Diagnostic and therapeutical algorhythm in lower critical limb ischemia where immediate revascularization procedures are impossible;Algoritmo diagnostico e terapeutico dell'ischemia critica degli arti inferiori non immediatamente rivascolarizzabile

Trends in Medicine

Volumn 6, Issue 3, 2006, Pages 201-234

  Melillo, Elio ^a   Nuti, Marco ^a   Balbarini, Alberto ^a  

^a UNIVERSITY HOSPITAL OF PISA   (Italy)

Author keywords

Critical limb ischemia; Iloprost; Transcutaneous oxygen and carbon dioxide measurements

Indexed keywords

ANTICOAGULANT AGENT; ILOPROST; PROSTAGLANDIN E1; PROSTANOID;

ALGORITHM; ARTERY DISEASE; CAPILLAROSCOPY; DIABETES MELLITUS; DISEASE CLASSIFICATION; DRUG USE; EARLY DIAGNOSIS; FOLLOW UP; HEART DEATH; HUMAN; LIMB ISCHEMIA; LIMB SALVAGE; PREVALENCE; PROGNOSIS; REVASCULARIZATION; REVIEW; SPINAL CORD STIMULATION; TRANSCUTANEOUS CARBON DIOXIDE MONITORING; TRANSCUTANEOUS OXYGEN MONITORING;

EID: 33746873299     PISSN: 15942848     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (135)

1. Second European Consensus Document. Eur J Vasc Surg 1992; 6(Suppl A):1-32.
2. TransAtlantic Inter-Society Consensus (TASC). Management of Peripheral Arterial Disease. Supplement to Journal of Vascular Surgery 2000; 31:1-296.
3. Dolan NC, Liu K, Criqui MH, et al. Peripheral artery disease, diabetes, and reduced lower extremity functioning. Diabetes Care 2002; 25:113-120.
4. Matzke S, Lepantalo M. Claudication does not always precede critical leg ischemia. Vasc Med 2001; 6:77-80.
5. Dormandy JA, Belcher G, Broos P, et al. A prospective study of 713 below-knee amputations for ischaemia and the effect of a prostacyclin analogue on healing. Br J Surg 1994; 81:33-37.
6. Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978; 1:1379-1381.
7. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand 1982; 211:249-256.
8. De Backer IG, Kornitzer M, Sobolski J, et al. Intermittent claudication: epidemiology and natural history. Acta Cardiol 1979; 34:1115-1124.
9. Smith WCS, Woodward M, Tunstall-Pedoe. Intermittent claudication in Scotland. In Fowkes FGR, ed: Epidemiology of Peripheral Vascular Disease. London: Springer-Verlag, 1991:109-115.
10. Novo S, Avellone G, Di Garbo V, et al. Prevalence and risk factors in patients with peripheral arterial disease: a clinical and epidemiological evaluation. International Angiology 1992; 11:218-229.
11. Fowkes FGR, Housley E, Cawood EH, et al. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epid 1992; 20:384-392.
12. Widmer LK, Greensher A, Kannel WB. Occlusion of peripheral arteries: a study of 6400 working subjects. Circulation 1964; 30:836-842.
13. Gofin R, Kark JD, Friedlander Y, et al. Peripheral vascular disease in a middle-aged population sample. The Jerusalem Lipid Research Clinic Prevalence Study. Isr J Med Sci 1987; 23:157-167.
14. Kannel WB, Skinner JJ Jr, Schwartz MJ, et al. Intermittent claudication: incidence in the Framingham study. Circulation 1970; 41:875-883.
15. Bowlin SJ, Medalie JH, Flocke SA, et al. Epidemiology of intermittent claudication in middle aged men. Am J Epidemiol 1994; 140:418-430.
16. Criqui MH, Fronek A, Barrett-Connor, et al. The prevalence of peripheral arterial disease in a defined population. Circulation 1985; 71:510-515.
17. Stoffers HE, Rinkens PE, Kester AD, et al. Prevalence of asymptomatic and unrecognised peripheral arterial occlusive disease. Int J Epidemiol 1996; 25:282-290.
18. Mejer WT, Hoes AW, Rutgers DM, et al. Peripheral arterial disease in the elderly: the Rotterdam study. Arterioscler Thromb Vasc Biol 1998; 18:185-192.
19. Widmer LK, Da Silva A. Historical perspectives and the Basle study. In Fowkes FGR, ed: Epidemiology of Peripheral Vascular Disease. London: Springer-Verlag, 1991:69-83.
20. Brevetti G, Oliva G, Silvestro A, et al; Peripheral Arteriopathy and Cardiovascular Events (PACE) Study Group. Prevalence, risk factors and cardiovascular comorbidity of symptomatic peripheral arterial disease in Italy. Atherosclerosis 2004; 175:131-138.
21. Heliovaara M, Karvonen MJ, Vilhunen R, et al. Smoking, carbon monoxide, and atherosclerotic diseases. Br Med J 1978; 1:268-270.
22. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 2004; 172:95-105.
23. Hiatt Wr, Hoag S, Hammen RF. Effect of diagnostic criteria on the prevalence of peripheral artery disease. Circulation 1995; 92:1472-1479.
24. Dormandy JA, Murray GD. The fate of the claudicant: a prospective study of 1969 claudicants. Eur J Vasc Surg 1991; 5:131-133.
25. The Vascular Surgical Society of Great Britain and Ireland. Critical limb ischaemia: management and outcome. Report of a national survey. Eur J Vasc Endovasc Surg 1995; 10:108-113.
26. Melillo E, Nuti M, Bongiorni L, et al. Major and minor amputation rates and lower critical limb ischemia: the epidemiological data of western Tuscany. Ital Heart J 2004; 5:794-805.
27. Dormandy J, Heeck L, Vig S. Predicting which patients will develop chronic critical leg ischemia. Semin Vasc Surg 1999; 12:138-141.
28. Melillo E, Nuti M, Buttitta F, et al. Salvataggio d'arto farmacologico mediante iloprost nella ischemia critica degli arti inferiori non rivascolarizzabile: conferme e modifiche della nostra condotta terapeutica negli ultimi otto anni. Min Cardioang 2003, 51(Suppl 1-6):253-255.
29. Gordon T, Kannel WB. Predisposition to atherosclerosis in the head, heart and legs. The Framingham study. JAMA 1972; 221:661-666.
30. Lifestyle measures to tackle atherosclerotic disease. DTB 2001; 39:21-24.
31. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics on obesity and diabetes in the United States. JAMA 2001; 286:1195-1200.
32. Kjaergaard SC, Hansen HH, Fog L, et al. In-hospital outcome for diabetic patients with acute myocardial infarction in the trombolytic era. Scand Cardiovasc J 1999; 33:166-170.
33. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229-234.
34. Farkouh ME, Rihal CS, Gersh BJ, et al. Influence of coronary heart disease on morbidity and mortality after lower extremity revascularization surgery: a population-based study in Olmsted County, Minnesota (1970-1987). J Am Coll Cardiol 1994; 24:1290-1296.
35. Makin A, Lip GY, Silverman S, et al. Peripheral vascular disease and hypertension: a forgotten association? J Hum Hypertens 2001; 15:447-454.
36. Prevention of Atherosclerotic Complications with Ketanserin Trial Group. Prevention of atherosclerotic complications: controlled trial of ketanserin. Br Med J 1989; 298:424-430.
37. Balsano F, Violi F; and the ADEP group. Effect of Picotamide on the clinical progression of peripheral vascular disease: a double-blind placebo-controlled study. Circulation 1993; 87:1563-1569.
38. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intake. JAMA 1995; 274:1049-1057.
39. Taylor LM Jr, DeFrang RD, Harris EJ, et al. The association of elevated plasma homocyst(e)inemia with progression of symptomatic peripheral arterial disease. J Vasc Surg 1991; 13:128-136.
40. Molgaard J, Malinow MR, Lassvik C, et al. Hyperhomocyst(e)inemia: an independent risk factor for intermittent claudication. J Intern Med 1992; 231:273-279.
41. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324:1149-1155.
42. Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med 2002; 112:49-57.
43. Smith FB, Lowe GD, Lee AJ, et al. Smoking, hemoreologic factors, and progression of peripheral arterial disease in patients with claudication. J Vasc Surg 1998; 28:129435.
44. Pedrinelli R, Dell'Omo G, Barchiolli A, et al. Fibrinogen and mortality in Chronic Critical Limb Ischaemia. J Int Med 1999; 245:75-81.
45. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340:115-126.
46. Bassuk SS, Rifai N, Ridker PM. High-Sensivity C-Reactive Protein: Clinical Importance. Curr Probl Cardiol 2004; 29:439-493.
47. Ridker PM, Cushmann M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 1998; 97:425-428.
48. Kok FJ, Kromhout D. Atherosclerosis: Epidemiological studies on the health: effects of a Mediterranean diet. Eur J Nutr 2004; 43(Suppl 1):12-15.
49. Martinez-Gonzalez MA, Sanchez-Villegas A. The emerging role of Mediterranean diets in cardiovascular epidemiology: monounsaturated fats, olive oil, red wine or the whole pattern? Eur J Epid 2004; 19:9-13.
50. Ventura P, Bini A, Panini R, et al. Red wine consumption prevents vascular oxidative stress induced by a high-fat meal in healthy volunteers. Int J Vitam Nutr Res 2004; 74:137-143.
51. Casani L, Segales E, Vilahur G, et al. Moderate daily intake of red wine inhibits mural thrombosis and monocyte tissue factor expression in an experimental porcine model. Circulation 2004; 110:460-465.
52. Estruch R, Sacanella E, Badia, et al. Different effects of red wine and gin consumption on inflammatory biomarkers atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers. Atherosclerosis 2004; 175:117-123.
53. Menotti A, Lanti M, Puddu PE, et al. Coronary heart disease incidence in northern and southern European populations: a reanalysis of the seven countries study for a European coronary risk chart. Heart 2000; 84:238-244.
54. Antiplatelet Trialist' Collaboration. Collaborative overwiew of randomized trials of antiplatelet therapy, II: maintenance of vascular grafts or arterial patency by antiplatelet therapy. Br Med J 1994; 308:159-168.
55. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71-86.
56. Patrono C, Bachmann F, Baigent C, et al. European Society of Cardiology. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J 2004; 25:166-181.
57. Aronow WS, Nayak D, Woodworth S, et al. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am J Cardiol 2003; 92:711-712.
58. Schillinger M, Exner M, Mlekusch W, et al. Statin therapy improves cardiovascular outcome of patients with peripheral arten? disease. Eur Heart Journal 2004; 25:742-748.
59. Ostergren J, Sleight P, Yusuf S, et al. HOPE study investigators. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J 2004; 25:17-24.
60. Warner GT, Perry CM. Ramipril: a review of its use in the prevention of cardiovascular outcomes. Drugs 2002; 62:1381-1405.
61. Wolfe JN. Defining the outcome of critical ischaemia: a one year prospective study. Br J Surg 1986; 73:321.
62. The ICAI Group (gruppo di studio sull'ischemia cronica critica degli arti inferiori). Long term mortality and its predictors in patients with critical leg ischaemia. Eur J Vasc Endovasc Surg 1997; 14:91-95.
63. Rieker O, Duber C, Neufang A, et al. CT angiography versus intraarterial digital subtraction angiography for assessment of aortoiliac occlusive disease. Am J Roentgenol 1997; 169:1133-1138.
64. Owen RS, Carpenter JP, Baum RA, et al. Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease. N Engl J Med 1992; 326:1577-1581.
65. Melillo E. La diagnostica microcircolatoria In F. Manusia: "La Malattia ischemica periferica" Edizioni Aurelia, Grosseto; Novembre 2001: 77-90.
66. Rooke TW, Osmundson PJ. Variability and reproducibility of transcutaneous oxygen tension measurements in the assessment of peripheral vascular disease. Angiology 1989; 695-698.
67. Melillo E, Catapano G, Ferrari M, et al. Transcutaneous oxygen tension measurement in patient with chronic arterial obstructive disease: reliability and long term variability of the method. Angiology 1994; 45:469-475.
68. Scheffler A, Rieger H. Clinical information content of transcutaneous oxymetry (tcpO2) in peripheral arterial occlusive disease (a review of the methodological and clinical literature with a special reference to critical limb ischaemia). Vasa 1992; 21:111-126.
69. Bongard O, Krahenbuhl B. Predicting amputation in severe ischaemia. The value of transcutaneous PO2 measurement. J Bone Joint Surg Br 1988; 70:465-467.
70. Wyss CR, Matsen FA 3rd, Simmons CW, et al. Transcutaneous oxygen tension measurements on limbs of diabetic and non diabetic patients with peripheral vascular disease. Surgery 1984; 95:339-346.
71. Samson RH, Gupta SK, Goldstein R, et al. Use of transcutaneous oxygen tension measurements [PtcO2] in the diagnosis of peripheral vascular insufficiency. Ann Surg 1985; 202:130-131.
72. Becker F, Gabrielle F, Raoux MH, et al. Value of measuring transcutaneous oxygen pressure in arterial disease of the legs. Ann Cardiol Angeiol 1989; 38:465-472.
73. Ubbink DT, Spincemaille GH, Reneman RS, et al. Prediction of imminent amputation in patients with non-reconstructible leg ischemia by means of microcirculatory investigations. J Vasc Surg 1999; 30:114-121.
74. Melillo E, Catapano G, Dell'Omo G, et al. Transcutaneous oxygen and carbon dioxide measurement in peripheral vascular disease. Vascular Surgery 1995; 29:273-280.
75. Melillo E, Pedrinelli R, Nuti M, et al. Can limb loss in patients with lower limb critical ischemia (CLI) be predicted by transcutaneous oxygen and carbon dioxyde measurements? Int Angiology 2004; 23(Suppl 1):197.
76. Melillo E, Iabichella ML, Pedrinelli R, et al. Riproducibilità del segnale laser Doppler in soggetti adulti, sani, non fumatori e di sesso maschile mediante valutazione clino-ortostatica agli arti inferiori. Minerva Cardioangiol 2003; 51(Suppl 1):169-171.
77. Melillo E, Iabichella ML, Berchiolli R, et al. Laser-Doppler Flowmetry in Peripheral Arterial Occlusive Disease (PAOD) Int Angiology 1995; 14(Suppl 1):269.
78. Scheffler A, Rieger H. Spontaneous oscillation of laser Doppler skin flow flux in peripheral arterial occlusive disease. J Microcirc Clin Exp 1992; 11:249.
79. Belcaro G, Vasdekis S, Rulo A, et al. Evaluation of skin blood flow and veno-arteriolar response in patients with diabetes and peripheral vascular disease by laser Doppler flowmetry. Angiology 1989; 40:953.
80. Seifert H, Jager K, Bollinger A. Analysis of flow motion by Laser Doppler technique in patients with peripheral arterial occlusive disease. J Microcirc Clin Exp 1988; 7:223.
81. Hoffmann U, Seifert H, Beinder E, et al. Skin Flow Flux in Peripheral Arterial Occlusive Disease. In Laser Doppler edited by Belcaro G, Hoffmann U, Bollinger A, Nicolaides AN; MED-ORION Publishing Company; London, Los Angeles, Nicosia, 1994.
82. Fagrell B, Fronek A, Intaglietta M. A microscope-television system for studying flow velocity. Am J Physiol 1977; 233:318.
83. Bollinger A, Fagrell B. Clini cal capillaroscopy. Toronto, Hogrefe and Huber Pubbl 1990; 24-25.
84. Fagrell B, Eriksson, Malmstrom S, et al. Computerized data analysis of capillary blood cell velocity. J Microcirc Clin Exp 1988; 7:276.
85. Thulesius O. Capillaroscopy with fibreoptic video microscopy. Vasa 1992; 21:87.
86. Curri SB. Una nuova tecnica capillaroscopica per lo studio della microcircolazione cutanea in sedi corporee di interesse dermocosmetologico: la Videocapillaroscopia a sonda ottica. Atti del XIV Congresso Naz It Med Est 1992; 10-12.
87. Fagrell B. Vital capillary microscopy. A clinical method for studying changes of the nutritional skin capillaries in legs with arteriosclerosis obliterans. Scand J Clin Lab Invest Suppl 1973; 133:2-50.
88. Fagrell B, Lundberg G. A semplified evaluation of vital capillary microscopy for predicting skin viability in patients with severe arterial insufficiency. Clin Phisiol 1984; 4:403.
89. Criqui MH. Sistemic Atherosclerotic Risk and the Mandate for Intervention in Atherosclerotic Peripheral Arterial Disease. Am J Card 2001; 88:43J-47J.
90. Vecht RJ, Nicolaides AN, Brandao E, et al. Resting and treadmill electrocardiographic findings in patients with intermittent claudication. Int J Angiol 1982; 1:119-121.
91. Brewster DC, Okada RD, Strass HW, et al. Selection of patients for preoperative coronary angiography: use of dipyridamole-stress-thallium myocardial imaging. J Vasc Surg 1985; 2:504-510.
92. Valentine RJ, Grayburn PA, Eichorn EJ, et al. Coronary artery disease is highy prevalent among patients with premature peripheral vascular disease. J Vasc Surg 1994; 19:668-674.
93. Hertzer NR, Beven EG, Young JR, et al. Coronary artery disease in peripheral vascular patients. A classification of 1.000 coronary angiograms and results of surgical management. Ann Surg 1984; 199:223-233.
94. Hugson WG, Mann JI, Tibbs DJ, et al. Intermittent claudication: factors determining outcome. BMJ 1978; 1:1377-1379.
95. Alexandrova NA, Gibson WC, Norris JW, et al. Carotid artery stenosis in peripheral vascular disease. J Vasc Surg 1996; 23:645-649.
96. McDermott MM, Mehta S, Ahn H, et al. Atherosclerotic risk factors are less intensively treated in patients with peripheral arterial disease than in patients with coronary artery disease. J Gen Intern Med 1997; 12:209-215.
97. Janzon L, Bergquist D, Boberg J. Prevention of miocardial infarction and stroke in patients with intermittent claudication: effects of ticlopidine: results from STIMS, the Swedish Ticlopidine Multicentre Study. J Int Med 1990; 227:301-308.
98. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329-1339.
99. Katsumura T, Mishima Y, Kamiya K, et al. Therapeutic effects of ticlopidine, a new inhibitor of platelet aggregation on chronic arterial occlusive diseases, a double-blind study versus placebo. Angiology 1982; 2:357-367.
100. Gauthier O. Efficacy and safety of CY216 in the treatment of specific leg ulcers. In Breddin K, Fareed J, Samama M (eds.): Fraxiparine: analytical and structural data, pharmacology, clinical trials. Stuttgart, Schattauer 1987; 21.
101. Jornekog G, Brismar K, Fagrell B. Low molecular weight heparin seems to improve local capillary circulation and healing of chronic foot ulcers in diabetic patients. VASA 1993; 22:137-142.
102. Kretschmer G, Herbet F, Prager M, et al. A decade of oral anticoagulant treatment to maintain autologous vein grafts for femoropopliteal atherosclerosis. Arch Surg 1992; 127:112-115.
103. The European Study Group. Intravenous pentoxifylline for the treatment of chronic critical limb ischemia. Eur J Vasc Endovasc Surg 1995; 9:426-436.
104. Norwegian Pentoxifylline Multicenter Trial Group. Efficacy and clinical tolerance of parenteral pentoxifylline in the treatment of critical lower limb ischemia: a placebo controlled multicenter study. Int Angiol 1996; 15:75-80.
105. Fagrell B, Hermansson IL. Effect of buflomedil on microcirculation of the skin in acral gangrene. Fortschr Med 1985; 103:23-27.
106. Horsch S. Über den Einsatz von naftidrofuryl im Stadium III-IV einer peripher arteriellen Verschlusskrankheit. VASA 1988; 24:38-43.
107. Greenhalgh RM. Naftidrofuryl for ischemic rest pain: a controlled trial. Br J Surg 1981; 68:265-266.
108. Dormandy J. Clinical use of calcium antagonists in peripheral circulatory disease. Ann NY Acad Sci 1988; 522:611-620.
109. Bode-Boger SM, Boger RH, Alfke H, et al. L-arginine induces nitric oxide-dependent vasodilatation in patients with critical limb ischemia: a randomised, controlled study. Circulation 1996; 93:85-90.
110. Nilsson L, Apelqvist J, Edvinsson L. Effects of alfa-Trinositol on peripheral circulation in diabetic patients with critical limb ischemia. A pilot study using laser doppler fluximetry, transcutaneous oxygen tension measurements and dynamic capillaroscopy. Eur J Vasc Endovas Surg 1998; 15:331-336.
111. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomised, multicenter trial. Arch Intern Med 1999; 159:2041-2050.
112. Isner JM, Walsh K, Symes JF, et al. Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. Circulation 1995; 91:2687-2692.
113. Baumgartner I, Pieczeck A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97:1114-1123.
114. Shyu KG, Chang N, Wang BW, et al. Intramuscular endothelial growth factor gene therapy in patients with critical limb ischemia. Am J Med 2003; 114:85-92.
115. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275:964-967.
116. Kalka C, Masuda H, Takahashi T, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci 2000; 97:3422-3427.
117. Tateishi-Yuyama E, Matshuara H, Murohara T, et al; for the therapeutic Angiogenesis using Cell Transplantation (TACT) Study investigators. Therapeutic Angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360:427-435.
118. Minamino T, Toko H, Tateno K, et al. Peripheral-blood or bone-marrow mononuclar cells for therapeutic Angiogenesis. Lancet 2002; 360:2083-2084.
119. Inaba S, Egashira K, Komori K. Peripheral-blood or bone-marrow mononuclar cells for therapeutic Angiogenesis. Lancet 2002; 360:2083.
120. Loosemore TM, Chalmers TC, Dormandy JA. A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease. Intern Angiol 1994; 13:133-142.
121. Trubestein G, Diehm C, Gruss JD, et al. Prostaglandin E1 in chronic arterial disease: a multicenter study. VASA 1987; 17(Suppl):39-43.
122. Alstaedt HO, Berzewski B, Taschke C, et al. Treatment of patients with peripheral arterial occlusive disease Fontaine stage IV with intravenous iloprost and PGEl: a randomized open controlled study. Prostaglandins, Leukotrienes and Essential Fatty Acids 1993; 49:573-578.
123. The ICAI Study Group. Prostanoids for chronic critical leg ischaemia: a randomized, controlled, open-label trial with prostaglandin E1. Ann Int Med 1999; 130:412-421.
124. Grant SM, Goa KL. Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in pe-ripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures. Drugs 1992; 43:889-924.
125. Pola R, Gaetani E, Flex A, et al. Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: a possibile role for peroxisome proliferator-activated receptors. J Mol Cell Cardiol 2004; 36:363-370.
126. Bliss B, Wilkins D, Campbell WB. Treatment of limb threatening ischaemia with intravenous Iloprost: a randomised double blind placebo-controlled study. Eur J Vasc Endovasc Surg 1991; 5:511-516.
127. Norgren L, Alwmark A, Angqvist KA, et al. A stable prostacyclin analogue (Iloprost) in the treatment of ischaemic ulcers of the lower limb: a Scandinavian-Polish placebo-controlled randomized multicentre study. Eur J Vasc Endovasc Surg 1990; 4:463-467.
128. Brock FE, Abri O, Baitsch G, et al. Iloprost in the treatment of ischemic tissue lesions in diabetics: Results of a placebo-controlled multicenter study with a stable prostacyclin derivative. Schweitz Med Wochenschr 1990; 120:1477-1482.
129. GISAP Study. Evaluation of a conservative treatment with Iloprost in severe peripheral occlusive arterial disease (POAD). International Angiology 1994; 13:70-74.
130. Staben P, Albring M. Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 patients. Prostaglandins, Leukotrienes and Essential Fatty Acids 1996; 54:327-333.
131. DAWID Study Group. Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. VASA 1998; 27:15-19.
132. Duthois S, Cailleux N, Benosman B, et al. Tolerance of Iloprost and results of treatment of chronic severe lower limb ischaemia in diabetic patients. A retrospective study of 64 consecutive cases. Diabetes Metab 2003; 29:36-43.
133. Melillo E, Iabichella L, Berchiolli R, et al. Transcutaneous oxygen and carbon dioxide during treatment of Critical Limb ischemia with iloprost, a prostacyclin derivative. Int J Microcirc 1995; 15:60-64.
134. Labs KH, Dormandy JA, Jaeger KA, et al. On Behalf of the Basel PAD Clinical Trial Methodology Group. Circulation 1999; 26:1-7.
135. Melillo E, Ferrari M, Balbarini A, et al. Transcutaneous Gases Determination in Diabetic Critical Limb Ischemia. Diabetes Care 2005; 28:2081-2082.