Intermittent pneumatic compression: Physiologic and clinical basis to improve management of venous leg ulcers
2010; Elsevier BV; Volume: 53; Issue: 4 Linguagem: Inglês
10.1016/j.jvs.2010.08.059
ISSN1097-6809
Autores Tópico(s)Central Venous Catheters and Hemodialysis
ResumoVenous leg ulcers (VLUs) are a significant health problem that afflicts 1% of the population at some point during their lifetime. Intermittent pneumatic compression (IPC) is widely used to prevent deep venous thrombosis. However, IPC seems to have application to a broader base of circulatory diseases. The intermittent nature of pulsatile external compression produces beneficial physiologic changes, which include hematologic, hemodynamic, and endothelial effects, which should promote healing of VLUs. Clinical studies of the management of VLUs show that IPC increases overall healing and accelerates the rate of healing, leading to current guideline recommendations for care of patients with VLUs. Proper prescription of IPC to improve the management of patients with VLUs requires further definition. It seems that application of IPC in combination with sustained graduated compression improves outcome in patients with the most advanced venous disease. Venous leg ulcers (VLUs) are a significant health problem that afflicts 1% of the population at some point during their lifetime. Intermittent pneumatic compression (IPC) is widely used to prevent deep venous thrombosis. However, IPC seems to have application to a broader base of circulatory diseases. The intermittent nature of pulsatile external compression produces beneficial physiologic changes, which include hematologic, hemodynamic, and endothelial effects, which should promote healing of VLUs. Clinical studies of the management of VLUs show that IPC increases overall healing and accelerates the rate of healing, leading to current guideline recommendations for care of patients with VLUs. Proper prescription of IPC to improve the management of patients with VLUs requires further definition. It seems that application of IPC in combination with sustained graduated compression improves outcome in patients with the most advanced venous disease. Intermittent pneumatic compression (IPC) is an effective treatment for a variety of circulatory disorders. Its use for venous thromboembolism prophylaxis and treatment of lymphedema are well established.1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar IPC also improves walking distance in patients with intermittent claudication and is effective in patients with critical limb ischemia (CLI). However, the focus of this discussion will be the utility of IPC for the management of advanced chronic venous disease, specifically venous ulceration.1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar Venous leg ulcers (VLUs) impose a major healthcare burden on the patient and the healthcare system. The direct and indirect costs of chronic venous disease (CVD) have been estimated at one billion U.S. dollars per annum.2Weingarten M.S. State-of-the-art treatment of chronic venous disease.Clin Infect Dis. 2001; 32: 949-954Crossref PubMed Scopus (51) Google Scholar This review addresses the etiology of VLUs, the importance of compression in their management, the hemodynamic and hematologic effects of IPC, and the clinical outcomes observed when IPC is used to treat VLUs. VLUs occur in approximately 1% to 2% of the population.3Nicolaides A.N. Investigation of chronic insufficiency: a consensus statement.Circulation. 2000; 102: e126-e163Crossref PubMed Google Scholar, 4Clarke-Moloney M. Lyons G.M. Burke P.E. O'Keeffe D. Grace P.A. A review of technological approaches to venous ulceration.Crit Rev Biomed Eng. 2005; 33: 511-556Crossref PubMed Scopus (13) Google Scholar, 5Tinkler A. Hotchkiss J. Nelson E.A. Edwards L. Implementing evidence-based leg ulcer management.Evid Based Nurs. 1999; 2: 6-8Crossref Scopus (12) Google Scholar The underlying pathophysiology is ambulatory venous hypertension resulting from valvular incompetence, obstruction of the vein lumen, or both. Valve incompetence can result from a primary defect in the vein wall or be secondary to the inflammatory and fibrotic sequelae of venous thrombosis. Acute deep venous thrombosis (DVT) can obstruct the vein, subsequently causing valvular dysfunction in nonthrombosed distal veins, and impair calf muscle pump function. Prolonged immobility and obesity also result in calf muscle pump dysfunction, venous pooling, and chronic edema. Valvular dysfunction can occur when individuals with a genetic predisposition for venous insufficiency are exposed to risk factors, such as pregnancy or periods of prolonged standing. Regardless of its etiology, however, the ensuing venous stasis, which is characterized by the formation of edema and a rise in tissue pressure, plays a major role in the development of venous ulcers. Two important hemodynamic pumps (the calf and foot pumps) propel blood proximately from their respective venous reservoirs. Contraction of calf muscles activates the calf pump, which drains blood from both calf and foot, whereas pressure on the plantar arch (during ambulation) empties blood from the plantar venous plexus through the lateral plantar vein. Ineffective leg pumps, together with incompetent venous valves, lead to elevated tissue pressure and edema. Individuals with associated venous obstruction have the highest ambulatory venous pressure. Venous hypertension increases capillary permeability, and the resulting blood and fluid leakage into tissue causes edema, pigmentation, and tissue fibrosis.6Easterbrook J. Walker M.A. The unilateral swollen lower limb: etiology, investigation, and management.Int J Low Extrem Wounds. 2002; 1: 242-250Crossref PubMed Google Scholar, 7Kumar S. Walker M.A. The effects of intermittent pneumatic compression on the arterial and venous systems of the lower limb: a review.J Tissue Viability. 2002; 12 (62-6): 58-60Abstract Full Text PDF PubMed Scopus (16) Google Scholar The mechanism by which prolonged venous hypertension causes venous ulcers is the subject of several theories. Browse and Burnand8Browse N.L. Burnand K.G. The cause of venous ulceration.Lancet. 1982; 2: 243-245Abstract PubMed Scopus (444) Google Scholar suggested that venous hypertension resulted in a distended capillary bed and enlarged endothelial pores, allowing fibrinogen to escape into the interstitial fluid. They proposed a “fibrin-cuff” hypothesis based on their observation that pericapillary fibrin formed a “cuff” around an enlarged dermal capillary bed, with the fibrin acting as a barrier to tissue oxygenation, causing hypoxia-induced ulceration. The “fibrin-cuff” hypothesis has been superseded by more recent theories, indicating that chronic inflammation plays a crucial role in the progression of CVD.9Bergan J.J. Schmid-Schönbein G.W. Smith P.D. Nicolaides A.N. Boisseau M.R. Eklof B. Chronic venous disease.N Engl J Med. 2006; 355: 488-498Crossref PubMed Scopus (675) Google Scholar Although the precise events that initiate this inflammatory response are not known, it seems to involve leukocyte-endothelial interactions triggered by abnormal venous return and venous hypertension.9Bergan J.J. Schmid-Schönbein G.W. Smith P.D. Nicolaides A.N. Boisseau M.R. Eklof B. Chronic venous disease.N Engl J Med. 2006; 355: 488-498Crossref PubMed Scopus (675) Google Scholar Prolonged pooling of venous blood distends the vein and distorts venous valves, allowing leakage through the valves. This pooling creates a region of low flow and zero-shear stress. The resultant venous hypertension, leukocyte activation, and adhesion to and emigration through the venous endothelium trigger inflammatory reactions, further increasing capillary permeability.10Margolis D.J. Berlin J.A. Strom B.L. Risk factors associated with the failure of a venous leg ulcer to heal.Arch Dermatol. 1999; 135: 920-926Crossref PubMed Scopus (176) Google Scholar, 11Iglesias C. Nelson E.A. Cullum N.A. Torgerson D.J. VenUS TeamVenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.Health Technol Assess. 2004; 8 (iii): 1-105Crossref Scopus (83) Google Scholar Regardless of its etiology, however, prolonged venous hypertension initiates the progression of a series of pathologic events, causing effects at a cellular level and resulting in the clinical signs and symptoms of CVD, which can ultimately result in skin breakdown and ulceration. Sustained compression is the cornerstone of VLU therapy, the goal of which is to promote ulcer healing and prevent recurrence. However, the healing of venous ulcers, especially those that are large and longstanding, may not occur, even after many months of treatment.10Margolis D.J. Berlin J.A. Strom B.L. Risk factors associated with the failure of a venous leg ulcer to heal.Arch Dermatol. 1999; 135: 920-926Crossref PubMed Scopus (176) Google Scholar Several randomized studies have shown that only 37% to 55% of ulcers heal completely after 12 weeks of compression therapy.11Iglesias C. Nelson E.A. Cullum N.A. Torgerson D.J. VenUS TeamVenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.Health Technol Assess. 2004; 8 (iii): 1-105Crossref Scopus (83) Google Scholar, 12O'Brien J.F. Grace P.A. Perry I.J. Hannigan A. Clarke Moloney M. Burke P.E. Randomized clinical trial and economic analysis of four-layer compression bandaging for venous ulcers.Br J Surg. 2003; 90: 794-798Crossref PubMed Scopus (53) Google Scholar, 13Lyon R.T. Veith F.J. Bolton L. Machado F. Clinical benchmark for healing of chronic venous ulcers Venous Ulcer Study Collaborators.Am J Surg. 1998; 176: 172-175Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The VenUS I trial, which randomized two types of compression bandages for treating VLUs in 387 patients, found that 37% healed with short-stretch bandages at 12 weeks vs 46% treated with four-component, multilayer bandages.11Iglesias C. Nelson E.A. Cullum N.A. Torgerson D.J. VenUS TeamVenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.Health Technol Assess. 2004; 8 (iii): 1-105Crossref Scopus (83) Google Scholar The respective healing rates at 24 weeks were 68% and 55% (P = .05). Short-stretch bandages retain some elasticity, whereas four-component, multilayer bandages are essentially inelastic and apply persistent pressure to the limb, more when the patient is upright, less when supine. In a trial of 200 patients with VLUs randomized to treatment with either four-component bandages or usual care (control group), O'Brien et al12O'Brien J.F. Grace P.A. Perry I.J. Hannigan A. Clarke Moloney M. Burke P.E. Randomized clinical trial and economic analysis of four-layer compression bandaging for venous ulcers.Br J Surg. 2003; 90: 794-798Crossref PubMed Scopus (53) Google Scholar reported that the healing rate at 3 months was 54% with four-component bandages vs 34% with usual care (P < .001). However, only 5 patients in the “usual care” group received compression, which seems to be a common scenario in many medical communities. Lyon et al13Lyon R.T. Veith F.J. Bolton L. Machado F. Clinical benchmark for healing of chronic venous ulcers Venous Ulcer Study Collaborators.Am J Surg. 1998; 176: 172-175Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar treated 165 patients with chronic venous ulcers with a hydrocolloid dressing and application of an Unna boot. Healing was achieved in 55% by 12 weeks. A subsequent analysis of the data by Phillips et al14Phillips T.J. Machado F. Trout R. Porter J. Olin J. Falanga V. Prognostic indicators in venous ulcers.J Am Acad Dermatol. 2000; 43: 627-630Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar suggested that ulcers that are large, longstanding, and slow to heal after 3 weeks of optimal therapy are unlikely to resolve rapidly and may benefit from alternative treatments. Tinkler et al5Tinkler A. Hotchkiss J. Nelson E.A. Edwards L. Implementing evidence-based leg ulcer management.Evid Based Nurs. 1999; 2: 6-8Crossref Scopus (12) Google Scholar found that 34% of ulcers treated with three-component bandages and 32% of those treated with four-component bandages healed by 12 weeks. Because the degree of compression was likely similar with the two bandaging techniques, similar results would be anticipated. Table I summarizes the hemodynamic and hematologic effects of IPC.Table IPhysiologic effects of IPCCategoryPhysiologic effect1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar, 10Margolis D.J. Berlin J.A. Strom B.L. Risk factors associated with the failure of a venous leg ulcer to heal.Arch Dermatol. 1999; 135: 920-926Crossref PubMed Scopus (176) Google Scholar, 18Cooke J.P. Stamler J. Andon N. Davies P.F. McKinley G. Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol.Am J Physiol. 1990; 259: H804-H812PubMed Google ScholarPotential direct and indirect benefits1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar, 10Margolis D.J. Berlin J.A. Strom B.L. Risk factors associated with the failure of a venous leg ulcer to heal.Arch Dermatol. 1999; 135: 920-926Crossref PubMed Scopus (176) Google Scholar, 24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 25Malanin K. Kolari P.J. Havu V.K. The role of low resistance blood flow pathways in the pathogenesis and healing of venous leg ulcers.Acta Derm Venereol. 1999; 79: 156-160Crossref PubMed Scopus (10) Google Scholar, 28van Bemmelen P.S. Mattos M.A. Faught W.E. Mansour M.A. Barkmeier L.D. Hodgson K.J. et al.Augmentation of blood flow in limbs with occlusive arterial disease by intermittent calf compression.J Vasc Surg. 1994; 19: 1052-1058Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarHemodynamic/hematologic↓Venous stasis↑ Flow velocity in deep veins↑ Fibrinolysis↓Venous pressure↑Interstitial edema↑Thrombogenicity↑Intravascular coagulation↑Blood volume flow↑Endothelial shear stress↓A-V pressure gradient↑Venous emptying↓Stasis↓Edema↑Arterial inflow↑Shear stress/on endothelial strain cells↑Fibrinolysis↑Vasodilation↓ThrombosisCategoryPhysiologic effect24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 25Malanin K. Kolari P.J. Havu V.K. The role of low resistance blood flow pathways in the pathogenesis and healing of venous leg ulcers.Acta Derm Venereol. 1999; 79: 156-160Crossref PubMed Scopus (10) Google ScholarPotential direct and indirect benefits20Nollert M.U. Diamond S.L. McIntire L.V. Hemodynamic shear stress and mass transport modulation of endothelial cell metabolism.Biotechnol Bioeng. 1991; 38: 588-602Crossref PubMed Scopus (106) Google Scholar, 21Comerota A.J. Chouhan V. Harada R.N. Sun L. Hosking J. Veermanolsunemi R. et al.The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis.Ann Surg. 1997; 226 (discussion 313-4): 306-313Crossref PubMed Scopus (186) Google Scholar, 22Chouhan V.D. Comerota A.J. Sun L. Harada R. Gaughan J.P. Rao A.K. Inhibition of tissue factor pathway during intermittent pneumatic compression: a possible mechanism for antithrombotic effect.Arterioscler Thromb Vasc Biol. 1999; 19: 2812-2817Crossref PubMed Scopus (49) Google Scholar.24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 25Malanin K. Kolari P.J. Havu V.K. The role of low resistance blood flow pathways in the pathogenesis and healing of venous leg ulcers.Acta Derm Venereol. 1999; 79: 156-160Crossref PubMed Scopus (10) Google ScholarHemodynamic/hematologic(cont'd)↑Prostacyclin production↓Endothelial-derived relaxing factor↓Platelet-derived growth factorFibrinolytic/hematologic↑Fibrinolytic activity↓tPA antigen↑tPA activity↓PAI-1 antigen↓PAI-1 activity↑Endogenous fibrinolytic activity↓FVIIa levels↑TFPI levels↑Thrombosis↓Intravascular coagulation↓HypercoagulabilityCategoryPhysiologic effect26Henry J.P. Winsor T. Compensation of arterial insufficiency by augmenting the circulation with intermittent compression of the limbs.Am Heart J. 1965; 70: 79-88Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 27Eze A.R. Comerota A.J. Cisek P.L. Holland B.S. Kerr R.P. Veeramasuneni R. Comerota Jr, A.J. Intermittent calf and foot compression increases lower extremity blood flow.Am J Surg. 1996; 172 (discussion 135): 130-134Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 28van Bemmelen P.S. Mattos M.A. Faught W.E. Mansour M.A. Barkmeier L.D. Hodgson K.J. et al.Augmentation of blood flow in limbs with occlusive arterial disease by intermittent calf compression.J Vasc Surg. 1994; 19: 1052-1058Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarPotential direct and indirect benefits26Henry J.P. Winsor T. Compensation of arterial insufficiency by augmenting the circulation with intermittent compression of the limbs.Am Heart J. 1965; 70: 79-88Abstract Full Text PDF PubMed Scopus (13) Google Scholar, 28van Bemmelen P.S. Mattos M.A. Faught W.E. Mansour M.A. Barkmeier L.D. Hodgson K.J. et al.Augmentation of blood flow in limbs with occlusive arterial disease by intermittent calf compression.J Vasc Surg. 1994; 19: 1052-1058Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarTissue oxygen tension↑TcPO2 levels↓Interstitial fluid volume↓Venous stasis↑Oxygen diffusion barrier↓Leg edema↑Skin temperatureEdema↓Arteriovenous shunting↓Edema↑Capillary perfusion↑Skin nutritionA-V, Arterio-venous; FVIIa, factor; IPC, intermittent pneumatic compression; PAI-1, plasminogen activator inhibitor-1; TcPO2, transcutaneous oxygen tension; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; VIIa. Open table in a new tab A-V, Arterio-venous; FVIIa, factor; IPC, intermittent pneumatic compression; PAI-1, plasminogen activator inhibitor-1; TcPO2, transcutaneous oxygen tension; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; VIIa. Sustained compression applied by multilayer bandages reduces venous hypertension; however, it only passively promotes venous return compared to IPC.9Bergan J.J. Schmid-Schönbein G.W. Smith P.D. Nicolaides A.N. Boisseau M.R. Eklof B. Chronic venous disease.N Engl J Med. 2006; 355: 488-498Crossref PubMed Scopus (675) Google Scholar IPC actively compresses the leg, mimicking the action of the leg muscle pumps. The device, which may have one or more chambers, consists of a pneumatic pump that inflates air into garments wrapped around the foot, calf, thigh, or combinations thereof. Devices with multiple chambers can provide sequential compression in an ascending pattern up the limb. Pumps vary in their timing cycle and amount of pressure produced, ranging from low-pressure, slow-inflation to high-pressure, and rapid-inflation devices. IPC reduces venous stasis and increases flow velocity in the deep veins, resulting in favorable hemodynamic changes such as decreased venous pressure and interstitial edema.1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar, 7Kumar S. Walker M.A. The effects of intermittent pneumatic compression on the arterial and venous systems of the lower limb: a review.J Tissue Viability. 2002; 12 (62-6): 58-60Abstract Full Text PDF PubMed Scopus (16) Google Scholar IPC produces increases in venous volume flow and increased venous flow velocity, causing increased shear stress.15Lurie F. Awaya D.J. Kistner R.L. Eklof B. Hemodynamic effect of intermittent pneumatic compression and the position of the body.J Vasc Surg. 2003; 37: 137-142Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Research studies in animals have shown that these mechanical forces result in endothelial cell responses that contribute to the profibrinolytic, vasodilatory, and antithrombotic effects of IPC.1Chen A.H. Frangos S.G. Kilaru S. Sumpio B.E. Intermittent pneumatic compression devices--physiological mechanisms of action.Eur J Vasc Endovasc Surg. 2001; 21: 383-392Abstract Full Text PDF PubMed Scopus (122) Google Scholar Malone et al16Malone M.D. Cisek P.L. Comerota Jr, A.J. Holland B. Eid I.G. Comerota A.J. High-pressure, rapid inflation pneumatic compression improves venous hemodynamics in healthy volunteers and patients who are post-thrombotic.J Vasc Surg. 1999; 29: 593-599Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar compared the effects of high-pressure, rapid-inflation IPC vs low-pressure, slow-inflation IPC on 11 healthy subjects and 11 patients with postthrombotic venous disease. Although both systems increased the velocity in femoral and popliteal veins in all study participants, the high-pressure, rapid-inflation devices produced the highest peak velocities (P < .05). All venous velocities, both baseline and stimulated by IPC, were significantly attenuated in postthrombotic patients. The mechanisms by which IPC induces hematologic alterations has been studied and clarified. Changes in blood coagulation are attributed to increased shear stress on the vein wall. This is consistent with the results of studies in cell culture models showing that increasing shear stress on endothelial cells increases production of prostacyclin, endothelial-derived relaxing factor, platelet-derived growth factor, and tissue-type plasminogen activator.17Frangos J.A. Eskin S.G. McIntire L.V. Ives C.L. Flow effects on prostacyclin production by cultured human endothelial cells.Science. 1985; 227: 1477-1479Crossref PubMed Scopus (970) Google Scholar, 18Cooke J.P. Stamler J. Andon N. Davies P.F. McKinley G. Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol.Am J Physiol. 1990; 259: H804-H812PubMed Google Scholar, 19Hsieh H.J. Li N.Q. Frangos J.A. Shear stress increases endothelial platelet-derived growth factor mRNA levels.Am J Physiol. 1991; 260: H642-H646PubMed Google Scholar, 20Nollert M.U. Diamond S.L. McIntire L.V. Hemodynamic shear stress and mass transport modulation of endothelial cell metabolism.Biotechnol Bioeng. 1991; 38: 588-602Crossref PubMed Scopus (106) Google Scholar IPC alters fibrinolytic activity and seems to affect two of the three limbs of Virchow's triad: stasis and hypercoagulability. Endogenous fibrinolysis results from the conversion of plasminogen to plasmin through the action of one of two activators, tissue-type plasminogen activator (tPA) and/or urokinase-type plasminogen activator (uPA). Lytic activity is neutralized when plasminogen activator is bound by circulating plasminogen activator inhibitor-1 (PAI-1) and when plasmin is bound by α-2-antiplasmin. Comerota et al21Comerota A.J. Chouhan V. Harada R.N. Sun L. Hosking J. Veermanolsunemi R. et al.The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis.Ann Surg. 1997; 226 (discussion 313-4): 306-313Crossref PubMed Scopus (186) Google Scholar proposed the mechanism by which IPC increases fibrinolytic activity based on the results of a controlled study evaluating normal subjects and patients with post-thrombotic CVD. Fibrinolytic activity was assessed using a calibrated fibrin-plate assay, which assesses total fibrinolytic activity in the blood. Also studied were tPA and PAI-1 antigen and activity, plasmin generation, and von Willebrand factor (vWF) as a gauge of endothelial stimulation. Interestingly, but not surprisingly, baseline endogenous fibrinolytic activity was significantly attenuated in postthrombotic patients (P < .01). IPC increased endogenous fibrinolytic activity in all patients. However, the increase of fibrinolytic activity of postthrombotic patients was attenuated, essentially reaching baseline levels observed in healthy patients. Interestingly, IPC reduced tPA antigen, whereas tPA activity significantly increased tPA activity. IPC reduced PAI-1 antigen and activity; however, there was no change in vWF. These observations suggest that the increase in fibrinolytic activity is due to a reduction in PAI-1, most likely resulting from increased clearance. Unlike cell culture studies, there was no increase in the release of tPA from endothelial cells. Extending the findings of Comerota et al,21Comerota A.J. Chouhan V. Harada R.N. Sun L. Hosking J. Veermanolsunemi R. et al.The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis.Ann Surg. 1997; 226 (discussion 313-4): 306-313Crossref PubMed Scopus (186) Google Scholar Chouhan et al22Chouhan V.D. Comerota A.J. Sun L. Harada R. Gaughan J.P. Rao A.K. Inhibition of tissue factor pathway during intermittent pneumatic compression: a possible mechanism for antithrombotic effect.Arterioscler Thromb Vasc Biol. 1999; 19: 2812-2817Crossref PubMed Scopus (49) Google Scholar examined the onset of intravascular coagulation through the tissue factor (TF) pathway. IPC reduced factor VIIa (FVIIa) levels for both healthy patients and post-thrombotic patients compared with their baseline values (P < .001). There was a greater (P < .05) decrease in FVIIa levels in healthy patients (18% to 24% of baseline values) than in patients with postthrombotic venous disease (40% to 43% of baseline values). Likewise, there was a greater increase in tissue factor pathway inhibitor (TFPI) levels in healthy patients than in post-thrombotic patients (P < .001). An inverse relationship was found between FVIIa and TFPI levels, demonstrating inhibition of the TF-dependent pathway. These findings suggest that IPC stimulates the release of TFPI from the endothelial TFPI pool and indicate that reduction of intravascular coagulation through inhibition of the TF pathway may be a key mechanism for the anti-thrombotic effect of IPC. When edema occurs and increases extravascular pressure, perfusion pressure decreases, reducing dermal oxygen tension. Kolari et al23Kolari P.J. Pekanmäki K. Pohjola R.T. Transcutaneous oxygen tension in patients with post-thrombotic leg ulcers: treatment with intermittent pneumatic compression.Cardiovasc Res. 1988; 22: 138-141Crossref PubMed Scopus (54) Google Scholar postulated that IPC would increase transcutaneous oxygen tension (TcPO2) and contribute to ulcer healing by decreasing interstitial fluid volume and venous stasis. They compared the effect of IPC in 10 patients with post-thrombotic leg ulcers and 9 healthy patients and found that TcPO2 increased in 9 of 10 patients. Baseline TcPO2 was greater in healthy patients (P < .01) than in patients with leg ulcers, both before and after IPC. The change in TcPO2 of patients directly correlated with a reduction of leg edema and inversely correlated with skin temperature (P < .002).3Nicolaides A.N. Investigation of chronic insufficiency: a consensus statement.Circulation. 2000; 102: e126-e163Crossref PubMed Google Scholar These results support the hypothesis that an oxygen diffusion barrier is present in the tissue surrounding venous ulcers and suggest that IPC increases tissue perfusion and decreases interstitial fluid volume in the leg, resulting in improved oxygen diffusion. A subsequent study by Nemeth et al24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar in patients with venous ulcers and pitting edema failed to show an increase of TcPO2 with IPC. Nemeth et al24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar and Kolari et al23Kolari P.J. Pekanmäki K. Pohjola R.T. Transcutaneous oxygen tension in patients with post-thrombotic leg ulcers: treatment with intermittent pneumatic compression.Cardiovasc Res. 1988; 22: 138-141Crossref PubMed Scopus (54) Google Scholar used different devices, with markedly different inflation times and cycles. The cycle times in the Kolari et al23Kolari P.J. Pekanmäki K. Pohjola R.T. Transcutaneous oxygen tension in patients with post-thrombotic leg ulcers: treatment with intermittent pneumatic compression.Cardiovasc Res. 1988; 22: 138-141Crossref PubMed Scopus (54) Google Scholar study were 30 seconds (12-second inflation, 18-second deflation) compared to 120 seconds (90-second inflation, 30-second deflation) in the Nemeth et al24Nemeth A.J. Falanga V. Alstadt S.P. Eaglstein W.H. Ulcerated edematous limbs: effect of edema removal on transcutaneous oxygen measurements.J Am Acad Dermatol. 1989; 20: 191-197Abstract Full Text PDF PubMed Scopus (29) Google Scholar study. Because normal venous refill times are 25 seconds or less, it is understandable that a 30-second cycle time (two compressions/mi
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