Correspondence
Spinal and Epidural Hematoma and Low-Molecular-Weight Heparin
N Engl J Med 1998; 338:1774-1775June 11, 1998
- Article
To the Editor:
From May 1993 through February 1998, the Food and Drug Administration (FDA) received reports of 43 patients in the United States who had spinal or epidural hematoma or bleeding after receiving the low-molecular-weight heparin enoxaparin (Lovenox, Rhône–Poulenc Rorer Pharmaceuticals). Emergency decompressive laminectomy to evacuate the hematoma was performed in 28 patients, and permanent paraplegia, often with a delay in diagnosis or surgical treatment, occurred in 16.
Of the 37 patients whose sex was reported, 29 (78 percent) were women. The median age was 75 years (range, 28 to 90). Three persons had histories of ankylosing spondylitis or vertebral compression fractures. Although the cardinal symptom of epidural hematoma is severe back pain,1 most patients reported sensory or motor deficits that progressed to paralysis, with the onset of symptoms occurring about 2 to 3 days (range, 0 to 12) after enoxaparin therapy had been initiated.
Thirty-six of 41 patients received enoxaparin for the prevention of deep-vein thrombosis associated with surgery (primarily knee or hip replacement with spinal or epidural anesthesia, epidural analgesia or attempted analgesia, or spinal surgery). Three patients received concomitant spinal corticosteroid injections. Only two had no identified spinal puncture or trauma.
The recommended dose of 30 mg of enoxaparin every 12 hours was exceeded in two patients. Four surgical patients received the first dose before, during, or immediately after surgery, and 12 other patients received the first dose within 12 hours after surgery. Spinal anesthesia was attempted but failed in two patients. Placement or attempted placement of an epidural catheter was reported in 26 of the surgical patients (72 percent), including multiple attempts or traumatic placement in 4. The epidural catheter was left in place for analgesia in at least 15 patients, although in 4, it was removed immediately or shortly after surgery. Bleeding or hematoma developed after the removal of the catheter in six patients.
Sixteen of the 43 patients (37 percent) received concomitant medications known to increase the risk of bleeding (e.g., heparin, warfarin, ketorolac, or other nonsteroidal antiinflammatory drugs).
Epidural or spinal hematoma after neuraxial anesthesia is a rare complication associated with anticoagulation.1,2 Factors suspected of predisposing patients to epidural hematoma include a dose of enoxaparin that exceeds the recommended dose, administration of enoxaparin to surgical patients before the establishment of hemostasis, use of epidural catheters,1,2 administration of concomitant medications known to increase bleeding,1,2 presence of vertebral-column abnormalities,1 older age,1 and female sex.
Because of the reports received by the FDA, published reports,1-5 and the likelihood of epidural hematoma with similar products, the FDA recently asked manufacturers of low-molecular-weight heparins (enoxaparin, dalteparin, and ardeparin) and the heparinoid danaparoid to include in their product labeling a black-box warning of this potential complication.
(The views expressed in this letter are those of the authors and do not necessarily represent the official position of the FDA.)
5 ReferencesDiane K. Wysowski, Ph.D.
Lilia Talarico, M.D.
Janos Bacsanyi, M.D.
Paula Botstein, M.D.
Food and Drug Administration, Rockville, MD 208571
Vandermeulen EP ,Van Aken H ,Vermylen J . Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994;79:1165-1177
CrossRef | Web of Science | Medline2
Horlocker TT ,Heit JA . Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg 1997;85:874-885
CrossRef | Web of Science | Medline3
Hynson JM ,Katz JA ,Bueff HU . Epidural hematoma associated with enoxaparin. Anesth Analg 1996;82:1072-1075
CrossRef | Web of Science | Medline4
Porterfield WR ,Wu CL . Epidural hematoma in an ambulatory surgical patient. J Clin Anesth 1997;9:74-77
CrossRef | Web of Science | Medline5
Christensen PH ,Johnstad B . Alvorlig neurologisk sekvele i tilslutning til spinal- og epiduralbedøvelse. Tidsskr Nor Laegeforen 1998;118:244-246
Medline
Author/Editor Response
Spokespersons for Rhône–Poulenc Rorer Pharmaceuticals reply:
To the Editor: Rhône–Poulenc Rorer Pharmaceuticals and the other manufacturers of low-molecular-weight heparins and heparinoids have been working closely with the FDA to address the risk of neuraxial hematoma (spinal or epidural hematoma) associated with neuraxial anesthesia and postoperative epidural analgesia in patients receiving anticoagulant therapy. This adverse event has been reported with various types of anticoagulants, including several low-molecular-weight heparins.1,2 In reference to the black-box warning mentioned by Dr. Wysowski and colleagues, all the manufacturers of low-molecular-weight heparins and heparinoids have incorporated such a warning in their U.S. package inserts in order to highlight this potentially serious complication.
Since the first reports of neuraxial hematoma were received, Rhône–Poulenc Rorer has been working closely with the FDA to provide safety information to the medical community in the enoxaparin sodium package insert. We also support medical education to address this concern. The first change in the package insert, in 1995, and the subsequent revisions, in 1996 and 1998, were made as more was learned about the characteristics of patients and factors potentially contributing to the development of neuraxial hematomas.
Low-molecular-weight heparins are important pharmacologic agents for the prevention of potentially fatal venous thromboembolic complications. Enoxaparin (Lovenox Injection) accounts for approximately 96 percent of all low-molecular-weight heparins and heparinoids administered in the United States, with an estimated 33 million doses dispensed since its introduction in 1993.
On February 5, 1998, the Anesthetic and Life Support Drugs Advisory Committee of the FDA and the various manufacturers met to discuss the clinical issues with regard to neuraxial hematoma. In addition, efforts are under way to develop clinical-practice guidelines for the use of neuraxial anesthesia and epidural analgesia in patients receiving anticoagulant therapy. We support these initiatives and will continue to work with the FDA and the medical community on this matter.
2 ReferencesPhilip Chaikin, Pharm.D., M.D.
Janet Lim, M.D.
Rhône–Poulenc Rorer, Collegeville, PA 19426-01071
Vandermeulen EP ,Van Aken H ,Vermylen J . Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994;79:1165-1177
CrossRef | Web of Science | Medline2
Christensen PH ,Johnstad B . Alvorlig neurologisk sekvele i tilslutning til spinal- og epiduralbedøvelse. Tidsskr Nor Laegeforen 1998;118:244-246
Medline
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