• Rasha S. Jabri, MD

       INTRODUCTION

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 THERAPY

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.

Figure 70–1. Role of platelets in coagulation. Platelets carry out their role in hemostasis through three basic reactions: adhesion, activation (and secretion), and aggregation. When the blood vessels are stripped of endothelium, platelets rapidly bind to the subendothelium by a process termed adhesion.

Figure 70–2. Role of platelets in coagulation. Another important task of the platelet is to support plasma coagulation reactions. When activated, platelets bind several important plasma protein complexes. They secrete an activated form of factor V (factor Va), which binds to the platelet surface and binds factor Xa. Platelet-bound factor Xa then markedly accelerates the conversion of prothrombin to thrombin.

        The Ivy bleeding time was considered to be a reliable predictor of abnormal bleeding in patients receiving antiplatelet drugs.” 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 ofin 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.

Clinical Pearls

        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.

       ORAL ANTICOAGULANTS

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.

Figure 70–3. Vitamin K-dependent coagulation factor synthesis. Vitamin K is necessary for posttranslational modification of prothrombin, proteins C and S, and factors VII, IX, and X. Vitamin K is stored in hepatocytes.

Figure 70–4. Coagulation reaction: Factors responsible for a prolonged PTT are in the shaded area. Patients who have an abnormal PTT but whose PT and other tests are normal can be divided in two groups: those who are prone to bleeding and those that are not. The patients who do not bleed may have an extremely prolonged PTT (90 seconds or more) but do not have a history of bleeding. They will have deficiency in factor XII, prekalikrein, or high-molecular-weight kininogen. These patients should not be denied surgery or epidural anesthesia. The other group, patients who bleed, have both prolonged PTT and a history of bleeding. They will have a deficiency of factor VII (hemophilia A), factor IX (hemophilia B or Christmas disease), or factor XI.

        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 through 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.

Figure 70–5. Coagulation reaction: Factors involved in prothrombin time (PT) are in the shaded area. The PT is carried out by adding a source of tissue factor to the patient’s plasma along with calcium or phospholipid. Tissue factor forms a complex with and activates factor VII. (Ca = calcium; PL = phospholipid.)

Figure 70–6. Coagulation reaction: Factors involved in partial thromboplastin time (PTT) are in shaded area. In assessing the PTT, coagulation is initiated by an agent that activates the Hageman factor-kininogen-prekalikrein complex. Most coagulation factors are screened by PTT, except factors VII and XIII, the protein that stabilizes fibrin clots by cross-linking them, as well as components of the fibrinolytic system. (Ca = calcium; PL = phospholipid.)

Clinical Pearls

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Stimulating Catheters. Ultrasound-Assisted Nerve Blocks in Adults. Cutaneous Blocks for the Upper Extremity. Cervical Plexus Block.

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