Hynson, James M. MD; Katz, Jeffrey A. MD; Bueff, H. Ulrich MD
Enoxaparin sodium (Lovenox Registered Trademark; Rhone-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, PA) is a low molecular weight heparin (LMWH) approved in the United States for use in preventing deep venous thrombosis in patients undergoing total hip arthroplasty and total knee arthroplasty. Compared with standard small-dose unfractionated heparin (UH), enoxaparin has been shown to reduce the incidence of proximal deep venous thrombosis after total hip arthroplasty [1-3]. Enoxaparin has a much longer duration of action than UH and a predictably high bioavailability when given subcutaneously . Other advantages of enoxaparin include a decreased incidence of heparin-induced thrombocytopenia compared with UH .
In this report, we present a case of an elderly woman who received enoxaparin perioperatively and developed an extensive thoracolumbar epidural hematoma after otherwise uneventful percutaneous hip pinning under lumbar epidural anesthesia.
A 78-year-old, 75-kg woman presented for percutaneous pinning (fixation) of a Garden 1 femoral neck fracture after falling at home. Prior to her injury, she was active, ambulatory, and had no significant physical or mental disability. She had no history of cardiac, pulmonary, neurologic, orthopedic, or hematologic disease. Her only medication prior to hospitalization was occasional acetaminophen for pain.
During preoperative consultation the evening before surgery, the patient expressed a preference for a regional anesthetic. Risks and alternatives were discussed. Perioperative thromboprophylaxis with enoxaparin 30 mg subcutaneously every 12 hours was planned by the surgical team and initiated the evening before surgery. Preoperative hematocrit was 42.8%, and the platelet count was 151,000/micro Liter. The next morning at approximately 10 AM, the patient arrived in the operating room and was placed in the left lateral decubitus position. After sterile preparation and local infiltration with lidocaine 1%, an 18-gauge Tuohy-Schliff needle was introduced at the level of the L3-4 interspace using a left paramedian approach, approximately 1 cm from the midline. Using the same skin entrance site, the needle was redirected approximately six times to "walk off" the lamina. The epidural space was identified using the loss-of-resistance technique and an air-filled syringe. The needle depth was 6 cm when the epidural space was identified. A 20-gauge epidural catheter (Perifix Registered Trademark; B. Braun Medical, Inc., Bethlehem, PA) was advanced 5 cm into the epidural space. After removal of the needle, the catheter was drawn back and taped with the 10-cm mark at the skin. No blood or cerebrospinal fluid was observed at any time during placement of the needle or catheter, and none was aspirated from the catheter.
The patient was positioned supine, and an epidural test dose (3 mL of lidocaine 2% with epinephrine 1:200,000) was administered. The test was negative for intravascular or intrathecal injection, and an additional 12 mL of lidocaine 2% with epinephrine 1:200,000 was administered. A sensory block to the 10th thoracic dermatome was achieved bilaterally. The patient was then positioned on a fracture Table withthe right leg extended in traction. During positioning (approximately 30 min after placement of the epidural catheter), enoxaparin 30 mg was administered subcutaneously into the left anterior thigh for prophylaxis against postoperative deep venous thrombosis. Surgery was completed uneventfully. Total operative time was 55 min, and the estimated blood loss was 25 mL. Blood pressure and heart rate were stable throughout the procedure. The patient was turned laterally, and the catheter was removed intact before transporting her to the postanesthesia care unit. Again, no blood was observed on the catheter or at the insertion site.
The patient recovered uneventfully from the epidural anesthetic. Both sensory and motor function had recovered before discharge to the ward. No pain medications were required. That evening, enoxaparin 30 mg was administered subcutaneously.
At approximately 1 AM on the first postoperative day (14 h after removal of the epidural catheter), the patient complained of cramps in her left (nonoperative) leg. The pain was relieved with morphine sulfate. On awakening at 6 AM, she was unable to move either leg or urinate. The anesthesia service was notified, and a neurosurgical consultation was immediately obtained. Evaluation revealed complete paralysis of the left lower extremity. Except for slight dorsiflexion of the foot, the right lower extremity was also without motor function. Deep tendon reflexes at the knee and ankle were absent bilaterally. Sensory function was intact throughout both lower extremities and in sacral distributions. Anal sphincter tone was decreased, and her bladder was distended.
The clinical presentation was felt to be most consistent with an anterior spinal artery syndrome. A magnetic resonance imaging (MRI) scan was urgently requested to investigate the possibility of an epidural hematoma. The MRI revealed an epidural hematoma extending from the fifth thoracic vertebra to nearly the third lumbar vertebra. The patient was immediately taken to the operating room for decompressive laminectomy. Preoperative laboratory evaluation revealed normal prothrombin and partial thomboplastin times of 12.8 s and 24.5 s, respectively. With the patient under general anesthesia with isoflurane, nitrous oxide, and fentanyl, a T-4 through L-3 laminectomy was performed and an extensive clot removed. No active bleeding was noted by the surgeons, and inspection of the dura revealed no puncture sites. Postoperatively, the patient was taken to the intensive care unit for mechanical ventilation and monitoring. The next morning, she was able to move both legs and feet, although only slightly.
Review of the patient's medication administration record revealed that the scheduled morning enoxaparin dose had been given on the ward before her hip surgery. Therefore, she had received enoxaparin 30 mg the evening before surgery, the morning of surgery (9 AM), and again immediately before the start of the operative procedure (10:45 AM). The postoperative evening dose was given as scheduled.
Over the first several postoperative days, the patient's neurologic function improved rapidly. She continued in physical therapy in a rehabilitation unit for approximately 4 wk. At the time of discharge from this unit, she had recovered essentially all of her motor function but still required intermittent bladder catheterization for urinary retention. Approximately 2 wk later, she regained bladder control.
In a recent review of regional anesthesia and anticoagulants, Vandermeulen et al.  identified four published case reports of epidural hematomas after epidural or spinal anesthesia in patients treated with LMWH. Two additional cases have been published since the review by Vandermeulen et al. [7,8]. None of these were published in an English-language journal.
Eight spinal epidural hematomas associated with neuraxial anesthesia (including our case and one of those reported in the European literature) have been reported to the manufacturer of Lovenox Registered Trademark, Rhone-Poulenc Rorer Pharmaceuticals, Inc., and subsequently to the Food and Drug Administration.* Unfortunately, few details could be obtained on follow-up of these cases by the manufacturer. Several cases were thought to be related to the timing or dose of enoxaparin, i.e., preoperative use or administration shortly after completion of the surgical procedure. * Three of the reports described spinal epidural hematomas that occurred in association with epidural catheters used for postoperative analgesia. * In each of these, the diagnosis of epidural hematoma was made after an epidural catheter had been in place for at least 48 hours. Our case, and the others reported to Rhone-Poulenc Rorer, raises the issue of whether the combination of enoxaparin and epidural or spinal anesthesia is safe.
* Information obtained from Rhone-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, PA.
Prior to the introduction of enoxaparin to the U.S. market, several reviews and commentary on the safety issue of LMWH and regional anesthesia appeared in European anesthesia journals [4,9-13]. Bergquist et al.  and Wolf  argue that LMWH and regional anesthesia are probably safe based on experience gained in clinical trials. Both investigators reviewed large clinical trials and identified groups of approximately 9000 patients who received LMWH and were operated on under spinal or epidural anesthesia. No neurologic complications were identified. However, details regarding the timing of drug administration and performance of the anesthetic or removal of epidural catheters were not given. Furthermore, epidural catheters were apparently not used for postoperative analgesia.
Extrapolation of the European experience with enoxaparin to anesthesia practice in the United States is also complicated by the fact that the recommended dose of enoxaparin in the United States, 30 mg every 12 hours, differs from that recommended in European countries (40 mg daily for orthopedic surgery, 20 mg daily for general surgery). dagger Although early in vitro and animal studies suggested that the antithrombotic effect and the antihemostatic effect of LMWHs could be disassociated , clinical studies have indicated that both continue to be dose-dependent phenomena . In an optimal-dose-finding study, Spiro et al.  found that enoxaparin 30 mg twice daily and enoxaparin 40 mg daily, initiated within the first 24 hours postoperatively, were associated with fewer venogram-positive deep venous thromboses than enoxaparin 10 mg once daily. However, the larger dose regimens were associated with more postoperative hemorrhagic complications (13% and 11% vs 5%, respectively) .
dagger Product prescribing information, Clexane Registered Trademark (enoxaparin), 1994, Rhone-Poulenc Rorer SA, Croix de Berny, France.
The recommendations for use of enoxaparin and other LMWHs in European countries typically suggest giving the first 40-mg dose 12 hours before surgery. dagger Preoperative use of enoxaparin is not yet approved in the United States. double dagger Nevertheless, the American College of Chest Physicians officially recommends the preoperative use of LMWH in patients with hip fractures . Interestingly, in April 1995, five months after our case occurred, the U.S. product prescribing information for Lovenox Registered Trademark was changed to recommend that the first dose be given "… within 12-24 hours after surgery …" section rather than "as soon as possible after surgery …" parallel. This change was apparently made because of increased concern regarding postoperative bleeding. In addition, a warning that "Lovenox Registered Trademark … should be used with extreme caution in … patients with indwelling intrathecal or epidural catheters, or in patients treated concomitantly with platelet inhibitors" was added in the April 1995 revision.section
double dagger Fragmin Registered Trademark, or dalteparin (Kabi Pharmacia, Piscataway, NJ), has been approved by the Food and Drug Administration for use preoperatively in general surgery patients. The recommended dose is 20 mg to be given two hours before the start of surgery. The manufacturer has not begun marketing it.
section Product prescribing information, Lovenox Registered Trademark, Rev. 4/95, Rhone-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, PA, 2/95.
parallel Product prescribing information, Lovenox Registered Trademark, Rev. 3/93, Rhone Poulenc Rorer Pharmaceuticals, Inc., Collegeville, PA.
Unfortunately, little is known about the safety of using enoxaparin in patients with indwelling epidural catheters for postoperative analgesia. Some authors believe there may be a continuous risk of bleeding in patients with indwelling epidural catheters and do not recommend their concurrent use with enoxaparin . Flexion or extension of the lumbar spine may result in movement of the catheter within the epidural space, and the catheter may puncture a vein or dislodge a previously formed clot [4,19].
In a frequently cited study, Rao et al.  reported the safe use of epidural and subarachnoid catheters in approximately 4000 heparinized patients. However, these patients were likely at bed rest during the 24-hour study period. Studies in ambulatory hospitalized patients receiving enoxaparin or UH in whom epidural catheters were used for postoperative pain management have not been performed.
Clinical decisions regarding the use of LMWH and spinal or epidural anesthesia/analgesia should be made after carefully considering the risks and benefits of each therapy. Excellent alternatives exist for either treatment. Patient-controlled analgesia is an effective and well-accepted form of pain management . Moreover, other forms of deep venous thrombosis prophylaxis are available (e.g., sequential compression stockings) and should be considered in those patients who may benefit from postoperative epidural analgesia . Alternatively, a smaller dose of enoxaparin, or less frequent dosing, i.e., once daily, may prove safer for patients with indwelling catheters.
If the combination of enoxaparin (or other LMWH) and spinal or epidural anesthesia is used, recommendations suggested by Vandermeulen et al.  [modified from Tryba ] and the product prescribing information for Lovenox Registered Trademark should be considered: 1) central neural blockade should be delayed for at least 10-12 hours after the last dose of enoxaparin for patients receiving the drug preoperatively; 2) postoperative treatment with enoxaparin should be delayed at least 12 hours after completion of the surgical procedure section; and 3) removal of epidural or spinal catheters used for postoperative analgesia should occur 10-12 hours after the last dose, with subsequent dosing delayed for at least two hours [6,9]. Unless additional clinical information establishes a greater safety profile for enoxaparin and spinal or epidural anesthesia, clinicians should remain cautious when using this combination.
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