Review
Acta Anaesthesiol Scand 1992: 36: 605-609
Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia - is there a risk? D. BERGQVIST, B. LINDBLAD and T. MATZSCH Department of Surgery, Lund University, General Hospital, Malmo, Sweden
This article reviews the problem of bleeding in connection with epidural/spinal anaesthesia, with special emphasis on the use of low molecular weight heparins for thromboprophylaxis. There are methodological difficulties to studying the problem in a scientifically correct way because of the rarity of the complication. However, from the data in the literature there are no indications of an increased risk in using the combination of low molecular weight heparin in prophylactic doses and epidural/spinal anaesthesia. So far, there is only a single case report, of spinal haematoma, although low molecular weight heparins have been used in combination with epidural/spinal anaesthesia in at least 1000000 patients. In controlled studies, at least 10000 patients have been given the combination without complications.
Key words: Epidural anesthesia; low molecular weight heparin; regional anesthesia; spinal anesthesia; throm boproph ylaxis.
Most surgeons dealing with major surgery practise some form of pharmacological prophylaxis against postoperative venous thromboembolism. There are various opinions on how to define risk factors and which of the prophylactic methods is best. There are also several more controversial issues, one being the use of epidural or spinal anaesthesia in patients with heparin prophylaxis due to the risk ofspinal haematoma and subsequent paraparesis. In 1981, Stanton-Hicks stated “that not only would it be redundant to combine mini-dose heparin with major conduction anaesthesia but that its concurrent use would indeed be contraindicated in the light of the foregoing risks” (1). Some anaesthesiologists have undoubtedly followed this warning, whereas others have shown no reluctance to use low-dose heparin in patients with epidural/spinal block, be it before, during or after. In 1989, Tryba reported from a consensus conference that “Low-dose heparin prophylaxis is no contraindication to spinal or epidural anaesthesia” (2). In view of a reported higher frequency of bleeding complications in early studies on low molecular weight heparin (LMWH), it was, however, stated that the combination of LMWH and spinal/epidural anaesthesia “should be performed in controlled studies only” (2). The aim of this review is to analyse the problem of the development of spinal haematoma in relation to epidural-spinal anaesthesia, and especially in patients in whom low molecular weight heparin fragments have been used to prevent postoperative venous thromboembolism.
LOW MOLECULAR WEIGHT HEPARIN AND THROMBOPROPHYLAXIS There is no doubt that the various LMWH fragments available today are effective in preventing postoperative venous thromboembolism. The number of studies of different patient populations is rapidly increasing and in this context it seems sufficient to refer to recent surveys (3-6). Although each LMWH fragment must be evaluated as a specific pharmacological substance, there are no data which indicate a clinically relevant difference, whether pharmacokinetics or prophylactic effect is concerned (7). O n the basis of early in vitro studies and animal experiments, it was thought that it would be possible to separate the anti-thrombotic effect from an anti-haemostatic (8). However, it soon became apparent that like all other thromboprophylactic drugs LMWH also had a dose-dependent influence on the frequency of bleeding and that the level of antifactor Xa activity was a rather good indicator of this risk (9). However, after extensive clinical studies it has been possible to define doses of LMWH which are prophylactically effective without increasing the bleeding risk (3-6). The advantages with LMWH in low doses as compared with unfragmented low dose heparin are a higher and more predictable bioavailability after subcutaneous injection, a longer biological half-life which makes one injection daily sufficient, and a smaller influence on platelet function and lipolysis (8). LMWH also has a better effect in patients undergoing
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orthopaedic surgery, a real high-risk group for thromboembolic complications (10). SPINAL/EPIDURAL ANAESTHESIA AND THROMBOPROPHYLAXIS As early as 1943, the Swedish surgeon Bohmansson claimed that patients at risk of thrombosis should be operated on using spinal anaesthesia (1 1 ) . That epidural anaesthesia might have a certain thromboprophylactic effect was suggested in some uncontrolled studies performed during the 1970’s (12-14). In recent years prospective randomized studies have confirmed that epidural/spinal anaesthesia is associated with a significantly lower risk for postoperative deep vein thrombosis in patients undergoing total hip replacement ( 15-18), hip fracture surgery (19, 20) or open prostatectomy (21, 22). The relative risk reduction for deep vein thrombosis following hip surgery is 46-55% (23). Besides having a haemodynamic effect (1, 22, 24), epidural block may stimulate fibrinolysis ( 16, 22). The latter effect is, however, controversial (25, 26). Coagulation may be influenced (27, 28). Epidural anaesthesia extending over the segments Th4-S5 blocks the adrenaline secretion usually recorded during general anaesthesia (29). Whether epidural/spinal block and various pharmacological methods potentiate each other to prevent venous thromboses is not known. SPINAL/EPIDURAL ANAESTHESIA AND LOCAL BLEEDING COMPLICATIONS Haematoma giving loss of sensory and/or motor function in connection with spinal/epidural anaesthesia is extremely rare. Considering the seriousness of this complication, it would seem remarkable if it was not reported in studies dealing with complications of various types of regional anaesthesia. Lund (30) analysed complications after 150 000 epidural anaesthetic procedures and reported no instance of intraspinal haematoma, and neither did Bonica et al. (31) in 3137 patients, nor Moore & Bridenbaugh (32) in l 1574 patients. Case reports do exist, especially in connection with therapeutic doses of anticoagulation (33-39). The number of case reports is small, indicating that the fear of spinal haematoma should not be overemphasized and moreover, it is important to know that such haematomas may also occur spontaneously in patients on anticoagulants (40-44). This phenomenon obviously complicates the situation and makes it almost impossible to show a causal relationship between the anaesthesiological technique and the complication. The rarity of this specific complication also makes it impossible to perform prospective randomized
studies on the safety in this respect of various thromboprophylactic methods. As far as standard low-dose heparin prophylaxis is concerned, there arc two rcported cases of epidural haematoma with neurological deficit in connection with epidural anaesthesia (45, 46). Alleman et al. (47) retrospectively analysed data from a prospective study on heparin in combination with dihydroergotamine and found no complications in 2259 epidural/spinal anaesthesias. Rao et al. (48) prospectively analysed 40 15 patients undergoing peripheral vascular procedures and given small doses of heparin (although not conventional unfragmented low dose heparin). In four cases blood was freely aspirated and the anaesthetic procedure was abandoned. In no case were neurological complications recorded. During therapeutic anticoagulation, on the other hand, spinal anaesthesia appears to be a real risk for the development of intraspinal haemorrhage (34-36). LITERATURE SURVEY OF PATIENTS WITH LMWH PROPHYLAXIS AND EPIDURAL/ SPINAL ANAESTHESIA From the data base Excerpta Medica and through the authors’ own contacts, 44 articles on low molecular weight heparin for thromboprophylaxis have been identified and analysed. None of the studies has been stratified on the basis of anaesthesiological method. The anaesthesiological method used is not mentioned at all in some studies where epidural or spinal anaesthesia would have been possible from the surgical point of view: gynaecological surgery (49, 50), transurethral prostatic resection (51,52), peripheral vascular surgery (53, 54), and hip surgery (55-59). Others have specifically stated that they used general anaesthesia: gynaecological surgery (60, 61), and hip surgery (62-66). Details on anaesthesiological techniques are never given Table 1 shows the studies where epidural or spinal anaesthesia has been used in combination with LMWH in all patients or part of the patient population. The total number of patients with the combination is 9013. The study by Ang et al. (67) is the only one where interest was focused on complications of the epidural or spinal block. In four cases there was lumbar pain, in three headache and in one, reversible symptoms of lumbago-ischias type. The investigations by Muhr et al. (68), Wolf et al. (69) and Haas & Floosbach (70) were large prospective studies with the aim of investigating the safety and effect of LMWH in combination with dihydroergotamine. The study design included no control groups, which, however, is of minor importance and interest from our point of view. O n the other hand, the studies were specifically
607
LOW MOLECULAR WEIGHT HEPARIN Table 1
Author
Type of surgery
Ang et al. (67) Barre et al. (72) Bergqvist et al. (73) Eriksson et al. (74) Haas & Flosbach (70) Muhr et al. (68)
Orthopaedic Elective hip Abdominal Elective hip General General Gynaecological Neurosurgical Orthopaedic Elective hip Elective hip Abdominal Elective hip General Urological Gynaecological Orthopaedic
Matzsch et al. (75) Matzsch et al. (76) Ockelford et al. (77) Planes et al. (71) Wolf et al. (69)
No. of patients on low molecular weight heparin
No. of patients with epidural/spinal anaesthesia
308 40 505 49 8738 942
308 40 101 45 1657 179
Fraxiparin Fragmin Fragmin Fragmin Enoxaparin Sandoz
45
Logiparin Logiparin Fragmin Enoxaparin Sandoz
47 120 95 126 33421
designed to analyse complications, and there were no complications which could be attributed to the epidural or spinal block in the 8231 patients. All other studies were made to compare LMWH with some other type of prophylaxis. One problem is that, except for the studies by Ang et al. (67) and Planes et al. ( 7 1), nothing is reported on anaesthesiological complications. The time interval between LMWH injection and anaesthesia is not given. However, epidural/spinal haematoma with neurological complications is such a serious event that it would certainly have been reported. Thus this type of complication was not reported in 901 3 patients where spinal/epidural anaesthesia was used in combination with LMWH. The number of patients given the combination outside clinical studies is not known, but the rapidly increasing use of LMWH would indicate that there are many. Manufacturing companies estimate it to be at least 1 000 000 patients. Tryba (2) reported on irreversible paraplegia in a 45-year-old male. He had minimal bleeding at insertion of the catheter and 3 h after the third LMWH injection he developed paraplegia and a haematoma was evacuated from the epidural space Th9-L4. When a spinal haematoma develops, urgent decompression is mandatory. More extensive observation routines than those used today would, however, probably not be cost-effective because of the extreme rareness of the complication. It is not known how soon after heparin injection an epidural cathether may be removed without risk. If there is an effect of heparin, the risk of withdrawing the catheter must be weighed against the risk of having
114
3 126 6395
Type of low molecular weight heparin
a potentially moveable catheter left in the spinal/epidural space during anticoagulation. It is concluded that neurological complications after epidural or spinal anaesthesia in patients with postoperative thromboprophylaxis with LMWH in low doses as well as with unfragmented low dose heparin are extremely rare, and the combination therefore seems safe. Whether the combination potentiates the prophylactic effect is not known. It is very important that the type of anaesthesia used is clearly stated in future studies and that this specific complication is negated or, of course, reported if it occurs, also outside clinical investigations.
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8. Andersson L-0. Prevention and treatment of thrombosis by low molecular weight heparins. Drug Design and Delivery 1989: 5: 1-11. 9. Levine M, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M. The relationship between anti-factor X a level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. ‘Thromb Haemost 1989: 62: 940-944. 10. Bergqvist D, Lindblad B, Matzsch T. Glycosaminoglycans in prophylaxis against venous thromboembolism. In: Lindahl U, Lane D eds. Heparin and related polysaccharides. Plenum Press. In press. I I , Bohmansson G. Discussion on the incidence of thromboembolism in the Department ofsurgery 1932-41 ( M Fellander). Nord Med 1943: 17: 182-187. 12. Lahnborg G, Bergstrom K. Clinical and haemostatic parameters related to thromboembolism and low-dose heparin prophylaxis in major surgery. Acta Chir Scand 1975: 141:590-595. 13. Lahnborg G, Bergstrom K, Friman L, Lagergren H. Effect of low-dose heparin on incidence of postoperative pulmonary embolism detected by photoscanning. Lancet 1974 i: 329-331. 14. Thorburn J, Loudon J R, Vallance R. Spinal and general anaesthesia in total hip replacement; frequency of deep vein thrombosis. Br 3 Anaesth 1980: 52: 11 17-1 121. 15. Modig J, Hjelmstedt A, Sahlstedt B, Maripuu E. Comparative influences of epidural and general anaesthesia on deep venous thrombosis and pulmonary embolism after total hip replacement. Acta Chir Scand 1981: 147: 125-130. 16. Modig J, Borg T, Bagge L, Saldeen T. Role of extradural and of general anaesthesia in fibrinolysis and coagulation after total hip replacement. Br 3 Anaesth 1983: 55: 625-629. 17. Modig J, Maripuu E, Sahlstedt B. Thromboembolism following total hip replacement. A prospective investigation of 94 patients with emphasis on the efficacy of lumbar epidural anesthesia in prophylaxis. Reg Anesth 1986: 11: 72-76. 18. Davis F M, Laurensen V G, Gillespie W J, Wells J E, Foate J, Newman E. Deep vein thrombosis after total hip replacement. A comparison between spinal and general anaesthesia. j Bone Joint Surg 1989: 71-B:181-185. 19. Davis F M, Laurensen V G. Spinal anaesthesia or general anaesthesia for emergency hip surgery in elderly patients. Anaesth Intensive Care 1981: 9: 352-358. 20. McKenzie P J, Wishart H Y, Gray I, Smith G. Effects of anaesthetic technique on deep vein thrombosis. Br 3 Anaeslh 1985: 57: 853-85 7. 2 1. Hendolin H, Mattila M A K, Poikolainen E. The effect oflumbar epidural analgesia on the development of deep vein thrombosis of the legs after open prostatectomy. Acla Chir Scand 1981: 147: 425-429. 22. Poikalainen E, Hendolin H. Effects of lumbar epidural analgesia and general anaesthesia on flow velocity in the femoral vein and postoperative deep vein thrombosis. Acta Chir Scand 1983: 149: 361-364. 23. Prim M, Hirsh J. A comparison of general anaesthesia and regional anesthesia as a risk factor for deep vein thrombosis following hip surgery: a critical review. Thromb Huemost 1990: 64:497-500. 24. Haljamae H, Frid 1, Holm J, Akerstrom G. Epidural vs general anaesthesia and leg blood flow in patients with occlusive atherosclerotic disease. Eur J Vasc Surg 1988: 2: 395-400. 25. Brcdbacka S,Blomback M, Hagnevik K, Iwestedt L, Raake N. Per- and post-operative changes in coagulation and fibrinolytic variables during abdominal hysterectomy under epidural or general anaesthesia. A d a Anaesthesiol Scand 1986: 30: 204-210. 26. Engquist A, Askgaard B, Funding J. Impairment of blood fibrinolytic activity during major surgical stress under combined
extradural blockade and general anaesthesia. B r J Anaesth 1976: 48: 903-906. 27. Lindblad B, Bergqvist D, Hallbook T, Lindhagen A, Hednrr U.
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Postoperative haemostatic changes in patients given thromboembolic prophylaxis with dextran 70 - alone or in combination with dihydroergotarnine. Acta Chir Scand 1984: 150: 525-529. Modig J. The role of lumbar epidural anaesthesia as antithrombotic prophylaxis in total hip replacement. A d a Chir Scand 1985: 151:589-594. Engquist A, Brandt M R, Fernandes A, Kehlet H. The blocking effect of epidural analgesia on the adrenocortical and hyperglycemic responses to surgery. Acta Anaesthesiol Scand 1977: 21: 330-335. Lund P C. Peridural anesthesia. Springfield, Illinois: Charles C Thomas, 1966. Bonica J, Backup P H, Andersson C E, Hadfield D, Crepps W F, Monk B F. Peridural block: analysis of 3637 cases and a review. Anaesthesist 1957: 18: 723-727. Moore D C, Bridenbaugh L D. Spinal (subarachnoid) block: a review of 11 574 cases. JAMA 1966: 195: 907-912. Gingrich T F. Spinal epidural hematoma following continuous epidural anesthesia. Anesfhesiology 1968: 29: 162-1 63. Butler A B, Green C D. Haematoma following epidural anaesthesia. Can Anaesth Soc 3 1970: 17:635439. De Angelis J. Hazards of subdural and epidural anesthesia during anticoagulant therapy: a case report and review. Anesfh Analg 1972: 51: 676479. Varkey G P, Brindle G P. Peridural anaesthesia and anti-coagulant therapy. Can Anaesth Soc J 1974: 21: 106-109. Bamford C R. Spinal epidural hematoma due to heparin. Letter to the Editor. Arch Neurol 1978: 35: 693494. Sadjapour K. Hazards of anticoagulation therapy shortly after lumbar puncture. Letters to the Editor. J A M A 1977: 237: 1692-1 693. Brem S S, Hafler D A, van Uitert R L, Ruff R L, Reichert W H. Spinal subarachnoid hematoma. A hazard of lumbar puncture resulting in reversible paraplegia. N Engl J M e d 1981: 304: 1020-1021. Alderman D B. Extradural spinal-cord hematoma: report of a case due to dicumarol and review of the literature. .N Engl 3 M e d 1956: 255: 83F842. Markham J W, Lynge H N, Stahlman G E 8 . The syndromr of spontaneous spinal epidural hematoma. Report of three cases. 3 Neurosurg 1967: 26: 334-342. Harik S I, Reichle M E, Reis 0 J. Spontaneously remitting spinal epidural hematoma in a patient on anticoagulants. N Engl J M e d 1971: 284: 135551357, McQuarrie I G. Recovery from paraplegia caused by spontaneous spinal epidural hematoma. Neurology 1978: 28: 224-228. Dahlin P A, George J. Intraspinal hematoma as a complication of anticoagulant therapy. Clin Pharm 1984: 3: 656-661. Darnat S, Guzziari M, Grob R, Guillaume A, Viars P. Un cas d’hkmatome extradural vachien au cows de la mise en place d’un cathtter pkridural. Ann Fr Anuslh RCanim 1986: 5: 550-552. Metzger G, Singbartl G. Spinal epidural hematoma following epidural anesthesia Venus spontaneous spinal subdural hematoma. Two large reports. Acta Anaesthesiol Scand 1991: 35: 105-107. Alleman B H, Gerber H, Gruber U F. Ruckenmarksnahe Anaesthesie und subkutan verabreichtes low-dose Heparin-Dihydergot zur Thromboembolieprophylaxe. Anaesthesist 1983: 32: 80-83. Rao T L K, Gorski D, El-Etr A A. Epidural and subarachnoid catheters and anticoagulants. Anesthesiology 1980: 53: S2 13. Brie1 R C , Doller P, Hermann P. Thromboembolie-prophylaxe bei Hysterektomien mit dem niedermolekularen Heparin Fragrnin. Geburfshilfc Frauenheilkd 1988: 48: 160-1 64. Steiner R A, Keller K , Liischer T, Schreiner W E. A prospective
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LOW MOLECULAR WEIGHT HEPARIN randomized trial of low molecular weight heparin - DHE and conventional heparin-DHE (with acenocoumarol) in patients undergoing gynaecological surgery. Gynecol Obstet 1989: 244: 141-1 50. 51 ten Cate H, Henny P, ten Cate J, Biiller H, Dabhoiwala N. Randomized double-blind, placebo-controlled safety study of a low molecular weight heparinoid in patients undergoing transurethral resection of the prostate. Thromb Hacmost 1987: 57: 92-96. 52. Cortellini P, Peletti F, Simonazzi M. Prevention of post-operative thromboembolism. A clinical trial in urological patients treated with a new low molecular weight heparin. Acta Therapeutica 1988: 14: 135-144. 53. Speziale M, Verardi S, Taurino M, Nicolini G, Rizzo L, Fiorono P, Palazzini E. Low molecular weight heparin prevention of post-operative deep vein thrombosis in vascular surgery. Pharmatherapeutica 1988: 5: 261-268. 54. Gossetti B, Irace L, Gattuso R, et al. Prevention of deep venous thrombosis in vascular surgical procedures by LMW-heparin. Int Angiol 1988: 7 (suppl 3): 25-27. 55. Monreal M, Lafoz E, Navarro A et al. A prospective doubleblind trial of a low molecular weight heparin once daily compared with conventional low-dose heparin three times daily to prevent pulmonary embolism and venous thrombosis in patients with hip fracture. 3 Trauma 1989: 29: 873-875. 56. Chiapuzzo E, Orengo G B, Ottria G, Chiapuzzo A, Palazzini E, Fusillo M. The use of low molecular weight heparins for postsurgical deep vein thrombosis prevention in orthopaedic patients. J Int Med Res 1988: 16: 359-366. 57. Pini M, Tagliaferri A, Manotti C. Lasagni F, Rinaldi E, Dettori A G. Low molecular weight heparin (Alfa LMWH) compared with unfractionated heparin in prevention of deep-vein thrombosis after hip fractures. Int Angiol 1989: 8: 134-139. 58. Turpie A, Levine M, Hirsh J et al. A randomized controlled trial of a low-molecular weight heparin (Enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. X Engl j' Med 1986: 315: 925-929. 59. Barsotti J, Dab0 8, Andreu J et at. Etude comparative de deux posologres d'hkparine de faible masse molkculaire PK 10169 dans la prkvention des accidents thromboemboliques au cours du traitment de 103 fractures de col du fkmur. 3 Malad Vasc 1987: 12: 96-98. 60. Palareti G, Legnani C, Bianchini B et al. Pharmacodynamic effects on blood coagulation of a new low molecular weight heparin (alfa-LMWH) in healthy volunteers and gynecological surgery patients. Int Angiol 1989: 8: 47-52. 61. Borstad E, Urdal K, Handeland G, Abildgaard U. Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery. Acta Obstet Gynecol Scand 1988: 67: 99-103. 62. Dechavanne M, Vilk D, Berruyer M et al. Randomized trial of a low molecular-weight heparin (Kabi 2165) versus adjusteddose subcutaneous standard heparin in the prophylaxis of deepvein thrombosis after elective hip surgery. Huemostasis 1989 1: 5-12. 63. Haas S, Stemberger A, Fritsche H-M, Lechner F. Untenuchungen zur antithrombotischen Wirksamkeit von niedermolekularen Heparin Kabi. Med Welt 1987: 38: 714-720. 64. Haas S, Stemberger A, Fritsche H-M, Welzel D, WolfH, Lechner F, Blumel G. Prophylaxis of deep vein thrombosis in high risk
patients undergoing total hip replacement with low molecular weight heparin plus dihydroergotamine. Drug Res 1987: 37: 839-843. 65. Planes A, Vochelle N, Ferru J et al. Enoxaparine low molecular weight heparin: its use in the prevention of deep venous thrombosis following total hip replacement. Huemostusis 1986: 16: 152-158. 66. Planes A, Vochelle N, Mazas et al. Prevention of postoperative venous thrombosis: a randomized trial comparing - unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. lhromb Hutmost 1988: 60:407-410. 67. Ang E T, Khon S, Delefosse D, Galet C, Goldfarb G, Jolis P. Incidence des complications locales apris anesthksie rachidienne chez les Datients trait& Dar hharine des bas Doids molkculaire. Ann Fr A k t h Rcanim 1989: 8: iuppl, R163. 68. Muhr G, Josten C, Polensky U. Priifung der Vertraglichkeit und Wirksamkeit von niedermolekularem Heparin 1599 IE, in fixer Kombination mit 0.5 mg Dihydroergotamin. Med Wclt 1987: 38: 1277-1281. 69. Wolf R, Welzel D, Kaiser H et al. Bewertung der perioperativen Thromboembolie-Prophylaxe mit niedermolekularem Heparin und Dihydroergotamin. Drug Res 1988: 3 8 1516-1519. 70. Haas S, Flosbach C W. Prevention of post-operative thrombosis in general surgery with enoxaparin: preliminary findings. Acta Chir &and 1990 Suppl 556: 96-102. 7 1. Planes A, Vouchelle N, Fagola M et al. Eficacy and safety of a perioperative enoxaparin regimen in total hip replacement under various anesthesias. A m J Surg 1991: 161: 525-531. 72. Barre J, Pfister G, Potron G et al. EfficacitC et tolerance comparke du Kabi 2165 et de I'hkparine standard dans la prkvention des thromboses veineuses profondes au cours des prothbes totales de hanche. 3 Malad Vosc 1987: 12: 90-95. 73. Bergqvist D, Matzsch T, Burmark U S et al. Low molecular weight heparin given the evening before surgery compared with conventional low dose heparin in the prevention of thrombosis after elective general abdominal surgery. Br 3 Surg 1988: 75: 888-89 1. 74. Eriksson B, Zachrisson B, Teger-Nilsson A-C, Risberg B. Thrombosis prophylaxis with low molecular weight heparin in total hip replacement. Br J Surg 1988: 75: 1053-1057. 75. Matzsch T, Bergqvist D, Fredin H, Hedner U. Low molecular weight heparin versus dextran as prophylaxis against thrombosis after total hip replacement. Acta Chi7 Scand 1990: 1 5 6 445-450. 76. Matzsch T, Bergqvist D, Fredin H, Hedner U, Lindhagen A, Nistor L. Comparison of the thromboprophylactic effect of a low molecular weight heparin versus dextran in total hip replacement. Thromb H a m o w h Dis 1991: 3: 25-29. 77. Ockelford P, Pattersson J, Johns A. A double-blind randomized placebo controlled trial of thromboprophylaxis in major elective general surgery using once daily injections of a low molecular weight heparin fragment (Fragmin). Thromb Haemost 1989: 62: 1046-1 049. a
Address: David Bcrgqvist, M.D., Ph.D. Department of Surgery Malmo General Hospital 5-21401 Malmo Sweden
Acta Anaesthesiol Scand 1992: 36: 605-609
Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia - is there a risk? D. BERGQVIST, B. LINDBLAD and T. MATZSCH Department of Surgery, Lund University, General Hospital, Malmo, Sweden
This article reviews the problem of bleeding in connection with epidural/spinal anaesthesia, with special emphasis on the use of low molecular weight heparins for thromboprophylaxis. There are methodological difficulties to studying the problem in a scientifically correct way because of the rarity of the complication. However, from the data in the literature there are no indications of an increased risk in using the combination of low molecular weight heparin in prophylactic doses and epidural/spinal anaesthesia. So far, there is only a single case report, of spinal haematoma, although low molecular weight heparins have been used in combination with epidural/spinal anaesthesia in at least 1000000 patients. In controlled studies, at least 10000 patients have been given the combination without complications.
Key words: Epidural anesthesia; low molecular weight heparin; regional anesthesia; spinal anesthesia; throm boproph ylaxis.
Most surgeons dealing with major surgery practise some form of pharmacological prophylaxis against postoperative venous thromboembolism. There are various opinions on how to define risk factors and which of the prophylactic methods is best. There are also several more controversial issues, one being the use of epidural or spinal anaesthesia in patients with heparin prophylaxis due to the risk ofspinal haematoma and subsequent paraparesis. In 1981, Stanton-Hicks stated “that not only would it be redundant to combine mini-dose heparin with major conduction anaesthesia but that its concurrent use would indeed be contraindicated in the light of the foregoing risks” (1). Some anaesthesiologists have undoubtedly followed this warning, whereas others have shown no reluctance to use low-dose heparin in patients with epidural/spinal block, be it before, during or after. In 1989, Tryba reported from a consensus conference that “Low-dose heparin prophylaxis is no contraindication to spinal or epidural anaesthesia” (2). In view of a reported higher frequency of bleeding complications in early studies on low molecular weight heparin (LMWH), it was, however, stated that the combination of LMWH and spinal/epidural anaesthesia “should be performed in controlled studies only” (2). The aim of this review is to analyse the problem of the development of spinal haematoma in relation to epidural-spinal anaesthesia, and especially in patients in whom low molecular weight heparin fragments have been used to prevent postoperative venous thromboembolism.
LOW MOLECULAR WEIGHT HEPARIN AND THROMBOPROPHYLAXIS There is no doubt that the various LMWH fragments available today are effective in preventing postoperative venous thromboembolism. The number of studies of different patient populations is rapidly increasing and in this context it seems sufficient to refer to recent surveys (3-6). Although each LMWH fragment must be evaluated as a specific pharmacological substance, there are no data which indicate a clinically relevant difference, whether pharmacokinetics or prophylactic effect is concerned (7). O n the basis of early in vitro studies and animal experiments, it was thought that it would be possible to separate the anti-thrombotic effect from an anti-haemostatic (8). However, it soon became apparent that like all other thromboprophylactic drugs LMWH also had a dose-dependent influence on the frequency of bleeding and that the level of antifactor Xa activity was a rather good indicator of this risk (9). However, after extensive clinical studies it has been possible to define doses of LMWH which are prophylactically effective without increasing the bleeding risk (3-6). The advantages with LMWH in low doses as compared with unfragmented low dose heparin are a higher and more predictable bioavailability after subcutaneous injection, a longer biological half-life which makes one injection daily sufficient, and a smaller influence on platelet function and lipolysis (8). LMWH also has a better effect in patients undergoing
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orthopaedic surgery, a real high-risk group for thromboembolic complications (10). SPINAL/EPIDURAL ANAESTHESIA AND THROMBOPROPHYLAXIS As early as 1943, the Swedish surgeon Bohmansson claimed that patients at risk of thrombosis should be operated on using spinal anaesthesia (1 1 ) . That epidural anaesthesia might have a certain thromboprophylactic effect was suggested in some uncontrolled studies performed during the 1970’s (12-14). In recent years prospective randomized studies have confirmed that epidural/spinal anaesthesia is associated with a significantly lower risk for postoperative deep vein thrombosis in patients undergoing total hip replacement ( 15-18), hip fracture surgery (19, 20) or open prostatectomy (21, 22). The relative risk reduction for deep vein thrombosis following hip surgery is 46-55% (23). Besides having a haemodynamic effect (1, 22, 24), epidural block may stimulate fibrinolysis ( 16, 22). The latter effect is, however, controversial (25, 26). Coagulation may be influenced (27, 28). Epidural anaesthesia extending over the segments Th4-S5 blocks the adrenaline secretion usually recorded during general anaesthesia (29). Whether epidural/spinal block and various pharmacological methods potentiate each other to prevent venous thromboses is not known. SPINAL/EPIDURAL ANAESTHESIA AND LOCAL BLEEDING COMPLICATIONS Haematoma giving loss of sensory and/or motor function in connection with spinal/epidural anaesthesia is extremely rare. Considering the seriousness of this complication, it would seem remarkable if it was not reported in studies dealing with complications of various types of regional anaesthesia. Lund (30) analysed complications after 150 000 epidural anaesthetic procedures and reported no instance of intraspinal haematoma, and neither did Bonica et al. (31) in 3137 patients, nor Moore & Bridenbaugh (32) in l 1574 patients. Case reports do exist, especially in connection with therapeutic doses of anticoagulation (33-39). The number of case reports is small, indicating that the fear of spinal haematoma should not be overemphasized and moreover, it is important to know that such haematomas may also occur spontaneously in patients on anticoagulants (40-44). This phenomenon obviously complicates the situation and makes it almost impossible to show a causal relationship between the anaesthesiological technique and the complication. The rarity of this specific complication also makes it impossible to perform prospective randomized
studies on the safety in this respect of various thromboprophylactic methods. As far as standard low-dose heparin prophylaxis is concerned, there arc two rcported cases of epidural haematoma with neurological deficit in connection with epidural anaesthesia (45, 46). Alleman et al. (47) retrospectively analysed data from a prospective study on heparin in combination with dihydroergotamine and found no complications in 2259 epidural/spinal anaesthesias. Rao et al. (48) prospectively analysed 40 15 patients undergoing peripheral vascular procedures and given small doses of heparin (although not conventional unfragmented low dose heparin). In four cases blood was freely aspirated and the anaesthetic procedure was abandoned. In no case were neurological complications recorded. During therapeutic anticoagulation, on the other hand, spinal anaesthesia appears to be a real risk for the development of intraspinal haemorrhage (34-36). LITERATURE SURVEY OF PATIENTS WITH LMWH PROPHYLAXIS AND EPIDURAL/ SPINAL ANAESTHESIA From the data base Excerpta Medica and through the authors’ own contacts, 44 articles on low molecular weight heparin for thromboprophylaxis have been identified and analysed. None of the studies has been stratified on the basis of anaesthesiological method. The anaesthesiological method used is not mentioned at all in some studies where epidural or spinal anaesthesia would have been possible from the surgical point of view: gynaecological surgery (49, 50), transurethral prostatic resection (51,52), peripheral vascular surgery (53, 54), and hip surgery (55-59). Others have specifically stated that they used general anaesthesia: gynaecological surgery (60, 61), and hip surgery (62-66). Details on anaesthesiological techniques are never given Table 1 shows the studies where epidural or spinal anaesthesia has been used in combination with LMWH in all patients or part of the patient population. The total number of patients with the combination is 9013. The study by Ang et al. (67) is the only one where interest was focused on complications of the epidural or spinal block. In four cases there was lumbar pain, in three headache and in one, reversible symptoms of lumbago-ischias type. The investigations by Muhr et al. (68), Wolf et al. (69) and Haas & Floosbach (70) were large prospective studies with the aim of investigating the safety and effect of LMWH in combination with dihydroergotamine. The study design included no control groups, which, however, is of minor importance and interest from our point of view. O n the other hand, the studies were specifically
607
LOW MOLECULAR WEIGHT HEPARIN Table 1
Author
Type of surgery
Ang et al. (67) Barre et al. (72) Bergqvist et al. (73) Eriksson et al. (74) Haas & Flosbach (70) Muhr et al. (68)
Orthopaedic Elective hip Abdominal Elective hip General General Gynaecological Neurosurgical Orthopaedic Elective hip Elective hip Abdominal Elective hip General Urological Gynaecological Orthopaedic
Matzsch et al. (75) Matzsch et al. (76) Ockelford et al. (77) Planes et al. (71) Wolf et al. (69)
No. of patients on low molecular weight heparin
No. of patients with epidural/spinal anaesthesia
308 40 505 49 8738 942
308 40 101 45 1657 179
Fraxiparin Fragmin Fragmin Fragmin Enoxaparin Sandoz
45
Logiparin Logiparin Fragmin Enoxaparin Sandoz
47 120 95 126 33421
designed to analyse complications, and there were no complications which could be attributed to the epidural or spinal block in the 8231 patients. All other studies were made to compare LMWH with some other type of prophylaxis. One problem is that, except for the studies by Ang et al. (67) and Planes et al. ( 7 1), nothing is reported on anaesthesiological complications. The time interval between LMWH injection and anaesthesia is not given. However, epidural/spinal haematoma with neurological complications is such a serious event that it would certainly have been reported. Thus this type of complication was not reported in 901 3 patients where spinal/epidural anaesthesia was used in combination with LMWH. The number of patients given the combination outside clinical studies is not known, but the rapidly increasing use of LMWH would indicate that there are many. Manufacturing companies estimate it to be at least 1 000 000 patients. Tryba (2) reported on irreversible paraplegia in a 45-year-old male. He had minimal bleeding at insertion of the catheter and 3 h after the third LMWH injection he developed paraplegia and a haematoma was evacuated from the epidural space Th9-L4. When a spinal haematoma develops, urgent decompression is mandatory. More extensive observation routines than those used today would, however, probably not be cost-effective because of the extreme rareness of the complication. It is not known how soon after heparin injection an epidural cathether may be removed without risk. If there is an effect of heparin, the risk of withdrawing the catheter must be weighed against the risk of having
114
3 126 6395
Type of low molecular weight heparin
a potentially moveable catheter left in the spinal/epidural space during anticoagulation. It is concluded that neurological complications after epidural or spinal anaesthesia in patients with postoperative thromboprophylaxis with LMWH in low doses as well as with unfragmented low dose heparin are extremely rare, and the combination therefore seems safe. Whether the combination potentiates the prophylactic effect is not known. It is very important that the type of anaesthesia used is clearly stated in future studies and that this specific complication is negated or, of course, reported if it occurs, also outside clinical investigations.
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Address: David Bcrgqvist, M.D., Ph.D. Department of Surgery Malmo General Hospital 5-21401 Malmo Sweden
