Chapter 70. Neuraxial Anesthesia & Peripheral Nerve Blocks in Patients on Anticoagulants

Intraspinal hematoma is a relatively rare condition resulting from a variety of causes. Its incidence is approximately 0.1 per 100,000 patients per year.1,2 Traumatic causes include lumbar puncture and neuraxial anesthesia as well as a complication of spinal surgery. It is more likely to occur in anticoagulated or thrombocytopenic patients, patients with neoplastic disease, or in those with liver disease or alcoholism.3,4 Spontaneous bleeding is rare but may be seen from a spinal arteriovenous malformation or vertebral hemangioma. Approximately one quarter to one third of all cases are associated with anticoagulation therapy.5,6

Hemorrhage into the spinal canal commonly occurs in the epidural space because of the presence of a prominent epidural plexus of veins. Puncture of epidural vessels during placement of epidural catheters occurs in approximately 3–12% of cases. The incidence of symptomatic epidural hematoma associated with epidural analgesia is difficult to estimate, but combined case series of more than 100,000 epidural anesthetics have been reported without a single epidural hematoma. Spinal hematoma is a rare but devastating event. The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is unknown; the incidence cited in the literature is estimated to be 1 in 150,000 epidural and 1 in 220,000 spinal anesthetics. However, the incidence increased significantly after the introduction of low-molecular-weight heparin (LMWH), before the Food and Drug Administration issued a warning, and before the American Society of Regional Anesthesia (ASRA) issued its initial consensus statement in 1998.7

The risk of formation of intraspinal hematoma after administration of neuraxial anesthesia and analgesia is increased in patients who received anticoagulant therapy or have a coagulation disorder.8 For that reason neuraxial anesthesia is often contraindicated in the presence of a coagulopathy. Other risk factors for development of epidural or spinal hematoma include technical difficulty (multiple attempts) in the performance of the neuraxial procedures due to anatomic abnormalities of the spine and multiple or bloody punctures. Intraspinal hematoma is more often associated with epidural catheter use than with the other neuraxial block techniques.

ASRA has recommended guidelines for the safer performance of neuraxial blocks in patients who are on anticoagulants.7,9 These guidelines were based on extensive review of the literature and of the pharmacology of the different anticoagulants. Recommendations were made on the timing of the neuraxial block and removal of the epidural catheter and the administration of the anticoagulants. In particular, the use of low concentrations of local anesthetics for epidural infusion (preservation of motor strength for easier monitoring) and subsequent neurologic monitoring were recommended by ASRA. The initial consensus guidelines, published in 1998 and updated in 2003,7,9 greatly assisted clinicians in decision making with regard to the use of neuraxial procedures in the setting of anticoagulation therapy and possibly decreased the incidence of epidural and spinal hematoma. In this chapter, we discuss the significance of common antiplatelet, anticoagulation, and fibrinolytic therapy and hope to offer the reader a guide in decision making about the use of neuraxial anesthesia and PNBs in clinical practice.

Antiplatelet medications, including aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and dipyridamole, have been in the past considered relative contraindications to central neural blockade by some authors due to prolongation of the bleeding time and a theoretically greater risk of formation of spinal hematoma. Antiplatelet medications inhibit the platelet cyclooxygenase enzyme and prevent the synthesis of thromboxane A2. Thromboxane A2 is a potent vasoconstrictor and facilitates secondary platelet aggregation and release reactions. Platelets from patients on these medications have normal platelet adherence to subendothelium and normal primary hemostatic plug formation. An adequate, although potentially fragile, clot may form.10 However, although such plugs may be satisfactory hemostatic barriers for smaller vascular lesions, they may not ensure adequate perioperative hemostatic clot formation. The role of platelets in coagulation and hemostasis is shown in Figures 70–1 and 70–2.

The Ivy bleeding time was considered to be a reliable predictor of abnormal bleeding in patients receiving antiplatelet drugs.11 However, the postaspirin bleeding time is not a reliable indicator of platelet function.12,13 There is large intra- and interpatient variability in the results of the test. Although the bleeding time may normalize within 3 days after aspirin ingestion, platelet function as measured by platelet response to adenosine diphosphate (ADP), epinephrine, and collagen may take up to a week to return to normal. There is no evidence to suggest that bleeding time can predict hemostatic function, and studies failed to show a correlation between aspirin-induced prolongation of the bleeding time and surgical blood loss.1,14 Therefore, measurement of an Ivy bleeding time before induction of spinal or epidural anesthesia may not identify those patients at increased risk for hemorrhagic complications. Other NSAIDs (naproxen, piroxicam, ibuprofen) produce only a short-term, mild defect that normalizes within 3 days.15 Platelet function in patients receiving antiplatelet medications should be assumed to be decreased for 1 week with aspirin and 1–3 days with NSAIDs. This assumption does not take into consideration the continuous formation of new, functional platelets. This continuous production of fresh, normally functioning platelets, combined with the residual function of already circulating platelets may explain the relative safety of performing neuraxial procedures in these patients.

Special platelet function assays are now available to monitor platelet aggregation and degranulation. The platelet function analyzer (PFA) is a test of in vitro platelet function. It is a good screening test for von Willebrand disease and monitors the effect of desmopressin administration. The PFA is prolonged after antiplatelet therapy.16,17 The test simulates the process of platelet adhesion and aggregation by measuring the ability of platelets to occlude a microscopic aperture in a membrane coated with collagen and epinephrine (C-EPI) or collagen and ADP (C-ADP) under controlled high shear rates. The time required to obtain a complete platelet plug is the closure time in seconds. The normal closure times are 60–160 sec for C-EPI and 50–124 sec for C-ADP. The intake of aspirin and NSAIDs prolongs the closure time of C-EPI, but von Willebrand disease, low platelet count (<100,000/UL), low hematocrit (<30%), and renal failure prolong the closure time for C-ADP.

Possible clinical significance of antiplatelet therapy and the risk of epidural and spinal hematoma in patients on antiplatelet therapy has been raised by a case report of spontaneous epidural hematoma formation in the absence of spinal or epidural anesthesia in a patient with a history of aspirin ingestion.18 The patient developed severe lower extremity weakness after ingestion of 1500 mg of aspirin in the form of an aspirin-containing antacid. A myelogram revealed intraspinal hematoma and neurologic defect at the T5 to T6 level. The cerebrospinal fluid was clear, although prolonged bleeding from the lumbar puncture site was noted after myelography. A laminectomy was performed, and the intraspinal hematoma was removed. The patient's neurologic function gradually improved. Nevertheless, the risk associated with the administration of spinal or epidural anesthesia to a patient receiving antiplatelet medications remains very controversial. Although Vandermeulen and colleagues implicated antiplatelet therapy in 3 of the 61 cases of spinal hematoma occurring after spinal or epidural anesthesia.19 Several large studies have demonstrated the relative safety of central neural blockade in combination with antiplatelet therapy. The Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) Group20 included 1422 high-risk obstetric patients who were administered 60 mg of aspirin daily and underwent epidural anesthesia without any neurologic sequelae. However, no data regarding difficulty of the procedure or bleeding during the placement or removal of the epidural needle or catheter were noted.20 In a retrospective study of 1013 spinal and epidural anesthetics in which antiplatelet drugs were taken by 39% of the patients including 11% of patients who were on multiple antiplatelet medications, no patient developed signs of spinal hematoma; however, patients on antiplatelet medications showed a higher incidence of blood aspiration through the spinal or epidural needle or the catheter.21 In a subsequent prospective study in 1000 patients, 39% of whom reported preoperative antiplatelet therapy, there were no hemorrhagic complications.22 Blood was noted during needle or catheter placement in 22% of patients, and there was frank blood in 7% of the patients. Therefore, preoperative antiplatelet therapy was not a risk factor for bloody needle or catheter placement. Female gender, increased age, history of excessive bruising or bleeding, continuous catheter technique, large needle gauge, multiple attempts, and difficult needle placement were noted to be significant risk factors. Clinical studies in pain clinic patients are similar to those undergoing surgery. Patients on aspirin10 or NSAIDs23 who underwent epidural steroid injections did not develop signs and symptoms of intraspinal hematoma.

The lack of correlation between antiplatelet medications and bloody needle or catheter placement provides strong evidence that preoperative antiplatelet therapy does not represent a significant risk factor for the development of neurologic dysfunction from spinal hematoma in patients on antiplatelet therapy. Although there have been case reports of intraspinal hematoma in patients on aspirin and NSAIDs, there were complicating factors in these case reports.24 These included concomitant heparin administration,25 coexisting epidural venous angioma,25 and technical difficulty in performing the procedure.26–28 Technical difficulties in performing the injection have been identified as major risk factors in the development of intraspinal hematoma after neuraxial injections.

Based on the available evidence, ASRA made several recommendations concerning antiplatelet medications.9,29 Preoperative antiplatelet therapy does not represent a significant risk factor for the development of neurologic dysfunction from spinal hematoma in patients on antiplatelet therapy. There is no wholly accepted test, including the bleeding time, to guide antiplatelet therapy. Careful preoperative assessment of the patient is important in identifying conditions that might lead to increased risk of bleeding. The timing of intake of the NSAIDs does not represent a specific concern in relation to the placement of single-shot spinal or catheter techniques, postoperative monitoring, or the timing of neuraxial catheter removal. The risk of bleeding complications, however, may be increased in patients on several antiplatelet medications and concurrent use of other medications affecting clotting mechanisms, such as oral anticoagulants, standard heparin, and LMWH.9,29

Cyclooxygenase-2 (COX-2) inhibitors gained popularity because of their analgesic properties and lack of platelet and gastrointestinal effects. Studies showed their perioperative analgesic property in a variety of perioperative settings.30–33 The drugs have minimal gastrointestinal (GI) toxicity and are ideal for patients who are at increased risk for serious upper GI adverse events. Compared with aspirin or NSAIDs, the effects of the COX-2 inhibitors on platelet aggregation and bleeding times were not different from a placebo.34–36 Blood loss did not increase during spinal fusion surgery when COX-2 inhibitors were given preoperatively.37 The platelet properties of these drugs make them ideal for perioperative use when neuraxial anesthetic is planned. Unfortunately, rofecoxib and valdecoxib have been withdrawn from the market because of their cardiovascular side effects38; only celecoxib is presently being used, but at dosages lower than previously recommended.

The thienopyridine drugs ticlopidine and clopidogrel have no direct effect on arachidonic acid metabolism. These drugs prevent platelet aggregation by inhibiting ADP receptor–mediated platelet activation.39,40 They also modulate vascular smooth muscle-reducing vascular contraction. Clopidogrel was noted to be 40–100 times more potent than ticlopidine.41 Clinical doses are usually 75 mg daily for clopidogrel and 250 mg twice a day for ticlopidine. Ticlopidine is rarely used at the present time because it causes neutropenia, thrombocytopenic purpura, and hypercholesterolemia. Clopidogrel is preferred because of its improved safety profile and proven efficacy. It was found to be better than aspirin in patients with peripheral vascular disease.42 The maximal inhibition of ADP-induced platelet aggregation with clopidogrel occurs 3–5 days after initiation of a standard dose (75 mg), but within 4 to 6 h after the administration of a large loading dose of 300 to 600 mg.43 The large loading dose is usually given to patients before they undergo percutaneous coronary intervention.40,44 There has been a case report of spinal hematoma in a patient on ticlopidine.45 Although there has been no case of intraspinal hematoma in a patient on clopidogrel alone, a case of quadriplegia in a patient on clopidogrel, diclofenac, and aspirin has been reported.46

As stated, ASRA concluded that neuraxial blocks may be performed in patients on aspirin, NSAIDs, or COX-2 inhibitors.9,29 For the thienopyridine drugs, it is recommended that clopidogrel be discontinued for 7 days and ticlopidine for 10 to 14 days before administration of a neuraxial injection. The longer interval for ticlopidine is due to the increase in its half-life with chronic administration; its half-life increases from 12 h after a single dose to 4 to 5 days after a steady state is reached.

Warfarin exerts its anticoagulant effect by interfering with the synthesis of the vitamin K–dependent clotting factors (VII, IX, X, and thrombin)47–49 (Figure 70–3).

It also inhibits the anticoagulants protein C and S. Factor VII has a relatively short half-life (6–8 h) and the prothrombin time (PT) may be prolonged into the therapeutic range (1.5–2 times normal) within 24 to 36 h. The anticoagulant protein C also has a short half-life (6–7 h). The initial prolongation of the international normalized ratio (INR) is therefore the result of competing effects of reduced factor VII and protein C and the washout of existing clotting factors. Because of this, the INR is unpredictable during the initial stage of treatment with warfarin.50,51 Factor VII participates only in the extrinsic pathway, and adequate anticoagulation is not achieved until the levels of biologically active factors II (half-life of 50 h) and X are sufficiently depressed. This requires 4–6 days. High loading doses of warfarin (15 mg) are occasionally employed for the first 2–3 days of therapy, and the desired anticoagulant effect is achieved within 48 to 72 h.52 The anticoagulant effect of warfarin persists for 4 to 6 days after termination of therapy while new biologically active vitamin K factors are synthesized. The effect of warfarin can be reversed by the transfusion of fresh frozen plasma and vitamin K injections. The risks of warfarin usage are bleeding and the rare occurrence of skin necrosis. Its drawbacks also include the necessity of monitoring its effect with serial monitoring of INR, its interaction with other drugs, and the fact that it has to be discontinued a few days before surgery.47,48

Few data exist regarding the risk of spinal hematoma in patients with indwelling spinal or epidural catheters who are subsequently anticoagulated with warfarin. Odoom and Sih53 performed 1000 continuous lumbar epidural anesthetics in 950 patients who underwent vascular procedures and received preoperative oral anticoagulant. The thrombotest (a test measuring factor IX activity) was decreased and the activated partial thromboplastin time (aPTT) was prolonged in all the patients prior to the epidural placement. Heparin was also administered intraoperatively. The epidural catheters remained in place for 48 h postoperatively; the coagulation status of the patients at the time of catheter removal was not described. There were no neurologic complications. Although the results of this study are reassuring, the obsolescence of the thrombotest as a measure of anticoagulation combined with the unknown coagulation status of the patients at the time of catheter removal limits the usefulness of the study.

The use of an indwelling epidural or intrathecal catheter and the timing of its removal in an anticoagulated patient is controversial. Although the trauma of needle placement occurs with both single-dose and continuous catheter techniques, the presence of an indwelling catheter could provoke additional injury to tissues and vascular structures. No spinal hematomas were reported in 192 patients receiving postoperative epidural analgesia in conjunction with low-dose warfarin after total knee arthroplasty.54 In this study, the patients received warfarin to prolong their PTs to 15.0 to 17.3 sec. The epidural catheters were left indwelling for 37 ± 15 h (range 13–96 h). The mean PT at the time of epidural catheter removal was 13.4 ± 2 s (range 10.6–25.8 s). This and several subsequent studies documented the relative safety of low-dose warfarin anticoagulation in patients with an indwelling epidural catheter.51,55 However, patients varied greatly in their response to warfarin, and the authors recommended close monitoring of coagulation status to avoid excessive prolongation of the PT. Since intraspinal hematomas have occurred after removal of the catheter,19 it is recommended that the same laboratory values apply to placement and removal of the epidural catheter.56 Factors responsible for a prolonged PT and PTT are illustrated in Figures 70-4, 70-5, and 70-6.

The ASRA recommended an INR value of 1.4 or less as acceptable for the performance of neuraxial blocks.9,48 The value was based on studies that showed excellent perioperative hemostasis when the INR value was ≤1.5.49 Studies on the levels of clotting factors at different INR values showed that the decline of these factors may not be significant at an INR of 1.5. At INR values of 1.5 to 2.0, the concentrations of factor II were noted to be 74% to 82% of baseline, whereas factor VII levels were 27% to 54% of baseline values.50 At INR values of 2.1 ± 1 during the initial phase of warfarin administration, factors II and VII were 65 ± 28% and 25 ± 20% of control values.57 Levels of 20% of normal are considered adequate for normal hemostasis at the time of major surgery. Another study58 found that at INRs of 1.3 to 2, under stable anticoagulation with warfarin, the concentrations of the clotting factors VII, IX, and X were within normal limits.

The clinician should be aware of the interactions of warfarin on the coagulation cascade and the role of the INR in monitoring its effect. To minimize the risk of complications, ASRA recommended several precautions.9,48 Chronic oral therapy should be stopped and the INR measured before a neuraxial block is performed. 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. If an initial dose of warfarin is given prior to surgery, the INR should be checked if the dose was given more than 24 h earlier. If patients are on low-dose warfarin treatment (mean daily dose approximately 5 mg) during epidural analgesia, the INR should be checked daily and before catheter removal if the initial dose was given more than 36 h previously. Higher daily doses may need more intensive monitoring. The warfarin dose should be held or reduced when the INR is >3 in patients with indwelling neuraxial catheters to prevent epidural hematoma and hemarthroma. While on warfarin therapy, the patient's neurologic status should be checked routinely during epidural analgesic infusion, as well as 24 h after the catheter has been removed. Dilute concentrations of local anesthetic should be utilized to minimize the degree of sensory and motor blockade. Clinical judgment must be exercised in making decisions about removing or maintaining neuraxial catheters in patients with therapeutic levels of anticoagulation during neuraxial catheter infusion. The warfarin dose should be reduced for patients who are likely to have an enhanced response to the drug, especially the elderly. For patients on chronic oral anticoagulation, the warfarin must be stopped and the INR measured.

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.59

In addition, unfractionated heparin releases a tissue factor pathway inhibitor from endothelium, enhancing its activity against factor Xa.60 The anticoagulant effect of heparin increases disproportionately with increasing dosages. The anticoagulant effect of subcutaneous heparin takes 1–2 h, but the effect of intravenous heparin is immediate. In fact, the coagulation time is prolonged two to four times the baseline level 5 min after the intravenous injection of 10,000 units of heparin. Heparin has a half-life is 1.5–2 h. It should be noted that patients with acute thromboembolic disease clear heparin more rapidly. Within 4 to 6 h of its administration, the therapeutic dose of heparin ceases. 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.61 The aPTT is usually not prolonged by the subcutaneous administration of low doses of heparin and is not monitored. Protamine neutralizes the effect of intravenously administered heparin.

Heparin is not the ideal anticoagulant since it is a mixture of molecules only a fraction of which has anticoagulant activity. It binds to platelet factor 4 and to the von Willebrand factor.62,63 The heparin–antithrombin complex is also not very effective in neutralizing clot-bound thrombin. Finally, heparin is associated with immunologic thrombocytopenia and immune-mediated thrombosis.62 For patients receiving standard heparin therapy, the risk of bleeding complications is increased in the presence of other medications that affect other clotting mechanisms, including aspirin, NSAIDs, LMWH, and oral anticoagulants.

Several studies demonstrated the safety of spinal or epidural anesthesia followed by systemic heparinization if certain precautions are observed. Rao and El-Etr64 reported no spinal hematomas in over 4000 patients who underwent lower extremity vascular surgery under continuous spinal or epidural anesthesia. In their study, patients with preexisting coagulation disorders were excluded, heparinization occurred at least 60 min after catheter placement, the level of anticoagulation was carefully monitored, and the indwelling catheters were removed at a time when heparin activity was low. Surgery was canceled in patients when frank blood was noted in the needle and performed the following day under general anesthesia. The same findings were noted in a subsequent report in the neurologic literature. Ruff and Dougherty65 noted spinal hematomas in 7 of 342 (2%) patients who underwent lumbar puncture and subsequent heparinization for evaluation of cerebral ischemia. The presence of blood during the procedure, concomitant aspirin therapy, and heparinization within 1 h were identified as risk factors in the development of spinal hematoma.

ASRA made several recommendations when a neuraxial technique is used in the presence of intraoperative anticoagulation.9,66 The technique should be avoided in patients with other coagulopathies. There should be at least a 1-h delay between needle placement and heparin administration. The catheter should be removed 2–4 h after the last heparin dose and 1 h before subsequent heparin administration. The PTT or ACT should be monitored to avoid excessive heparin effect. The patient is followed postoperatively for early detection of reoccurrence of motor blockade. Dilute concentrations of local anesthetics are recommended to minimize motor blockade. Although there may be an increased risk in the event of a traumatic (bloody) or difficult needle placement, there are no data to support mandatory cancellation of surgery. The decision to proceed should be based on appropriate clinical judgment and full discussion with the surgeon and the patient.

Neuraxial procedures are occasionally performed in patients who undergo cardiopulmonary bypass. The following precautions have been recommended to prevent the development of intraspinal hematoma67:

1. Neuraxial procedures should be avoided in patients with known coagulopathy.

2. Surgery should be delayed 24 h in the patient with a traumatic tap.

3. The time from the neuraxial procedure to the systemic heparinization should exceed 1 h.

4. Heparinization and reversal should be monitored and controlled tightly.

5. The epidural catheter should be removed when normal coagulation is restored, and the patient should be monitored closely for signs of spinal hematoma.

Subcutaneous Heparin

The therapeutic basis of low-dose subcutaneous heparin (5000 units every 8–12 h) is heparin-mediated inhibition of activated factor X. Smaller doses of heparin are required when administered as prophylaxis rather than as treatment for thromboembolic disease. Following intramuscular or subcutaneous injection of 5000 units of heparin, maximum anticoagulation effect is observed in 40 to 50 min and returns to baseline within 4 to 6 h. 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 (minidose) prophylaxis, but the risk of bleeding may be reduced by delaying the heparin administration until after the block. Bleeding may be increased in debilitated patients or after prolonged therapy. The safety of major neuraxial anesthesia in the presence of anticoagulation with subcutaneous doses of unfractionated heparin was documented by several publications.66 Although the anticoagulant effect of subcutaneous heparin is less significant than that of intravenous heparin, ideally subcutaneous low-dose heparin should also not be administered within 4 to 6 h of neuraxial anesthesia to allow for normalization of the heparin effect.

Low-Molecular-Weight Heparin

Unfractionated heparin is a heterogeneous mixture of polysaccharide chains that can be separated into fragments of various molecular weights.68,69 Each low-molecular-weight heparin (LMWH) fractionation contains heparins of different molecular weights, and each is evaluated as a specific pharmacologic substance. The anticoagulant effect of LMWH is similar to that for unfractionated heparin; it activates antithrombin, accelerating antithrombin's interaction with thrombin and factor Xa. LMWH also releases tissue factor pathway from the endothelium. LMWH has a greater activity against factor Xa, whereas unfractionated heparin has equivalent activity against thrombin and factor Xa. The plasma half-life of the LMWHs ranges from 2 to 4 h after an intravenous injection and 3–6 h after a subcutaneous injection; its half-life is two to four times that of standard heparin. The longer half-life of LMWH and its dose-independent clearance results in a more predictable anticoagulant response than occurs with heparin. It has a low affinity for plasma protein, resulting in a greater bioavailability. The advantages of LMWH over unfractionated heparin include a higher and more predictable bioavailability after subcutaneous administration and a longer biological half-life. Also, laboratory monitoring of the anticoagulant response of LMWH is not measured and dose adjustment for weight is not necessary (although an overdose may occur in smaller patients). LMWH exhibits a dose-dependent antithrombotic effect that is accurately assessed by measuring the anti-Xa activity level. The recovery of anti-factor Xa activity after a subcutaneous injection of LMWH approaches 100%,70 making laboratory monitoring unnecessary except in patients with renal insufficiency or those with body weight less than 50 kg or more than 80 kg.68 The r time from the thrombelastogram appears to correlate with the serum anti-Xa concentration.71 The three commercially available LMWH in the United States are enoxaparin (Lovenox), dalteparin (Fragmin), and tinzaparin (Innohep). Enoxaparin is either given once daily or every 12 h when used as a prophylaxis, and the two other drugs are given once a day. The three drugs appear to have comparable efficacy in the treatment and prevention of venous thromboembolism.72 Enoxaparin and dalteparin have comparable efficacy in the prevention of death or myocardial infarction among patients with unstable angina.72

The current recommended thromboprophylactic dose in the United States is 30 mg enoxaparin twice daily. The FDA has recently approved enoxaparin 40 mg once daily, which is similar to the European dosing schedule. It should be noted that patients in Europe get their starting dose 12 h before surgery. Since most patients in the United States are admitted on the day of their surgery, it is not practical for them to get their first dose of LMWH 12 h before surgery. Many elderly patients forget to take their medications, and it is not guaranteed that they will take their LMWH at home before their surgery.

Numerous cases of neuraxial hematoma occurred in the United States, prompting the FDA to issue a health advisory in December 1997 and the convening of the first ASRA consensus conference on anticoagulation and neuraxial anesthesia.73 The smallest effective dose of LMWH should be administered. The postoperative administration of LMWH therapy should be delayed as long as possible, with a minimum of 12 h and ideally 24 h postoperatively. A single-dose spinal anesthetic may be the safest neuraxial technique in patients receiving preoperative LMWH. Waiting for at least 12 h after the LMWH prophylactic dose is recommended before performing a spinal technique. Patients who receive higher doses of LMWH (eg, enoxaparin 1 mg/kg twice daily) require longer delays (24 h). The catheter should be removed when anticoagulation activity is low, at least 12 h after prophylactic LMWH administration and 2–4 h before the next dose. Extreme vigilance of the patient's neurologic status must be observed if LMWH thromboprophylaxis is implemented while an indwelling catheter is infusing. Dilute local anesthetic solution is recommended so that neurologic function can be better monitored. The use of other medications affecting hemostasis, such as antiplatelet drugs, standard heparin, dextran, or oral anticoagulants, in combination with LMWH, creates an additional risk of bleeding complications.

Thrombolytic agents actively dissolve fibrin clots that have already formed. Exogenous plasminogen activators such as streptokinase and urokinase not only dissolve thrombus but also affect circulating plasminogen, leading to decreased levels of both plasminogen and fibrin. Recombinant tissue-type plasminogen activator (rt-PA), an endogenous agent, is more fibrin-selective and has less effect on circulating plasminogen levels. Clot lysis leads to elevation of fibrin degradation products, which themselves have an anticoagulant effect by inhibiting platelet aggregation. In addition to the fibrinolytic agent, patients frequently receive intravenous heparin to maintain an aPTT of 1.5 to 2 times normal. Patients with acute myocardial infarction who are treated with thrombolytic therapy (streptokinase or rt-PA) and subsequently heparinized have their fibrinogen and plasminogen levels maximally depressed at 5 h after thrombolytic therapy and remain significantly depressed at 27 h.

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 not well defined. Two cases of spinal hematoma in patients with indwelling epidural catheters who received thrombolytic agents have been reported in the literature.74,75 A case of epidural hematoma occurred in a patient with femoral artery occlusion who received an epidural anesthetic for surgical placement of an intraarterial catheter for infusion of urokinase.74 Three hours postoperatively, the patient complained of back pain that progressed to paraplegia despite discontinuation of the urokinase infusion. An emergency decompressive laminectomy was performed, and a large hematoma compressing the thecal sac was evacuated. The patient recovered full neurologic function within 3 days. Another patient with superficial femoral artery occlusion underwent epidural catheter placement for femoral-popliteal artery bypass.75 Blood was noted in the epidural catheter during placement. The patient was given 6300 units of heparin 90 min later, and urokinase was also injected intraarterially during the surgical procedure. A heparin infusion of 1000 U/h was initiated and continued postoperatively for 24 h. The epidural catheter was removed in the recovery room. The patient developed paraplegia on the fourth postoperative day. An MRI revealed an epidural hematoma that extended from T10 through L2. An emergency decompressive laminectomy was performed without improvement in the patient's neurologic status.

Fibrinolytic and thrombolytic agents create a coagulation state that poses a unique problem in performing neuraxial anesthesia. There may also be an increased use of these drugs in the perioperative period due to advances in fibrinolytic or thrombolytic therapy, thus requiring increased vigilance. The ASRA guidelines made recommendations with respect to neuraxial procedures after thrombolytic or fibrinolytic therapy.9,76 The concurrent use of heparin with fibrinolytic and thrombolytic drugs places patients at high risk of adverse neuraxial bleeding during spinal or epidural anesthesia. Except in highly unusual circumstances, patients receiving fibrinolytic and thrombolytic therapy should be cautioned against receiving spinal or epidural anesthesia. The time frame for avoidance of these drugs and puncture of noncompressible vessels is 10 days. There are no available data to clearly determine the length of time after discontinuation of these drugs and the safe performance of a neuraxial technique. Frequent neurologic monitoring is recommended for an appropriate length of time in patients who have had neuraxial blocks after fibrinolytic or thrombolytic therapy. If a patient has a continuous epidural infusion and received fibrinolytic or thrombolytic therapy, drugs that minimize sensory and motor blockade should be used. There has been 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 catheter removal or maintenance.

Thrombin Inhibitors

Recombinant hirudin derivatives, including desirudin, lepirudin, and bivalirudin, inhibit both free and clot-bound thrombin.9 Argatroban, an l-arginine derivative, has a similar mechanism of action. These drugs are primarily used in the treatment of heparin-induced thrombocytopenia. There is no pharmacologic reversal to the effect of these drugs. There have been no case reports of spinal hematoma related to neuraxial anesthesia in patients who have received a thrombin inhibitor. However, spontaneous intracranial bleeding has been reported.9 According to ASRA guidelines, no statement regarding risk assessment and patient management can be made.

Fondaparinux

Fondaparinux is a synthetic anticoagulant that produces its antithrombotic effect through selective inhibition of factor Xa.77 The drug exhibits consistency in its anticoagulant effect since it is chemically synthesized. It is 100% bioavailable. Rapidly absorbed, it reaches maximum concentration within 1.7 h of administration. Its half-life is 17 h.77 Fondaparinux is recommended as an antithrombotic agent following major orthopedic surgery78 and in the initial treatment of pulmonary embolism.79 The extended half-life (approximately 20 h) allows once-daily dosing. The FDA released fondaparinux with a black box warning similar to that of the LMWHs and heparin.

The actual risk of spinal hematoma with fondaparinux is unknown. The daily dosing makes safe catheter removal harder to predict. Both ASRA9 and the American College of Chest Physicians recommend against the use of fondaparinux in the presence of an indwelling epidural catheter. Their recommendations were based on the sustained and irreversible antithrombotic effect of fondaparinux, early postoperative dosing, and the spinal hematoma reported during the initial clinical trials of the drug. Close monitoring of the literature for risk factors associated with surgical bleeding may be helpful in risk assessment and patient treatment. Performance of neuraxial techniques should occur under conditions used in clinical trials (single needle pass, atraumatic needle placement, avoidance of indwelling neuraxial catheters).9 If this is not feasible, an alternative method of prophylaxis should be considered.

The most commonly used herbal medications are garlic, ginkgo, and ginseng. Garlic inhibits platelet aggregation, and its effect on hemostasis appears to last 7 days. Ginkgo inhibits platelet-activating factor, and its effect lasts 36 h. Ginseng has a variety of effects: it inhibits platelet aggregation in vitro and prolongs both thrombin time and aPPT in laboratory animals; its effect lasts 24 h.9 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. Mandatory discontinuation of these medications, or cancellation of surgery in patients in whom these medications have been continued, is not supported by available clinical data. However, the concurrent use of other medications that affect clotting mechanisms, such as oral anticoagulants or heparin, may increase the risk of bleeding complications in these patients. There is no accepted test to assess adequacy of hemostasis in the patient who took herbal medication(s). 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.9

Patients who develop spinal hematoma usually present with sudden, severe, constant back pain with or without a radicular component. Percussion over the spine aggravates the pain as well as maneuvers that increase intraspinal pressure, including coughing, sneezing, or straining. In addition, the return of the motor weakness and/or sensory deficit after the apparent resolution of the epidural or spinal blockade is highly suggestive of epidural or spinal hematoma formation. Motor and sensory findings depend entirely on the level and size of the hematoma, but may include weakness, paresis, loss of bowel or bladder function, and virtually any sensory deficit. MRI is the diagnostic study of choice. The differential diagnosis includes spinal abscess, epidural neoplasm, acute disk herniation, and spinal subarachnoid hemorrhage. Recovery without surgery is rare, and surgical consultation for consideration of emergent decompressive laminectomy must be obtained. Functional recovery is related primarily to the length of time the symptoms are present, and recovery after 72 h of symptoms is rare. The clinical features, diagnosis and differential diagnosis, and treatment of a patient with a spinal hematoma are discussed in more detail in Chapter 71 (Diagnosis and Management of Intraspinal, Epidural, and Peripheral Nerve Hematoma).

Anesthesiologists are urged to be up to date on their knowledge of new anticoagulant medications, anticoagulation protocols, and updated guideline recommendations (Table 70–1). Since spinal hematoma may occur even in the absence of identifiable risk factors, vigilance in monitoring is critical for early evaluation of neurologic dysfunction and prompt intervention. The decision to perform neuraxial blockade and the timing of catheter removal in a patient receiving anticoagulant therapy should be made on an individual basis, weighing the benefits of regional anesthesia against the small though definite risk of spinal hematoma.

In contrast to neuraxial procedures in the presence of anticoagulants, there have been no studies on peripheral nerve blocks in the presence of anticoagulants. Nevertheless, there have been case reports of hematomas when peripheral blocks are performed in patients who were on these drugs.

One should realize that spontaneous hematomas in various locations have been reported in patients who took anticoagulants. These include hematomas of the abdominal wall, intracranial hemorrhage, and psoas hematoma with enoxaparin80–82 and intrahepatic hemorrhage with LMWH.83 In fact, major hemorrhagic complications occur in 1.9% to 6.5% of patients on enoxaparin.84

A case of psoas hematoma and lumbar plexopathy was reported in a patient who was on enoxaparin and had a lumbar plexus block.85 The patient suffered a calcaneal fracture and was placed on enoxaparin 30 mg twice a day for deep vein thrombosis prophylaxis. In addition, she was on aspirin 325 mg a day. She had two surgeries for her calcaneal fracture; the first one was done under sciatic nerve block and the second under lumbar plexus block. She finally had a right below-the-knee amputation. Several attempts were made at lumbar plexus block, but the authors were unsuccessful, so a sciatic nerve block was ultimately performed. The enoxaparin was given 19.5 h before the block and 4.5 h after the block. The patient had hip pain and subsequently was unable to move her right leg. Computed tomography (CT) showed a right retroperitoneal hematoma involving the right psoas muscle. The enoxaparin was stopped and the hematoma was allowed to resorb. The patient regained motor function over the next 5 days and had no sensory or motor deficit at the 4-month follow-up visit.85 It should be noted that the timing of enoxaparin administrations was within the current ASRA guidelines.9 Although aspiration during the procedure showed no blood, bleeding probably occurred during the attempts at lumbar plexus block. The intake of aspirin, in addition to the enoxaparin, probably contributed to the bleeding during the procedure. Other cases of retroperitoneal hematoma were reported after psoas compartment block.86 One was a patient who was given enoxaparin 30 mg the day after the block (postoperative day 2). The psoas catheter was removed 1 h, 40 min after the enoxaparin, at the peak effect of the drug. Another was a patient who was given heparin infusion 8 h after the block and warfarin (Coumadin) the evening of surgery (postoperative day 1). Both patients complained of paravertebral pain and CT scan showed a large psoas hematomas86 (Figure 70–7).

Bleeding after sympathetic block in patients on ticlopidine and clopidogrel has been reported.87 One patient had the block while on ticlopidine; the other patient had the block 3 days after clopidogrel was discontinued. Both patients complained of groin pain; one patient also had medial thigh numbness.87 Eventually, both patients were found to have retroperitoneal hematoma. Bleeding after intercostal block in a patient on heparin has also been reported.88

The symptoms of hematoma formation after peripheral nerve block may include pain (flank or paravertebral pain or groin pain in psoas bleeding), tenderness in the area, steady decline in hemoglobin/hematocrit, hypotension due to hypovolemia, and sensory–motor deficit. Definite diagnosis is made by CT; ultrasound can also be used to detect the presence of renal subcapsular hematoma after psoas compartment block.89 Treatment may include surgical consultation, reversal of anticoagulation, blood transfusion as necessary, and watchful waiting versus surgical drainage.

It is probably too restrictive to adapt the same ASRA guidelines on neuraxial blocks to patients undergoing peripheral nerve blocks.9 The ASRA guidelines may be applicable to blocks in vascular and noncompressible areas such as celiac plexus blocks, superior hypogastric plexus blocks, and lumbar plexus blocks. Clinicians should individualize their decision and should discuss the risks and benefits of the block with the patient and the surgeon. Most important, the clinician should follow the patient closely after the block placement. Prospective studies are obviously needed to help guide clinicians in their decision.