Eur J Vasc Endovasc Surg 16, 465-471 (1998)

REVIEW ARTICLE

Lower Limb Oedema Following Distal Arterial Bypass Grafting

C. V. Soong and A. A. B. Barros D'Sa

Vascular Surgery Unit, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6B], Northern Ireland, U.K.

Lower-limb oedema following arterial bypass surgery for zschemia is a common sequela whzch can comphcate wound heahng or delay resumptwn of mobihty. Its exact pathogenesls remains uncertain but many theories have been proposed. Lymphatic &sruptlon during arterial exposure, and endothehal damage from atrophy of the media and oxygen-derived free ra&cal release are currently favoured hypotheses Infrequently, deep veto thrombosis follows surgery and may exacerbate the condition. Efforts aimed at reducing the oedema, such as the use of lymphatzc preserving mcisional approaches or the use of antiox~dants, have given conflicting results. The use of compresswn hosiery and leg elevation appear to be the most effective measures in reducing postoperatwe lower hmb oedema

Introduction Table 1. The incidence of lower limb oedema following distal arterial bypass surgery for ischaemia.

Intermittent claudication affects 5-10% of the popu- Authors Incidence of oedema (%) lation over 65 years of age, and a significant proportion Hamers 95 of these individuals will require surgical or inter- Elckhoffand Engell1° 100 ventional radiological procedures to alleviate in- Herreroseta112 93 capacitating claudication or critical ischaemia. 1 This PorterHannequm et a115 et al. ~s 4864 makes lower-limb bypass surgery one of the most Abu-Rahmanet al. ~7 40 commonly performed vascular procedures in affluent Campbell et a127 85 societies. Unfortunately these procedures can be as- sociated with significant morbidity, one of which is post-revascularisation lower-limb oedema. This com- plication has been reported in up to 100% of patients degree which makes fasciotomy obligatory, but this undergoing femoropopliteal bypass grafting and, al- measure is fortunately only necessary in less than 0.5% though usually mild, may lead to an increase of as of all cases of elective arterial reconstruction. 3'4 much as 30% in initial limb volume (Table 1). In Despite the frequency with which postoperative addition to causing undue anxiety, it may delay am- oedema occurs, its aetiology and the manner in which bulation and compromise healing in patients with excess fluid is distributed in the various compartments associated ischaemic ulcers or in those who require of the limb remain controversial and incompletely distal amputation. The use of compression stockings understood. Melberg et al. 5 demonstrated significant in the elderly may necessitate extra supervision and elevation in intramuscular pressure 2 days after sur- contribute towards prolonging inpatient hospital stay gery, reaching levels twice that of the initial pressure, and a higher cost to the National Health Service. The then gradually decreasing but still elevated even by control of dependency swelling has been found to be the sixth postoperative day. This rise in intramuscular important in minimising wound complications fol- pressure was unrelated to the severity of preoperative lowing pedal bypass. 2 Rarely, the oedema may be ischaemia or length of surgery. In patients whose severe enough to cause compartment syndrome of a reconstructive arterial surgery was unsuccessful, intra- muscular pressure and calf circumference remained * Please address all correspondenceto' C V Soong,Vascular Surgery unchanged postoperatively. More recent evidence of Unit, Royal Group of Hospitals, Belfast, BT12 6BJ, U K. oedema mainly confined to the subcutaneous tissue,

1078-5884/98/120465+07512.00/0 © 1998 W B. Saunders Company Ltd 466 C. V, Soong and A. A. B. Barros D'Sa however, refutes earlier findings of intramuscularpres- Table 2. The incidence of deep venous thrombosis following sure elevation. Using computer tomography and mag- femoropopliteal bypass grafting. netic resonance imaging, an increase in volume of up Incidence of to 40% has been shown to occur in the subcutaneous Authors DVT (%) Diagnostic technique tissue with little change observed in the muscle com- Hamers 41 Phlebography partments. 6'7 This observation, despite previous sug- Herreroset a112 7 Phlebography Porter et a115 0 Phlebography gestions, is supported by the lack of elevation in Abu-Rahmanet al i7 8 Phlebography interstitial fluid pressure in the muscle compartments Myhre et al. 19 8 Phebography compared to that in the subcutaneous tissue, the latter Storen et a120 7 Pl-debography rising by more than 10%. Husm23 9 Phlebography Farkas et al 5s 3 Duplex/phlebography Even more controversial is the precise cause of the increase in limb volume. It is becoming clearer that many conducive factors are likely to be responsible, different elements contributing to a varying degree in each individual patient. The diversity of these aetio- following lower-limb bypass grafting is lymphatic. logical factors has meant thatprevention and treatment The lymphatic drainage of the leg converges at the of oedema has proved elusive. Until the contribution inguinal region via channels, most of which are dis- made by each of those factors has been clarified, a tributed anterior to the femoral vessels along with simple therapeutic strategy is precluded, some lateral and medial extensions. Numerous lymph- atics also surround the neurovascular bundle in the popliteal fossa. Both these sets of lymphatic channels communicate with neighbouring veins. 9 Dissection in Deep vein thrombosis the groin and popliteal region is accompanied by significant disruption of these lymphatic channels and Deep vein thrombosis is not a common occurrence their venous communications quite independently of following femoropopliteal bypass grafting but may the outcome of surgery. 1° A bypass procedure, there- exacerbate the oedema when present. The incidence fore, is not a prerequisite to postoperative oedema, as of deep vein thrombosis, in this cohort of patients, even simple exploration may lead to its development. 11 varies from series to series and ranges from 0-40% It has been observed that patients undergoing pro- (Table 2). In one study, s thrombosis of the major deep phylactic reconstruction without ischaemia for pop- veins was demonstrated to be common in those whose liteal aneurysm developed the same degree of limb lower limb circumference increased by more than oedema as those whose operation was performed for 4.5 cm; no patient whose leg swelling was less than critical limb ischaemia, and that the degree of swelling 1.5 cm had associated deep vein thrombosis, while all is proportionate to the level of bypass, viz. minimally those whose legs showed a circumferential increase following suprainguinal and maximally after below- exceeding 4.5 cm were found to have thrombosis of knee bypass surgery. 1~'~2 In addition, the use of au- the deep veins. This report also showed that vein tologous vein graft, the harvesting of which requires thrombosis was more prevalent in patients undergoing extensive dissection, is associated with much more below-knee bypass, particularly in those with critical swelling than when a prosthetic graft is used. ischaemia. Others have not substantiated these find- Using lymphoscintigraphy, postoperative mor- ings, and the incidence of deep vein thrombosis is phological changes in those who developed oedema found to be much less than the number of patients differed markedly from those who did not, even developing significant oedema (Table 2). This dis- though no significant difference was observed in the crepancy would suggest that other aetiological factors rate of lymph flow.13 This evidence concurs with the are of greater importance, even though the presence finding that propulsion of lymph remains intact and of thrombosed deep veins may be a compounding that the defect in lymph transport is secondary to factor in some. lymph vessel disruption. 14 It has also been observed that the duration and severity of the lower hmb oed- ema correlates with the magnitude of lymphatic dis- ruption. ~5 The number of superficial lymphatic Lymphatic disruption channels may be reduced four-fold following femoro- popliteal bypass surgery and the degree of oedema On the evidence available from many studies, the most has been found to be inversely proportional to the important aetiologlcal factor contributing to swelling number of remaining intact lymphatic channels. 16

Eur J Vasc Endovasc Surg Vol 16, December 1998 Limb Oedema Following Arterial Bypass 467

Porter et al. 15 showed clearly that postoperative swell- wall during revascularisation, z2'23 The associated hy- ing may be averted by minimising damage to lymph- peraemia consequent upon reperfusion of an ischaemic atics. In their study, patients underwent a limb may be a predictive indicator of oedema which femoropopliteal bypass either through a conventional manifests itself with ambulation; the severity and dur- or a lymphatic sparing groin dissection: six out of ation of oedema parallels that of hyperaemia. This eight patients who had a conventional groin approach hyperaemic response affected mainly those whose by- developed swelling, whereas only three out of six did pass surgery was successful and lasted from 6 to 60 so when the approach was modified to preserve the days. 24 Pitting oedema was present only in those whose lymphatics, hyperaemia lasted more than a week after surgery, More recently, AbuRahmanetal.~Tnotedthatlymph - while none of those with immediate failure of the atic sparing femoral and popliteal dissection resulted reconstruction developed hyperaemia or oedema even in much lower degrees of oedema than when con- though dissection to expose the arteries would have ventional exposures of these respective arteries were damaged the major lymphatic channels. Hyperaemic employed. In a more extensive study, they randomised distension of the limb vasculature as a result of an patients into four groups: the first had lymphatic increased head of pressure and decreased resistance conserving inguinal and conventional popliteal dis- may account for the initial increase in limb volume section, the second a lymphatic sparing popliteal but prior to ambulation. It may also explain the relative conventional inguinal dissection, the third lymphatic increase in limb volume which follows percutaneous preserving inguinal and popliteal dissections, and the transfemoral angioplasty for lower limb ischaemiaY fourth had conventional approaches to both inguinal This loss of vascular tone may lead to a rise in the and popliteal regions. Oedema was observed to be capillary filtration coefficient, a measure of capillary highest in the fourth group of patients, permeability at a given pressure. 26 Another factor The inference that lymphatic disruption is the major thought to contribute to the increase in capillary fil- cause of lower limb oedema following infrainguinal tration is the elevation in hydrostatic pressure due to bypass grafting is by no means irrefutable as con- fadure of the venous pump during ambulation, the tradictory evidence could be cited. Firstly, in the study latter considered to be due to chronic ischaemic skeletal by Porter et al., ~5 regardless of lymphatic sparing dis- muscle dystrophy.8 sections 50% of patients developed swelling, perhaps The increase in capillary permeability and filtration because preservation of lymphatic channels in the permits leakage of macromolecules into the interstitial popliteal fossa, found beneficial by some, had not space. Using 1125 labelled albumin, Campbell et al. 27 been achieved. 17'18 Secondly, leakage of lymph from demonstrated a three-fold increase in albumin con- interrupted lymph channels observed in those who centration an the operated leg compared to the contra- suffered postoperative oedema can also occur in those lateral leg. The accumulation of albumin was found who do not develop oedemaJ 9 Storen et al. 2° found to occur in the entire leg, including the muscular no difference m the extent of lymphatic disruption compartment. Samples obtained of subcutaneous between patients who developed oedema and those, interstitial fluid using the blister suction technique with no increase in limb circumference; in addition demonstrated an increase in ~2-macroglobulin and pronounced oedema was present in those patients with immunoglobulin G. 28 This sequestration of macro- normal lymphangiograms and venograms. Thirdly, molecules in the limb was accompanied by a fall in Fernandez et al. 2~ demonstrated increased lymph flow plasma protein and albumin concentrations sustained in the superficial lymphatics, inferring that in some for at least 10 days postoperatively. Although this patients the post-reconstructive oedema may not be increase in capillary filtration has been attributed to due to lymphatic disruption. Finally, the lesser degree smooth muscle atrophy and mechanical disruption of of swelling observed in those whose bypass failed the capillary consequent upon increased flow, there is simply implies that factors dependent on a successful evidence to suggest that the generation of oxygen- revascularisation are important, derived free radicals can damage the vascular endo- thelium.Z2,29-31

Increased capillary filtration Oxygen-derived free ra&cals It has been shown that chronic arterial insufficiency leads to medial atrophy, which may result in over- It is now well established that restoration of blood stretching, fragmentation and rupture of the vessel flow to ischaemic tissues can lead to complications, at

Eur J Vasc Endovasc Surg Vol 16, December1998 468 C.V. Soong and A. A. B. Barros D'Sa

]Lymphaticdisruption [ [ Atrophyof media ] the complement cascade. 37 Arachidonic acid is then I. I Revaseulansatlon] converted to thromboxanes or leucotrienes depending - on whether it follows the cycloxygenase or lip- oxygenase pathways. Some of these arachidonic acid Fragmentation~-/] metabolites and breakdown products of complements and ruptureof are potent chemoattractants which can stimulate arterial wall ReperfumonmBury [ [ neutrophils and up-regulate adhesive molecules on ] the endothelial membrane)2'Bs'B9 A consequence of this is the margination and adhesion of neutrophils along [~ducedfluid clearance [ [Artena! wall, lnjury~-[ Oxygen-free radicals[ the wall of the vessel leading to release of more oxygen- ~ derived free radicals and other proteolytic enzymes inereasedcaplllarypermeablhty I further damaging the endothelium. In addition, the accumulation of neutrophils in the capilllaries may -~ Deep veto thrombosis [ cause sludging and reduction of blood flow, namely the "no reflow" phenomenon.4° Fig. 1. The possible aetlologxcal factors of lower hrnb oedema Cytokines may also be released from reperfused following artenal bypass grafting, ischaemic skeletal muscle, as has been demonstrated in the isolated leg, which led to a rise in tumour necrosis factor, interleukin(IL)-i and IL-6. 41-~B This is supported by the finding in the venous effluent of best local damage, at worst injury to multiple remote gracilis muscle rendered ischaemic of thromboxane organs provoked by the generation of oxygen-derived A2 and IL-1 in concentrations which were sigmficantly free radicals during reperfusion. B2-z4These free radicals higher than those noted systemically.43 The production are cytotoxic species which injure cells through pro- of these cytokines may be related to the generation of cesses such as lipid peroxidation which damage the cell membrane via a series of reactions. B° Normally oxygen-derived free radicals by endothelial cells and may be attenuated by pretreatment with superoxide this free radical induced injury is limited in vivo by dismutase and glutathione peroxidase. 44 In addition antioxidants such as ascorbic acid (vitamin C) and the to causing local damage to the revascularised limb, major lipid phase, u-tocopherol (vitamin E), which is incorporated in the cellular membrane. It has been spillage of these agents into the systemic circulation suggested that the major source of oxygen-derived may have deleterious effects on remote organs. B2 free radicals following ischaemia-reperfusion injury is In skeletal muscles the fall in transmembrane po- the xanthine oxidase pathway. B5 This enzyme occurs tential difference was worse during reperfusion when naturally as the xanthine dehydrogenase and is found compared to that in ischaemia alone.45 Although Pers- in abundance in the brain, heart, intestine and skeletal son et al. 46 were not able to show a rise in the con- muscles. The dehydrogenase form catalyses the re- centration of malondialdehyde in reperfused action which converts xanthine and water to uric ischaemic muscle following arterial bypass surgery, acid and a proton with reduction of the nicotinamide they demonstrated its increase with iron stimulation, dinucleotide molecule. During ischaemia the de- suggesting a greater susceptibility to free radical in- hydrogenase form is converted by a calcium de- duced lipid peroxidation. However, by serially meas- pendent proteolytic enzyme to xanthine oxidase which uring the concentration of malondialdehyde, an generates uric acid and superoxide anzon from hypo- elevation was observed during revascularisation fol- xanthine and oxygen. Together with the accumulation lowing femoropopliteal bypass grafting. B3 This was of hypoxanthine from the catabolism of adenosine accompanied by a fall in the concentration of vitamin triphosphate during ischemia, conditions favour the E, suggesting its consumption by free radicals. In generation of oxygen-derived free radicals m response addition, the peak malondialdehyde rise and max- to the surge of oxygen concentration during re- imum fall in antioxidant was found to be significant perfusion. Support for this chain of events is the only in those who subsequently developed lower- ability of allopurinol (a xanthine oxidase inhibitor) limb oedema. The finding that lipid peroxidation was and mannitol (a hydroxyl radical scavenger) to reduce significant only in patients whose bypass was suc- the tissue damage following revascularisation) 1'34'36 cessful may explain their greater degree of post- In addition to the production of oxygen-derived operative limb swelling compared to those whose radicals, the calcium paradox can activate phos- revascularisation was not optimal. 47 Corollary studies pholipase A2 releasing arachidonic acid as well as showed that by using allopurinol or a cocktail of

Eur J Vasc Endovasc Surg Vol 16, December1998 Limb Oedema Following Arterial Bypass 469 vitamin A, vitamin C and vitamin E to minimise the allopurinal to oxypurinol takes at least 12 h, a fact generation of oxygen-derived free radicals lowerqimb which explains the failure of allopurinol to show any swelling can be significantly reduced. 34"48 The fact that beneficial effect when used shortly before the isch- the increase in leg volume is confined to subcutaneous aemia-reperfusion insult. It is also felt that the pro- tissue may be attributable to its rich store of poly- tective effect of oxypurinol may not be sustained unsaturated fatty acids, which would be vulnerable beyond 6 h of reperfusion and that short-term ad- to lipid peroxidation, ministration may only delay rather than prevent tissue The more recent discovery that percutaneous trans- damage after reperfusion. Perler et al., 52 however, dem- femoral angioplasty is associated with some swelling onstrated that both allopurinol and oxypurinol are would support the free radical theory of causation, effective in preventing the development of corn- particularly as lymphatic.channels are not disrupted partment syndrome following 6 h to 12 h of hind-limb by this procedure. 25 No attempt has been made so far ischaemia. to determine whether the degree of swelling which A cocktail of antioxidants containing alpha-to- follows suprainguinal and infrainguinal angioplasties copherol, ascorbic acid and retmol may reduce ox- is the same or not. It may be argued that oedema found idative damage found in patients undergoing lower in patients undergoing radiological revascularisationis limb revascularisation procedures. 48 Intravenous ad- due to hyperaemic distension of the vascular network ministration of the concoction prior to the start of secondary to loss of vascular tone, but this does not reperfuslon prevented the postoperative elevation of explain the delayed increase in limb volume. 25 plasma concentration of malondialdehyde and lower- limb swelling observed in patients who were not given the mixture of antioxidants. Unfortunately, this study48 consisted of a heterogenous group of patients suffering both acute and chronic ischaemia of the lower and Treatment upper limbs. Mannitol, another hydroxyl radical scav- enger, has also been found to be effective in abrogating oedema after embolectomy. In a study conducted by Unfortunately many questions regarding the oedema Buchbinder et al., 53 15 consecutive patients undergoing which follows lower limb bypass grafting for isch- aemia remain unexplained. There is no doubt that the emergency vascular revascularisation for critical limb condition has a multifactorial pathogenesis, each factor ischaemia were given 20% mannitol intravenously just being of varying importance depending on the cir- prior to the re-establishment of blood flow, followed cumstances in each case (Fig. 1). Lymphatic disruption, by an infusion for up to 24 h thereafter: none of these increased capillary filtration and ischaemia-re- patients suffered compartment syndrome or required perfusion injury are possible common contributory fasclotomy, leading to the inference that manmtol factors, and in a mere handful the development of exerted a protective influence in ischaemia-reperfusion deep vein thrombosis will exacerbate the problem. It injury of skeletal muscle. Nevertheless, this was not a is precisely the lack of understanding of the exact randomised controlled study and therefore any con- aetiology which accounts for the absence of a thera- clusions drawn from the results must be viewed with peutic protocol either to treat or to prevent the corn- caution. In addition, Persson et al. 54 were unable to plication, demonstrate any advantage in using mannitol in a Antioxidants have been used successfully by some, very small group of patients undergoing lower-limb but widespread acceptance of such recommendations bypass surgery, but once again criticisms with regard tends to be poor and often viewed with scepticism, to the lack of randomisation are equally applicable to Preadministration of allopurinol has been shown to this study. Many other antioxidants have been found reduce lower limb oedema: in a randomised controlled to be effective in reducing cellular damage following study, patients receiving allopurinol were found to ischaemia-reperfusion injury, but their role in this develop an almost 50% reduction in swelling corn- cohort of patients remains undetermined. 31 pared to a placebo group. 34 Although allopurinol limits Iloprost, a prostacyclin analogue, has been shown lower limb swelling, its mode of action is still not to minimise capillary endothelial swelling following entirely clear. It has been suggested that it acts by femorodistal reconstruction.55 Capillary damage with inhibiting xanthine oxidase activity, while others pro- endothelial swelling was shown to be a generahsed pose that its beneficial effect may be related to its more phenomenon not localised to the region of reperfusion active metabolite, oxypurinol, which is a scavenger of and may be precipitated by the systemic release of hydroxyl radicals. 49-5~ The process of convermon of vasoactive agents following revascularisation; in this

Eur J Vasc Endovasc Surg Vol 16, December1998 470 C.V. Soong and A. A. B. Barros D'Sa

randomised controlled clinical study, they found that of leg oedema following arterial reconsfructions Eur J Radzol 1982, 2 113-116. this endothelial swelling may be limited by treatment 8 HAMER JD, Investigation of oedema of the lower hmb following with iloprost, successful femoropophteal bypass surgery the role of phlebology m demonstrating venous thrombosis. Br J Surg 1972, 59 979-982 The benefit of lymphatic sparing approaches to the 9 PI~LUG JI, CALNAN JS The normal anatomy of the lymphatic femoral and popliteal arteries aimed at reducing lower- system m the human leg Br J Surg 1971; 58 925-930. limb oedema has not been demonstrated consistently. 10 Eicr,~o~F JH, ENGELL HC Local regulatmn of blood flow and In a prospective randomised study, Haaverstad et the occurrence of oedema after arterial reconstruction on the lower limb Ann Surg 1982, 95:474-478 al. s6 were unable to show that swelling in patients 11 PERSSON NH, TAKOLANDERR, BERGQVISTD Lower-hmboedema undergoing lower-limb reconstruction surgery using after arterial reconstructive surgery Influence of preoperative lymphatic preserving groin incision was lower than ischaemla,type of reconstruction and postoperative outcome. Acta Chlr Scand 1989; 155 259-266 in those subjected to a conventional approach. 12 HERREROSJ, SERENAA, CASILLASJA, ARCAS LLORENS R, RICHTER JA Study of venous and lymphatic components m the production of oedema following femoropophteal bypass. J Cardmvasc Surg 1988, 29' 540-546 Conclusion 13 HANNEQUIN P, CLEMENT C, LIEI-IN JC, EHtRARD P, NICAISE H, VALEYRE J Superficial and deep lymphoscmtigraphlc findings before and after femoropophteal bypass Eu7 J Nucl Med 1988, In view of the multiplicity of contributing factors, op- 14:141-146 14 STRANDEN E, KRAMER K Lymphatic and transcaplllary forces ritual prevention of oedema following lower-limb ar- m patients with oedema following operations for lower limb terlal bypass surgery may be achieved only by applying atherosclerosls Lymphology 1982, 15. 148-155 a combination of therapeutic regimens. Dissection car- 15 PORTER JM, LINDELLTD, LAKINPC Leg oedema following ried out using the lymphatic sparing approach, pre- femoropophteal autogenous veto bypass. Arch Surg 1972, 105 883-888 administration of an antioxidant as well as prophylaxis 16 VAUGHAN BF, LAVOTINEK AH, JEPSON RP Edema of the lower against deep vein thrombosis could all be re- limb after vascular operations Sung Gynecol Obstet 1970; 131 282-290 commended. Further studies, however, are necessary 17 ABu-RAHMAN AF, WOODRUFF BA, LUCENTE FC Edema after in order to examine more clearly the role of each of these femoropophteal bypass surgery lymphatic and venous theorms contributory factors in the development of lower-limb of causation J Vasc Surg 1990, 11 461-467. oedema before sound and effective therapy can be ira- 18 STILLMANRM, FITZGERALDI F, VARUGHESEG Edema following femoropophteal bypass' etiology and preventmn Vasc Surg 1983, plemented. It is worth quoting Bone57 in his comment on 17 354-360 the Systemic Inflammatory Response Syndrome (SIRS), 19 MYI-IRE HO, SOREN EJ, ONGI~ A The incidence of deep venous "... spend more time on achieving an accurate dia- thrombosis m patients with leg oedema after arterml re- constructmn Scand J Thor Cardwvasc Surg 1974, 8 73-76 gnosis and less time searching for a magic bullet". 20 STOREN EJ, MYHRE HO, STIRIS G Lymphanglographlc findings Therefore, at this point in time, leg elevation and corn- m patients with leg oedema after arterial reconstruction Acta pression stockings may represent the most effective Chzr Scand 1974, 140-385-387. measures available until a more definitive therapeutic 21 FERNANDEZ MJ, DAVIES WT, TYLER A, OWEN GM Post-arterml reconstruction edema - are lymphatzc channels to blame? An- regimen is clearly established. 2'53 gzology 1984, 35 475-479 22 HUSNI EA, MaroON WC Response of the arterml wall to locahsed chronic hypotenslon Czrculatwn 1961; 24 962 23 [-IUSNIEA The edema of arterial reconstruction Czrculatwn 1967, 35 (Suppl 1) 1969-1973 References 24 SIMEONE FA, HUSNI EA. The hyperemm of reconstructive arterml surgery Ann Surg 1959, 150 575-585 1 MCDANIEL MD, CRONENWETTJL Basic data related to the natural 25 PAYNESPK, JONES K, PAINTERD, GALLAND RB, COLLIN J Does the hzstory of intermittent claudlcatmn Ann Vasc Surg 1989, 3 1Lmb swell after revascularlsatlonby percutaneous translummal 273-277 angloplasty~ Eur J Vasc Endovasc Surg 1995, 9. 272-276 2 ROBISON JG, Ross JP, BROTHERS TE, ELLIOT BM Distal wound 26 STRANDEN E Transcapfllary fired filtration in patients with leg complications following pedal bypass" analyms of risk factors oedema following arterml reconstruction for lower-hmb athero- Ann Vasc Surg 1995, 9 53-59 sclerosis VASA 1983, 12 219-224 3 PATMAN RD. Compartmental syndromes m peripheral vascular 27 CAMPBELL H, HARRIS PL. Albumin kinetics and oedema fol- surgery Chn Orthop 1975; 113' 103-110. lowing reconstructwe arterial surgery of the lower hmb J Car- 4 JENSEN SL, SANDERMANN J. Compartment syndrome and &ovasc Surg 1985, 26. 110-115. fasclotomy in vascular surgery A revmw of 57 cases Eur J Vasc 28 HAAVERSTAD R, ROMSLO I, MYHRE HO The concentration of Endovasc Surg 1997, 1997; 13. 48-53 Ingh molecular weight compounds m interstitial tissue fluid a 5 MELBERG P-E, STYr J, BIBER B, HASSELGREN P-O, KORNER L, study m patmnts with post-reconstructive leg oedema Eur J SEEMAN T Muscular compartment pressure following re- EndovascSurg 1997, 13 355-360 constructwe arterial surgery of the lower hmbs. Acta Chzr Scand 29 PERRY MO, FANTINI G Ischaemm' profile of an enemy J Vasc 1984, 150. 129-133. Surg 1987, 6 231-234 6 I-tAAVERSTADR, NILSEN G, MYHRE HO, SAErHER OD, RINCK PA 30 MCCORD JM. Oxygen-derived free radicals m post-lschaemlc The use of MRI m the investigation of leg oedema Eur J Vasc tissue injury N Engl J Med 1985, 312 159-163 Surg 1992, 6 124-129 31 KORTHIUS RJ, GRANGER DN, TOWNSLEY MI, TAYLOR AE The role 7 STRANDEN E, ENGE I Computed-tomography m the investigation of oxygen-derived free ra&cals m lschaemla-mduced increases

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in canine skeletal muscle vascular permeability. Clrc Res 1985, 46 PERSSON NH, BERGQVIST D, FEX G, MARKLUND SL, N1LSSON B, 57 599-609 TAKOLANDEi~ R Lipid peroxldation and activity of anhoxldant 32 GOLDMAN G, WELBOURN R, KLAUSNER J-M et aI Mast cells and enzymes m muscle of the lower leg before and after arterial leucotrlenes mediate neutrophll sequestration and lung oedema reconstruction Eur J Vasc Surg 1989; 3- 399-403 after remote lschaemla in rodents Surgery 1992, 112 576--586 47 RABL H, KHOSCHSORUR G, COLOMBO T, TATZBER F, ESTERBAUER 33 SOONG CV, YOUNG IS, BLAIR PHB, HOOD J1V[, ROWLANDS BJ, H Human plasma hpld peroxide levels show a strong transient BARROS D'SA AAB Lipid peroxidatlon as a cause of lowerqlmb increase after successful revasculansation operations. FreeRa&caI swelling following femoropophteal bypass grafting Eur J Vasc Bzol Med 1992; 13 281-288 Surg 1993, 7. 540-545 48 RABL H, KII-IOSCHSORURG, PETEK W Antioxidatave vltalIun treat- 34 SOONG CV, YOUNG IS, HOOD JM, TRIMBLE ER, ROWLANDS BJ, ment effect on lipid peroxldatlon and hmb swelling after re- D'SA AAB Reduction of free radical generation mlmmises lower vascularlsation operations. World J Surg 1995, 19' 738-744 hmb swelling following femoropophteal bypass surgery Eur J 49 WERNS SW, GRUM CM, VENTURA A et al Xanthme oxldase Vasc Surg 1994; 8' 435--440 inhibition does not limit camne infarct size Czrculatwn 1991, 83. 35 CHARLAT ML, O'NEILL PG, EGAN JM et al Evidence for a 995-1005 pathogenetic role of xanthme oxldase m the stunned myo- 50 MOOREHOUSE PC, GROOTVELD M, HALLIWELL B, QUINLAN JG, cardmm Am ] Physwl 1987, 252 H566--577 GUTTERIDGE JMC Allopurmol and oxypurmol are hydroxyl 36 PATERSON IS, KLAUSNERJIV[, GOLDMAN Get al. Pulmonary edema radical scavengers. FEBS Lett 1987, 213- 23-28 after aneurysm surgery is modlhed by manmtol Ann Surg 1989, 51 REIMER KA, JENNINGS RB. Failure of the xmlthme oxldase m- 210 796-801. hlbltor allopurmol to hmlt infarct size after lschaemla and re- 37 WEISER MR, WILLIAMS JP, MOORE FD et al Reperfuslon injury perfusion m dogs. Czrculatwn 1985, 71 1069-1075 of lschaermc skeletal muscle IS mediated by natural antibody 52 PERLER BA, TOHMEH AG, BULKLEY GB IlthlbitIon of the corn- and complement. J Exp Med 1996, 183. 2343-2348. partment syndrome by the ablation of free radical-mediated 38 GRISHAM MB, BROCK AF, SCAFER AI. Leukotriene B4 stimulates reperfuslon Injury Surgery 1990; 108 40-47 polylnorphonuclear leukocytes adhesion to cultured vascular 53 BUCHBINDER D, KARMODY AN{, LEATHER RP, SHAH DM Hyper- endothelial cells J Chn Invest 1984, 74. 1552-1555. tonic mannltol. Its use m the prevention of revasculansataon 39 GEARING AJH, NEWMAN W Circulating adhesion molecules in syndrome after acute arterial lschaemia Arch 1981, 116 414-421 disease Immunol Today 1993; 14. 506-512 54 PERSSON IX,~-I,TAKOLANDER R, BERGQVISTD Edema after lower 40 HARDY SC, HOMER-VANNIASINKAM S, GOUGH MJ The trlphaslc limb arterial reconstructaon Influence of background factors, pattern of skeletal muscle blood flow in reperfusIon injury an surgacal technique and potentially prophylactic methods VASA expernnental model with lmphcatlons for surgery on the acutely 1991, 20 57-62 lschaemlc lower lunb. Eur J Vasc Surg 1990; 4 587-590 55 THOMSON IA, EGGINGTON S, SIMMS MH, HUDLINKA O. Effect of 41 SEEKAMI" A, WARREN JS, REMICK DG, TILL GO, WARD PA muscle ischaerma and lloprost during femorodlstal re- Requirements for tumour necrosis factor-alpha and interleukin- construction on capillary endothelial swellmg Int J Mzctoczrc 1 m hmb lschaemia/reperfuslon injury and associated lung Chn Exp 1996, 16 284-290 injury. Am J Pathol 1993, 143 453-463 56 HAAVERSTAD R, JOHNSEN H, SAETHER OD, MYHRE HO Lymph 42 STERNBERG WC III, TUTTLE TM, MAKHOUL RG, BEAR HD, SoBEr drainage and the development of post-reconstructive oedema is M, FOWLER AA III Post-lschaemic extremities exhibit release not influenced by the type of inguinal recision A prospective oftumour necrosis factor J Vasc Surg 1994, 20 474-481 randormsed study m patients undergoing femoropophteal by- 43 ASCER E, MOHAN C, GENNARO M, CuPo S. Interleukm-1 and pass surgery Eur J Vasc Endovasc Surg 1995, 10:316-322 thromboxane release after skeletal muscle lschaemla and re- 57 BONE RC Sir Issac Newton, sepsis, SIRS and CARS Ctzt Care perfuslon. Ann Vasc Surg 1992, 6" 69-73 Med 1996, 24 1125-1128 44 ALA Y, PALLUY O, FAWRO J, BONNE C, MODAT G, DORNAND J 58 FARKAS JC, CHAPIUS C, COMBE Set al. A randolmsed controlled Hypoxia/reoxygenatlon stimulates endothehal ceils to promote trial of a low-molecular weight heparm (Enoxaparm) to prevent lnterleukm-1 and mterleukm production Effects of free radical deep vein thrombosis in patients undergoing vascular surgery. scavengers. Agents and Actions 1992, 37- 134-139 Eur J Vasc Surg 1993, 7 554-560 45 PERRYMO, SHIRES GT, ALBERTSA Cellular changes with graded limb ischaemla and reperfuslon. J Vasc Surg 1984, 1 536-540 Accepted11 August 1998

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