2. Ausgabe 1995

Incidence of severe complications due to systemic anticoagulation during continuous techniques of major conduction blocks

T. T. Horlocker

Spinal hematoma is a rare and potentially catastrophic complication of spinal or epidural anesthesia. The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with central neural blockade is unknown; however, the incidence cited in literature is estimated to be less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics (Tryba, 1993). Hemorrhage into the spinal canal most commonly occurs in the epidural space because of the prominent epidural venous plexus.

Although hemorrhagic complications can occur after virtually all regional anesthetic techniques, bleeding into the spinal canal is perhaps the most serious hemorrhagic complication associated with regional anesthesia because the spinal canal is a concealed and nonexpandable space. Spinal cord compression from spinal hematoma may result in neurologic ischemia and paraplegia. Spinal hematoma may occur due to vascular trauma from needle or catheter placement into the subarachnoid or epidural space. However, it may also occur in association with neoplastic disease or pre-existing vascular abnormalities. Of special interest to the anesthesiologist are those spinal hematomas which have occured spontaneously with or without the presence of antiplatelet or anticoagulation therapy. Over 100 spontaneous epidural hematomas have been reported, 25% of which are associated with anticoagulation therapy (Spurny, 1964).

In a review of the literature between 1906 and 1994, Vandermeulen et al. (1994) reported 61 cases of spinal hematoma associated with epidural or spinal anesthesia. In 42 of the 61 patients (68%), the spinal hematomas associated with central neural blockade occured in patients with evidence of hemostatic abnormality. Twenty-five of the patients had received intravenous or subcutaneous heparin, while an additional five patients were presumably administered heparin, as they were undergoing a vascular surgical procedure. In addition, 12 patients had evidence of coagulopathy or thrombocytopenia or were treated with antiplatelet medications (aspirin, indomethacin, ticlopidin), oral anticoagulants (phenprocoumone), thrombolytics (urokinase), or dextran 70 immediately before or after the spinal or epidural anesthetic. Needle and catheter placement was reported to be difficult in 15 (25%), or bloody in 15 (25%) patients. Thus, in 53 of the 61 cases (87%), either a clotting abnormality or needle placement difficulty was present.

In order to reduce the risk of spinal hematoma associated with central neural blockade, it is necessary to understand the mechannisms of blood coagulation, the pharmacologic properties of the anticoagulant and antiplatelet medications, and also the clinical studies involving patients undergoing central neural blockade while receiving these medications. While this lecture will deal mainly with continuous techniques of major conduction blocks and anticoagulants, the same principles apply to all regional anesthetic techniques.

Intravenous heparin

Heparin is a complex polysaccharide which exerts its anticoagulant effect by accelerating the inhibition of activated coagulation factors by antithrombin III. There are at least 6 activated clotting factors that are inhibited by antithrombin III (thrombin, factors XIIa, XIa, Xa, IXa, and kallikrein) (Joist, 1979). Heparin also potentiates the action of activated factor X inhibitors (anti Xa) (Linn, 1986). The key position of factor X in the coagulation cascade enables it to generate thrombin through the intrsinsic or extrinsic pathway. Therefore inhibitors of this enzyme's activation will prevent thrombin formation.

Five minutes after intravenous injection of 10,000 units of heparin, coagulation time is prolonged 2 to 4 times the control level. heparin has a half-life in circulating blood of 1 1/2-2 hours (Joist, 1979). Patients with acute thromboembolic disease may clear heparin even more rapidly. Within 4 to 6 hours of the administration of a therapeutic dose of heparin, its effect has ceased. Intravenously administered heparin can be promptly neutralized by protamine.

In perhaps the most important study evaluating the safety of systemic heparinization and central neural blockade, Rao and El-Etr (1981) reported on 3,164 patients who had continuous epidural anesthesia and 847 patients who had continuous spinal anesthesia for lower extremity cascular procedures. Patients with a history of pre-existing coagulation abnormalities, thrombocytopenia, or preoperative anticoagulation therapy were excluded. All catheters were placed through a 17-gauge Tuohy needle. In 4 patients, following insertion of the needle into the epidural space, blood was freely aspirated. The needle was withdrawn and the patients were given general anesthesia the following day. Heparin was administered 50-60 minutes after catheter placement to maintain the activated clotting time (ACT) twice the baseline value. The heparin dose was repeated every 6 hours following measurement of the ACT throughout the period of anticoagulation therapy. The catheters were removed the following day 1 hour prior to administration of the maintenance dose of heparin. No patient developed signs or symptoms of epidural or subarachnoid hematoma, including the 4 patients who had traumatic needle placement and subsequently received general anesthesia. In summary, while the patients in this study safely underwent placement of indwelling epidural or spinal catheters followed by systemic heparinization, the heparin activity was closely monitored and the indwelling catheters were removed at a time when circulating heparin levels were relatively low. There were also no neurologic sequelae reported by Baron et al. (1987) in 912 vascular surgical patients who received continuous epidural anesthesia and underwent transient intraoperative anticoagulation with heparin (ACT >100 seconds). The catheters were removed immediately after surgery.

Although the two previous studies suggest that central neural blockade (administered through an indwelling catheter) followed by heparinizytion can be safely conducted, Ruff and Dougherty (1981) reported documented spinal hematomas in 7 of 342 patients (2%) who underwent a diagnostic lumbar puncture with a 20-gauge needle. The patients presented with signs of cerebral ischemia after subarachnoid hemorrhage was ruled out, were subsequently anticoagulated with intravenous heparin. The amount of heparin used and coagulation studies were not reported. Patients were followed neurologically. Five patients developed paraparesis. There were also 18 patients with severe or radicular back pain lasting more than 48 hours. Seven of these patients subsequently died of unrelated causes, and at autopsy, one patient had findings of chronic epidural hematoma while another showed an organized subdural hematoma. The authors identified traumatic needle placement, initiaion of anticoagulation within 1 hour of lumbar puncture or concomitant aspirin therapy as being risk factors in the development of spinal hematoma in anticoagulated patients.

The conflicting results of these studies and the rarity of this complication make it difficult to assess the relative risk and contributing variables of spinal hematoma associated with continuous catheter techniques of central neural blockade in anticoagulated patients. However, possible factors contributing to increased risk in these patients appear to be pre-existing coagulopathy or thrombocytopenia, concomitant aspirin therapy, traumatic or difficult needle placement, heparinizytion within 1 hour of spinal or epidural puncture, and absence of monitoring the anticoagulant activity (Ruff, 1981; Rao, 1981; Vandermeulen, 1994).

Subcutaneous heparin

The therapeutic basis of low-dose subcutaneous heparin (5000 unnits every 8-12 hours) is based on heparin-mediated inhibition of activated factor X. Inhibition of small amounts of activated factor X prevents amplification of the coagulation cascade. Smaller doses of heparin are therefore 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 40-50 minutes and usually returns to baseline within 4-6 hours (Malinovsky, 1979). The activated partial thromboplstin time (APTT) may remain in the normal range and often is not monitored (Ockelford, 1986). However, wide variation in individual patient response to subcutaneous heparin has been reported (Poller, 1982).

This wide variation in response to subcutaneous low-dose heparin makes it difficult to formulate a generalized recommendation regarding central neural blockade in these patients. Lowson and Goddchild (1989) and Alleman et al. (1983) reported no cases of spinal hematoma in a combined total of 204 epidural and 119 spinal anesthetics performed on patients who had received 5000 U of unfractionated heparin subcutaneously 2 hours prior to needle placement. A review of the literature by Schwander and Bachmann in 1991 (Schwander, 1991) noted no spinal hematomas in over 5000 patients who received varying doses of subcutaneous heparin in combination with spinal or epidural anesthesia. Spinal hematoma in patients who undergo major conduction blocks while receiving low-dose heparin are extremely rare; there are only 3 reported cases in the literature, two of which involved a continuous epidural anesthetic technique (Darnat, 1986; Dupeyrat, 1990; Metzger, 1991).

Low molecular weight heparin

Unfractionated heparin is a heterogenous mixture of polysaccharide chains that can be separated into fragments of various molecular weights. Since each low molecular weight heparin (LMWH) fractionation contains heparins of different molecular weights, each must be evaluated as a specific pharmacological substance. Several LMWH preparations are in clinical use in Europe (Fraxiparin, Fragmin, Logiparin, Sandoz), however it remains in investigational status in the United States. LMWH exhibits a dose-dependent antithrombotic effect that is most accurately assessed by measuring the anti-Xa activity level. The advantages of LMWH over unfractionated heparin include a higher and more predictable bioavailability after subcutaneous administration, a longer biological half-life which makes one injection per day sufficient, and a smaller impact on platelet function (Andersson, 1989).

In a review of the literature, Bergqvist et al. (1992) identified 44 articles on LMWH for thromboprophylaxis. If those studies in which the mode of anesthesia was noted are combined, LMWH was administered in conjunction with spinal or epidural anesthesia in 9,013 patients. There are no reported cases of spinal hematoma with neurologic dysfunction in these patients. Although the actual number of patients who have received LMWH in combination with central neural blockade is not known, pharmaceutical companies estimate it to be at least 1,000,000 patients (Bergqvist, 1992). Four cases of spinal hematoma in patients receiving LMWH who underwent epidural or spinal anesthesia have been reported; three of the patients had indwelling epidural catheters (Chiquet, 1993; Tryba, 1989; Tryba, 1991).

Oral anticoagulants

Oral anticoagulants, including warfarin, exert their anticoagulant effect indirectly by interfering with the synthesis of the vitamin K-dependent clotting factors (VII, IX, X, and thrombin). The effects of warfarin are not apparent until a significant amount of biologically inactive factors are synthesized. Since factor VII has a relatively short half-life (6-8 hours), the prothrombin time (PT) may be prolonged into the therapeutic range (1.5-2 times normal) in 24-36 hours. However, since factor VII participates only in the extrinsic pathway, adequate anticoagulation is not achieved until the levels of biologically active factors II and X are sufficiently depressed which, because of their longer half-lives, requires 4-6 days (Joist, 1979). With initial high loading doses of warfarin (15-30 mg) for the first 2-3 days of therapy the desired anticoagulant effect is achieved within 48-72 hours (Linn, 1986). Similarly, the anticoagulant effects persist for 4-6 days after termination of therapy while new biologically active vitamin K factors are synthesized. In an emergent situation, the anticoagulant effects can be reversed by transfusing fresh frozen plasma and vitamin K injections.

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 Sih (1983) performed 1000 continuous lumbar epidural anesthetics in 950 patients undergoing vascular procedures who were receiving oral anticoagulants preoperatively. The thrombotest (a test measuring factor IX activity) was decreased and the APTT was prolonged in all patients prior to needle placement. Heparin was administered intraoperatively. Epidural catheters remained in place for 48 hours postoperatively. The coagulation status at time of catheter removal was not described. There were no neurologic complications. While 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 limit their usefulness.

The use of an indwelling epidural or intrathecal catheter and the timing of its removal in an anticoagulated patient is also controversial. Although the trauma of needle placement occurs with both single dose and continuous catheter techniques, the presence of an indwelling catheter could theoretically provoke additional injury to tissue and vascular structures. There were no reported spinal hematomas in 192 patients receiving postoperative epidural analgesia in conjunction with low-dose warfarin after total knee arthroplasty. Patients received warfarin to prolong the PT to 15.0-17.3 s (normal 10.9-12.8 s). Epidural catheters were left indwelling 37 +/- 15 h (range 13-96 h). Mean PT at the time of epidural catheter removal was 13.4 +/- 2 s (range 10.6-25.8 s). This study documents the relative safety of low-dose warfarin anticoagulation in patients with an indwelling epidural catheter. However, there was a large variability in patient response to warfarin, and the authors recommended close monitoring of coagulation status to avoid excessive prolongation of the PT (Horlocker, 1994).

Thrombolytic therapy

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 as well, 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 (Hirsh, 1990). 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, these patients frequently receive intravenous heparin to maintain an APTT of 1.5 to 2 times normal (Rao, 1988).

In a study involving 290 patients with acute myocardial infarction who were treated with thrombolytic therapy (streptokinase or rt-PA) and subsequently heparinized, fibrinogen and plasminogen are maximally depressed at 5 hours after thrombolytic therapy and remain significantly depressed at 27 hours. Hemorrhagic events occured in 33% of the rt-PA patients and 31% of the streptokinase patients. For more than 70% of the patients with hemorrhagic events in each group, the primary bleeding site was the catheterization or other puncture site. The authors recommended avoiding invasive procedures in patients receiving thrombolytic therapy (Rao, 1988).

While epidural or spinal needle and catheter placement with subsequent heparinizytion appears relatively safe, the risk of spinal hematoma in patients who receive thrombolytic therapy is less well defined. Two cases of spinal hematoma in patients with indwelling epidural catheters who received thrombolytic agents have been reported in the literature. Dickman et al. (1990) reported a case in which a patient with femoral artery occlusion received an epidural anesthetic for surgical placement of an intra-arterial catheter for infusion of urokinase. Three hours postoperatively, the patient complained of back pain which progressed to paraplegia despite discontinuation of the urokinase infusion. An emergency decompressive was performed, and a large solidified hematoma compressing the thecal sac was evacuated. The patient recovered full neurologic function within 3 days. Onishchuk and Carlsson (1992) reported a patient with superficial femoral artery occlusion who underwent epidural catheter placement for femoral-popliteal artery bypass. Blood was noted in the epidural catheter during placement. The patient was bolused with 6300-units of hepartin 90 minutes later, and a single bolus of urokinase was also injected intra-arterially during the surgical procedure. A heparin infusion of 1000 U/h was initiated and continued postoperatively for 24 hours. The patient was taken to the recovery room and the epidural catheter removed. On the fourth postoperative day, it was noted the patient developed paraplegia. An MRI revealed an epidural hematoma extending from T10-L2. An emergency decompressive laminectomy was performed without any improvement. The authors recommended that epidural anesthesia be avoided in patients who are to receive thrombolytic therapy.

Antiplatelet therapy

Antiplatelet therapy, including such medications as aspirin, naproxen, piroxicam, and dipyridamole, has been considered a relative contra-indication to central neural blockade by some authors due to the associated prolongation of the bleeding time and theoretically greater risk of spinal hematoma formation.

Antiplatelet medications inhibit platelet cyclooxygenase and prevent the synthesis of thromboxane A2. Thromboxane A2 is not only a potent vasoconstrictor, but also facilitates secondary platelet aggregation and release reactions. Platelets from patients who have been taking these medications have normal platelet adherence to subendothelium and normal primary hemostatic plug formation. Thus an adequate, although potentially fragile, clot may form. While such plugs may be satisfactory hemostatic barriers for smaller vascular lesions, they may not ensure adequate perioperative hemostatic clot formation.

It has been suggested that the Ivy bleeding time is the most reliable predictor of abnormal bleeding in patients receiving antiplatelet drugs (Rapaport, 1983). However, the "post-aspirin" bleeding time is not a relaible indicator of platelet function (Hindman, 1986; Rodgers, 1990). Although the bleeding time may normalize within 3 days after aspirin ingestion, platelet function as measured by platelet response to ADP, epinephrine, and collagen may take up to a week to return to normal. There is no evidence to suggest that a bleeding time can predict hemostatic compromise; studies have failed to show a correlation between aspirin-induced prolongation of the bleeding time and surgical blood loss (Rodgers, 1990; Ferraris, 1983). 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 and is clinically not indicated. Other nonsteroidal analgesics (naproxen, piroxicam, ibuprofen) produce a short-term defect which normalizes within 3 days (Cronberg, 1984). Platelet function in patients receiving antiplatelet medications should be assumed to be decreased for 1 week with aspirin and 1 to 3 days with other non-steroidal anti-inflammatory drugs. Special platelet function assays are also available to monitor platelet aggregation and degranulation.

There has been a single reported case of spontaneous epidural hematoma formation (in the absence of spinal or epidural anesthesia) in a patient with a history of aspirin ingestion (Locke, 1976). The patient self-adminstered 1500 mg of aspirin in the form of an aspirin-containing antacid and a short time later complained of severe lower extremity weakness. A myelogram revealed complete epidural block at T5-6 level. The cerebrospinal fluid was clear, although prolonged bleeding from the lumbar puncture site was noted after myelography. A laminectomy was performed and the hematoma removed. Neurologic function gradually improved.

The risk associated with administration of spinal or epidural anesthesia to a patient receiving antiplatelet medications remains controversial. Althrough Vandermeulen et al. (1994) implicated antiplatelet therapy in 3 of the 61 cases of spinal hematoma occuring after spinal or epidural anesthesia, 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) Group included 1422 high-risk obstetric patients administered 60 mg aspirin daily who underwent epidural anesthesia without any neurologic sequelae. However, no data regarding difficulty or bleeding during epidural needle or catheter was reported (CLASP, 1994). Horlocker et al. (1990) retrospectively reported 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. While no patient developed signs of spinal hematoma, patients on antiplatelet medications showed a higher incidence of blood aspirated through the spinal or epidural needle or catheter.

This study was subsequently performed prospectively on an additional 1000 patients, 39% of whom reported preoperative antiplatelet therapy (Horlocker, 1995). As before, there were no spinal hematomas. Blood was noted during needle or catheter placement in 22% of patients, including 7% of patients with frank blood. Preoperative antiplatelet therapy was not a risk factor for bloody needle or catheter placement. However, many patients and anesthetic variables including female gender, increased age, a history of excessive bruising or bleeding, continuous catheter technique, large needle gauge, multiple needle passes, and difficult needle placement were significant risk factors. The lack of correlation between antiplatelet medications and bloody needle or catheter placement (producing clinically insignificant collections of blood within the spinal canal) is strong evidence that preoperative antiplatelet therapy is not a significant risk factor for the development of neurologic dysfunction from spinal hematoma in patients who undergo spinal or epidural anesthesia while receiving these medications.

Anesthetic management

The decision to perform central neural blockade on a patient receiving thrombolytics, anticoagulants, or antiplatelet medications should be made on an individual basis, weighing the small, though definite risk of spinal hematoma with the benefits of regional anesthesia for a specific patient. Preoperatively, the patient's history should be reviewed for medical conditions associated with bleeding tendencies such as preeclampsia, severe liver disease, or recent chemotherapy, and the patient questioned about previous episodes of sustained bleeding after trauma or surgery. Because patients react to anticoagulants with varying sensitivities, it may be useful to verify reversal of heparin or warfarin effects prior to performance of spinal or epidural blockade.

The following statements, based on the pharmacology of anticoagulant, thrombolytic and antiplatelet drugs, as well as case reports and clinical studies involving patients undergoing central neural blockade while receiving these medications will guide the clinician faced with this difficult decision.

Except in extraordinary circumstances, the risk of spinal hematoma outweighs the potential benefits of central neural blockade in patients who have known coagulopathies, significant thrombocytopenia, or have received thrombolytic therapy within the previous 24 hours. While the data by Odoom and Sih (1983) are reassuring, central neural blockade should also probably be avoided in fully anticoagulated patients. Patients who have received only 1 or 2 doses of an oral anticoagulant (i.e., 5-10 mg warfarin) will generally not have an increased prothrombin time and may safely undergo regional anesthesia. A prothrombin time may be measured prior to needle placement.

Patients fully anticoagulated with a continuous heparin infusion should have the infusion discontinued 4-6 hours prior to needle or catheter placement, unless early normalization is verified by an APTT. While the anticoagulant effect of subcutaneous heparin is typically less significant than that of intravenous heparin, ideally subcutaneous low-dose heparin should also not be administered within 4-6 hours of a spinal or epidural anesthetic to allow for normalization of the heparin effect.

Epidural or spinal anesthesia followed by systemic anticoagulation with heparin or warfarin is probably safe, provided adequate precautions are taken (Horlocker, 1994; Rao, 1988). Heparinization should not be initiated for at least an hour after needle placement (Andersson, 1989; Rao, 1981; Ruf, 1981). If needle placement is traumatic or difficult, the decision to proceed with surgery should be reevaluated (Andersson, 1989; Rao, 1981; Ruff, 1981). In addition, patients receiving antiplatelet medications who will undergo subsequent heparinization appear to be at increased risk for spinal hematoma and should be followed closely (Ruff, 1981). The APTT and PT should be monitored carefully to avoid excessive levels of anticoagulation therapy (Horlocker, 1994; Rao, 1981).

Little data exist on the timing of spinal or epidural catheter removal in an anticoagulated patient. In Vandermeulen's series, bleeding occured at the time of catheter removal in almost 50% of cases (Vandermeulen, 1994). The most conservative practice is to remove an indwelling catheter under the same conditions in which placement is considered safe. Removal of an indwelling epidural catheter in a patient receiving intravenous or subcutaneous heparin should ideally occur 4-6 hours after the last heparin dose and anticoagulation should not be reinstituted for at least 1 hour after catheter removal. In a patient with a perioperative coagulopathy such as diffuse intravascular coagulation or dilutional thrombocytopenia, every attempt should be made to normalize the coagulation status prior to catheter removal. If the coagulation defect is expected to be prolonged, then the decision on when to remove the indwelling catheter should be made on an individual basis, taking into account the evolving coagulation status of the patient during the perioperative period.

Epidural and spinal anesthesia can be safely performed in a patient receiving antiplatelet therapy (CLASP, 1994; Horlocker, 1990; Horlocker, 1995). It is important to note that while the platelet defect of most antiplatelet medications reverses in 3 to 5 days, the defect produced by aspirin is present for 1 week.

Needle and catheter placement during central neural blockade should be as atraumatic as possible. Utilization of small gauge needles and catheters and minimal catheter insertion distances (3-4 cm) may help reduce trauma to epidural or subarachnoid vessels.

Short-acting local anesthetics should be used in patients at increased risk of spinal hematoma in order that their neurologic status may be evaluated immediately postoperatively. Likewise, a central neural block should be allowed to regress sufficiently to allow neurological evaluation before initiating a continuous local anesthetic infusion for postoperative analgesia. A narcotic rather than local anesthetic infusion would allow continuous monitoring of neurologic function and may be a more prudent choice in high risk patients.

The patient should be monitored closely in the perioperative period for early signs of cord compression. If spinal hematoma is suspected, the treatment of choice is immediate decompressive laminectomy. Recovery is unlikely if surgery is postponed for more than 8-12 hours; less than 40% of the patients in Vandermeulen's series had partial or good recovery of neurologic function (Harik, 1971; Vandermeulen, 1994).

Keywords
Anaesthesie, Antikoagulation, rückenmarksnahe Leitungsanaesthesie, Komplikationen

Anschrift

Literatur
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