ANTICOAGULANTS AND REGIONAL ANAESTHESIA. HOW SERIOUS IS THE PROBLEM? WHICH PATIENTS ARE AT RISK?

ANTICOAGULANTS AND REGIONAL ANAESTHESIA

HOW SERIOUS IS THE PROBLEM?

WHICH PATIENTS ARE AT RISK?

Eriphili Argyra

Faculty of Medicine, University of Athens, Greece

For the full text in pdf form click here.

Thromboembolic Disease and Thromboprophylaxis

Almost all contemporary hospital patients have at least one risk factor for venous thromboembolism (VTE) and approximately 40% have three or more risk factors [1]. Surgery is associated with a 20-fold increase in the risk of VTE [2]. VTE, deep venous thrombosis (DVT) and pulmonary embolism (PE), are the most common complications following surgical procedures [3], [4]. Major orthopaedic surgery (total hip and knee arthroplasty and hip fracture repair), major general, gynaecological and urological surgery, neurosurgery, cardiothoracic and major vascular surgery are identified as procedures having the highest risk for VTE. Common risk factors include older age, malignancy, prior DVT, surgery or trauma, hypercoagulable disorders, medications such as oral contraceptives and oestrogen replacement therapies, and possibly obesity [5], [6]. Patients who have postoperative infectious complications, bleeding, or MI are at particular risk [7].

Most of these factors can be determined by a thorough history on admission and perioperative planning is of paramount importance. VTE risk assessment and stratification followed by the administration of the appropriate venous thromboprophylaxis, is ranked as the number one best intervention for creating safer health care practices [8].

Excellent consensus guidelines exist to determine patient risk and recommend prophylaxis regimens [3], [9]. The numerous current VTE protocols in use can be classified into three groups: 1) those that rely on the use of potent anticoagulants (low-molecular-weight heparin, ximelagatran, fondaparinux, or rivaroxaban), 2) those that target venous stasis, endothelial damage, and hypercoagulability (Virchow’s triad) during the period at risk for VTE, and rely on the use of epidural anaesthesia, pneumatic compression devices, and aspirin in the majority of patients without predisposing factors for PE, the so-called multimodal prophylaxis [10] and 3) those that rely on slow-acting oral anticoagulants (warfarin).

During the last decade the reported incidence of fatal PE has decreased substantially at least to the special group of orthopaedic patients to a rate of 0% to 0.2% [11], [12], result attributed to a better understanding of the pathogenesis of thromboembolic disease during and after surgery and advancements in anaesthesia, surgical technique, perioperative care. Even with aggressive VTE prophylaxis however, this event still occurs and suggests other undefined factors may play a role in VTE occurrence.

Nevertheless there are risks involved in thromboprophylaxis. Of interest is a recent metaanalysis of articles published from 1998 to 2007, suggesting higher incidence of all-cause mortality and nonfatal PE (0.41% versus 0.19%) in orthopaedic patients receiving low-molecular-weight heparin compared to regional anaesthesia, pneumatic compression, and aspirin [13], and as was shown in the ESCORTE study, while the current rate of postoperative VTE in orthopaedic patients after hip fracture surgery is low, overall mortality remains high [14].

Regional Anaesthesia and Thromboprophylaxis: Magnitude of the Problem

Anaesthesiologists today not uncommonly find themselves dealing with patients who are under thromboprophylaxis or do not have normal coagulation. Of particular interest for them is perioperative bleeding and for those who practice regional anaesthesia predisposition to vertebral canal haematoma. The problem is the large overlap between patients who are at the moderate or high risk for VTE for whom thromboprophylaxis is considered prudent and regional anaesthesia is considered appropriate. Perioperative epidural and perineural catheter techniques are widely practiced in this population as there is superior analgesic efficacy and evidence of a beneficial effect of epidural anaesthesia and analgesia in terms of some variables of cardiac and pulmonary function [15].

Spinal haematoma is a rare but potentially catastrophic complication of spinal or epidural anaesthesia. The actual incidence of neurological dysfunction resulting from hemorrhagic complications associated with central neural blockade is unknown. In an extensive review of the literature, Tryba identified 13 cases of spinal hematoma following 850,000 epidural anesthetics and seven cases among 650,000 spinal techniques. The calculated incidence was less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics [16]. 

In May 1993 the scene has changed as enoxaparin, the first low-molecular-weight heparin (LMWH) approved by the United States Food and Drug Administration (FDA), was distributed for thromboprophylaxis in major surgery. Over the next 5 years nearly 60 cases associated with regional anaesthesia and any LMWH use were reported. The risk associated with an indwelling epidural catheter in the presence of twice daily administration of low molecular weight heparin (LMWH) has been estimated to be 1 in 3,100 patients [17]. In response to the first of these reports of spinal haematoma in patients undergoing epidural or spinal block, while receiving thromboprophylaxis with enoxaparin, the manufacturer revised the warnings section of the drug’s label and altered the prescribing information [18]. In 1997, the FDA issued a health advisory and requested all manufacturers of LMWH’s to include warnings on the drug’s labeling [19]. By 1998, practice guidelines were issued from the American Society of Regional Anaesthesia [20] and were revised in 2003 [21].

In Europe LMWH is administered on a once daily schedule and with a smaller total daily dose (40 mg) than that approved in the United States (30 mg twice daily). A retrospective analysis in Sweden came to similar conclusions, despite low dosages of enoxaparin (1 x 40 mg). The risk was found to be 1 in 18,000 after epidural anaesthesia and 1 in 156,000 after spinal anaesthesia, with bleeding complications occurring much more rarely after epidural anaesthesia in obstetrics (1: 200,000) than in female orthopaedic patients (1: 3600) [22].  

Practice guidelines among the European societies had been established in order to minimize bleeding complications bas ed on placing and removing needles and catheters during periods of decreased LMWH [23], [24], [25], including guidelines for monitoring the patient’s neurologic function. It should be emphasized though that these guidelines are not evidenced based, but rely on the evaluation of case reports and pharmacokinetics of the drugs involved. Thus, appropriate evaluation should be carried out and the risk should be adjusted to every individual patient.

Patients at Risk

Despite following guidelines epidural haematomas resulting in neurological injury are still occurring [26], [27]. Spinal haematoma in the absence of trauma or anticoagulant therapy rarely occurs. Risk factors are increased age, female gender, and decreased weight, history of gastrointestinal bleeding, concomitant aspirin use, and length of therapy.  The patient factors for spinal haematoma under antithrombotic therapy are similar to those for spontaneous bleeding, plus the intensity of the anticoagulant effect and the combination of drugs exerting anticoagulant activity.

Obviously any patient with a clinically active coagulation disorder or a history of easy bruising and/or bleeding, is considered to have an absolute contraindication to regional anaesthesia (RA). Coagulation disorders, thrombocytopenia or drug-induced platelet function disturbances are frequent findings in series or reports of spinal bleeding [28], [29], [30].

Not only LMWH but any agent that interferes with haemostasis can compromise safety of RA. During warfarin therapy, an international normalized ratio (INR) of 2.0 to 3.0 is associated with a low risk of bleeding: < 3% during a three-month treatment period. Higher intensity regimens (INR > 4) are associated with a significantly greater risk of bleeding (7%). The incidence of hemorrhagic complications during therapeutic anticoagulation with standard heparin, as well as LMWH, is < 3%. Thrombolytic therapy represents the greatest risk of bleeding; between 6% and 30% of patients. Patients who require preoperative anticoagulant therapy, such as those with a history of atrial fibrillation or cardiac valve replacement, are not ideal candidates for neuraxial techniques. Often the anticoagulant effect is only partially reversed to avoid thrombotic complications and/or they are aggressively anticoagulated postoperatively. Normal haemostasis for needle placement/catheter removal is present only for a short interval.

Additional risk factors include bloody or traumatic punctures and anatomic changes (e.g., Spina bifida, Bechterew’s disease). Due to the smaller needle diameter, the risk of haemorrhage is lowest in spinal anaesthesia and highest in catheter epidural anaesthesia. Nearly half of all cases of bleeding occur during the removal of an epidural catheter, so that this phase must be regarded as critical as catheter placement[31].

In a series of 40 spinal haematomas associated with LMWH thromboprophylaxis, 75% of the patients were elderly women. Decreased weight is a risk factor as LMWH dosing is not weight adjusted and the anticoagulant effect of LMWH is not monitored.Concomitant hepatic or renal disease may also exaggerate the anticoagulant response and theoretically increase the risk. Warfarin pharmacology for example is significantly affected by patient age, diet and activity [32].

Although renal insufficiency is known to prolong and increase the anti-Xa effect, a baseline serum creatinine is not routinely measured prior to initiation of LMWH thromboprophylaxis. Severe renal insufficiency, defined by a calculated creatinine clearance (CrCl b 30 mL/ min) exists in about 30% of ICU patients. An additional 30% or more patients may have moderate (CrCl 30-50 mL/min) or mild renal insufficiency (CrCl 51-80 mL/min). ICU patients with renal insufficiency are at high risk for DVT and they accordingly are considered for thromboprophylaxis. Although there are preliminary data suggesting that low-dose LMWH would be safe when used for DVT prophylaxis in patients with renal insufficiency, the lack of clinical trials assessing this issue precludes definitive conclusions [33]. Some of them might have an epidural catheter already in place for postoperative analgesia and should be observed as patients at risk.

Pregnancy and the immediate postpartum period are associated with a hypercoagulable state. However, in the series by Vandermeulen et al., five of 61 spinal hematomas involved parturients. In two cases, a clotting disorder (thrombocytopenia, preeclampsia) was present. It should be emphasized that an increasing number of patients are receiving anticoagulant medications during pregnancy, including LMWH. To date, there have been no spinal haematomas associated with peripartum antithrombotic therapy. However the relative risk is unknown as there is no large series documenting the safety of neuraxial block in the presence of the therapeutic levels of anticoagulation among this patient population.

Patients who developed epidural haematoma frequently had one or more risk factors for bleeding which included coadministered therapeutic-dose anticoagulants, such as intravenous heparin or warfarin, coadministered antiplatelet or nonsteroidal anti-inflammatory drugs, thrombocytopenia, coagulopathy, and traumatic epidural catheter insertion or removal.  Obviously, patient factors are not “controllable”, but should be considered when selecting a regional technique and intensity of neurologic monitoring perioperatively.

Peripheral Nerve Blocks

They cause less serious complications and are devoid of the risk of spinal epidural hematoma. Superficial peripheral nerve blocks, such as axillary plexus, femoral or distal sciatic nerve block are not considered a contraindication in the presence of anticoagulation [34]. Major bleeding has been reported only in cases in which psoas compartment or lumbar sympathetic block was performed [35], [36], [37]. Therefore due to the severe consequences of retroperitoneal haematoma, patients receiving a lumbar plexus blockade or psoas compartment should be treated like patients receiving a neuraxial blockade [38]. 

References

[1] Anderson FA, Spencer FA: Risk factors for venous thromboembolism. Circulation 2003;107:I9-I16

[2] Heit JA, O’Fallon WM, Petterson TM, et al: Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population- based study. Arch Intern Med 2002;162:1245-1248

[3] Geerts WH, Pineo GF, Heit JA, et al: Prevention of venous thromboembolism. The Seventh Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S

[4] Kaboli P, Henderson MC, White RH: DVT prophylaxis and anticoagulation in the surgical patient. Med Clin North Am 2003; 87:77-110,

[5] Henke PK., Schmaier A, Wakefield TW. Vascular thrombosis due to hypercoagulable states. Chapter 34, 6th ed: Philadelphia, PA: Elsevier Saunders; 2005

[6] White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med 2000; 343:1758-64.

[7] Gangireddy C, MD, Rectenwald JR, Upchurch GR, et al. Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007;45:335-42

[8] Shojania K.G., Duncan B.W., McDonald K.M., et al. 2001. Making health care safer: a critical analysis of patient safety practices. Evidence Report/Technology Assessment No 42.

[9] Autar R.: NICE guidelines on reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients undergoing surgery. Journal of Orthopaedic Nursing 2007; 11:169–176,

[10] Salvati EA, Sharrock NE, Westrich G, Potter HG, Valle AG, Sculco TP. The 2007 ABJS Nicolas Andry Award: three decades of clinical, basic, and applied research on thromboembolic disease after THA: rationale and clinical results of a multimodal prophylaxis protocol. Clin Orthop Relat Res. 2007; 459: 246–254.

[11] Fender D, Harper WM, Thompson JR, Gregg PJ. Mortality and fatal pulmonary embolism after primary total hip replacement: results from a regional hip register. J Bone Joint Surg Br. 1997;79:896–899.

[12] Gonzalez Della Valle A, Serota A, Go G, Sorriaux G, Sculco TP, Sharrock NE, Salvati EA. Venous thromboembolism is rare with a multimodal prophylaxis protocol after total hip arthroplasty. Clin Orthop Relat Res. 2006;444:146–153.

[13] Sharrock N. E, Della Valle A.G, Go G., et al Potent Anticoagulants are Associated with a Higher All-Cause Mortality Rate After Hip and Knee ArthroplastyClin Orthop Relat Res 2008; 466:714–721

[14] Rochester N, Vielpeau C., Emmerich J, Fagnani F § and. Samama C. M Venous thromboembolism and mortality after hip fracture surgery: the ESCORTE study. J Thromb Haemost 2005; 3: 2006–14.

[15] Rathmell JP, Wu CL, Sinatra RS et al. Acute post-surgical pain management: A critical appraisal of current practice. Reg Anesth Pain Med 2006;31:1-42.

[16] Tryba M. Epidural regional anesthesia and low molecular heparine: pro (German). Anasthesiol Intensivmed Notfallmed Schmerzther 1993;28:179–81.

[17] Schroeder DR. Statistics: detecting a rare adverse drug reaction using spontaneous reports. Reg Anesth Pain Med 1998; 23(Suppl 2): 183–9.

[18] Landow L. Bedford RA. Low-molecular weight heparin, spinal hematomas, and the FDA: what’s wrong with this picture? Reg Anesth Pain Med 1999; 24:8 –10.

[19] Lumpkin MM. FDA public health advisory. Anesthesiology 1998; 88:27A–28A.

[20] Horlocker TT, Wedel DJ. Anticoagulation and neuraxial block: historical perspective, anesthetic implications, and risk management. Reg Anesth Pain Med 1998; 23(Suppl 2):129 –34.

[21] Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28:1 72–97.

[22] Moen V, Dahlgren N, Irestedt L. Severe Neurological Complications After Central Neuraxial Blockades in Sweden 1990-1999. Anesthesiology 2004; 101: 950-959.

[23] Gogarten W, Van Aken H, Buttner J, et al. Neuraxial blockade and thromboembolism prophylaxis/ antithrombotic therapy: revised recommendations of the German Society of Anaesthesiology and Intensive Care. Anaesth Intensivmed 2003; 44:218–230.

[24] Vandermeulen EP, Singelyn F, Vercauteren M, et al. Belgian guidelines concerning central neural blockade in patients with drug-induced alteration of coagulation: an update. Acta Anaesthesiol Belg 2005; 56:139–146.

[25] Kozek-Langenecker SA, Fries D, Gu¨ tl M, et al. Locoregional anesthesia and coagulation inhibitors: recommendations of the Task Force on Perioperative Coagulation of the Austrian Society for Anesthesiology and Intensive Care Medicine. Anaesthesist 2005; 54:476–484.

[26] Tam NLK, Pac-Soo C, Pretorius PM: Epidural hematoma after a combined spinal-epidural anaesthetic in a patient treated with clopidogrel and dalteparin. Br J Anaesth 2006;96: 262-265,

[27] Schwarz SK, Wong CL, McDonald WN. Spontaneous recovery from a spinal epidural hematoma with atypical presentation in a nonagenarian. Can J Anesth 2004; 51: 557–61.

[28] Vandermeulen EP, Van Aken H, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994; 79:1165–77.

[29] Vandermeulen E. Is Anticoagulation and Central Neural Blockade a Safe Combination? Curr Opin Anaesthesiol 1999; 12: 539-543.

[30] Wulf H. Epidural Anaesthesia and Spinal Haematoma. Can J Anaesth 1996; 43: 1260-1271.

[31] Gogarten W, Van Aken H, Büttner J, Riess H, Wulf H, Bürkle H (2007) Rückenmarknahe Regionalanästhesie und Thromboembolieprophylaxe/ Antithrombotische Medikation – 2. überarbeitete Empfehlung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI). Anästhesiologie und Intensivmedizin, 48; Suppl. Nr. 4 , 2007, S109-S124

[32] Horlocker T.T Editorial. What’s a nice patient like you doing with complication like this? Diagnosis, prognosis and prevention of spinal hematoma. Can J Anesth 2004; 51 (6): 527–534

[33] Douketis J.D, Rabbat C, Crowther M.A, Anticoagulant prophylaxis in special populations with an indwelling epidural catheter or renal insufficiency. Journal of Critical Care 2005; 20, 324– 329

[34] Gogarten W. The influence of new antithrombotic drugs on regional anesthesia. Curr Opin Anaesthesiol 2006;19:545–550.

[35] Klein SM, D’Ercole F, Greengrass RA, Warner DS. Enoxaparin associated with psoas hematoma and lumbar plexopathy after lumbar plexus block. Anesthesiology 1997;87:1576 –9.

[36] Maier C, Gleim M, Weiss T, Stachetzki U, Nicolas V, Zenz M. Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors. Anesthesiology 2002; 97: 740–3.

[37] Weller RS, Gerancher JC, Crews JC, Wade KL. Extensive retroperitoneal hematoma without neurologic deficit in two patients who underwent lumbar plexus block and were later anticoagulated. Anesthesiology 2003; 98: 581–5.

[38] Buttner J, Burkle H, Gogarten W, Wulf H. Thromboembolism prophylaxis and peripheral nerve blocks: guideline of the German Society of Anaesthesiology and Intensive Care. Anaesth Intensivmed 2005; 46: 319–322.