In May 1993, enoxaparin (Lovenox®; Aventis Pharmaceuticals), the first low-molecular-weight heparin (LMWH) approved by the United States (US) Food and Drug Administration (FDA), was distributed for general use, including an indication for thromboprophylaxis in major orthopedic surgery (1). Within 1 yr, 2 cases of spinal hematoma had been voluntarily reported, and over the next 5 yr the FDA compiled a total of nearly 60 cases associated with regional anesthesia and any LMWH use. In response to the first of these reports, which detailed instances of spinal hematoma occurring in patients undergoing epidural or spinal block while receiving LMWH thromboprophylaxis with enoxaparin (2), the manufacturer of enoxaparin revised the warnings section of the drug’s label and altered the prescribing information. In late 1997, the FDA issued a health advisory (3) and requested all manufacturers of LMWHs to include “black-boxed” warnings on their drug’s labeling (1). By 1998, the first set of practice guidelines to deal with this particular complication, from the American Society of Regional Anesthesia (ASRA) Consensus Conference on Neuraxial Anesthesia and Anticoagulation, was made available to clinicians (4). Despite these changes and precautions, cases of spinal hematoma continued to be reported—although much less frequently—fueling the continued concern over the use of regional anesthesia with LMWH prophylaxis (1). It is in this context that an updated ASRA Consensus Conference statement was published in May 2003.
A close reading of these latest guidelines can result in several useful observations—useful not only for anesthesiologists but also for surgeons, hospitalists, nurses, or other health care professionals who care for orthopedic patients. First, spinal hematoma, although a serious complication, is rare (1,5). Concern about its possible occurrence should not outweigh the benefit of regional anesthesia in total hip or knee arthroplasty or its moderating effects as prophylaxis for thromboembolic events—themselves much more common complications of major orthopedic surgery with or without prophylaxis (6–9). Second, as the 2003 Consensus Conference statement makes clear, regional anesthesia may be used safely with LMWH prophylaxis (1). The key to optimizing patient safety, however, depends on a careful calibration of the total daily dose and the timing of the first and subsequent doses of the LMWH drug in relationship to the regional anesthetic procedure. Finally, the challenge of successfully providing regional anesthesia in the presence of LMWH thromboprophylaxis is, above all, a clinical one. Anesthesiologists should do what they can to ensure that all members of the surgical team, including the nurses on the surgical floor, have an understanding of the ASRA guidelines and their clinical applications.
Clinical Trial Results
LMWHs have been shown in clinical trials to be safe and effective forms of thromboprophylaxis for total hip and knee arthroplasty and are recommended as first-line therapy by the latest practice guidelines relevant to major orthopedic surgery, including those of the American College of Chest Physicians (ACCP) (9).
Current Standards in Medical Thromboprophylaxis
When compared with other classes of established anticoagulants such as small-dose or adjusted-dose unfractionated heparin, LMWHs have been shown to be more effective or as effective, with better or comparable safety (10–12). More recently, both enoxaparin and dalteparin (Fragmin®; Pfizer Inc.), the two most widely used LMWHs, have compared favorably with warfarin (Coumadin®; DuPont Pharmaceuticals) for short-term, in-hospital efficacy and safety (13,14). With respect to long-term, out-of-hospital use up to 35 days postoperatively, LMWHs are safe and effective and provide an ease of use and patient convenience not available with monitored drugs such as unfractionated heparin and warfarin (15–18). Results comparing enoxaparin or dalteparin with newer drugs such as fondaparinux (Arixtra®; Organon-Sanofi) and ximelagatran (Exanta®; AstraZeneca) have been more variable depending on which two were compared. These results may have been affected by certain factors (e.g., timing of the initial dose) that still need to be sorted out by further trials and metaanalyses (19–21), so caution is advised with respect to their use with regional anesthesia because of the lack of data and clinical experience (1).
Dosing Regimens of LMWHs
Within their class, LMWHs share a similar mechanism with respect to the inhibition of factor Xa, yet demonstrate different relative inhibitory effects on factor Xa as well as thrombin (22). Thus, LMWHs offer clinicians a range of options for dosing, such as preoperative versus postoperative dosing and once-daily versus twice-daily dosing—differences that in some instances manifest themselves geographically. For example, enoxaparin and dalteparin are typically started preoperatively in Europe and postoperatively in North America (23). The standard dose of enoxaparin is 40 mg once a day in Europe, versus 30 mg twice a day in the US and Canada. The standard maintenance dose of dalteparin (5000 U subcutaneously [s.c.] every day) is the same on the two continents, but the initial dose of 2500 U s.c. is usually given the evening before surgery in Europe, compared with 6–8 h postoperatively in North America.
Clinical trials involving LMWH in major orthopedic surgery have examined a range of different dosing regimens using different comparators. When matched with adjusted-dose warfarin, for example, a 30-mg dose of enoxaparin, initiated 12–24 h postoperatively and then given every 12 h thereafter, was comparable in the infrequent mortality, morbidity, and bleeding overall (13). The investigators also found enoxaparin to be superior in preventing venous thromboembolism (VTE) during the in-hospital period—4 events (0.3%) with enoxaparin versus 17 (1.1%) with warfarin (P = 0.0083)—although that difference essentially evened up by the end of the out-of-hospital recovery phase of the trial, 3 mo after discharge. A year later, Hull et al. (14) demonstrated that postoperative dalteparin, initiated at half the usual dose (2500 IU s.c.) approximately 4–8 h after surgery and then given at full dose (5000 IU s.c.) once every morning thereafter, was safer than the preoperative or “European” regimen and as safe as warfarin (1). The efficacy of the two dalteparin regimens was the same, and both were superior to warfarin (Table 1). The relative risk reduction for proximal deep vein thrombosis (DVT) for both regimens compared with warfarin was 72%, and the investigators found the proximal DVT rate of patients receiving dalteparin to be unusually infrequent compared with those found in European trials initiating LMWH prophylaxis 12 h preoperatively and significantly more effective than studies comparing 12- to 24-h postoperative LMWH regimens with other anticoagulants (24–29).
ASRA Guideline Recommendations
The recommendations of the 2003 ASRA Consensus statement for anesthetic management of patients receiving LMWHs speak directly to the issue of different dosing regimens among the available drugs (1). Because preoperative dosing is done infrequently in North America—a circumstance that is unlikely to change in the foreseeable future, given the additional costs incurred by patients required to stay in-hospital the night before surgery—this discussion focuses on the recommendations for postoperative LMWH. The ASRA guidelines emphasize that both single-injection and continuous catheter techniques are safe for patients receiving LMWH prophylaxis when regard is shown for total daily dose, timing of the initial dose, and the overall dosing schedule of the chosen drug.
Twice-Daily LMWH Dosing
Because it may be associated with an increased risk of spinal hematoma, twice-daily dosing should not be initiated before 24 h after surgery after neuraxial anesthesia. The guidelines also strongly recommend stricter regulations on the use of indwelling catheters with twice-daily dosing of enoxaparin. If a continuous epidural analgesic technique is chosen for a patient in whom twice-daily enoxaparin is planned, the indwelling epidural catheter may be left overnight but should be removed the next day—at least 2–4 h before the first dose of LMWH.
Single-Daily LMWH Dosing
The European approach to regional anesthesia and LMWH thromboprophylaxis has demonstrated greater safety than that of North America; it may be attributable to the preference in Europe for single-daily dosing. This regimen should be initiated with a half dose (2500 U s.c.) given 6–8 h postoperatively, and the next dose (5000 U) should not be given until 24 h later. This is similar to the dosing regimen investigated by Hull et al. in 2000 (14). Unlike with the twice-daily regimen, neuraxial catheters may be safely maintained during LMWH thromboprophylaxis with single-daily dosing. Because dalteparin has a half-life of about 6 h, neuraxial catheters should not be removed before “a minimum of 10–12 h” have passed since the previous dose of this LMWH. Clinicians should wait at least 2–4 h after catheter removal before continuing LMWH therapy. Clearly, the use of indwelling catheters needs to be coordinated with the entire patient care team, including the orthopedists, who are likely writing the anticoagulation orders, and the nurses who will be administering the drugs.
Timing of Initial Dose
What do the ASRA guidelines, when contrasted with the clinical literature in orthopedic surgery, tell us about neuraxial anesthesia and LMWH thromboprophylaxis? It is definitely clear that timing of initial and maintenance doses does matter. The more-than-quadrupled number of spinal hematoma cases in the US received by the FDA between 1993 and 1998 (nearly 60 cases), compared with the number reported (13 cases) in Europe for the decade between 1989 and 1998, suggests that the standard European regimen of single-daily dosing, with a smaller total daily dosage of enoxaparin, was a significant factor (1,4). In addition, by the mid-to-late 1990s, several sets of practice guidelines had been established in Europe, issuing fairly consistent recommendations for time intervals between the course of LMWH therapy and needle placement and catheter removal (30–32).
Even before the establishment of such guidelines, however, studies surveying the European experience with LMWH thromboprophylaxis through 1992–1993 found a very small risk of neurologic complications for patients undergoing spinal or epidural anesthesia with LMWH prophylaxis (33,34). After finding only 1 reported case of spinal hematoma in a review of 19 articles involving 9013 patients—out of the several million that pharmaceutical companies had estimated received neuraxial blockade with LMWH therapy—Bergqvist et al. (34) concluded that neurologic complications in such a setting are very rare and that the combination of LMWH therapy with epidural or spinal anesthesia seemed to be safe. Today, epidural analgesia is not contraindicated with concomitant LMWH prophylaxis in current European practice guidelines (31,32).
The North American experience with LMWH thromboprophylaxis and neuraxial anesthesia is especially instructive with respect to timing. When LMWH thromboprophylaxis after major orthopedic surgery was introduced in the US, the approved dose schedule for enoxaparin was 30 mg every 12 h, with dosing initiated as soon as possible after surgery (1). After the initial reports of spinal hematoma in the US, the recommended timing for the first dose in the drug’s prescribing information was changed to 12–24 h after surgery, and this has remained the standard regimen for starting enoxaparin therapy. However, the recommended timing in the 2003 ASRA guidelines for the first dose of LMWH with twice-daily dosing is no earlier than 24 h postoperatively. This is later than many orthopedic surgeons prefer to initiate LMWH thromboprophylaxis and may not be as effective as prophylactic regimens initiated earlier (35).
In their systematic review of timing of initial LMWH thromboprophylaxis in elective hip arthroplasty trials, Hull et al. (35) found that the range between 2 h before the beginning of surgery and 6 h after its conclusion represents the optimal window for initiating LMWH prophylaxis. Since the publication of the 1998 ASRA guidelines (4), a new dosing regimen of LMWH thromboprophylaxis—half the usual dose (2500 U) of dalteparin initiated 6–8 h postoperatively, with subsequent doses given at full strength (5000 U) beginning 24 h later—was shown to be safe and effective (14) and corresponds to the single-daily regimen recommended by the 2003 ASRA guidelines (1). “This regimen approximated the European dosing schedule, but without the preoperative dose,” write the ASRA panelists. “Thus, it should be possible to manage patients according to European guidelines.”
Is there an optimal regimen for LMWH thromboprophylaxis with neuraxial anesthesia? Citing the lack of clinical trial data comparing LMWH drugs head-to-head, the ASRA Consensus statement does not recommend one drug over another. However, a trial examining anticoagulant effects at the time of epidural catheter removal in patients receiving twice-daily versus once-daily LMWH may provide further insight. Douketis et al. (36) investigated the trough anticoagulant effect, as measured by the level of anti-Xa heparin, in 25 patients receiving enoxaparin, 30 mg twice a day, and 25 patients receiving dalteparin, 5000 IU once a day. All 25 patients who received once-daily dalteparin, measured at an average of 21.8 h after the previous dose, had an anti-Xa heparin level of <0.10 U/mL at the time of catheter removal. Of the 25 patients who received twice-daily enoxaparin, 5 had an anti-Xa heparin level of ≥0.20 U/mL (P = 0.05) and 7 had one of ≥0.10 U/mL (P = 0.009) at the time of catheter removal. The investigators concluded that, of the two regimens, twice-daily enoxaparin prophylaxis is more likely to be associated with a significant—and, in these cases, unwanted—anticoagulant effect at the time of epidural catheter removal. This result might help account, in part, for the more frequent epidural hematomas reported in North America compared with Europe. It should be noted, however, that monitoring of the anti-Xa level is not recommended by the ASRA Consensus statement because it is not widely available to clinicians nor is it predictive of bleeding (1).
Beyond the choice of LMWH regimen as it relates to dose and timing of dosage, clinicians concerned about patient safety have several options, including changing the type of anesthetic technique or form of thromboprophylaxis and avoiding either regional anesthesia or pharmacoprophylaxis. None of the former options is without risk of complications, and both of the latter options are fraught with problems. Avoidance of regional anesthesia during antithrombotic drug use was one of the patient safety issues propelling the 2002–2003 update of the ASRA guidelines (1,4); yet, there is ample evidence for the benefits of spinal and epidural anesthesia in postoperative outcome across a wide range of disorders and procedures, including total hip replacement, major knee surgery, femoral neck fractures, myocardial infarction, and overall mortality (6–8,37–39). For example, a systematic review of 141 clinical trials accounting for >9500 patients found that patients receiving neuraxial blockade had less mortality (by about a third), DVT (by 44%), pulmonary embolism (by 55%), transfusion requirements (by 50%), pneumonia (by 39%), and respiratory depression (by 59%), compared with those who did not receive regional anesthesia (37).
Similarly, clinicians weighing the use of regional anesthesia without pharmacoprophylaxis or with no prophylaxis at all should consult such guidelines as those of the ACCP (9) to assess the comparative risk of DVT with and without prophylaxis. The risk of spinal hematoma—with estimates ranging from <1 in 150,000 epidural anesthetics and <1 in 220,000 spinal anesthetics in general (1) to 1 in 3000 continuous epidural anesthetics and 1 in 40,000 spinal anesthetics in cases involving LMWH prophylaxis (5)—is significantly smaller than that of DVT and pulmonary embolism. Data tabulated in the latest ACCP guidelines for different forms of thromboprophylaxis used in total hip arthroplasty show the prevalence of total DVT ranging from 14.0% with adjusted-dose heparin to 41.7% with elastic stockings (9). Among historical control or placebo groups in clinical trials that used contrast venography, the prevalence of total DVT at 7–14 days after total hip or knee arthroplasty or hip fracture surgery is reported to be about 50%–60% (Table 2). Although prevention of VTE is itself associated with a risk of bleeding and other complications, VTE remains a primary cause of surgically related mortality and morbidity and warrants prophylaxis (1,40). It has been estimated that >2 million deaths a year in the US are attributable to some form of thrombosis, and annual US incidence rates for DVT and pulmonary embolism have been estimated to be as much as approximately 450,000 and 355,000, respectively (41–45).
Thus, more viable options would involve switching one or the other form of therapy—that is, altering the thromboprophylactic regimen or the regional anesthetic technique. Although the scope of this article is not broad enough to include detailed discussion of other anticoagulants, it is sufficient to reiterate the observation in the ASRA Consensus statement that bleeding is the major complication of any anticoagulant therapy. Clinicians in general, and particularly anesthesiologists, are encouraged to consult the ASRA guidelines for recommendations on the use of unfractionated heparin, warfarin, and other anticoagulants such as fondaparinux when patients are to undergo invasive procedures (1). For example, when thromboprophylaxis with warfarin is initiated, neuraxial catheters should be removed when the international normalized ratio is <1.5, whereas performance of neuraxial techniques with fondaparinux is only recommended when conditions approximate those used in clinical trials. Furthermore, anesthesiologists should note the caution that, although the ASRA guidelines are focused on spinal and epidural anesthesia, the same principles apply when the alternatives of plexus and peripheral blocks are to be used. The associated risk of spinal hematoma is not relevant to most cases involving plexus or peripheral block, yet complications related to bleeding are always a clinical concern.
Several case studies can be instructive in the absence of traditional clinical investigations. Several cases of vascular injury, some of which resulted in nerve dysfunction, have been described involving the use of plexus or peripheral techniques in patients with normal or abnormal hemostasis (46–48). Major bleeding has been reported only in cases in which psoas compartment or lumbar sympathetic block was performed. One case involved a patient with a mechanical heart valve who had received warfarin and was switched to standard heparin in advance of a knee replacement (47). Heparin infusion as well as oral anticoagulation with warfarin were restarted 8 h after needle placement. Two of the cases involved patients who received perioperative LMWH with psoas compartment block. In one case, enoxaparin was initiated 40 h postoperatively, well beyond the earliest time recommended; however, the catheter was removed just 2 h after the previous dose was given, at a time of peak anticoagulant effect. The second case involved a patient hospitalized with a calcaneal fracture and who was then administered twice-daily enoxaparin therapy (48). After two successful surgical debridement procedures performed under combined psoas-sciatic block, attempts at psoas needle placement—made approximately 20 h after the last dose of LMWH had been given—were unsuccessful and traumatic when a third procedure was required.
One can see from these cases that, as with neuraxial techniques, successful use of plexus and peripheral blockade depends largely on timing and handling of needle placement and catheter removal in conjunction with the timing of the anticoagulant regimen. Although the writing panel counsels “conservative” application of the ASRA Consensus Conference statement to plexus and peripheral techniques, the guidelines conclude with a recommendation aimed at anesthesiologists interested in keeping their options open for regional anesthesia (1): “The decision to perform spinal or epidural anesthesia/analgesia and the timing of catheter removal in a patient receiving antithrombotic therapy 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. Alternative anesthetic and analgesic techniques exist for patients considered an unacceptable risk.”
Clinicians conversant with the recommendations provided in these latest guidelines, including those pertaining to postoperative initiation of LMWH thromboprophylaxis (as summarized in Table 3), will be better equipped to reduce that risk for their patients. Communication and coordination among the entire clinical team will then go a long way toward ensuring the prevention of disastrous outcomes.
1. 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;28:172–97.
2. 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.
3. Lumpkin MM. FDA public health advisory. Anesthesiology 1998;88:27A–28A.
4. 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.
5. Schroeder DR. Statistics: detecting a rare adverse drug reaction using spontaneous reports. Reg Anesth Pain Med 1998;23:183–9.
6. Liu SS, Carpenter RL, Neal JM. Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology 1995;82:1474–506.
7. Modig J. The role of lumbar epidural anaesthesia as antithrombotic prophylaxis in total hip replacement. Acta Chir Scand 1985;151:589–94.
8. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999;91:8–15.
9. Geerts WH, Heit JA, Clagett CP, et al. Prevention of venous thromboembolism. Chest 2001;119:132S–75S.
10. Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991;114:545–51.
11. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. J Bone Joint Surg Am 1994;76:3–14.
12. Eriksson BI, Kälebo P, Risberg B. Clinical experience of a low molecular weight heparin (Fragmin) in the prevention of thromboembolism after total hip replacement. Semin Thromb Hemost 1993;19(Suppl 1):122–7.
13. Colwell CW Jr, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty: evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am 1999;81:932–40.
14. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2199–207.
15. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin in hip arthroplasty patients: a double-blind, randomized comparison. Arch Intern Med 2000;160:2208–15.
16. Bergqvist D. The postdischarge risk of venous thromboembolism after hip replacement: the role of prolonged prophylaxis. Drugs 1996;52(Suppl 7):55–9.
17. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. J Bone Joint Surg Am 2001;83:336–45.
18. Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery: results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997;77:26–31.
19. Turpie AG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001;344:619–25.
20. Heit JA, Colwell CW, Francis CW, et al.; AstraZeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001;161:2215–21.
21. Eriksson BI, Arfwidsson AC, Frison L, et al. A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002;87:231–7.
22. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114(Suppl):561S–78S.
23. Hull RD, Pineo GF, MacIssaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patients undergoing elective hip surgery. Thromb Res 2001;101:V155–62.
24. Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991;303:543–8.
25. Bergqvist D, Benoni G, Bjorgell O, et al. Low molecular weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996;335:696–700.
26. Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomized comparison of enoxaparin versus placebo. Lancet 1996;348:224–8.
27. Eriksson B, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1197;337:1329–35.
28. Hamulyak K, Lensing AWA, van der Meer J, et al. Subcutaneous low molecular weight heparin or oral anticoagulants for the prevention of deep vein thrombosis in elective hip and knee replacement? Thromb Haemost 1995;74:1428–31.
29. Hull RD, Raskob GE, Pineo GF, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993;329:1370–6.
30. Tryba M, Wedel DJ. Central neuraxial block and low molecular weight heparin (enoxaparine): lessons learned from different dosage regimes in two continents. Acta Anaesthesiol Scand 1997;41:100–4.
31. Llau JV, de Andres J, Gomar C, et al. Drugs that alter hemostasis and regional anesthetic techniques: safety guidelines. Consensus Conference [in Spanish]. Rev Esp Anestesiol Reanim 2001;48:270–8.
32. Gogarten W, Van Aken H, Wulf H, et al. Regional anesthesia and thromboembolism prophylaxis/anticoagulation. Anaesthesiol Intensivmed 1997;12:623–8.
33. Bergqvist D, Lindblad B, Matzsch T. Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia: is there a risk? Acta Anaesthesiol Scand 1992;36:605–9.
34. Bergqvist D, Lindblad B, Matzsch T. Risk of combining low molecular weight heparin for thromboprophylaxis and epidural or spinal anesthesia. Semin Thromb Hemost 1993;19:147–51.
35. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med 2001;161:1952–60.
36. Douketis JD, Kinnon K, Crowther MA. Anticoagulant effect at the time of epidural catheter removal in patients receiving twice-daily or once-daily low-molecular-weight heparin and continuous epidural analgesia after orthopedic surgery. Thromb Haemost 2002;88:37–40.
37. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 2000;321:1–12.
38. Sorenson RM, Pace NL. Anesthetic techniques during surgical repair of femoral neck fractures: a meta-analysis. Anesthesiology 1992;77:1095–104.
39. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg 2001;93:853–8.
40. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119:108S–21S.
41. Bick RL. Therapy for venous thrombosis: guidelines for a competent and cost-effective approach. Clin Appl Thromb Hemost 1999;5:2–9.
42. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–93.
43. Bick RL, Fareed J. Current status of thrombosis: a multidisciplinary medical issue and major American health problem—beyond the year 2000. Clin Appl Thromb Hemost 1997;3(Suppl 1):1.
44. Bergqvist D, Lundblad B. Incidence of venous thromboembolism in medical and surgical patients. In: Bergqvist D, Comerota A, Nicolaides A, Scurr J, eds. Prevention of venous thromboembolism. London: Med-Orion Press, 1994.
45. Ramaswami G, Nicolaides AN. The natural history of deep vein thrombosis. In: Bergqvist D, Comerota A, Nicolaides A, Scurr J, eds. Prevention of venous thromboembolism. London: Med-Orion Press, 1994.
46. Ben-David B, Stahl S. Axillary block complicated by hematoma and radial nerve injury. Reg Anesth Pain Med 1999;24:264–6.
47. 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;98:581–3.
48. 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.