1. Anticoagulants and Neuraxial and Peripheral Nerve Blocks Gholamreza moradi, Cardiac Anesthesiologist, Kermanshah University of Medical Sciences

2.  In 1997, the American Society of Regional Anesthesia and Pain Medicine (ASRAPM) convened a panel of experts to discuss the increased number of reports of epidural hematoma secondary to the then newly introduced low molecular weight heparin (LMWH) enoxaparin.  The same panel revised their guidelines in 2003 to include the newer antiplatelet drugs.  The third edition of the guidelines was published in 2010 partly to make recommendations on the issue of anticoagulants and plexus and peripheral nerve blockade.

3. PERIOPERATIVE DEEP VENOUS THROMBOSIS

4.  Some 50% of DVTs after total joint surgery begin intraoperatively;the highest incidence occurs during surgery and the first postoperative day. Almost 75% of DVTs develop within the first 48 hr after surgery.  Some of the risk factors for the development of DVTs are previous history of DVT or pulmonary embolism,major surgery, age over 60, obesity, malignancy,increased duration of surgery, prolonged immobilization,presence of varicose veins, and the use of estrogen.  B-mode compression ultrasonography with and without Doppler is the first-line modality for confirming diagnosis in symptomatic patients. It is portable and the most accurate noninvasive study of DVTs. Failure of the vein to compress is indirect evidence that a thrombus is present.

5. PERIOPERATIVE PROPHYLAXIS OF DEEP VENOUS THROMBOSIS IN TOTAL JOINT SURGERY

6.  The prevention of DVT after total joint surgery includes intraoperative, mechanical, and pharmacologic measures.  The use of epidural hypotensive anesthesia is associated with improved visualization of the operative field, less intraoperative blood loss, and shorter duration of surgery.  Mechanical devices decrease stasis by augmenting venous flow in the lower legs,9 and appear to have a fibrinolytic effect through a reduction in plasminogen activator inhibitor.(calf-length sleeve, thigh-length stockings, and foot pump devices)  The pharmacologic management of DVTs includes the use of aspirin, warfarin, LMWH, thrombin inhibitors, and the newer drugs including rivaroxaban.

7.  For aspirin, most regimens use doses of 325 to 650 mg twice a day. The incidence of DVT when aspirin alone is used in TKR ranges from 41% to 78%.  For warfarin, the usual dosing regimen is 5 mg given the night of surgery, followed by adjustment of the dose to maintain an international normalized ratio (INR) of 2.0 to 2.5. Higher INRs may result in hemarthromas.The incidence of DVT with warfarin is 25% to 59%.  Heparin is not widely used for postoperative prophylaxis after total joint surgery probably because of the better bioavailability and predictability of LMWH.  LMWH is an effective prophylaxis against DVT after total joint surgery,12–14 and appears to be more effective than warfarin.The incidence of DVT in patients who had total hip surgery is 5% with enoxaparin and 12% with warfarin.  Dalteparin is also associated with lower incidence of DVTs after total hip arthroplasty when compared to warfarin(13% versus 24%).  Fondaparinux, a specific Xa inhibitor, is given for 5 to 9 days after surgery at a daily dose of 2.5 mg. The drug reduces the incidence of venous thromboembolism by 57%, comparable to enoxaparin.

8. RELEVANT PHARMACOLOGY OF ANTICOAGULANTS AND IMPLICATIONS FOR NEURAXIAL BLOCKADE

9. ASRA RECOMMENDATIONS FOR ANTIPLATELET THERAPY AND NEURAXIAL BLOCK

10.  The ASRA concluded that neuraxial blocks may be performed in patients on aspirin or NSAIDs.  Neuraxial blocks in patients on COX-2 inhibitors are safe, although the concomitant use of COX-2 inhibitors and warfarin may increase the risk of bleeding.  Aspirin and NSAIDs alone do not significantly increase the risk of spinal hematoma. The combination of these drugs, however, increases the risk of spontaneous hemorrhagic complications, bleeding at puncture sites, and spinal hematoma.  Case reports of intraspinal hematoma after aspirin and NSAIDs had complicating factors such as concomitant administration of other anticoagulant, epidural vascular abnormalities, and technical difficulties. The intake of different antiplatelet medications has been identified as a major risk factor in the development of spinal hematoma after neuraxial injections.

11.  In the pain clinic the interventional physician has to decide whether it is prudent to continue the aspirin or NSAIDs before a neuraxial injection.  If the indication forthe aspirin is not strong, such as routine daily aspirin in an elderly but healthy patient, then the physician may choose to stop the medication especially in cervical and thoracic injections. This is because in these patients it is difficult to differentiate between new or old symptoms (numbness and weakness) or between real and imagined pathology.  Greater caution is advised in cervical and thoracic injections since the epidural space is narrower in these levels, the presence of the spinal cord in the area, and the fact that the studies on neuraxial injections in the presence of antiplatelet therapy were done mostly in patients who had lumbar injections.

12.  ASRA recommended that clopidogrel be stopped for 7 days before a neuraxial injection. If a neuraxial injection has to be performed at 5 days after discontinuation of clopidogrel, then a PFA II or a P2Y12 assay must be performed. Platelet inhibition of less than 10% in the P2Y12 assay signifies safe neuraxial injection.  A delay of 10 to 14 days is recommended with ticlopidine.This is because the half- life of ticlopidine increases from 12 hr after a single dose to 4 to 5 days after a steady state is reached.  For patients on clopidogrel and aspirin, it is recommended that the clopidogrel be stopped for 7 days and the patient placed on aspirin therapy. The aspirin is then continued up to the time of injection, after which the patient is switched back on clopidogrel after the block.

13. WARFARIN: PHARMACOLOGY AND ASRA RECOMMENDATIONS

14.  Warfarin is an oral anticoagulant that interferes with the synthesis of the vitamin K– dependent clotting factors II,VII, IX, and X. It also inhibits the anticoagulant protein C. Both factor VII and protein C have short halflives(6–7 hr) and increase in the INR is the result of the competing effects of reduced factor VII and protein C and the washout of existing clotting factors.  Prophylactic anticoagulation (INRs of 2.0–2.5) is reached 48 to 72 hr after the initial dose. Maximal anticoagulation is reached in 4 to 5 days.  An INR value of 1.4 or less is considered by ASRA as a safe value for placement or removal of an epidural catheter. There is very little correlation between the INR and factor VII during the early phase of warfarin therapy. At 12 to 14 hr after warfarin, it is probably safe to remove the epidural catheter in the presence of an elevated INR of up to 1.9 since the activity of factor VII were noted to correlate with adequate hemostasis.

15. HEPARIN AND LMWH: PHARMACOLOGY AND ASRA RECOMMENDATIONS

16.  Heparins are glycosaminoglycans that consist of chains of alternating residues of d- glucosamine and uronic acid,either glucuronic acid or iduronic acid. Unfractionated heparin is a heterogeneous mixture of polysaccharide chains ranging in molecular weight from 3000 to 30,000.A unique pentasaccharide sequence, randomly distributed along the heparin chains, binds to antithrombin (AT).The binding of the heparin pentasaccharide to AT causes a conformational change in AT that accelerates its ability to inactivate thrombin, factor Xa, and factor IXa. In addition,UFH releases tissue factor pathway inhibitor from endothelium, enhancing its activity against factor Xa.  The anticoagulant effect of subcutaneous heparin takes 1 to 2 hr but the effect of intravenous heparin is immediate.  The aPTT is used to monitor the effect of heparin; therapeutic anticoagulation is achieved with a prolongation of the aPTT to greater than 1.5 times the baseline value or a heparin level of 0.2 to 0.4 U/ml.  For patients who are scheduled for vascular procedures and given intravenous UFH during the surgery, it was noted that it was safe to perform preoperative neuraxial blocks if some precautions are observed.

17.  In summary, the ASRA guidelines on the performance of neuraxial procedures in patients who are anticoagulated with heparin are as follows:  (1) the neuraxial technique should be avoided in patients with other coagulopathies;  (2) although the occurrence of bloody or difficult needle placement increases the risk of hematoma, discussion with the surgeon of the risk/benefit ratio should determine cancellation or noncancellation of the case;  (3) the heparin administration should be delayed for 1 hr after needle placement;  (4) indwelling neuraxial catheters should be removed 2 to 4 hr after the last heparin dose, and the patient’s coagulation status is evaluated and reheparinization occurs 1 hrafter catheter removal  (5) minimal concentrations of local anesthetics should be used for early detection of signs of spinal hematoma and the patient is monitored postoperatively for signs of hematoma.

18.  Subcutaneous TID heparin is associated with increased bleeding. ASRA recommended against neuraxial injections in patients on subcutaneous TID heparin because of reports of increased bleeding and the absence of prospective studies in this setting.  There appears to be a continuing debate as to whether neuraxial procedures should be performed in patients who undergo cardiopulmonary bypass. In these patients the following precautions have been recommended:  (1) neuraxial procedures should be avoided in patients with a known coagulopathy,  (2) surgery should be delayed 24 hr in the patient with a traumatic tap  (3) the time from the neuraxial procedure to the systemic heparinization should exceed 1 hr  (4) heparinization and reversal should be monitored and controlled tightly  (5) theepidural catheter should be removed when normal coagulation is restored and the patient should be monitored closely for signs of spinal hematoma after the catheter is removed.

19. LOW-MOLECULAR-WEIGHT HEPARIN

20.  Low-molecular-weight heparins are the fractionated forms of heparin with a mean molecular weight of 5000.85 Similar to unfractionated heparin, LMWH activates antithrombin,accelerating antithrombin’s interaction with thrombin and factor Xa. LMWH, like unfractionated heparin, also releases tissue factor pathway from the endothelium.  The LMWHs have a longer half-life and doseindependent clearance compared to heparin, resulting in a more predictable anticoagulant response.  The plasma half-life of the LMWHs ranges from 2 to 4 hr after an intravenous injection and 3 to 6 hr after a subcutaneous injection. It should be noted that anti-Xa activity is still present 12 hr after injection of LMWH.

21.  The recommendations of the ASRA for patients receiving LMWH and neuraxial anesthesia are as follows:  Monitoring of the anti-Xa level is not recommended.  The administration of antiplatelet or oral anticoagulant medications with LMWHs may increase the risk of spinal hematoma.  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 hr postoperatively.  The first dose of LMWH prophylaxis after twice-daily enoxaparin should be given no earlier than 24 hr postoperatively and only in the presence of adequate hemostasis.  It may be given 6 to 8 hr after a once-daily dosing of enoxaparin.

22.  In patients who are on LMWH, needle/catheter placement should occur at least 12 hr after the last prophylactic dose of enoxaparin or 24 hr after dalteparin (120 U/kg every 12 hr or 200 U/kg every 12 hr), or after higher doses of enoxaparin (1 mg/kg every 12 hr; 1.5 mg/kg daily).  There should be a 12-hr interval between the last prophylactic dose of enoxaparin and removal of the epidural catheter.  For higher doses of enoxaparin, a 24-hr delay is recommended.  The LMWH may be administered 2 hr after the epidural catheter is removed.

23. FONDAPARINUX

24.  Fondaparinux is a synthetic anticoagulant that is a selective Xa inhibitor.Because it is synthesized chemically, it exhibits batch-to-batch consistency.  The drug is rapidly absorbed, reaching a maximum concentration within 1.7 hr of dosing and has a half-life of 21 hr.  It has 100% bioavailability. A dose of 2.5 mg is given subcutaneously 6 hr after surgery, and subsequently once a day.  The risk of spinal hematoma in patients on fondaparinux is not known at this time, so ASRA recommended that neuraxial injections should involve single- needle pass, atraumatic needle placements, and avoidance of intraspinal catheters

25. HERBAL THERAPIES

26.  Garlic inhibits platelet aggregation and its effect on hemostasis appears to last 7 days.  Ginkgo inhibits platelet-activating factor and its effect lasts 36 hr, while the effect of ginseng lasts 24 hr.  In spite of their effect on platelet function, herbal drugs by themselves appear to present no added significant risk in the development of spinal hematoma in patients having epidural or spinal anesthesia.  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.

27. ANTICOAGULATION AND PERIPHERAL NERVE BLOCKS

28.  ASRA recommended that the same guidelines on neuraxial injections be followed for peripheral nerve blocks.  This is especially important in deep plexus and noncompressible blocks (e.g., lumbar plexus block, deep cervical plexus blocks) or blocks near vascular areas such as celiac plexus blocks or superior hypogastric plexus blocks.