <1 in 220,000 with spinal anesthetics. The risk of formation of intraspinal hematoma after administration of neuraxial injections is increased in patients who received anticoagulant therapy or have a coagulation disorder, technical difficulties in the performance of the neuraxial procedures due to anatomic abnormalities of the spine, and multiple or bloody punctures. The American Society of Regional Anesthesia and Pain Medicine (ASRA) issued recommended guidelines for the safe performance of neuraxial blocks in patients who are on anticoagulants.^3,⁴ The third edition of the ASRA guidelines was published in 2010.

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 performing neuraxial procedures in these patients.

Although Vandermeulen et al⁶ 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 Group⁷ 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 included 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 ticlopidine¹³ 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; <10% activity probably means that a neuraxial block is safe.¹⁶

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; <10% activity probably means that a neuraxial block is safe.¹⁶

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 al¹⁹ and Wu and Perkins²⁰ 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 anticoagulant 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 continuous spinal or epidural anesthesia.²² In this study, patients with preexisting coagulation disorders were excluded, heparinization occurred at least 60 minutes after catheter placement, the level of anticoagulation was carefully monitored, and the indwelling catheters were removed at a time when heparin activity was low. Ruff and Dougherty²³ noted the occurrence of spinal hematomas in patients who underwent lumbar puncture with subsequent heparinization. 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 therapeutic basis of low-dose subcutaneous heparin (5000 units every 8–12 hours) is heparin-mediated inhibition of activated factor X. Following intramuscular or subcutaneous injection of 5000 units of heparin, maximum anticoagulation effect is observed in 40 to 50 minutes and returns to baseline within 4 to 6 hours. The aPTT may remain in the normal range and often is not monitored. However, wide variations in individual patient responses to subcutaneous heparin have been reported. Neuraxial techniques are not contraindicated during subcutaneous (mini-dose) prophylaxis. Some have suggested that the risk of bleeding can be further reduced by delay of the heparin administration until after the block.⁴

The 2008 ACCP guidelines have suggested a more frequent dosing of subcutaneous heparin to three times a day.²⁴ Case reports show an increased risk for bleeding in patients receiving thrice-daily subcutaneous heparin.²⁵ In view of this increased bleeding and in the absence of prospective studies that looked into the implications of neuraxial injections in this setting, the third edition of the ASRA guidelines will advise that patients not receive thrice-daily heparin when receiving epidural infusions.

Low Molecular Weight 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 weight <50 kg or >80 kg.

The summary of recommendations for patients receiving LMWH and neuraxial anesthesia are as follows⁴:

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.

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