REGIONAL ANESTHESIA SECTION EDITOR TERESE T. HORLOCKER MEDICAL INTELLIGENCE Neuraxial Anesthesia and Low-Molecular-Weight Heparin Prophylaxis in Major Orthopedic Surgery in the Wake of the Latest American Society of Regional Anesthesia Guidelines John C. Rowlingson, MD*, and Peter B. Hanson, MD��� *Department of Anesthesiology, University of Virginia, Charlottesville, Virginia and the ���Department of Orthopedics, Sharp Grossmont Hospital, LaMesa, California In May 2003, the Second American Society of Regional Anesthesia Consensus Conference statement was is- sued partly in response to continued safety concerns over the use of regional anesthesia���in particular, neuraxial techniques���with low-molecular-weight heparin (LMWH) prophylaxis in major orthopedic surgery. As the 2003 Consensus statement makes clear, regional anesthesia may be used safely with LMWH prophylaxis. The key to optimizing patient safety, how- ever, depends on a careful calibration of the total daily dose and the timing of the first and subsequent doses of the LMWH drug with the timing and management of the regional anesthetic procedure. Because the chal- lenge of successfully providing regional anesthesia in the presence of LMWH thromboprophylaxis is a clini- cal one, anesthesiologists should do what they can to ensure that every member of the surgical team has an understanding of current literature and practice guide- lines such as those recently published by the American Society of Regional Anesthesia. (Anesth Analg 2005 100:1482���8) I n May 1993, enoxaparin (Lovenox�� Aventis Phar- maceuticals), the first low-molecular-weight hepa- rin (LMWH) approved by the United States (US) Food and Drug Administration (FDA), was distrib- uted 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 manu- facturer of enoxaparin revised the warnings section of the drug���s label and altered the prescribing informa- tion. 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 Soci- ety of Regional Anesthesia (ASRA) Consensus Confer- ence 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 fre- quently���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 thromboem- bolic events���themselves much more common com- plications 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 This article was developed from a first draft written by Fred Balzac of Chase Medical Communications, Inc., Wilton, CT, who also assisted the authors with editing and revising subsequent drafts. All editorial work provided by Chase Medical Communica- tions was funded with an unrestricted educational grant by Pfizer Inc., which also provided an honorarium to the authors. Accepted for publication October 8, 2004. Address correspondence and reprint requests to John C. Rowl- ingson, MD, UVA Health System, PO Box 800710, Charlottesville, VA 22908-0710. Address e-mail to JCR3T@virginia.edu. DOI: 10.1213/01.ANE.0000148683.54686.0F ��2005 by the International Anesthesia Research Society 1482 Anesth Analg 2005 100:1482���8 0003-2999/05

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 proce- dure. Finally, the challenge of successfully providing regional anesthesia in the presence of LMWH throm- boprophylaxis is, above all, a clinical one. Anesthesi- ologists 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 rel- evant 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 an- ticoagulants such as small-dose or adjusted-dose un- fractionated heparin, LMWHs have been shown to be more effective or as effective, with better or compara- ble 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 effec- tive and provide an ease of use and patient conve- nience 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 metaanaly- ses (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 demon- strate different relative inhibitory effects on factor Xa as well as thrombin (22). Thus, LMWHs offer clini- cians a range of options for dosing, such as preoper- ative versus postoperative dosing and once-daily ver- sus twice-daily dosing���differences that in some instances manifest themselves geographically. For ex- ample, 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 postopera- tively 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 thromboembo- lism (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 dalte- parin, 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��� regi- men 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 reduc- tion 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 com- pared with those found in European trials initiating LMWH prophylaxis 12 h preoperatively and signifi- cantly more effective than studies comparing 12- to 24-h postoperative LMWH regimens with other anti- coagulants (24���29). ASRA Guideline Recommendations The recommendations of the 2003 ASRA Consensus statement for anesthetic management of patients re- ceiving LMWHs speak directly to the issue of different dosing regimens among the available drugs (1). Be- cause 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 ANESTH ANALG MEDICAL INTELLIGENCE ROWLINGSON AND HANSON 1483 2005 100:1482���8 NEURAXIAL ANESTHESIA AND LOW-MOLECULAR-WEIGHT HEPARIN PROPHYLAXIS