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Meanwhile, other evidence in favour of the lipid oxidation hypothesis accumulates inexorably. Antioxidants have been shown to inhibit formation of lesions in hypercholesterolaemic rabbits;21,22 vitamin E and other antioxidants, carried in the LDL particle, protect it from oxidation;23 in various European populations there seems to be an association between low plasma concentrations of vitamin E and coronary artery disease ;24,25 and evidence from cell cultures suggests that lipid oxidation may explain the important event of onset of macrophage necrosis in the developing plaque.26 We still lack real proof of the lipoprotein oxidation hypothesis, but if it were eventually proved correct it would hold out the serious prospect that antioxidant supplements might hinder the development of atherosclerosis. Because macrophage activity seems to continue even in advanced lesions,8 intervention might even be effective in those who are already threatened with complications of the disease. The truth may emerge from trials of an antioxidant such as vitamin E in high-risk groups. 1.

Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc

Natl Acad Sci USA 1980; 77: 2214-18. 2. Mitchinson MJ. Insoluble lipids in human atherosclerotic plaques. Atherosclerosis 1982; 45: 11-15. 3. Morel DW, Di Corleto PE, Chisholm GM. Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis 1984; 4: 357-64. 4. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 1984; 81: 3883-87. 5. Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 1979; 76: 333-37. 6. Mitchinson MJ. Macrophages, oxidised lipids and atherosclerosis. Med Hypoth 1983; 12: 171-78. 7. Cathcart MK, Morel DW, Chisolm GM. Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukocyte Biol

1985; 38: 341-50. Aqel NM, Ball RY, Waldmann H, Mitchinson MJ. Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies. J Pathol 1985; 146: 197-204. 9. Gown AM, Tsukada T, Ross R. Human atherosclerosis: II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol 1986; 125: 191-207. 10. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915-24. 11. Witztum JL, Steinberg D. Role of oxidised low density lipoprotein in atherogenesis. J Clin Invest 1991; 88: 1785-92. 12. Parums DV, Brown DL, Mitchinson MJ. Serum antibodies to oxidised LDL and ceroid in chronic periaortitis. Arch Pathol Lab Med 1990; 8.

114: 383-87. 13. Haberland ME, Fong D, Cheng L. Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science 1988; 241: 215-18. 14. Ylä-Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 1989; 84: 1086-95. 15. Rosenfeld ME, Palinski W, Yla-Herttuala S, Butler S, Witztum JL. Distribution of oxidation-specific lipid-protein adducts and apo B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 1990; 10: 336-49. 16. Rosenfeld ME, Khoo JC, Miller E, Parthasarathy S, Palinski W, Witztum JL. Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote

oxidation of low density lipoproteins and contain oxidation-specific lipid-protein adducts. J Clin Invest 1991; 87: 90-99. 17. Ball RY, Carpenter KLH, Mitchinson MJ. What is the significance of ceroid in human atherosclerosis? Arch Pathol Lab Med 1987, 111: 1134-40. 18. Boyd HC, Gown AM, Wolfbauer G, Chait A. Direct evidence for a protein recognised by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit. Am J Pathol 1989; 135: 815-25. 19. Haberland ME, Olch CL, Fogelman AM. Role of lysines in mediating interaction of modified low density lipoproteins with the scavenger receptor of human monocyte macrophages. J Biol Chem 1984; 259: 11305-11. 20. Haberland ME, Fogelman AM. Scavenger receptor-mediated recognition of maleyl bovine plasma albumin and the demaleylated protein in human monocyte macrophages. Proc Natl Acad Sci USA 1985; 82: 2693-97. 21. Carew TE, Schwenke DC, Steinberg D. Anti-atherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit LDL degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the WHHL rabbit. Proc Natl Acad Sci USA 1987; 84: 7725-29. 22. Björkhem I, Henriksson-Freyschuss A, Breuer O, Diczfalusy U, Berglund L, Henriksson P. The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscl Thromb 1991; 11: 15-22. 23. Esterbauer H, Jurgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty adds and vitamin E and generation of aldehydes. J Lipid Res 1987; 28: 495-509. 24. Gey KF, Puska P, Jordan P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 1991; 53: 326S-34S. 25. Riemersma RA, Wood DA, Macintyre CCA, Elton RA, Gey KF, Oliver MF. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet 1991; 337: 1-5. 26. Reid VC, Brabbs CE, Mitchinson MJ. Cellular damage in mouse peritoneal macrophages exposed to cholesteryl linoleate. Atherosclerosis 1992; 92: 251-60.

Amputation or arterial reconstruction? patient has symptoms of critical ischaemia--eg, rest pain, ulcer, or gangrene-what are the chances of avoiding amputation? The annual incidence of critical ischaemia in Western Europe is between 500 and 1000 per million population, and 25% of these patients undergo major amputations.1-3 In some, major amputation may be avoided simply by When

a

of associated medical conditions such as cardiorespiratory disorders, anaemia, sepsis, and diabetes combined with conservative local measures including transluminal angioplasty, phenol sympathectomy, infusions of vasoactive agents, and minor amputations. The benefit derived is often transient. Other patients, being terminally ill, die without active treatment. Thus only about 50% are treated by arterial reconstruction. However, it is clear that a much higher proportion of legs could be saved. Simms’ group in Birmingham, UK, lately reported a consecutive series of 315 patients with 329 critically ischaemic limbs treated over 5 years.4 9 were moribund, 45 underwent primary amputation, and arterial reconstruction was attempted in 315 (88%), of which femorocrural reconstruction was performed in 239 (73%). Longterm follow-up showed remarkable patency rates of 96% at 30 days, 85% at 1 year, and 82% at 5 years. Other groups have likewise reported high success rates. 5-7 treatment

901

For many

common

surgical conditions—eg, arthritis of the hip-

gallstones, appendicitis, standard surgical treatment confidently predicted within or

and

be 2 or 3%. Not so with critical ischaemia. There are large discrepancies in practice and outcome. In some hospitals various interventions will be used to preserve a limb whereas in others amputation may be the only treatment offered. Even when limb conservation is entertained, widely different management policies are applied. Some surgeons limit reconstruction to obstructed arteries of large calibre-aorta, iliac, femoralwhereas others are willing to restore circulation down to lower calf, ankle, or even foot. There are similar variations in radiological practice. Percutaneous transluminal recanalisation (eg, angioplasty, also has a place in limb atherectomy, laser, stenting) salvage, although the results have been poorly documented. In terms of quality of life the advantages of reconstruction over amputation are immense. In the UK National Health Service, for example, a major amputation costs over 10 000 per patient;8 primary arterial reconstruction costs about half as much, and even when secondary procedures are required, limb salvage surgery is still less expensive. So why are more limb saving operations not being carried out? We must look at what femorocrural reconstruction entails. Patients with critical ischaemia are usually either diabetics or elderly people with atherosclerosis whose vessels are blocked predominantly in the calf. What makes bypass possible is the fact that beyond the blocks there may be patent "run-off’vessels, albeit of only 2-3 mm calibre. Bypasses to these vessels are demanding in many respects. outcomes can

Preoperatively, special radiological techniques (digital subtraction angiography) and/or various vascular laboratory tests (doppler, pulse-generated run-off9) are used to detect an outflow artery suitable to receive a bypass. At operation most surgeons further assess the outflow by angiography or by measurements of peripheral resistance. The preferred bypass material is saphenous vein taken from the same leg, but if the cardiac surgeon or the varicose vein surgeon has been there first, a vein may have to be harvested from the other leg or an arm. For smallcalibre arteries the patency rates of prosthetic grafts are poor, but may be enhanced by interposition of a vein cuff or patch between prosthesis and recipient artery. Success depends on surgical skill and painstaking microsurgical technique. Towards the end of the operation graft function and run-off patency are checked by doppler, angiography, or angioscopy and the operation is not completed until optimum blood flow has been assured. Close monitoring is continued into the early postoperative period. After discharge, long-term follow-up continues in the outpatient clinic and the vascular laboratory.1O Any sign of impending or actual graft failure requires prompt reintervention by way of

thrombolytic therapy or reoperation. At all stages, patients deserve the attention of high-calibre nursing, laboratory, and middle-grade medical staff who have been trained in vascular care. Bypass surgery may take as little as 2 h or as long as 8 h and it commits the surgeon to long-term responsibilities. As Bellll lately remarked, "femorodistal grafting is not for the faint-hearted or casual surgeon who is in a hurry". An amputation, by contrast, takes 30-60 min and afterwards the surgeon can quickly devolve responsibility to the limb fitter and the rehabilitation specialist. If these reasons are not enough, there are others that may lead the surgeon to opt for amputation. In countries where most vascular surgeons also have busy general surgical practices, some have neither the time nor the experience to undertake femorocrural bypass. In such circumstances many lack the necessary radiological and vascular laboratory support and also the support of junior staff with vascular training. Time for operations has to be rationed among the gallbladders, colons, hernias, and varicose veins. The difficulties are exacerbated by the growth of minimally invasive general surgery, which consumes more theatre time than do conventional open operations. What are the solutions? First there is a need for better infonnation-audits at national level on variations in practice in the management of critical ischaemia. From this information one could arrive at a consensus on management, setting of standards, and resource implications. Finally there is the question of specialisation. Modem vascular surgery is simply incompatible with busy general surgical practice, as many countries have discovered. The fact that it requires different patterns of work and different resources and yet is often administratively submerged within general surgery creates difficulties. For health services where vascular surgery remains a cuckoo in the nest of general surgery, it is time to fly. 1. European Consensus on Critical Limb Ischaemia. Lancet 1989; i: 737-38. 2. Second European Consensus Document on critical limb ischemia. Circulation 1991; 84 (suppl). 3. Wolfe JHN. Defining the outcome of critical ischaemia: a one year prospective study. Br J Surg 1986; 73: 321. 4. Hickey NC, Thomson IA, Shearman CP, Simms MH. Aggressive arterial reconstruction for critical lower limb ischaemia. Br J Surg 1991; 78: 1476-78. 5. Veith FJ, Gupta SK, Samson RH, et al. Progress in limb salvage by reconstructive arterial surgery combined with new or improved adjunctive procedures. Ann Surg 1981; 194: 386-92. 6. Corson JD, Karmody AM, Shad DM, et al. In situ vein bypasses to the distal tibial and limited outflow tracts for limb salvage. Surgery 1984; 96: 756-63. 7. Dardik H, Miller N, Dardik I, et al. A decade of experience with the glutaraldehyde tanned human umbilical cord vein graft for revascularization of the lower limb. J Vasc Surg 1988; 7: 336-47. 8. Cheshire NJW, Wolfe JHN, Noone MA, et al. The economics of femorocrural reconstruction of critical leg ischemia with and without autologous vein. J Vasc Surg 1992; 15: 167-75. 9. Beard JD, Scott DJA, Evans JM, Skidmore R, Horrocks M. Pulse generated run off: a new method of determining calf vessel patency.

Br J Surg 1988; 75: 361-63. 10. Harris PL. Vein graft surveillance—all part of the service. Br J Surg 1992; 79: 97-98. 11. Bell PRF. Femoro-distal grafts—can the results be improved? Eur J Vasc

Surg 1991; 5: 607-09.