INVESTIGATION OF CHRONIC VENOUS INSUFFICIENCY. A consensus statement

A.N. Nicolaides, MS, FRCS, FRCSE*

From Irvine Laboratory for Cardiovascular Investigation and Research, Department of Vascular Surgery, Imperial College School of Medicine (St Mary´s Campus), London W2 1NY, UK. * See the apendix for a complete list of authors.

(Reproduced with permission from Circulation 2000; 102:e126- e163)


Abstract

This consensus document provides an up-to-date account of the various methods available for the investigation of chronic venous insuffíciency of the lower limbs (CVI), with an outline of their history, usefulness, and limitations. CVI is characterized by symptoms or signs produced by venous hypertension as a result of structural or functional abnormalities of veins. The most frequent causes of CVI are primary abnormalities of the venous wall and the valves and secondary changes due to previous venous thrombosis that can lead to reflux, obstruction, or both. Because the history and clinical examination will not always indicate the nature and extent of the underlying abnormality (anatomic extent, pathology, and cause), a number of diagnostic investigations have been developed that can elucidate whether there is calf muscle pump dysfunction and determine the anatomic extent and severity of obstruction or reflux. The difficulty in deciding which investigations to use and how to interpret the results has stimulated the development of this consensus document. The aim of this document was to provide an account of these tests, with an outline of their usefulness and limitations and indications of which patients should be subjected to the tests and when and of what clinical decisions can be made. This document was written primarily for the clinician who would like to learn the latest approaches to the investigation of patients with CVI and the new applications that have emerged from recent research, as well as for the novice who is embarking on venous research. Care has been taken to indícate which methods have entered the clinical arena and which are mainly used for research. The foundation for this consensus document was laid by the faculty at a meeting held under the auspices of the American Venous Forum, the Cardiovascular Disease Educational and Research Trust, the European Society of Vascular Surgery, the International Angiology Scientific Activity Congress Organization, the International Union of Angiology, and the Union Internationale de Phlebologie at the Abbaye des Vaux de Cernay, France, on March 5 to 9, 1997. Subsequent input by co-opted faculty members and revisions in 1998 and 1999 have ensured a document that provides an up-to-date account of the various methods available for the investigation of CVI.
Key Words: veins • valves • thrombosis • chronic venous insufficiency • tests


Chronic venous insufficiency of the lower limbs (CVI) is characterized by symptoms or signs produced by venous hypertension as a result of structural or functional abnormalities of veins. Symptoms may include aching, heaviness, leg-tiredness, cramps, itching, sensations of burning, swelling, the restless leg syndrome, dilatation or prominence of superficial veins, and skin changes. Signs may include telangiectasia, reticular or varicose veins, edema, and skin changes such as pigmentation, lipodermatosclerosis, eczema, and ulceration.
The most frequent causes of CVI are primary abnormalities of the venous wall and the valves and secondary changes due to previous venous thrombosis that can lead to reflux, obstruction, or both. Congenital malformations are rare causes of CVI.
Because the history and clinical examination will not always indicate the nature and extent of the underlying abnormality (anatomic extent, pathology, and cause), a number of diagnostic investigations have been developed that can elucidate whether there is calf muscle pump dysfunction and can determine the anatomic extent and functional severity of obstruction or reflux. The difficulty in deciding which investigations to use and how to interpret the results has stimulated the development of this consensus document. The aim of this document was to provide an account of these tests, with an outline of their usefulness and limitations and indications of which patients should be subjected to the tests and when and of what clinical decisions can be made.
The foundation for this consensus document was laid by the faculty at a meeting held under the auspices of the American Venous Forum (AVF), the Cardiovascular Disease Educational and Research Trust (CDER Trust), the European Society of Vascular Surgery (ESVS), the International Angiology Scientific Activity Congress Organization (IASACO), the International Union of Angiology (IUA), and the Union Internationale de Phlebologie (UIP) at the Abbaye des Vaux de Cernay, France, on March 5 to 9, 1997. Subsequent input by co-opted faculty members and revisions in 1998 and 1999 have ensured a document that provides an up-to-date account of the various methods available for investigating CVI.

Magnitude of the Problem
CVI has a considerable socioeconomic impact in Western countries due to its high prevalence, cost of investigations and treatment, and loss of working days.1-2 Varicose veins are present in 25% to 33% of female and 10% to 20% of male adults.3-13 In the Framingham study, the incidence of varicose veins per year was 2.6% in women and 1.9% in men.14 The prevalence of edema and skin changes such as hyperpigmentation and eczema due to CVI varies between 3.0%5 and 11%7 of the population.
Venous ulcers occur in +/- 0.3% of the adult population in Western countries.5,9,15-22 The prevalence of active and healed ulcers combined is +/- 1%.23-24 Healing of venous ulcers may be delayed in patients of low socioeconomic class, those who are single, and especially in those who do not have central heating.25
The overall prognosis of venous leg ulcers is poor: only 50% heal at 4 months,26 20% remain open at 2 years, and 8% remain open at 5 years.27 The annual recurrence rate varies from 6% to 15%.28-30 In 1 study, 12.5% of patients with ulcers took early retirement because of continued disability.31
Data from the Brazilian Security System show that CVI is the 14th most-frequently quoted disease for temporary work absenteeism and the 32nd most frequent cause of permanent disability and public financial assistance.32
The annual cost of venous ulcers has been estimated to be £400 to 600 million for the United Kingdom33, 34 and + $1 billion for the United States.35 The total cost of CVI to society, both direct and indirect, is estimated to be $1 billion (US dollars) in each of 3 European countries (Germany, France, and the United Kingdom).36, 37


Pathophysiology of CVI

The symptoms and signs of CVI are produced by ambulatory venous hypertension, which is itself the result of obstruction, reflux, or a combination.

Changes in the Major Veins
Varicose veins are the most common manifestation of CVI. It is believed that they are usually due to abnormal distensibility of connective tissue in the vein wall. Early work has suggested that veins from patients with varicosities are more distensible than those from patients with normal veins,38 indicating a probable systemic basis for the abnormality.
Varicosities usually start at points where superficial veins communicate with deep veins, particularly at the saphenofemoral and saphenopopliteal junctions and in the perforating system, because of valvular incompetence. Primary varicose veins result from venous dilatation without previous thrombosis. Secondary varicose veins are caused by valvular damage after deep vein thrombosis (DVT) and recanalization that gives rise to incompetent deep and perforating veins.
Sometimes, varicose veins may be associated with reflux through vulvar varices without any relation to the saphenofemoral junction or other deep-to-superficial reflux in the lower limb. Such varices also may be associated with clinical symptoms and signs suggestive of pelvic congestión, including uterine retroversion and dyspareunia. They are more common in women who have had several pregnancies and had had hemorrhoids and vulvar varicosities during and after pregnancy.39-41
Poor venous drainage and resulting venous hypertension increase transmural pressure in postcapillary vessels, producing skin capillary damage, fluid exudation, edema, and tissue malnutrition, which favors inflammation, infection, thrombosis, and tissue necrosis with lipodermatosclerosis and eventual ulceration.42-44
Reflux in deep veins can be due to past venous thrombosis and recanalization with destruction of venous valves, but it can also be idiopathic. Descending phlebography in limbs with deep venous reflux detected with duplex scanning fails to show any evidence of a previous DVT in +/- 30% of cases. In such limbs, reflux is the result of floppy valve cusps, valvular agenesis, or aplasia.45-47
Outflow obstruction can result from DVT without adequate subsequent recanalization and with poor development of collaterals. Less frequently, obstruction results from extramural venous compression48-49 or from congenital agenesis or hypoplasia of the femoral or iliac veins.50 Left common iliac vein compression by the right common iliac artery is the most frequent type of external obstruction seen in young subjects.51-54
Nearly 30% of fractures of the lower extremities result in venous thrombosis and postthrombotic sequelae.55-59 During military conflicts, severe injuries often involve major veins of the lower extremity. The long-term sequelae of postthrombotic changes become evident only many years after such injuries.60,61
Venous recanalization occurs in 50% to 80% of patients several months or even years after DVT.62-69 Rapid recanalization after DVT is associated with a higher incidence of valve competency.66 The chronic sequelae of DVT are most often ascribed to reflux rather than to obstruction.70-73
Several studies have investigated the relationship among acute DVT, long-term venous hemodynamic disturbances and the incidence of the postthrombotic syndrome.72,74-86 In these studies, the incidence of the postthrombotic syndrome was 35% to 69% at 3 years after DVT and 49% to 100% at 5 to 10 years, depending on the extent of the thrombosis.
The incidence of the postthrombotic syndrome and the severity of the hemodynamic abnormalities increased when the popliteal or more proximal veins were involved in the original thrombotic episode.
Patients with both chronic obstruction and reflux have the highest incidence of skin changes or ulceration.86 Ulceration was more frequent in patients with recurrent DVT.87
In recent studies in which patients with proximal thrombosis have been treated with adequate anticoagulation, early mobilization, and long-term prophylaxis with elastic compression, skin changes or ulceration were present in 4% to 8% depending on the severity of the hemodynamic changes, duration of follow-up, use of effective compression therapy, local hygiene, and the cause.88,89

Microcirculation: The Final Target of Venous Hypertension
New noninvasive techniques, such as laser Doppler,90,91 measurements of transcutaneous Po292 and interstitial pressure,93 capillaroscopy,94 and microlymphography,95 provide the means to study the extent of changes in the skin microcirculation of limbs with CVI.
The blood capillary circulation is often severely impaired in limbs with CVI,96,97 leading to skin changes, eczema, and ulceration.
Changes in skin capillaries may be moderate in patients with mild venous insufficiency. The capillaries become markedly dilated, elongated, and tortuous, especially at skin sites with hyperpigmentation and lipodermatosclerosis, and in patients with insufficiency of the perforating veins or the deep venous system. These changes are associated with a high microvascular blood flow.98,102.
As a late phenomenon, capillary thromboses successively lead to a reduction in nutritional skin capillaries and transcutaneous Po2, predisposing the patient to ulceration.94,103
A striking finding in the skin of patients with CVI is a "halo" formation around the dilated capillaries observed on capillaroscopy. This is associated with microedema and pericapillary fibrin,104 which possibly prevent normal nutrition to the skin cells as part of the final process in the development of venous leg ulcers.96, 97
Microangiopathy in lymphatics plays an important role (see Capillaroscopy) in the pathophysiology of skin changes and venous leg ulcers.105,106 Another finding is that white cells accumulate in legs with CVI on dependency.107 Indirect evidence suggests that this finding could be the result of leukocyte activation108,110 and adhesión to the endothelium.111,112 The implications for the development of capillary loss and venous ulceration require further evaluation.113

Associated Hematological Changes
Since the late 1970s, many studies in patients with CVI have shown progressive changes in fibrinogen and associated blood properties, and impaired fibrinolysis.
Since the original observation of pericapillary fibrin deposits,104 increased plasma fibrinogen levels have frequently been observed in patients with CVI.114,115 Elevated fibrinogen degradation products, particularly in patients with ulcers, indicate a rapid turnover of the macromolecule.116 Increased fibrinogen transport due to venous hypertension, high endothelial permeability, and plasma leakage found in such patients leads to significantly higher amounts of lymph fibrinogen than those found in normal subjects.117 Subsequent impaired fibrinolysis leads to hyperfibrinogenemia. Finally, although hyperfibrinogenemia can be related to aging and vascular risk factors, CVI is likely to play an independent role in the enhancement of the fibrinogen level.115
Elevated plasma fibrinogen levels are alleged to be the cause of rheological changes in viscosity and red cell aggregation.114,118-120 Whether fibrinogen-related red cell aggregates in the microcirculation are an additional factor in the pathogenesis of CVI is not known.
Impaired fibrinolysis has been determined in several studies in all kinds of patients with varicosities121,122 and venous disease with and without skin lesions.123-125
The precise mechanism for the defect in fibrinolysis in the majority of patients appears to be an increase in the inhibitor plasminogen activator-1 (PAI-1) ("poor responders" type I).126-128 A defect in tissue plasminogen activator ("poor responders" type II) is infrequent.127
PAI-1 is synthesized by the endothelium, particularly that of microvessels, and by smooth muscle cells of the microvessel walls. It is released by mechanical stress due to venous hypertension and by hypoxia.
The maximum effect of this inhibitor occurs in lipodermatosclerosis, which favors the hypothesis of an important role for the affected microvessels in the skin. PAI-1 may therefore be considered a marker for damage to the skin microcirculation.126-128
The rheological and fibrinolytic disorders are strongly correlated in CVI, particularly the PAI-1 levels and red cell aggregation. The red cell aggregation index is increased proportionally to the severity of the CVI.127 Hyperfibrinogenemia, enhanced erythrocyte aggregation, and hypofibrinolysis may be interrelated factors, with their main effect being damage of the skin of the lower limbs. In patients with CVI, there is a risk of subsequent thrombosis in association with hypofibrinolysis when the PAI-1 levels become very high.129
Other hematological alterations in CVI have not been fully explored. Abnormal levels of tissue factor can be detected in patients with CVI and functional tissue factor pathway inhibitor levels are decreased to create a thrombogenic state.130 Soluble thrombomodulin levels are increased in CVI, suggesting endothelial dysfunction. The severity of CVI is also proportional to the inflammatory response.101-128-131-132 The tissue factor pathway inhibitor has anti-inflammatory properties. Initial investigations have shown upregulation of tissue factor, resulting in increased consumption of tissue factor pathway inhibitor.
In patients with long-term skin damage (lipodermatosclerosis), immunohistochemical studies have shown that capillaries of the papillary plexus in the skin are surrounded by an infiltrate of inflammatory cells (macrophages and T-lymphocytes), as well as the fibrin cuff.133 The exact role of these cells is unclear, but they probably are important in the clinical changes seen in the skin.

Diagnostic Challenge
A careful clinical history and examination should reveal the patient's symptoms, their severity, and whether they are due to venous disease rather than to coexisting nonvenous musculoskeletal, arterial, or neurological pathology.
Subsequent noninvasive or, in some cases invasive, investigations may be required to confirm the clinical assessment.
The classic tourniquet tests provide some information about the sites of deep-to-superficial reflux, but they are difficult to interpret when varicose veins are not prominent and offer little information as to whether there is obstruction or reflux in the deep veins. They have been complemented by examination with hand-held continuous-wave Doppler; as a result, it is now realized that many "recurrent" varicose veins are the result of unsuspected incompetent perforating veins or reflux in the short saphenous vein.
Because the history and clinical examination will not always indicate the nature and extent of the underlying abnormality (anatomic extent, pathology, and cause), a number of diagnostic investigations have been developed.134-136 Provided they are performed and interpreted by physicians or technologists who have a good knowledge of venous disease, they can provide qualitative and quantitative information and offer answers to most questions posed in clinical practice. They can be used to elucidate whether there is calf muscle pump dysfunction and determine the anatomic extent and severity of obstruction or reflux.
The difficulty in deciding which investigations to use and how to interpret the results has stimulated the development of this consensus document.
The aim of this document was to provide an account of these tests, with an outline of their usefulness and limitations and indications of which patients should be subjected to the tests and when and of what clinical decisions can be made.


Methods of Investigation

Tests That Provide Information on Morphology

Ascending Phlebography
Until recently, ascending phlebography has been the method of choice to demonstrate patency of the veins, define the anatomy, and help to distinguish between primary and secondary disease. A second role has been to detect incompetent perforating veins.
It is still used as the "gold standard" to establish the accuracy of new investigations that determine the presence or absence of disease or its anatomic extent.
However, the development of several noninvasive tests, particularly duplex scanning, now makes it unnecessary in most cases. Its current application is limited to cases in which duplex scanning is unavailable, inadequate, or equivocal.
The examination is performed by injecting contrast medium into a vein on the dorsum of the foot and directing it into the deep veins with an ankle tourniquet. The ascent of the contrast is slowed down by a second midthigh cuff or by having the patient in a semierect position with use of a tilting table. It is possible to demonstrate deep veins consistently from the muscular veins in the calf up to the inferior vena cava but not the internal iliac or profunda femoris veins. 137-141
Good visualization of iliac veins and the inferior vena cava may require a percutaneous injection of contrast into the femoral vein combined with the Valsalva maneuver.
The phlebographic criterion for the diagnosis of DVT established by DeWeese and Rogoff142 is the presence of well-defined filling defects in opacified veins demonstrated on 2 or + radiographs. This criterion is also valid for chronic obstruction.
Nonvisualization of 1 or + calf veins is not considered diagnostic of thrombosis because frequently not all of these veins are visualized in normal limbs. Nonvisualization of a calf vein or a more proximal vein with good opacification of its proximal and distal parts in the presence of collateral vessels is evidence of thrombotic obstruction.
Loose thrombus appears as a cylindrical filling defect surrounded by a thin white line of contrast medium. Obliteration of the white line indicates adherence to the vein wall. Use of the image intensifier to obtain several views just before and after a Valsalva maneuver helps to distinguish most artifacts from thrombosis.
Fresh thrombus fills most of the venous lumen but is not adherent to the wall. Old thrombus with recanalization produces irregularity of the venous wall.
Incompetent perforating veins can be identified by the flow of contrast medium from deep to superficial veins.
Although phlebography has been deemed the gold standard in the detection of the presence, site, and anatomic extent of chronic venous obstruction, it cannot provide a quantitative functional assessment of its severity or the adequacy of collateral veins.143

Descending Phlebography
The aim of descending phlebography is to demonstrate reflux in either the superficial or deep veins and to determine the points of leakage from the pelvis to the lower limbs and from deep to superficial veins. It also is used to provide information on the anatomic localization and morphology of the venous valves, assess the extent of reflux, delineate the venous anatomy in complex cases, and differentiate primary from secondary disease.
The criticism that descending phlebography is a nonphysiological test because it involves the use of contrast agents that are heavier than blood merits recognition, but this does not invalidate the observations that are gained from a careful study.
Descending phlebography can be performed by introducing a cannula through a brachial, contralateral, or ipsilateral femoral144 or popliteal145 vein and injecting contrast medium with the patient in the standing position with the use of a tilting table. A Valsalva maneuver is required to elicit valve closure. A popliteal injection is necessary if distal reflux is suspected in the presence of competent proximal valves. Repeated boluses of contrast medium are injected with serial or continuous recording.
The competence of deep veins as well as the deep-to-superficial junctions is assessed by determining the extent and duration of distal reflux of contrast medium. Several variations in the technique of phlebography have been described.46,144-158
Five grades of phlebographic reflux (0 to 4) have been described as follows151,153,154: grade 0 indicates no reflux below the confluence of the superficial femoral and profunda femoris veins; grade 1, reflux into the superficial femoral vein but not below the middle of the thigh; grade 2, reflux into the superficial femoral vein but not through the popliteal vein, demonstrating competent popliteal valves; grade 3, reflux to a level just below the knee, indicating incompetent popliteal valves, but competent valves in the axial calf veins; and grade 4, reflux through the axial veins (femoral, popliteal, and calf) to the level of the ankle. Pathological reflux through the popliteal vein has been shown to be associated with symptoms, but the association is not clear cut.153
The disadvantages of descending phlebography are that it is invasive and costly and has potential complications. The development of duplex scanning that can be used to detect the presence and anatomic extent of reflux has resulted in a decrease in the number of descending phlebograms. The latter are now performed mainly when deep venous reconstruction is being considered or before redo surgery for varicose veins when duplex scanning is not conclusive.

Varicography
Varicography involves the direct injection of contrast medium through a butterfly cannula into the superficial vein under investigation. It is a simple and valuable technique that can supplement ascending phlebography. It has a particularly valuable clinical role, not so much in primary varicose veins but rather in the elucidation of the anatomic connections of recurrent varicose veins as a "road map" to guide the surgeon.159 On the operating table, it facilitates the use of minimal incisions and precise surgery.160,162 It is also used to define abnormal drainage patterns in patients with venous malformations.50

Per-uterine Phlebography
Per-uterine phlebography has been used to demonstrate veins in the broad ligaments, ovarian plexus, and ovarian veins in patients with a suspected pelvic congestión syndrome.163 After injection directly into the fundus of the uterus, pressure over the iliac fossa shows contrast filling the contralateral ovarian vein.164-166

Selective Ovarian and Internal Iliac Phlebography
Selective ovarian and internal iliac phlebography are used to investigate patients with leg varices that fill from vulvar veins and who are suspected to have incompetence of the ovarian veins with reflux into the vulvar veins via the internal iliac. In such patients, the finding of bilateral ovarian reflux is often associated with the pelvic congestion syndrome.163
The ovarian veins are investigated with selective catheterization via the basilic, right femoral, or internal jugular veins.141 After the injection of contrast medium, reflux is demonstrated by tilting the table or by a Valsalva maneuver. Contrast from either ovarian vein fills large varices in both the broad ligaments of the uterus and then passes through the obturator and internal pudendal veins to full varices in the thigh and even to extend down to the calf.
Sometimes, injection into 1 ovarian vein can be seen to reflux down both legs. Contrast medium may be returned to the pelvic varices and ovarian vein by reversing the table tilt.
During this investigation, the internal iliac veins may also be catheterized to assess this possible source of reflux.167 The description of ultrasound windows to abdominal and pelvic veins has made duplex scanning an alternative investigation.168
The complications of all types of phlebography are pain, contrast extravasation, deterioration of renal function, localized infection, idiosyncratic reactions, and venous thrombosis.169 Pain is alleviated by administering an analgesic agent to the patient and slowly injecting the contrast medium. Minimal pain, tenderness, or swelling on the day after the phlebogram are rarely severe and clear within days. The incidence of phlebographically induced thrombosis is reduced by flushing the veins with heparinized saline at the end of the examination. Nonionic contrast media should be used to minimize these complications.170

Duplex Scanning
Duplex scanning has been used since the early 1980s to diagnose DVT.171-174 Its use has now been extended to detect obstruction or reflux and to determine their anatomic extent in CVI.175-177
Color flow duplex imaging provides instant visualization of blood flow and its direction and has decreased examination time and improved its accuracy. It has become conventional to show cephalad flow as blue and distal flow as red.
A 4- to 7-MHz multifrequency transducer is used. The saphenofemoral junction is examined first with the patient standing, facing the examiner, and holding onto a frame, with most of the weight placed on the opposite limb. Holding onto a frame provides stability and prevents muscle contractions, which produce blood velocity artifacts.177 An alternative method would be to examine the patient in the 15° reverse Trendelenburg position with the Valsalva maneuver to elicit reflux, specifically for the examination of thigh veins.178
This method produces similar results to those achieved when a pneumatic cuff is placed below the level of interrogation and reflux is measured after rapid deflation with the patient in the standing position.
The advantage of the Valsalva maneuver in the 15° reversed Trendelenburg position is that it provides comfort for both patient and examiner. The disadvantage is that the test is dependent on a cooperative patient who is able to perform the maneuver.
The probe is placed longitudinally over the groin so that the distended femoral vein, the long saphenous vein, and their junction can be identified. If there is any difficulty, one can start with a transverse image, identify the 2 veins, and then visualize them longitudinally.177
Several features identify a normal vein; they include red cell aggregates shown as echogenic intraluminar structures that move slowly cephalad,179-181 movement of venous valve cusps phasic with respiration, smooth lining of ihe venous wall, and approximation of the anterior and posterior walls with compression.
High echoes in the lumen, irregular walls, and failure to fully approximate the walls by compression indicate old thrombosis with or without recanalization.
Additional help in the elucidation of the anatomy and pathology is provided with color-flow duplex imaging. In normal veins, cephalad flow phasic with respiration is indicated by the blue color in the lumen. This is enhanced with distal thigh or calf compression. On release of the compression, reflux is shown as red that lasts for + 0.5 second.182-184 In the absence of reflux, the lumen is black. In the presence of old thrombosis with recanalization, color-flow imaging shows blue among the luminal echoes on distal limb compression and red on release of the compression. The extent of venous changes can be determined by repeating these maneuvers throughout the length of the leg. If there is iliac occlusion, collateral circulation in the groin with suprapubic flow that crosses to the opposite groin can be visualized.
The short saphenous and popliteal veins are examined with the patient standing and facing away from the examiner and holding onto the frame. An alternative position is to sit on the edge of a couch with the foot on a chair or stool. In this position, both the popliteal and calf veins can be examined with comfort for both the patient and me examiner.177
The probe is placed over the popliteal fossa longitudinally to image the popliteal artery, which lies deepest; the popliteal vein lies more superficially and parallel to it; and the short saphenous vein is the most superficial. The main gastrocnemial veins (medial and lateral) are seen in the gastrocnemius muscle between the short saphenous and popliteal veins. The sites and levels of the junctions of these veins in relation to each other and the popliteal vein are identified. If an operation is contemplated, these levels can be marked on the skin. This is very helpful in view of the variable anatomy of the popliteal fossa.185-186
Features of normality, chronic obstruction with or without recanalization, or reflux are identical to those mentioned earlier.
The posterior tibial and peroneal veins can also be tested for reflux with anterolateral or posteromedial views.177 They are usually paired, lying on each side of the corresponding artery. Cephalad flow or reflux can be identified with compression of the foot or lower calf followed by sudden release.
Incompetent perforating veins are identified by sliding the transducer up and down the leg with dilated superficial varicose veins imaged in transverse section. A perforating vein appears as a vessel that joins the superficial vein being examined with a deep vein. At this point, the probe is held still, the color flow is switched on, and distal compression is performed. The presence of 1 color (eg, blue) on compression with a different color on release (eg, red) indicates reflux. Reflux is diagnosed by outward flow that lasts + 0.5 second.
Although duplex scanning can localize incompetent perforating veins, there is considerable controversy as to whether it can be used to assess their hemodynamic significance.187-191
Duplex scanning is operator dependent, and imaging can be difficult in certain circumstances, especially when operating above the inguinal ligament, in obese patients, and in those with swollen legs, in which case phlebography may be a better choice.192-194

Recent Applications of Duplex Scanning: New Messages That Have Emerged

Duplex Scanning in the Study of the Natural History of Thrombi. Recent studies have shown that duplex scanning is an ideal method for serial examinations to monitor the evolution of thrombi and to check for the appearance of reflux after acute DVT.66-69,196,196
These studies indicate that reflux develops progressively and that even a complete occlusion may alternately partially recanalize and reocclude before a final complete recanalization. However, the factors that cause reflux to develop in some patients and not in others remain unclear.
The process and rate of organization of a thrombus may have the potential to identify those patients most at risk of developing late symptoms. Analysis of echogenicity of thrombi in vivo shows that the organizational process and rate of thrombolysis differ greatly from patient to patient.68-69
The resolution of thrombi follows 1 of 3 distinctive sequences: (1) rapid spontaneous thrombolysis, which preserves valvular function and returns the vein to its normal appearance; (2) increasing echogenicity, indicating fibrosis of a thrombus that remains occlusive, with or without evidence of collateral veins and with no symptoms at 1 year; and (3) slow recanalization that causes the destruction of valves, resulting in reflux and early postthrombotic symptoms.

Relationship Between Anatomic Extent of Reflux and Grade of Chronic Venous Disease. Duplex scanning is a very sensitive diagnostic method. It can show whether reflux is in the deep, superficial, or perforating veins or in any combination thereof. It can detect small amounts of reflux in isolated segments of veins often present in "normal" asymptomatic individuals. It can determine whether reflux is confined to a vein above or below the knee or whether it extends through-out the whole limb.
In the absence of deep venous obstruction, limbs with reflux confined to the proximal (above knee) veins rarely develop skin changes or ulceration.197-198
In contrast, even in the presence of normal deep veins, symptoms and signs of CVI are more often found when the entire length of the greater saphenous vein is involved or when reflux is present in both the long and short saphenous veins.197, 198
Multisegmental reflux is significantly more prevalent in legs with ulcers than in nonulcerated limbs (75% versus 22%).199 A pattern of reflux that involves 2 or + of the venous systems (superficial and deep; superficial and perforating; or superficial, perforating, and deep) is found in about two thirds of patients with skin changes or ulceration.198-202
The available data suggest that there is a strong association between the severity of CVI and the anatomic distribution and extent of venous reflux.203 However, the information is fragmented in multiple studies that use different classifications and reporting methods. Therefore, further studies with uniform criteria that combine the anatomic information provided by duplex scanning and pressure or plethysmographic quantitative measurements are needed to establish such an association.

Significance of Gastrocnemial Reflux.
The importance of gastrocnemial reflux was recognized by Dodd204-205 and May and Nissl64 but has only recently obtained general recognition as a cause of primary venous insufficiency and, more important, as a common cause of recurrence.206-208
When gastrocnemial vein incompetence is suspected, the demonstration of reflux by duplex scanning is mandatory because reflux can be eliminated by surgical ligation.206,209-211

Liquid Crystal Thermography
Thermography immediately after a tiptoe exercise demonstrates incompetent perforating veins as "hot spots.212-215
When compared with operative findings and phlebography, it has a sensitivity of 94% and 98%, respectively.216-217
The recent development of liquid crystal thermographic plates174 has simplified the method, so it can be used as a screening test to localize incompelent perforators.218 The liquid crystal thermographic plates are applied to the thigh and leg after 20 tiptoe movements. Incompetent perforating veins appear as clearly defined hot spots.
Compared with duplex scanning, the positive predictive value of this test is 91%.218 It appears that liquid crystal thermography is an accurate, simple, relatively inexpensive, and rapid method that allows preoperative marking of incompetent perforating veins wilhout resorting to duplex scanning.


Tests That Provide Hemodynamic Information

Ambulatory Venous Pressure
Ambulatory venous pressure (AVP) measurements can supplement the anatomic information provided by phlebography. The test is based on the original observation made in the 1940s that the venous pressure in the foot decreases during walking219 and gradually returns to the resting value when walking stops.
It has been used extensively in Scandinavian countries to evaluate venous pathophysiology. 220-224 In the 1970s and 1980s, AVP measurements became the hemodynamic gold standard used in the development of noninvasive methods for screening and diagnostic evaluation. 225-230
Venous pressure is measured by inserting a needle into a vein on the dorsum of the foot; the needle is then connected through a pressure transducer and an amplifier to a potentiometric pen recorder. It has been suggested that erroneous results may be obtained if there is a competent valve in the foot and that the needle may have to be replaced in the lower leg.231
The patient supports himself of herself in the standing position by holding onto an orthopedic frame so the resting pressure is recorded. Holding the frame prevents contractions of the calf muscle, which may produce artifacts during the resting period before and immediately after exercise.
The patient then performs a standard exercise of 10 tiptoe movements230 or knee bends227 at the rate of 1 per second, synchronous with a metronome. Walking on a treadmill is technically more difficult to perform but can be taken as a reference stress test.
An alternative method with 10 manual compressions of the calf performed by the examiner has been shown to be more reproducible than the classical tiptoe method.178-232 At the end of the exercise, the patient remains still while recovery of the pressure to baseline level is recorded in seconds.
The exercise is then repeated after either the inflation of a 2.5-cm-wide pneumatic cuff at the ankle or the use of digital compression to occlude the superficial veins. The width of the cuff is critical because wider cuffs tend to compress deep as well as superficial veins.
Likely sites of deep-to-superficial reflux may be determined by repeating the exercise with the cuff positioned just below the knee and at the lower and upper thigh.230 However, the use of tourniquets to attempt to occlude the superficial veins does not reliably differentiate between deep and superficial venous reflux.233
AVP is the best method to assess venous hypertension. The pressure at rest (P0), the mean AVP during the steady state toward the end of the 10 tiptoe movements (P10), the calculated difference of the 2 pressures (P0-P10) (Table 1), and the RT are the most useful measurements.













Because of the exponential character of the refilling curve, it is much easier and more accurate to define the 50% (t/2) or the 90% RT than the 100% RT. Considerable variation has been found within normal groups as well as overlapping values between limbs with primary varicose veins or with the postthrombotic syndrome (Table 1). P10 is considered to be a measure of the severity of venous hypertension regardless of whether the latter results from obstruction or reflux in the superficial or deep venous systems or both.234
Values of P10 in different pathoanatomic states are shown in Table 2, the relationship of P10 with the prevalence of ulceration is shown in Table 3, and the range of values of 90% RT in limbs with different pathology identified with phlebography is shown in Table 4.




































If there is severe outflow obstruction and extensive deep venous reflux, including reflux in the popliteal vein, P10 may actually become higher than P0 because of the increased blood flow and venous volume due to exercise hyperemia. This is characteristic of a group of patients who complain of "bursting" pain on walking (venous claudication). In another subgroup with outflow obstruction and competent popliteal valves, venous pressure in the foot may become normal during exercise because the valves protect the leg despite the proximal occlusion, although extremely high pressures may develop in the veins in the thigh.
Because AVP testing is invasive, it cannot be repeated frequently or used for screening. Noninvasive screening tests such as photoplethysmography (PPG), Doppler ultrasound, air-plethysmography, and foot volumetry are more frequently used for routine investigation. Nevertheless, AVP testing remains the gold standard for the assessment of overall hemodynamic function and for validation of noninvasive tests.
As a research tool, it must be used to assess the hemodynamic effect of surgical reconstructive procedures in the deep veins to develop criteria for improved selection of patients.
An attempt was made to correlate AVP with the grades of reflux defined by descending phlebography in patients with skin changes or ulceration.235 If the popliteal valves were competent (grades 0 to 2), the range of AVP was 32 to 68 (mean 48) mmHg, and an ankle toumiquet to eliminate superficial reflux resulted in an AVP of + 45 mm Hg in all limbs. However, if the popliteal valves were incompetent (grades 3 and 4), the range of AVP was 50 to 95 (mean 72) mm Hg, and the application of an ankle toumiquet had little effect.

Femoral Vein Pressure Measurements
This method is used to determine the severity of iliocaval obstruction. A needle or catheter is inserted into the common femoral vein, and pressures are measured in the supine or semierect position at rest and after exercise. Exercise can be performed with 10 active dorsiflexions of the foot or 20 calf muscle contractions.
Elevated pressures after exercise are related to the severity of venous occlusion,236 but no set standards are available for femoral vein pressure parameters.237-238
Early investigations suggested that a pressure difference of 2 mm Hg between the femoral vein pressure and central venous pressure at rest and an increase of + 3 mm Hg after exercise were associated with a significant proximal occlusion.239 A 3-fold increase in femoral vein pressure after exercise indicated an uncompensated proximal occlusion.
More recently, a pressure difference of 5 mm Hg between the femoral and central venous pressures at rest in the supine position has been considered indicative of a significant proximal venous occlusion that requires surgical reconstruction.240

Arm/Foot Pressure Differential
The arm/foot pressure differential (delta p) provides hemodynamic information on the severity of obstruction and the adequacy of recanalization or of the collateral circulation.241-242 Venous pressures are recorded simultaneously in a vein of the foot and a vein in the hand, with the patient supine, and then repeated during reactive hyperemia or after the injection of papaverine.243-244 With these measurements, limbs with venous obstruction can be classified into 1 of 4 grades (Table 5).












The more proximal the obstruction, the poorer is the compensation and the higher is the grade. The technique provides a global measurement of hemodynamic obstruction due to outflow occlusion in + 1 vein. Venous obstruction involves + 1 anatomic segment in 75% of limbs,145 and additional direct femoral pressure measurements may be necessary for a more precise assessment of functional obstruction.
This method has the disadvantage of being invasive in that it require 2 venipunctures. The technique has been compared with measurements of resistance and outflow fraction, with conflicting results in 2 studies.245-246
In clinical practice, the main value of the method is to help select patients for venous reconstruction. A bypass procedure is not indicated unless a high arm/foot pressure differential (grade 3 or 4 obstruction) is present.241

PPG, Light Reflection Rheography, and Quantitative Digital PPG
PPG and light reflection rheography are noninvasive techniques that can detect local changes in the blood content of tissues. The principal application is to study blood flow and blood volume changes in the skin.247-253
A probe that consists of a light source and a light-sensitive diode is positioned on the skin. Although skin is essentially opaque to light, slight light transmission and backscattering do occur in the range of the visible and infrared light spectrum. The backscatter of light detected with the light-sensitive diode is affected by changes in the number of red blood cells in the dermis. Red blood cells absorb máximum light in the sitting or standing position when the pressure is high and the veins are full. Venous plexuses become less full and light absorption decreases as the venous pressure falls with exercise.

PPG Evaluation of Venous Reflux and Ejecting Capacity of the Calf Muscle Pump
In practice, the PPG probe can be fixed to the leg with transparent adhesive tape some centimeters proximal to the medial malleolus or to the dorsum of the foot.
The PPG is set at zero once a resting baseline is achieved, and venous emptying is then produced through repeated dorsiflexion and plantar flexión of the foot. Most investigators perform this with the patient sitting on a couch with the legs vertical.247,254-258 Others prefer the standing position and tiptoeing 10 times to empty the veins.252
When standing, it is essential for the patient to hold onto an orthopedic frame or table so artifacts from leg muscle contractions during the refilling period are avoided. When the test was performed in both the standing and sitting positions in the same patients, a better separation was obtained between patient groups when the patients were standing252 (Figure 1).


Figure 1. PPG-RT in nomal limb, limbs with superficial venous incompetence (SVI), and limbs with deep venous incompetence (DVI) in sitting and standing position (median and 90% range). Reproduced with permission from Nicolaides and Sumner.245







In the 1980s, PPG had a limited application for quantitative measurements because of the inability to calibrate the signal and failure of the recorded signal to return to the same baseline. Only postexercise RT measurements were reproducible.
A high degree of linear relationship was round for RTs measured with the simultaneous use of both PPG and venous pressure in 4 studies (r=0.93, 0.96, 0.98, and 0.88, respectively), 247,252,259,260 but this was not reproduced in a fifth study (r=0.41).261
In practice, PPG is performed with a diagnostic algorithm shown in Figure 2 when valvular incompetence is suspected.


Figure 2. Relationship between PPG RT and mean AVP obtained in standing position. Reproduced with permission from Nicolaides and Sumner.245








If the venous RT (VRT) is abnormally short (- 20 seconds in the sitting position247 or 25 seconds256-258 or 18 seconds in the standing position252), the test may be repeated after inflating a narrow (2.5 cm wide) cuff at the ankle or below the knee to occlude the superficial veins.
Failure of the cuff to normalize the RT suggests deep venous or perforator incompetence. Normalization of the RT after occlusion of the superficial veins suggests that reflux is confined to the superficial venous system and that the deep veins have competent valves.245,252,258 Although the PPG RT without and with occlusion of superficial veins can help to distinguish among limbs without major venous pathology, limbs with superficial venous incompetence, and limbs with deep venous incompetence, it is not considered to be a good indicator of the severity of deep venous insufficiency.262,63
Any AVP in the range of 45 to 100 mm Hg can be associated with a short RT of 2 to 10 seconds252 (Figure 3) because RT depends on several factors, including the diameter of the vein in which the reflux occurs and the size of the reservoir to be filled.




Figure 3. Algorithm showing that RT and its changes with application of cuffs to occlude superficial veins is a practical diagnostic tool (black circle, normal limbs; black triangle, limbs with superficial venous incompetence; white circle, limbs with deep venous incompetence). Reproduced with permission from Nicolaides and Sumner.245





A long RT may be observed when reflux occurs in small-diameter veins despite a low volume reflux. In contrast, when reflux occurs in large-diameter veins in which the volume flow is large and the reservoir is filled rapidly, reflux can be very short.
The PPG RT reflects regional rather than overall venous hemodynamics in the limb. It is related more to superficial than to deep venous insufficiency.264 An abnormally short RT in the absence of reflux in the main superficial trunks or deep veins on duplex examination suggests reflux through pelvic and vulvar veins.265 It is hardly surprising that PPG RTs correlate poorly with other methods.263,266
PPG can be used for screening to detect CVI or to assess the overall physiological function of the lower limb veins without resorting to more invasive or expensive tests.
Suspected reflux due to a short RT should always be confirmed with continuous-wave Doppler or, preferably, duplex scanning. The test should not be relied on to identify the anatomic distribution of disease.
Quantitative digital PPG255-258 is a more recent descendant of PPG. It incorporates modern computer technology with self-standardization and allows measurements of amplitude as well as time-related parameters.
Recent studies have demonstrated that these measurements have a better quantitative relationship with symptoms than conventional PPG or light reflection rheography (Figure 4).256 Evaluations of muscle pump efficiency and venous long-term monitoring are also possible with the quantitative PPG.253



Figure 4. Mean To and Vo values in patients with CVI. Stage I indicates skin complications absent; stage II, skin complications present but no venous ulcer; and stage III, presence of history of venous ulcer. Reproduced with permission from Schultz-Ehrenburg and Blazek.256




PPG Vein Occlusion Test: Evaluation of Venous Outflow Dynamics
The vein occlusion test measures VO during muscle rest. For the first time, it has become possible to measure VO rates with an optical sensor due to the calibration of the curve amplitude with quantitative PPG.
The patient lies supine, with the extremity raised. The optical PPG sensor is attached to the inner or outer aspect of the lower leg. The entire measurement process is automatically conducted with quantitative digital PPG.
Venous outflow is obstructed by means of a wide cuff (15 cm, 80 mm Hg) on the thigh for 2 minutes. In addition, a narrow cuff (2.5 cm, 80 mm Hg) is placed below the knee. The occlusion maneuver changes the optical properties of the skin by increasing the blood volume in the skin vessels, reflecting the changes in the total venous pool of the extremity.
Among other parameters, venous capacity in PPG% and VO in PPG%/min can be determined from the resulting PPG curve. In the venous emptying phase, the outflow kinetics are measured over 30 seconds. VO gives the change in the PPG signal between 1 and 2 seconds after release of the occlusion. This change is + 30%/min in healthy subjects.253
Although PPG is related more to superficial venous insufficiency, it is possible to assess deep VO dynamics when an additional narrow cuff is used, which forces the blood to make its way through the deep venous system. In the case of hemodynamically significant DVT or external tumor compression, the outflow value is reduced.267

Ambulatory Strain Gauge Plethysmography
Calf volume changes during exercise can be detected with strain gauge, and comparison with AVP measurements was proposed by Holm et al in 1974.268
Originally, the strain gauge was applied at midcalf level, and the exercise consisted of 5 tiptoe movements; it was later changed to 10.269 Other researchers used walking on a treadmill270 or dorsiflexion of the foot in the sitting position271 as exercise.
Alteration in the mode of exercise to knee bends, the application of double strain gauges in plastic chains (Gutmann strain gauges), and recording at the supramalleolar región reduced the coefficient of variation for repeated measurements on the same day and for day-to-day variation from 40% to 12%.272
Ambulatory strain gauge plethysmography (ASGP) is used to measure calf volume changes in the upright position without the need to change position from the supine to the upright. This avoids the venoarteriolar reflex, which causes precapillary arteriolar vasoconstriction that may influence the venous return time.273
Strain gauges are applied to both ankles above the malleolus to avoid artifacts related to calf muscle contraction. Strain gauges are electrically calibrated in situ to percentage volume change (mL/100 mL). The preferred exercise is in the form of 20 kneebends (knee flexión 60°) at a rate of 30 per minute. After the exercise, the patient must stand completely still until full-volume restitution takes place, which in a normal person occurs between 1 and 2 minutes after cessation of the exercise. The plethysmographic recording allows calculation of venous refilling time (RT) and expelled volume (EV).
The second part of the examination involves the application of a below knee compression cuff that is 2.5 cm wide and inflated to a pressure of 70 mm Hg. In patients with isolated superficial venous reflux, this compression will normalize the venous return time. Reference values for normal controls are RT of 42 to 96 seconds and EV of 0.7 to 3.1 mL/100 mL.
The reproducibility for ASGP was calculated with ANOVA.272 For consecutive measurements, the coefficients of variation for RT were 4.7% in normal limbs and 8.8% in limbs with CVI. Corresponding values for EV were 11.3% and 13.1%. The coefficients for day-to-day variation were 7.8% for RT and 11.5% for EV. The positive predictive value for the presence of CVI was 100% for both RT and EV, and the negative predictive value for absence of chronic venous disease was 94% for RT and 75% for EV.274 Thus, ASGP is suitable for screening to exclude venous disease.
AVP is the gold standard to which external volumetric methods refer. The coefficient of correlation between AVP and ASGP was 0.91 (p -0.001) for RT and 0.41 for EV (p -0.05), respectively, as determined in 41 patients and 8 normal control patients.273
The poor correlation between EV and AVP may be explained by possible variations in venous and tissue compliance that determine the shape of the pressure-volume relation curve; in addition, small EV leg changes reflect a high percentage of blood volume changes.275,276 ASGP is used to quantify the performance of the venous muscle pump in terms of venous reflux and expelled volume.
It may differentiate superficial from deep venous insufficiency, but it cannot precisely localize the site and extent of the reflux or obstruction in either system. For this purpose, duplex scanning with color flow imaging is required.
Symptoms of CVI such as pain, itching, swollen legs, pigmentation, heavy legs, and objective changes in the skin have been shown to correlate with the ASGP-derived parameters for venous muscle pump function.274 The lowest values of RT and EV were recorded in patients with venous ulceration.274
ASGP may be used to screen for and to quantify CVI.273 It may also be used to evaluate venous claudication.277 It can be used to differentiate between CVI and lymphedema.278 Although duplex scanning is excellent for localization and diagnosis of venous reflux, ASGP provides quantitative information and is suited for the assessment of surgical outoome274 and that of compression therapy.278 In 1 study, ASGP allowed a longitudinal follow-up and could demonstrate that venous function had progressively deteriorated through pregnancy but had normalized 3 months after term.279

Air-Plethysmography
Venous hypertension is the result of impaired venous return. The latter is often due to the combined effects of venous reflux, obstruction, and poor calf muscle pump function. Air-plethysmography has the ability to measure each of these 3 components and, by doing so, has improved the understanding of venous pathophysiology.
The air-plethysmograph consists of a 35-cm-long polyurethane tubular air chamber that surrounds the entire leg. The air chamber is inflated with air at 6 mm Hg and connected to a pressure transducer/amplifier and a recorder or computer. A syringe connected to the air circuit is used for calibration.
Changes in the volume of the leg as a result of filling or emptying of veins produce corresponding changes in the pressure of the air chamber. Thus, leg volume changes can be measured in milliliters according to the calibration.280

Evaluation of Venous Reflux
With the patient supine, the leg is elevated 45° with the knee slightly flexed to empty the veins. After a plateau is reached (Figure 5), the patient is asked to stand up with the knee of the examined leg slightly flexed and the weight on the opposite leg. An increase in leg volume is observed due to venous filling. The functional venous volume (VV) is 80 to 150 mL in normal limbs and up to 400 mL in limbs with CVI.280,281 The ratio of 90% of VV by the time taken for 90% filling (VFT90) is defined as the venous filling index (VFI = 90%VV/VFT90) (Figure 5).



Figure 5. Diagramatic representation of typical recording of volume changes during standard sequence of postural changes and excercise. a) Patient in supine position with leg elevated 45 degrees. b) patient standing with weight on nonexamined leg. c) Single tiptoe movements. d) Ten tiptoes movements. e) Return to resting standig position as in b. Reproduced with permission from Nicolaides and Sumner.245






This is a measure of the average filling rate of the veins expressed in mL/s. The VF1 is +/- 7 mL/min has a 73% sensitivity, a 100% specificity, and a 100% positive predictive value of identifying limbs with venous ulceration.282 The prevalence of sequelae from CVI in relation to VFl is shown in Table 6.












The prevalence of edema, skin changes, and ulceration increases with higher VF1 regardless of whether the reflux is in the superficial or deep veins. When VFI measurements were repeated after surgery283 or after reflux in the superficial veins was abolished with finger compression of the long saphenous vein at the level of the knee, VF1 was reduced to - 5 mL/s in limbs with primary varicose veins but not in those with reflux in the deep veins (Figure 6). Reflux through
the short saphenous vein is difficult to eliminate with finger compression.




Figure 6. VF1 (median and 90% range) without and with a tourniquet (T) that occluded superficial veins at knee in normal (N) limbs, limbs with primary varicose veins without sequelae of chronic venous disease (liposclerosis and ulceration) (PVV), limbs with primary varicose veins with sequelae of chronic venous disease PVV/S), and limbs with popliteal reflux (PR). Reproduced with permission from Nicolaides and Sumner.245













Evaluation of the Ejecting Capacity of the Calf Muscle Pump
The patient is asked to do 1 tiptoe movement with the weight on both legs and to return to the initial position (Figure 5c). The recorded decrease represents the expelled volume (EV). The ejection fraction (EF) of the calf muscle pump is derived from the formula EF=[(EV/VV)X 100]. EF is + 60% in limbs without venous disease, 30% to 70% in limbs with primary varicose veins, and possibly as low as 10% in limbs with deep venous disease.280
The ejection capacity is as important as reflux for the development of venous ulceration. A good EF (+60%) was associated with a low incidence of ulceration despite marked reflux, and a poor EF (- 40%) was found with ulceration in limbs with minimal reflux.281 The EF and VF1 measurements when used in combination have a good correlation with the incidence of ulceration and offer the potential for the selection of patients most likely to benefit from deep vein reconstruction (Figure 7) (see later). They also offer a means of hemodynamic follow-up in
natural history studies.



Figure 7. Incidence of leg ulceration in relacion to VF1 and EF of calf muscle pump in 175 limbs with venous problems. N indicates normal limbs. Reproduced with permission from Nicolaides and Sumner.245














Overall Performance of the Calf Muscle Pump The combined effect of venous reflux, obstruction, and ejection capacity is evaluated by measuring residual volume (RV) and residual volume fraction [RVF=(RV/VV)X100] after 10 tiptoe movements (Figure 5d). The RVF is in the range of 5% to 35% in normal limbs, 20% to 70% in limbs with primary varicose veins, and up to 100% in deep venous disease. It has a linear relationship with measurements of AVP (Figure 8) and the incidence of ulceration (Table 7). 280,284-285



Figure 8. Relationship between RVF and AVP at end of 10 tiptoe movements (white circle, limbs with superficial venous incompetence; black circle, limb with deep venous disease). DVD indicates deep venous disease; SVI, superficial venous incompetence. Reproduced with permission from Nicolaides and Sumner.245























Evaluation of Venous Outflow Venous outflow is evaluated with use ofthe venous occlusion technique with the patient supine.286-288 A thigh tourniquet (10 to 12 cm wide) is placed as proximally as possible and inflated to 80 mm Hg. Volume increases to a new plateau. The tourniquet is then deflated suddenly, and the VO curve is recorded. The outflow fraction at 1 second (OF1) is the VO expressed as a percentage of the total venous volume. The procedure is repeated after occlusion of the long saphenous vein at the knee. Figure 9 shows the measurements of OF, in limbs with and without venous obstruction according to phlebography, and Figure 10 shows the relationship between the OF, and measurements ofthe arm/foot pressure differential.241



Figure 9. Outflow fraction (OF) (median and 90% range) without and with occlusion of superficial veins (s) in limbs of 50 normal volunteers (N), 157 limbs with primary varicose veins (PVV), 70 limbs with deep venous incompetence (DVI), and 68 limbs with venographic evidence of deep venous occlusion (DVO). Reproduced with permission from Nicolaides and Sumner.245









Figure 10. Outflow fraction (OF) (median and 90% range) in 15 limb with deep venous reflux but not obstruction (arm/foot pressure differencial delta p +/- 5mmHg). Reproduced with permission from Nicolaides and Sumner.245














In clinical practice, an OF1, of + 38% is considered indicative of the absence of any functional obstruction; a range of 30% to 38% indicates moderate obstruction; and - 28% indicates severe obstruction.245,287,288 Measurement of Resistance Venous outflow resistance can be calculated from the outflow curves for volume and pressure obtained simultaneously. Pressure is measured by inserting a 21-gauge butterfly needle into a vein in the foot and volume by placing the air-plethysmograph around the leg. The foot is elevated 15 cm from the horizontal. A thigh cuff is inflated to 80 mm Hg for 2 minutes and then deflated suddenly (Figure 11). Flow (Q) can be calculated at any point on the volume outflow curve from the tangent at that point (Figure 12).


Figure 11. Posicion of leg and air chamber of phletysmograph (APG) for recording pressure and volume changes shown in figure 12. Reproduced with permission from Nicolaides and Sumner.245










Figure 12. Pressure and volume venous oclussion inflow and outflow curves recorded simultaneously in same leg. Pressure is recorded with a needle in a foot vein, and volume is recorded with air phletysmography. Reproduced with permission of Nicolaides and Sumner.245







Resistance (R) is calculated as R=P/Q at any time. The units are expressed in mm Hg • mL-1• min-1. By calculating resistance at several points along the outflow curve and plotting it against pressure, it is possible to demonstrate how resistance changes with different pressures. By measuring the outflow resistance in a large number of patients without and with various grades of obstruction (Raju test grades 1 to IV), the relationship between the resistance and grades of obstruction has been determined (Figure 13).



Figure 13. Relationship between outflow resistance curves and Raju’s classification of grade I to IV outflow obstruction. N indicates normal limbs; R, resistance in resistance units. Reproduced with permission from Nicolaides and Sumner.245














The resistance/pressure relationship is not linear. The resistance is relatively low at high pressure, when the veins and collateral channels are distended. It increases as the pressure decreases and the veins "collapse." The measurement of resistance is a new research tool that can be used in natural history studies of chronic venous obstruction. The reproducibility of the air-plethysmographic measurements is shown in Table 8.

















Recent Applications of Air-Plethysmography: New Messages That Have Emerged

In contrast to duplex scanning, which detects abnormalities in individual veins, air-plethysmography provides information derived from the entire leg. In contrast to segmental devices, because the air chamber includes all the muscles from ankle to knee, it avoids errors due to muscle movements during exercise.
Although it can be used as a simple screening test, it has the potential of offering a complete analysis of venous hemodynamics. Thus, it is useful for routine clinical practice as well as for research. Limbs with edema or ulceration due to causes other than venous, such as arterial, lymphatic, cardiac, or rheumatoid disease, can be distinguished from those affected by venous disease. In limbs with prominent varicosities, air-plethysmography can determine whether the latter act as collateral outflow channels.286,288
Venous hypertension usually results from the combined effect of reflux, obstruction, and poor ejection. With air-plethysmography, the contribution of each parameter can be measured so the appropriate intervention can be considered. Surgical abolition of venous reflux in the deep or superficial system has already been shown to normalize venous hemodynamics in properly selected patients with no obstruction and unimpaired calf muscle ejection.283,290-295 The air chamber can be applied over an elastic stocking so the hemodynamic effect of the latter can be demonstrated.280,296-299 The method should be used in future studies to assess different kinds of compression.
Absolute volume measurements are dependent on the size of the limbs studied; ideally, these values should be normalized for the mass of tissue involved in the measurements.280
The most important values, however, are the ratios EF and RVF, which are already normalized. Even in limbs with phlebographic evidence of DVT in the past, skin damage is rarely seen unless reflux is present. 85,86,201-300 Air-plethysmography has been used to demonstrate that the venous volume, VF1 (amount of reflux), and residual volume fraction worsen with increasing clinical severity. 203,284,300-302 Overall, it appears that the severity of reflux is strongly associated with the grade of disease.
Usually, the skin around venous ulcers is warm and hyperemic, and occasionally pulsation can be detected with Doppler ultrasound. To explain this, several authors postulated the presence of arteriovenous shunts or reduced capillary resistance.303,304
The introduction of air-plethysmography in the 1980s provided a method of measuring the arterial inflow into the entire leg in milliliters per minute. Arterial inflow was measured with the venous occlusion technique in 25 normal limbs and 126 limbs with different grades of venous disease. Resting arterial inflow was 60 to 95 mL/min in normal limbs; 60 to 110 mL/min in 45 limbs with uncomplicated varicose veins; 65 to 162 mL/min in limbs with swelling, lipodermatosclerosis, or pigmentation; and 120 to 235 mL/min in limbs with ulcers.299 These results support the evidence from work with other methods such as laser Doppler that not only is there hyperemia in limbs with CVI but also this hyperemia increases with the severity of the clinical grade.

Foot Volumetry
Dynamic foot volumetry was developed in the early 1970s.305,306 It is based on the water plethysmographic principle and provides measurement of volume changes of the foot during exercise.
The foot volumeter consists of an open, water-filled box. The water level, which is initially 14 cm high, is sensed with a critically dampened photoelectric float sensor, of which the output is monitored on a strip-chart recorder. During a series of knee bends (usually 20) performed at the rate of 1 every 2 seconds, the blood volume gradually decreases until it reaches a steady state. After the exercise is completed, the blood volume returns to its preexercise level. The refilling rate depends on the arterial inflow and amount of venous reflux, if any. To differentiate between superficial and deep venous insufficiency, the exercise is repeated after tourniquet compression of the superficial veins, initially below the knee and then at the ankle just above the volumeter.













The various measurements that can be made are listed in Table 9; the most important are the expelled volume (EV), the expelled volume rate (EVR), the refilling flow (Q), the ratio Q/EVR, and the half-refilling time (t/2). The ratio Q/EVR is a useful criterion for discrimination between healthy individuals and patients with CVI. Table 10 depicts normal values from 3 different studies.












The EV has been correlated with venous pressure during exercise (r=0.66 in controls; r=0.70 in a mixed patient population; r=0.72 with tourniquet compression of the superficial veins) and with phlebographic as well as clinical findings.307-309
Foot volumetry can quantify the degree of venous insufficiency and indicate its location (superficial, deep, or both).307,310,311 It can be used to evaluate therapeutic interventions and to follow patients after DVT to determine the extent of valve damage.250,308 The advantages of foot volumetry are that it can be used to assess the most distal parts of the leg (ie, those most affected by hydrostatic pressure) and that the local temperature is standardized. The use of knee bending demands mobility of the ankles. Contractures of the ankle joints reduce the movements and thereby also the expelled venous volume during exercise.312
Recently, a computerized version of foot volumetry was developed, which simplified the calculation of EV and Q. Foot volumetry has been used to study the effects of various treatments, such as surgery for varicose veins,250,313 compression treatment,314,315 venotonic drugs,316 and treatment of DVT.78,82,236,317-322
Venous function during pregnancy has also been studied.323-325 It must be stressed that like any plethysmographic method, foot volumetry provides a global indication of calf pump function and reflux.

Continuous-Wave Doppler Ultrasound
Continuous-wave Doppler ultrasound is a useful method of detecting reflux at the saphenofemoral and saphenopopliteal junctions.326-331 It has become routine in outpatient clinics for screening because it is quick, inexpensive, and noninvasive. Expectations that it would be useful for detecting and Iocalizing incompetent thigh and calf perforating veins were proved false by several studies in the 1970s.332-334
The saphenofemoral junction is examined with the patient standing facing the examiner while holding onto a rail or table to ensure complete immobility and to avoid muscular contractions in the leg. The probe of a continuous-wave Doppler ultrasonic blood velocity detector (5 to 10 MHz) is placed over the common femoral vein at a 45° angle to the horizontal. The common femoral vein is found just medial to the artery. Confirmation that the probe is correctly positioned is obtained by a marked increase in the blood velocity signal after manual compression of the thigh or calf. The position of the probe is adjusted during repeated calf compression to obtain the optimum signal, ensuring that the ultrasonic beam is at the same plane as the axial stream.
The patient is then asked to cough and to perform a Valsalva maneuver. Subsequently, the thigh or calf is compressed manually, producing a further augmented signal of flow toward the heart, and the compression is released suddenly. The absence of a detectable signal during the cough and Valsalva maneuver and on sudden release of thigh or calf compression means that there is no reflux. In contrast, a signal that lasts + 0.5 second (usually 1 to 4 seconds) indicates reflux.329-332-335 In the presence of reflux, the thigh or calf is again compressed, and the compression is suddenly released while the long saphenous vein is occluded manually or with rubber tubing placed around the thigh below the saphenofemoral junction.
Abolition of reflux means that the previously detected reflux is the result of an incompetent saphenofemoral junction. Persistence of reflux despite compression of the long saphenous vein indicates that it may be in the femoral vein. A duplex scan is often necessary to confirm reflux in the deep veins. In the presence of competent popliteal valves (see later), reflux in the superficial femoral is often associated with incompetent thigh perforating veins.
The saphenopopliteal junction is examined with the patient standing, facing away from the examiner and holding onto a railing or table. The weight of the body is taken mainly on the opposite limb. The knee on the side to be examined is flexed slightly with the heel on the ground and the foot slightly forward so as to relax the calf muscles.
The Doppler probe is positioned at the level of the skin crease behind the knee to obtain signals from the popliteal artery and popliteal vein. The venous signal is augmented by calf compression, and fine adjustment of the probe position ensures an optimum signal. The calf is then compressed manually to detect venous flow toward the heart. If there is no retrograde flow after the sudden release of calf compression, then there is no reflux, indicating the presence of competent valves.
If there is flow distally after the compression is released, then there is reflux in either the short saphenous or popliteal veins. If there is reflux, then calf compression with sudden release is repeated with an assistant compressing the short saphenous vein just distal to the probe. If reflux persists despite digital compression of the short saphenous vein, it is inferred that the reflux is in the popliteal or gastrocnemius veins.
Popliteal vein reflux can be detected by this method with a sensitivity of 100% and a specificity of 92% (ie, a false-positive rate of 8%).329 False-positive results are due to variations in the anatomy of the short saphenous vein and reflux in veins other than the popliteal.161
A limitation of continuous-wave Doppler ultrasound is that it cannot insonate an individual vessel because it detects flow in any artery or vein in the path of the ultrasound beam. At the level of the groin, reflux can be present in the long saphenous vein, its tributaries, or the common femoral vein. Doppler ultrasound cannot identify the exact site of reflux, and the findings should be confirmed with duplex scanning if surgery is contemplated.185 Continuous-wave Doppler cannot be used to detect the level of the saphenopopliteal junction.335 Reflux in the gastrocnemius or the Giacomini vein can give false-positive results, indicating deep venous reflux despite the presence of competent popliteal valves. For this reason, the finding of venous reflux in the popliteal fossa must be followed with duplex scanning if surgery is contemplated.

Duplex Scanning (Quantification of Reflux)
Duplex ultrasound techniques detect reflux in individual veins, whereas plethysmographic methods measure reflux in the entire leg. To date, it appears that plethysmographic measurements have an advantage because they provide evaluation of the severity of reflux. Duplex examination is performed with the patient standing.177 Reflux is elicited by manual or by pneumatic cuff compression of the calf with subsequent sudden release or rapid deflation. Three methods have been used in an attempt to evaluate the severity of reflux.

Rate of Reflux in at Peak Velocity
The rate of reflux (in mL/min) is calculated with the assumption that the veins are circular, so the cross-sectional área is calculated from the measured vein diameter. The reflux volume at peak reflux is calculated by multiplying the cross-sectional area by the mean peak velocity at the time of máximum reflux.336,337

Reflux Time
The valve closure time is the time taken for the valve to close after compression is released. Duplex scanning shows that the normal valvular closure time in the standing position is - 0.5 second,182 and reflux is considered to be present if the duration is longer. In limbs with multiple sites of reflux, individual valve closure times in the different vein segments have been added to produce the total valvular closure time, which has been reported as the total reflux time.199,266,337-342

Reflux Index
The reflux index is a modification of the valve closure time method. The ratio of backward to forward velocity (area under the curve) is calculated.343,344 It has been suggested that with the use of this method during exercise or postocclusive reactive hyperemia, it is possible to detect veins with inherent valvular weakness.
The severity of reflux quantified with duplex scanning with these techniques has shown a weak correlation with the plethysmographic quantification of reflux.262-345 This may be because there frequently are complex patterns of reflux in different vein segments.
It would be very complicated and laborious to arrive at an estimation of total reflux by adding reflux in superficial, perforator, muscular, and deep veins. In addition, in patients with primary varicose veins who are examined in the standing position, calf compression produces mainly cephalad flow in the deep veins, whereas on release of the compression, reflux is confined to the superficial veins. In the presence of reflux in both the superficial and deep veins, the ratio of cephalad flow in the superficial veins to that in the deep veins during calf compression may be different than that during reflux.
Quantification of reflux in individual veins with duplex scanning is not required in routine clinical practice. It is a research tool.

Venous Tone (Pressure-Volume Relationship)
The volume of blood contained within a segment of vein is a function of the transmural pressure (PTM), the mechanical properties (elasticity) of the venous wall, and the contractile state (tone) of smooth muscles within the media.
Transmural pressure is the difference between the intravascular pressure in expansión of the vein and the pressure in the surrounding tissues in compression of the vein. In normal limbs, interstitial fluid pressures are usually subatmospheric (mean - 2.5 mm Hg, range - 5 to 1 mm Hg).346
Venous volume compliance (Cv) can be defined as the ratio of change in venous volume (deltaV) to the change in transmural pressure (deltaPTM): CV=deltaV/deltaPTM. The venous pressure-volume curve is S shaped.
At subatmospheric transmural pressures when the outside pressure exceeds that of the blood on the inside and at high transmural pressure, venous compliance is low and little change in volume occurs in response to a relatively large change in transmural pressure. Between these 2 extremes, veins are very compliant, because large changes in venous volume occur in response to relatively small changes in venous pressures.347
Venous tone is minimal under normal resting conditions and is largely controlled by sympathetic alfa-adrenergic activity.348-350 When veins are filled sufficiently to produce a roughly circular cross section, the contraction of smooth muscle within the vessel wall has an important effect on venous volume.351
Peripheral veins have thicker walls with a higher smooth muscle content and constrict more intensely to sympathetic stimuli than do more centrally located veins. In general, veins contract in response to stimuli that increase cardiac output.352 Both direct cold exposure and increased sympathetic activity mediated by a reduced core temperature cause venous constriction.353 Warmth dilates cutaneous veins both directly by relaxing vascular smooth muscle and indirectly by decreasing sympathetic activity.
Methods of measuring compliance and venous tone depend on the simultaneous determination of transmural pressure and venous volume. Absolute venous volume cannot be measured directly, but changes in limb volume can be determined with air, water, or strain-gauge plethysmography. These changes are expressed as mL or mL/100 mL of tissue enclosed in the plethysmograph.
A disadvantage with plethysmographic methods is that they do not differentiate between volume changes in superficial and deep veins. Diameter changes in individual larger veins can be measured with B-mode scans.354,355
Because the measurement of tissue pressure is impractical, transmural pressure is estimated from the intraluminal venous pressure. Ideally, pressures are measured electronically through a catheter connected to a transducer with the catheter tip placed in the venous segment enclosed in the plethysmograph.356 Alternatively, pressures may be measured in a readily accessible superficial vein distal to the site of the plethysmograph.
This provides a reasonably accurate estimation of venous pressure in a supine individual, but corrections must be made to accommodate the change in hydrostatic pressure in standing subjects or whenever there is a vertical disparity in the location of the plethysmograph and catheter tip.
Another method is to calculate venous pressure from the length of the hydrostatic column from the site of volume measurement to the right atrium.348 This ignores the dynamic venous pressure produced by contraction of the left ventricle, but the error ís relatively small (5 to 15 mm Hg).
A third way of estimating venous pressure is to place a pneumatic cuff on the proximal part of the limb. The cuff is inflated to a pressure less than the arterial pressure, and venous pressure is assumed to approximate cuff pressure when the plethysmographic tracing reaches a plateau.
Because venous compliance varíes with the degree of venous distention, measurements are best made by plotting a pressure-volume curve over the physiological range of venous pressures. This can be accomplished by rapidly increasing and decreasing venous pressure with a proximal occluding cuff. Even then, the resulting curves describe a hysteresis loop, so the compliance as pressure increases differs from that as it decreases357,358 (Figure 14).





Figure 14. Tipical filling and outflow pressure-volume loops during venous oclussion in 3 individual legs. Each loop is traced counterclockwise and consist of inflow curve (white rhombus, rectangle, circle) and outflow curve (black). Lower half of loop represents pressure-volume relationship during inflow portion of oclussion plethysmography and is strong curvilinear with concave-facing pressure axis. Outflow curve starts at maximum volume reached at end of the inflow curve and traces from right to left. Note outflow of loop is less of a curve than inflow portion. Reproduced with permission fron Neglen and Raju.357






Due to viscous creep in the vein wall, these disparities are more pronounced when venous pressure is increased or decreased in increments, allowing the venous volume to stabilize at each succeeding pressure level.359 Moreover, at higher venous pressures, there is a slow loss of fluid through the capillary walls into the tissue spaces that causes a gradual increase in limb volume that is unrelated to venous elasticity. Tilting the patient to vary hydrostatic pressure is subject to the same errors.348
The measurement of venous compliance is not needed in routine clinical practice. It is a research tool that is helpful in elucidation of the pathophysiology of chronic venous disease and in assessment of the efficacy of therapeutic measures as indicated later. Clinical Significance and Potential Applications of Measurements of Venous Tone Venous compliance is crucial to our understanding of CVI and the venous pump mechanism.359,360 Venous compliance determines postural changes in limb volume, the rate of venous refilling, the shape and rapidity of VO during venous occlusion plethysmography, and the EF. The findings of recent research are summarized here.
It has been demonstrated that patients with varicose veins present a constitutional decrease in venous alfa adrenergic responsiveness,361 affecting not only the compliance of the varicose veins themselves but also that of those apparently healthy veins. By using strain-gauge plethysmography, Clarke et al362 demonstrated that the development of valve incompetence is probably secondary to reduced vein wall elasticity and increased arterial inflow. Postthrombotic legs are less compliant than normal legs mainly due to decreased compliance of the veins and surrounding tissues.360
Venotonic agents are able to decrease compliance and can be used clinically when the patient is experiencing discomfort because of venous hypertension.363 Dihydroergotamine is able to constrict not only normal but also varicose and postthrombotic veins.316 Several studies that compared the clinical and plethysmographic activities of venotonic drugs with those of a placebo in patients with CVI (with or without varicose veins, or the postthrombotic syndrome) have demonstrated that after 1 or 2 months of treatment, an increase in venous tone was accompanied by improvement in symptoms and in edema.364,365 Szendro et al366 studied patients with varicose veins before and after they wore elastic stockings for 6 weeks. There was improvement in the air-plethysmographic measurements and elastic modulus calculated from the pressure-volume curve.

Methods for Study of the Microcirculation
Microvascular investigations have been used as research tools and have provided information regarding the pathogenesis of skin lesions in limbs with CVI. Their usefulness in clinical decisión making has not yet been documented. However, because of their ability to detect early skin pathology, their prognostic value should be assessed in longitudinal studies.

Skin Biopsy
Skin biopsy samples can be taken from regions of interest through excision or punch biopsy. Different staining methods, including immunohistochemical, monoclonal antibody, or electron microscopic techniques, may be performed after fixation of the tissue. An indications for clinical use is the exclusion of malignancy in leg ulcers or in the diagnosis of skin changes when the underlying pathology is uncertain (eg, in vasculitis).367,368 In addition, biopsy has been extensively used as a research tool to study the pathophysiology of skin changes in CVI. Complex structural changes have been described in capillaries, lymphatics, and dermal tissue in CVI. Capillaries are dilated, elongated, and tortuous. The endothelium is damaged and shows an irregular luminal surface, increased cytopempsis, and dilated interendothelial spaces. The pericapillary space is enlarged to form "halos" from tissue edema. A glomerular-like appearance of "giant" capillaries that results from their elongation and distention is due to increased venous pressure and not to active proliferation, as can be demonstrated by the use of monoclonal antibodies (Ki-67) in the nuclei of proliferating endothelial cells.369,370
Changes in the pericyte envelope may also alter microvascular regulation and wound healing.371 Hemoglobin from extravasated erythrocytes and erythrocyte fragments is degraded to hemosiderin, which is responsible for hyperpigmentation. Microthrombosis in capillaries causes microinfarction. Microvascular ischemia is patchy and leads to the formation of granulation tissue from fibroblast and capillary proliferation. Wound healing results in scar tissue, which destroys the microlymphatic network.
Clinically, this process leads to lipodermatosclerosis and atrophy, and if compensating mechanisms are no longer able to repair the damage, ulceration ensues.369,372-374

Capilaroscopy
Different methods of intravital capillaroscopy can be used to study the morphology and function of skin capillaries in various parts of the body. Static capillaroscopy requires an ordinary light rnicroscope.94 For morphological studies, a magnification of X5 to X100 is appropriate. To enhance transparency, a drop of oil is applied to the skin area to be studied. Capillary loops can be easily identified in the nailfold because they run parallel to the skin surface, whereas only the apex of the loop can be observed in other parts of the body.
Morphometric evaluation includes the measurement of capillary diameter, capillary density, and shape indices obtained with digital ímage processing.375 Dynamic videomicroscopy enhances capillaroscopy. Red blood cell velocity can be measured with a video system.376 A computerized technique of capillaroscopy allows the recording of blood cell velocity over longer periods of time.94,377
Fluorescence videomicroscopy combines dynamic videomicroscopy with the intravascular injection of fluorescent dyes such as sodium fluorescein or indocyanine green.94 It delineates microvascular structures such as the pericapillary space or lymphatic capillaries that are not visible with ordinary capillaroscopy. Moreover, it can study dynamic processes such as microvascular flow distribution and transcapillary or interstitial diffusion of small solutes.378-379 These studies in patients with CVI show that the microvessels in areas with lipodermatosclerosis are dilated and coiled. The number of perfused capillaries is reduced in severe disease, and capillaries are lacking in areas with "atrophie blanche." Transcapillary diffusion of small solutes is increased and pericapillary halos are enlarged as a result of papillary edema.96,380,381 Mícrovascular alterations are patchy, and skin areas with normal capillaries usually coexist with regions that demonstrate microangiopathy. Capillarosopy is a research tool. Although it has enlarged knowledge of the pathophysiology of venous ulceration, it is currently of limited value in the clinical management of patíents with CVI.

Laser Doppler Fluxmetry
Laser Doppler fluxmetry (LDF) has been widely applied to assess local skin blood flow at various sites in human physiology studies and clinical medicine.382 Most laser Doppler instruments use a narrow beam of monochromatic light in the red to near-ínfrared range that is delivered to and diffused into the skin via an optic light guide. Photons that encounter moving objects (primarily erythrocytes) undergo a Doppler frequency shift. The back-scattered light is processed and a voltage signal is produced that is directly proportional to the velocity and number of moving cells within the sample volume.383,384
The technique is easy to use and provides a continuous and noninvasive measure of local blood flow, but to interpret the results, it is necessary to know its inherent limitations. The penetration depth of the laser light is assumed to be +/- 1 to 1.5 mm, but variations in optical properties of the skin (thickness, pigmentation, and so on) will greatly influence the penetration depth and the reading. The small sample volume that is used leads to considerable signal variability at adjacent skin sites, thus introducing problems of reproducibility. Despite this, changes in the laser Doppler signal correlate well with measurements obtained through other methods.385,386 However, because of differences in sample volume and interinstrument variability, the results are displayed in arbitrary units for which the term "red cell flux" has been proposed.
Because of methodological limitations, LDF is best suited to assess relative changes of local blood flow in response to various stimuli such as arterial occlusion, orthostasis, or thermal stress or to evaluate spontaneous changes of blood flux over time (fluxmotion).387 Flux is markedly increased at rest in dermatosclerotic skin.91,369 Results of fluxmotion analysis are conflicting. Some authors found no changes in fluxmotion patterns in relation to the severity of the CVI,135 whereas others reported an augmentation of fluxmotion frequency and amplitude.388 The physiological decrease in skin flow in response to lowering the foot (postural vasoconstriction) may be diminished in severe CVI.91,389 Because LDF mainly represents blood flow from the subcapillary level, these findings indicate hyperperfusion in affected skin areas in the deeper, nonnutritive microcirculation that persists during sitting and standing.
LDF has also been used to evaluate the effect of compression therapy on local skin blood flow. It has been demonstrated that elastic compression for several weeks or intermittent pneumatic compression for several hours tends to normalize the high red cell flux found in limbs with CVI and to induce normal vasomotion.91,390 Currently, LDF is an important technique for clinical microvascular research, but its application to routine clinical practice is limited.390,391

Transcutaneous Oxygen Tension
Transcutaneous oxygen tensión (TcPo2) is measured with a polarographic technique. The electrode is heated to 45°C to induce local skin hyperemia. TcPo2 can be defined as a measure of the surplus of oxygen molecules available for diffusion to the skin surface from the capillaries of the papillae under hyperemic conditions (expressed in mm Hg). Approximately 10 to 15 minutes is required to establish a steady-state condition.
With a transparent TcPo2 electrode, capillary microscopy and TcPo2 measurements may be performed simultaneously.92 A recent development is the incorporation of a laser Doppler probe.392 Patients with CVI and morphological changes in blood capillaries but without a reduction in capillary numbers already exhibit a significantly decreased TcPo2.92,393 Patients with more severe stages of CVI show a further decrease in TcPo2, which is linearly related to a reduction in capillary density. TcPo2 may even approach zero in areas of "atrophie blanche," indicating microvascular ischemia at these skin sites where blood-filled capillaries are totally lacking.92 TcPo2 measurements are of limited value for the clinical management of patients with CVI, but the technique is of great interest for studying the pathophysiology involved in the development of skin changes and ulceration.

Fluorescence Microlymphography
Fluorescence microlymphography is the only method available that can analyze structure and function of the initial lymphatics in the skin in humans in vivo. To stain the lymphatic microvessels, 0.01 mL of a 25% solution of fluorescein isothiocyanate (FITC)-dextran (molecular weight 150000) is injected subepidermally with a microneedle (external diameter 0.2 mm) and a microsyringe.379 FITC-dextran is mainly cleared by lymphatics, because it has a high molecular weight. The small size of the needle and minute volume injected guarantee that the puncture causes only minimal discomfort to the patient. The subepidermal depot is visualized with incident light fluorescence microscopy.
The network of lymphatic capillaries is filled from this depot. The dynamics of dye spread into the network, the extensión of the dye, and the morphology of the lymphatic network are observed and documented on tape recordings or photographically with high-speed fluorescence-sensitive film. Microlymphatic flow velocity can be determined during the filling of the superficial capillary network.394 Fluorescence microlymphography is virtually atraumatic and easily performed within 15 to 30 minutes.
Microlymphatic morphology is essentially normal in patients with CVI but without trophic skin changes,107 although the propagation of the dye into the superficial network is increased. However, definite microangiopathy is visible in skin areas, with induration and hyperpigmentation. Some network meshes are interrupted; and fragments of capillaries are stained far away from the dye deposit, probably due to valvular insufficiency and retrograde flow in collectors and precollectors107,394; and there is increased macrovascular leakage from the damaged microvessels.378 Fluorescence microlymphography is able to confirm the presence of lymphatic microangiopathy that contributes to lipodermatosclerosis. The technique is most valuable for clinical research into the pathophysiology of edema and skin changes in patients with CVl.108

Interstitial Pressure Measurements
Pressure measurements in the microcirculation and surrounding tissues became possible in the 1960s with the servonulling pressure system developed by Wiederhielm et al395 with further modifications by Intaglietta et al.396 In humans, pressure has been successfully determined in nailfold capillaries,397 microlymphatics,398-400 and the interstitium.400 Interstitial pressure can be measured in 2 phases.
In phase 1, the investigator visualizes the microcirculatory unit through a video microscope after staining with a subepidermal injection of FITC-dextran (molecular weight 150000). In phase 2, the interstitial pressure is determined by introducing a glass micropipette 2 nm in diameter connected to a servonulling pressure system.401-403 The tracing of the interstitial pressure is almost a flat line without the typical pressure waves recorded in capillaries or in microlymphatics.400 The measurement of interstitial pressure is useful in the study of the evolution of the disease but as yet has no clinical application.
The limitations of the method are the high cost of the equipment and the need to train operators, with at least 2 needed for this very delicate technique.

Lymphoscintigraphy
Lymphoscintigraphy with radioactive plasma protein to evaluate patients with lymphedema was first reported in the 1950s.404 Because of improved imaging and a better selection of optimal size of the labeled particles, there has been a continuous improvement in the past 2 decades.405-411
Significant experience has accumulated with technetium-99 antimony trisulfide colloid409,412-413 and Tc-human serum albumin.407 The optimal size of particles for delineation of lymph vessels and lymph nodes in extremity lymphoscintigraphy is between 10 and 40 nm. About 0.1 to 0.2 mL of the radiolabeled colloid (350 to 450 microCu) is injected into the web space between the second and third toes with a tuberculin syringe and a 27-gauge needle. A gamma-camera with a large field of view is positioned to include the inguinal región. Exercise with a foot ergometer starts immediately after the injection. The patient exercises for 5 minutes and then for 1 of every 5 minutes for the remainder of the first hour.
Dynamic anterior images are obtained every 5 minutes during the first hour. Total body images over 20 minutes are obtained at 1 and 3 hours after the injection. Six- and 24-hour total body images are obtained in selected patients.
Lymphatic function can be assessed qualitatively from visual interpretation of scintigraphic images. Semiquantitative interpretation includes the measurement of the appearance time of radioactivity in regional lymph nodes during dynamic imaging. Quantitative interpretation includes the measurement of colloid clearance from the injection site or its appearance at the groin.414 A semiquantitative scoring system was initially described by Kleinhans et al415 in which the "transport index" was graded from 0 for scans with normal transport to a maximum of 45 for scans with no evidence of lymphatic transport. In this scoring system, lymphatic transport kinetics, isotope distribution pattern, lymph node appearance time, assessment of lymph nodes, lymph vessels, and sites of abnormal tracer accumulation are assessed and scored (Table 11).











Significant activity in major regional nodes within 15 minutes indicates rapid lymphatic transport, and the absence of activity at 1 hour suggests delayed transport. Early visualization of the liver without activity in lymph nodes suggests that the injection of the tracer was intravenous.
Lymphoscintigraphic findings in patients with venous disorders may vary depending on the chronicity of the disease. Increased lymphatic transport is evident in acute venous occlusion when capillary filtration and edema in the extremity increase,416 but delayed transport may be seen in some patients with chronic venous disease.413-416
The site of the injection also affects results.417 The injection of tracer into an ulcer border may result in a decreased or absent uptake in the lymph nodes, whereas injection into the toe web may lead to increased uptake.417-418 Cambria et al413 reported a prospective evaluation of the transport index ín 386 extremities. The average transport index for asymptomatic extremities was 2.6; the value was 23.8 for lymphedematous limbs. A transport index of > 5 was highly suggestive of lymphedema (sensitivity 80% and specificity 94%) but could not be used to distinguish between primary and secondary lymphedema.
Lymphoscintigraphy excluded lymphatic pathology as a cause of extremity swelling in one third of the cases. Other authors also recommend time-activity curves from dynamic imaging over lymph nodes to analyze lymphatic function.410 However, Gloviczki et al412 showed that this was highly variable in normal extremities, so it was difficult to interpret the data. It appears that it is sufficient to use visual interpretation of images and the semiquantitative transport index to describe lymphatic transport. Contrast lymphangiography is the gold standard, but it has been performed in very few patients in most published series, so the true sensitivity and specificity for lymphoscintigraphy are not well defined.
Lymphoscintigraphy has now become established as the principal noninvasive technique for the evaluation of patients with chronic lymphedema. It is also suitable for the assessment of lymphatic function in patients with chronic venous disease. However, further studies are needed to demonstrate the ability of the lymphatic system to compensate for the effects of CVI by increasing lymphatic drainage and to determine whether the symptoms are made worse if lymphatic drainage is inadequate.


Measurement of Clinical Parameters

CEAP Classification of CVI
A classification system is a basic tool for uniform diagnosis and meaningful scientific communication on CVI. For too long, reliance has been placed on the clinical appearance of the superficial effects of CVI, such as varicose veins, skin changes, and ulceration, without requiring accurate objective testing of the venous system to substantiate the diagnosis. This practice has caused errors of diagnosis and has been largely responsible for the poor correlation of results between different treatment regimens.
There have been several classifications9,419-429 (Table 12) and severity scoring systems430 in the past that have added to our understanding of venous disease, but all lack the completeness and objectivity needed for scientific accuracy.


















The 1988 report of the Joint Council of the SVS/ISCVS was a step forward in addressíng the cause and pathogenesis of CVI in a more organized way.424 The consensus report of the American Venous Forum in 1994 presented the CEAP classification, which addressed the clinical, etiological, anatomic, and pathophysiological mechanisms of CVI with the need for objective testing.
This CEAP classification was the basis for the chronic venous portion of an SVS/ISCVS update on reporting standards by Porter and Moneta.429 It presents a new level of diagnosis in CVI but requires a change of habit for the physician. The requirements for CEAP are similar to those customarily followed in the diagnosis of arterial disease where it would be unthinkable to treat without knowing the cause (atherosclerosis or embolism), the anatomic distribution (iliac or femoral), and the pathophysiology (occlusion or stenosis). Relying on the clinical diagnosis alone for chronic venous disease would be the equivalent of trying to treat arterial disease by prescribing various medications after simply looking at the ischemic toe.
The CEAP classification is contained in Tables 13 through 17 with abbreviations conveniently expressed for easy and rapid presentation.






















































For example, a patient with symptomatic varicose veins that extend throughout the whole territory of the long saphenous vein and with swelling, pain, and lipodermatosclerosis associated with incompetent perforators in the calf with a normal deep system as shown by investigations is denoted C2, 3, 4s - Ep - As2, 3, p18 - Pr.
In addition, the consensus report describes methods of both severity scoring for the disease process and a disability rating for the patient (Tables 18 and 19). These make it possible to record a patient's condition at a given time that may then be altered with treatment so it can provide a measure of the efficacy of the treatment protocol. In this way, the CEAP classifícation can be used over time as a tool to measure change.























Practical use of the CEAP classification does not demand that every patient undergoes the full gamut of diagnostic investigations. A simple problem such as telangiectasia is always primary in cause and superficial in location. It is not concerned with a pathophysiological change in major veins, so a simple designation of C1 (a or s) is sufficient to show that the clinical problem is telangiectasia modified by whether it is symptomatic. Varicose veins (C2) may also be a simple clinical problem that is usually associated with reflux but can present many variations of differing causes, anatomically always superficial but varying from the greater to the lesser saphenous systems. The diagnosis requires the hand-held Doppler and is frequently improved with duplex scanning. Determination of the hemodynamic severity will require plethysmographic or pressure studies. Phlebography or varicography can help to map disease before or during surgery, although they are not indicated for the routine diagnosis of superficial varicose disease. As the severity progresses to C3 and above, vascular laboratory investigations become mandatory.
CEAP has been promulgated around the world. It has been published in 23 separate journals and books in 8 languages and in 5 continents (Table 20).





















Given this wide exposure, general adoption should occur when sufficient researchers are educated as to its advantages and begin to use it for their publications. A criticism has been raised that CEAP is too complex, but the alternative of continuing to work with inadequate diagnostic criteria is unacceptable. There is a need to educate those who publish CVI subjects regarding its advantages, while working to fínd an acceptable format. Several groups that have used it have found it valuable and practical.431-434
Although the CEAP classification provides a system for documentation of the severity of CVI, it is often necessary to evaluate individual symptoms, signs, or physiological parameters; clinical outcome; and quality of life. The available methodology is summarized here.

Pain
The assessment of pain is subjective but can be evaluated with analog scales and analgesic requirements.

Varicose Veins
Telangiectasia, reticular veins, and varicose veins can be assessed visually with photographs and diagrams.9

Lipodermatosclerosis
The degree of induration caused by lipodermatosclerosis can be measured with different techniques, including a 20-MHz ultrasound B-scan,435 a "durometer,"436 and a tissue compliance monitor.437

Edema and Leg Volume
Volumetry to measure leg volume is an old438 but recently updated noninvasive technique. Volumetry does not quantify edema but rather the short-term variations that reflect changes in edema. It can only show changes for each individual. It is reproducible provided measurement conditions are carefully standardized.
Volumetry allows an accurate comparison of changes in the same leg over time or with changing conditions as displayed by different amounts of edema (eg, morning versus evening, supine versus standing, resting versus after exercise, before versus after the application of a venous tourniquet, before versus after treatment, and at the beginning versus at the end of the follow-up period). In a recent consensus meeting, international experts considered volumetry to be the gold standard to prove and compare the efficacy of any treatment to reduce edema in CVI.439
The leg is immersed in a Plexiglas boot. The displaced water is collected, and its volume is measured.440,441 Other techniques have been described but are performed in a nonphysiological state: the supine position.442-448
Three parameters must be standardized: the position of the leg, the hour of measurement, and the water temperature. The accuracy of the method is 0.7% for 2 consecutive measurements in the same leg by 2 different observers; its intraindividual repeatability is 1.3%; and its interindividual variability is 6.2% in normal control subjects and 11.2% in patients with CVI.441
Volumetry has been use to prove that legs that ache are those that swell the most,449 that leg volume increases during daily activity and that this increase correlates with the severity of CVI,450 and that leg volume may increase during long distance flights448 and that it diminishes after venous surgery451 and after different drug treatments for venous or lymphatic insufficiency.452-455 Studies are now in progress to test whether changes in leg volume correlate with the severity and prognosis of CVI.
Other methods of measuring edema include leg circumference measurements with tape,454,456 electro-optic volumetry,444,446,447,457 and computerized limb volume measurements.445

Calf Muscle Pump Function
Calf pump failure is a concept that was introduced in the 1960s458 and further developed in the 1980s.459 The action of calf muscles on deep venous return has been compared with that of the heart muscle, and reproducible measurements of its efficacy are now possible.284-460 However, anatomic prerequisites for the calf pump system to function properly are often neglected in the clinical evaluation of CVI. A deficient calf pump is probably the key factor for the high rate of CVI among elderly persons.461,462 A normal plantar arch, normal ankle mobility, and normal painless calf muscle action are required for normal venous calf pump function. Clinical evaluation of CVI should therefore include assessment of the ankle joint135 and check for the presence of any associated muscular, articular, or neurological disease.459

Ulcer Healing
To quantify ulcer healing for clinical trials, it is necessary to develop methods to calculate and standardize the ulcer geometry and to define appropriate endpoints. The area of the ulcer can be measured with planimetry, with its outline drawn on a transparent sheet, with scaled photography, or with direct ultrasonic digitized measurements with a light pen.462
Alternatively, it can be calculated by multiplying the 2 maximal perpendicular diameters to obtain an area in cm2. If this is then multiplied by pi/4, the calculated rectangular area is transformed to an elliptic one. Gillman463 published a method for the calculation of wound-healing rates that corrects for differing sizes and shapes by dividing the area of the ulcer by its perimeter.
The changes in the geometrical measurements per unit time mentioned earlier are often used in clinical trials.464,465 However, complete healing and the initial healing rate are the most common end points used.26,466-467 Complete healing is quantified either by the time taken to achieve it for each ulcer or by calculating the percentage of ulcers healed during a finite period of time. The initial healing rate is defined as the rate of healing over the course of a first time period, such as the first 4 weeks. With Gillman's equation (A/P) and considering the change of the ulcer area corrected for size, the healing rate per unit time is derived as ∆A/P(a-b) = (Ab-Aa)/ ([Pa,+Pb] /2)(b-a), where A is the area of the ulcer, P is its perimeter, a is the start of the observation period, and b is its end.
Percentage of area decrease per unit time is not a valid end point, because this depends on the size of the ulcer.464 However, the Gillman equation corrects for different initial ulcer sizes, so it meets the needs of clinical studies for standardized and comparable measurements. 466,468, 469 From the patient's point of view, "complete healing" is the most important outcome, although from the practical point of view, the "initial healing rate" seems to be more suitable for reporting results. Possibly, a combination of both should be used.
Cumulative rates can be used for studies with adequate numbers of patients. The proportion of ulcers that healed in the North American Subfascial Endoscopic Perforator Surgery (NASEPS) study was estimated with the life table analysis.433 A cumulative distribution function for the period from the time of an intervention such as surgery to healing can also be used to determine its rapidity. In addition, long-term follow-up studies can use cumulative ulcer-free survival time to document the recurrence rate for venous ulcers.

Evaluation of Clinical Outcome
The best way to assess the clinical outcome after treatment for chronic venous disease depends to a great extent on the clinical presentation. As indicated earlier, it is difficult to evaluate improvement in cosmetic appearance or subjective symptoms such as cramps, itching, pain, or fatigue. Also, the patient's preference and acceptance of different treatments must be considered.
Symptoms can be evaluated by the clinician or by patient self-report. In the latter case, a questionnaire should be completed at leisure outside the physician's office. This method is used most frequently for evaluation before, during, and after treatment. Patients can be asked to provide global ratings of improvement in symptoms470 or to use quantitative scales such as a Likert scale471-472 or a visual-analog scale.473
It is much easier to accurately measure improvement in clinical signs, such as diminishing size, healing, or recurrence of an ulcer or change in the circumference or volume of the extremity, than to evaluate symptoms.
The efficacy of treatment is best established through the documentation of improvement in signs and symptoms, supported if possible with laboratory tests; recording of all adverse effects of treatment; and a follow-up of at least 6 months and preferably 1 year.
The updated CEAP classification of CVI that assigns patients into 1 of 7 clinical categories (C0-6) based on increasing severity of clinical symptoms and signs should be used. All patients should be assigned a CEAP clinical class before and after treatment. A lower clinical class after treatment represents clinical improvement.
A clinical scoring system to assess severity was suggested by the Consensus Committee of the American Venous Forum on Chronic Venous Disease. This system scores the severity of pain, edema, venous claudication, pigmentation, and lipodermatosclerosis; ulcer size, duration, and recurrence; and number of ulcers (Table 18).
An example of this system is the assessment of the outcome of operations on superficial and perforating veins assessed in a recently published study on the early results of the NASEPS registry.433 The researchers analyzed patients who underwent endoscopic perforator interruption to treat advanced chronic venous disease. Seventy percent had active ulcerations and 72% had surgery on the superficial veins in addition to perforator interruption. The average clinical score was 9.4 (range 0 to 18) before surgery and decreased to 2.9 after surgery (range 0 to 12, P= 0.0001) (Table 21).






















Adverse effects from treatment must be recorded. Complications from surgery or sclerotherapy such as death, wound infection, superficial thrombophlebitis, cellulitis, and saphenous neuralgia should be reported.
The level of disability before and after treatment can also be assessed with a disability score as suggested by the CEAP Consensus Committee (Table 19). This scoring system evaluates functional outcome and the ability to return to work with or without a support device. Patient compliance with conservative measures, such as elastic stockings, a compression pump or leg elevation, should be accurately recorded by a physician. The reliability, accuracy, and validity of the different scoring systems need further evaluation.

Quality of Life
Quality of life in patients with CVI has been assessed with generic and with disease-specific measures. These studies were recently analyzed in detail.2 The most frequently used generic measure is the Medical Outcome Study Short Form Health Survey (SF-36), a 36-item questionnaire that covers 8 health dimensions, including physical and social functioning, role limitations due to physical and emotional problems, mental health, vitality/energy, bodily pain, and general health perceptions. The SF-36 has been used both in patients with varicose veins and in those with venous ulcers.474,475 In the study by Garratt et al,474 SF-36 satisfied strict psychometric criteria for validity and internal consistency and confirmed a significantly lower quality of life in patients with varicose veins compared with an age-adjusted sample from the normal population.
Because specific complaints from patients with chronic venous disease were not identified with currently used generic quality-of-life questionnaires, specific questionnaires were developed to assess the functional and psychological effects of venous disease.25,476,477 The most recent of these is the Chronic Venous Insufficiency Questionnaire (CVIQ) used by Launois et al.477 The questionnaire has been validated and found to meet stringent psychometric criteria, including reliability, content, construct validity, and responsiveness. In a randomized trial of 934 patients, the CVIQ showed that quality-of-life scores were significantly lower in patients with venous insufficiency than in control subjects without venous disease.
Health-related quality-of-life studies should be used in the future to assess overall outcome and to justify treatment for chronic venous disease. Both generic and venous disease-specific measures should be used.


Application of Methods in the Investigation of Chronic Venous Insufficiency

General Remarks
The second part of this document demonstrates how different tests provide different information. There is no one test that can provide all of the information needed to make clinical decisions and to plan a managemenl strategy. By asking and answering relevant clinical questions, more information becomes available and the diagnosis becomes more precise.
What is needed is clear knowledge of the tests required to arrive at the correct clinical diagnosis with the minimum expense and inconvenience to the patient. Noninvasive venous investigations are performed by vascular technologists (or physicians) who are trained to apply the proper tests to provide answers to the key questions required by the clinician. The aim of the third part of this document is to demonstrate how venous investigations can be applied for both clinical management and research.
A number of clinically relevant questions should be asked by a physician when a patient presents with symptoms and signs suggestive of CVI.
Is there any CVI present? If there is, is it the result of obstruction, reflux, or both? What is the anatomic extent of the obstruction or reflux? What is the severity of the obstruction, and what is the severity of the reflux? Is there a calf muscle pump failure due to a musculoskeletal problem? What is the combined hemodynamic effect of obstruction, reflux, and calf muscle pump failure? Are the abnormalities that are found responsible for the clinical picture, and are they fully responsible, or are there any other contributory factors? What is the prognosis for the patient? What information is needed to make the correct therapeutic decision, and what is the way to obtain the information in the most efficient manner? How should the therapeutic results be evaluated?

Detection of Reflux and Obstruction
The initial evaluation of patients with CVI consists of determining the presence or absence of reflux, obstruction, or both. As stated in the first part, the history and clinical examination will indicate the clinical presentation. The use of a pocket Doppler ultrasound by the physician in the outpatient department can provide information to elicit the presence of reflux at the saphenofemoral junction, poplíteal fossa, and superficial veins and obstruction at the femoropopliteal or iliofemoral segmente in 80% to 90% of patients.
A proportion of patients (20% to 30%) have more complicated conditions and will require further investigation. Many will have had a previous operation on their veins or unclear results of their Doppler ultrasound test. Those with reflux in the veins of the popliteal fossa and the group in whom incompetent calf perforating veins are suspected will require further clarification.

Localization of Reflux and Obstruction
In the past, a phlebogram was required to localize venous obstruction, but duplex scanning has proved to be equally effective, particularly for lesions distal to the common femoral vein. Phlebography also can be accurately used to localize the sites of deep-to-superficial reflux (saphenofemoral, saphenopopliteal, incompetent perforating veins) and the extent of reflux in the deep veins.
Duplex scanning is proving to be simpler and more accurate, so ascending and descending phlebograms are now rarely performed. The main indication for descending phlebography is the detection of incompetent valves with floppy cusps in the deep veins. Preoperative duplex scanning is the method of choice to localize the sites of incompetent perforating veins and the level of the saphenopopliteal junction, which is extremely variable. As a result, the position of the incision in the popliteal fossa can be precise.

Quantification of Reflux and Obstruction
Quantitative measurements of outflow obstruction and reflux may be needed for research, particularly in the study of the natural history of CVI, and for the assessment of established and new methods of treatment. These quantitative measurements have opened new avenues that lead to a better scientific basis for patient management.
Until recently, AVP measurement was the only quantitative test available. Although it is invasive, it indicates the severity of venous hypertension as it measures the end result of both reflux and outflow obstruction. However, new noninvasive tests, such as air-plethysmography, can distinguish the relative contributions from venous obstruction, reflux in the superficial or deep veins, and calf muscle pump function, whether the result of intrinsic venous disease, a musculoskeletal problem, or both.288,478

Investigation of Patients in Different CEAP Clinical Classes
A simple method of selecting the appropriate tests is to grade the diagnostic investigations into 3 levels:
Level I involves the clinical examination (history, physical examination that includes an evaluation of the arterial circulation, and venous examination with the hand held Doppler).
Level II involves noninvasive investigations (duplex scanning, plethysmography).
Level III involves invasive investigations (ascending and descending phlebography, varicography, pressure measurements).
A simple guide to the level of investigation in relation to CEAP clinical classes (Table 14) is given here; this may be modified according to clinical circumstances and local practíce.

Class 0/1: No Visible or Palpable Signs of Venous Disease; Telangiectases or Reticular Veins
Level 1 investigations are usually sufficient. However, symptoms such as aching, heaviness, and leg-tiredness in the absence of visible or palpable varicose veins are an indication for duplex scanning to exclude reflux in the saphenofemoral, saphenopopliteal, or gastrocnemial veins, which often precedes the clinical manifestation of varices; Also, duplex screening should be performed to exclude proximal chronic deep venous occlusion, which, in the presence of competent popliteal valves, will not produce any skin changes or ankle edema.

Class 2: Varicose Veins Present Without Any Edema or Skin Changes
Level I may be sufficient, but level II (duplex scanning) should be used in many practices as indicated later. Level III may be needed in special cases.
Level I investigations are sufficient in patients with varicose veins confined to the long saphenous system on hand-held Doppler with reflux at the saphenofemoral junction and absence of reflux in the popliteal fossa and whose varicosities are controlled by pressure at the saphenofemoral junction or by a high thigh tourniquet. Many patients with primary varicose veins fall into this category.
Varicose veins that involve the short saphenous system, reflux in the popliteal fossa on hand-held Doppler, or suspected incompetent thigh or calf perforating veins because the varicosities are not controlled by a high thigh or below knee tourniquet, respectively, are indications for duplex scanning. In such circumstances, duplex scanning provides essential information for management by identifying the anatomic site of reflux in the popliteal fossa (short saphenous, gastrocnemial, or popliteal). Duplex scanning is also used to mark the position of incompetent perforators and the level of the saphenopopliteal junction before surgery.
Patients with recurrent varicose veins and those with a history of documented or possible DVT must be investigated with duplex scanning. Air-plethysmography to estimate the outflow fraction (OF1) is often used as a screening test to exclude functional obstruction. Level III investigations may be considered if a duplex scan shows deep venous reflux or obstruction.
The presence of varicose veins filling from unusual sites such as a lateral thigh incompetent perforator or vulvar veins is also an indication for duplex scanning. Filling of the varicose veins in the thigh and leg from vulvar veins may be an indication for descending ovarían phlebography.

Class 3: Edema With or Without Varicose Veins and Without Skin Changes
Level II investigations are used to determine whether reflux or obstruction in the deep veins is responsible for the edema. If obstruction is demonstrated or suspected as a result of duplex scanning, the use of plethysmography will grade its severity. In the presence of isolated edema if level II investigations are abnormal, level III investigations of the deep venous system must be considered. If venous investigations are normal, lymphedema is the most likely diagnosis. If the diagnosis is in doubt, lymphoscintigraphy may be necessary.

Class 4/5/6: Skin Changes Suggestive of Venous Disease, Including Healed or Open Ulceration With or Without Edema and Varicose Veins
Level I and II investigations will be required in the majority of these patients. Selected cases, mainly candidates for deep venous reconstruction, will proceed to level III.
Level I investigations may be sufficient in some patients with irreversible muscle pump failure due to neurological disease or severe and noncorrectable reduction of ankle movement or where there is a contraindication to surgical intervention. Some investigations may have to be deferred, particularly in patients with painful ulcers. Most patients will be subjected to level II investigation. Candidates for deep venous reconstruction will require level III.


Assessment of the Effect of Different Therapies

Compression
The pressure exerted on the leg with compression devices should be measured at different levels to show the proximal and distal pressure gradients at various time intervals and with the assumption of different bodily positions.
The clinical outcome of ulcer healing and rates of recurrence can be used to assess the effect of compression therapy. One reliable method is to measure the proportion of patients whose venous ulcers heal within 8 to 12 weeks.29,479-485 Another method is to record the diminution of a radius per unit time. The latter is more valid than the widely used percentage area reduction because it is independent of the initial ulcer size.463,464,486 The recurrence rate after healing is an important indicator of efficacy and patient compliance.89,487-491
Reduction in edema can be measured with tape,456,492 with volumetric methods such as water displacement, or with the use of optoelectronic instruments.441,442,445,447,455
The narrowing of veins through compression can be demonstrated with phlebography493 and with dúplex.29,494-496 Reduction in venous volume can be demonstrated with air-plethysmography.280,297,366,497 A shift of blood volume from the compressed extremity toward central regions of the body can be shown with labeled red blood cells.316,498
Reduction in venous reflux is an important effect of compression. It has been measured in the past with PPG499 and more recently with air-plethysmography.298 An increase in venous return may be demonstrated by injecting radioactive tracers into a dorsal foot vein and measuring the transit time in the compressed extremity.311 Duplex investigations for both reduction in reflux and increase in venous return have revealed equivocal results,29,494-496 probably due to methodological problems.
An improvement in venous pumping with elastic compression can be shown with foot volumetry,311,314,500,501 strain-gauge plethysmography,495,502 or air-plethysmography.280,298,497,503 The literature is equivocal concerning the effect of compression on AVP29,280,311,500,504 but this may be because of the different compression bandages that are used.
The effect of elastic compression on the skin microcirculation can be shown by laser Doppler fluxmetry,390,505,507 transcutaneous oxygen measurement,506,508 and skin biopsies.509 A reduction in arterial inflow toward normal can be demonstrated with clearance techniques and with plethysmography.299,510,511
The influence of compression on lymphatic drainage in CVI is a widely underestimated effect that can be assessed with lymphoscintigraphy, fluorescence microlymphography, and microlymphatic pressure measurements.512,515
Intermittent sequential pneumatic compression in combination with elastic compression increases the rate of ulcer healing far more than elastic compression alone,482 but the precise mechanism is not known. There is a marked reduction in laser Doppler flux and an improvement in vasomotor activity within minutes after its application.382

Medication
Although the effect of drugs on physiological parameters such as venous tone, venous hemodynamics, capillary leak-age, and lymphatic drainage can be evaluated with methods described in this monograph, the only valid way to evaluate the clinical effect of a drug is with a well-conducted clinica] trial that fulfills basic clinical, scientific, and ethical requirements.516 The trial must be randomized and ideally double-blind with adequate power and should try to answer a well-defined question that corresponds to the disease state. The clinical problem should be classified before and after, with the use of a scoring system such as CEAP.
Symptoms, signs, and quality of life should be evaluated as indicated here at the beginning, during, and at the end of the clinical trial. Hemodynamic evaluation should be performed, preferably with noninvasive techniques that are selected according to which is most likely to provide an answer to the question asked. The specific effects of the drug should be monitored under standardized conditions such as room temperature and time of day. Any unexpected events, both subjective and objective, should be noted and followed up.

Sclerotherapy
There are 2 consensus statements on guidelines for sclero-therapy.517,519 Sclerotherapy is effective for some forms of CVI, but it is very difficult to assess results because there are many different techniques. It is desirable to use the CEAP classification to define the precise venous problem. In addition, vein size must be measured so future prospective randomized trials with long-term follow-up can define the proper place of Sclerotherapy in relation to clinical outcome. The areas that require controlled trials of Sclerotherapy include perforating veins, superficial and residual veins, secondary varicose veins associated with the postthrombotic syndrome, prevention of ulcer recurrence, and some venous dysplasias.

Surgery of the Superficial and Perforating Veins
There are 3 reasons to evaluate the results of surgery. The first is to document long-term clinical improvement in individual patients and to establish whether further treatment is required. Second, a fundamental knowledge of the pathophysiology is required to evaluate established and new therapies for research purposes. Third, evaluation is needed to audit and assess cost effectiveness.
Clinical assessment with the CEAP classification may be sufficient for patients treated for isolated superficial vein incompetence. Postoperative investigation may be performed to evaluate completeness of surgical treatment in patients with more advanced CVI. Objective assessment is required for patients who fail to improve, develop recurrent symptoms or signs, or are participating in clinical trials. Duplex scanning is the test of choice to confirm the abolition of superficial or perforator reflux and air-plethysmography or foot volumetry to quantify the hemodynamic changes.

Deep Venous Reconstruction
Improved functional outcome after deep valve reconstruction has been established,242,520,521 but this challenging field requires further study and evaluation. A randomized study that compares traditional nonsurgical methods with surgical reconstruction must be performed. Clinical and quality-of-life outcomes should be complemented by appropriate investigations such as duplex scanning and air-plethysmography or foot volumetry, which should provide both anatomic and functional evaluation of the surgical outcome.


Investigation of Congenital Malformations

Congenital vascular malformations are present in a relatively small percentage of patients, but the magnitude and severity of the clinical manifestations can be staggering. The arterial, venous, and lymphatic systems may be involved, either alone or in combination, as in the Parkes-Weber, Maffucci, and Klippel-Trenaunay syndromes. The diagnosis and management of these congenital vascular malformations require a multidisciplinary approach and knowledge of the pathophysiology involved.
The physician must decide how far it is necessary to investigate a patient with a vascular malformation. If the clinical symptoms indicate that something should be done, the first challenge is to decide how to approach the problem. If not, then the instinct to investigate should be replaced by commonsense and consideration for the patient. Well-vascularized tumors may mimic vascular malformations522 and should be distinguished from the latter through biopsy where appropriate.

Diagnostic Process
The diagnostic process begins with a good clinical evaluation. The presence of tissue hypertrophy (gigantism), varicose veins, and a port wine stain suggests a genetic mutation that consists of the Klippel-Trenaunay, Parkes-Weber, and Sturges-Weber syndromes. Genetic investigations are justified only in specifíc research protocols related to genetics and in centers with the facilities to conduct them. Venous malformations as well as congenital arteriovenous fístulae cause venous hypertension, leading to CVI. Bone and cartilage anomalies are common in the Maffucci syndrome, where the presence of large hemangiomas and phleboliths makes it necessary to investigate the soft tissues in addition to the skeleton. The clinical examination will determine the system or systems that must be investigated.

Hemodynamic Evaluation
A bidirectional Doppler examination can assess reflux in the superficial venous system, the abnormal vena marginalis of the Klippel-Trenaunay syndrome, and the large perforating veins found in the presence of arteriovenous fistulas. Duplex scanning with color flow imaging detects the sites and extent of reflux, the presence or absence of a deep venous system, and venous aneurysms, which occur in 5% to 20% of patients with congenital venous malformations. Venous occlusion plethysmography can be used to measure increased resting blood flow in patients with arteriovenous fistulas. Plethysmographic methods may document the large venous capacitance typically seen in patients with the Klippel-Trenaunay and Parkes-Weber syndromes. Obstruction of VO due to deep venous atresia of the proximal trunks will also be documented. Readings should be repeated with compression of the entire large lateral collector shortly before the thigh cuff is deflated to assess the importance and contribution of the large vena marginalis in the VO of the limb. Air-plethysmography will quantify reflux in patients with venous insufficiency due to congenital avalvulia or phlebectasia. Air-plethysmography can document the hemodynamic derangement in the venous circulation and calf muscle pump function. AVP determinations are important to objectively document venous hypertension. This is especially necessary in patients with proximal venous obstruction when bypass procedures are contemplated. In patients with extensive congenital arteriovenous fistulas, cardiac catheterization is sometimes necessary to assess cardiac function and the magnitude of shunting. In such cases, serial arteriography or digital computed arteriography assists in mapping the areas of shunting and their magnitude. A small percentage of Klippel-Trenaunay patients have "hypoactive" arteriovenous shunts that can be detected only with isotopic techniques.523,524 Venous occlusion plethysmography as well as the estimation of volume flow in the common femoral veins by duplex scanning can be used to measure increased resting blood flow in patients with arteriovenous fístulas.

Venous Imaging
Ascending and descending phlebography and direct varicography are required in the investigation of venous malformations. Varicography demonstrates the anatomy of the region and locates the point al which the abnormal lateral collector drains into the deep system. Descending phlebography is used to assess reflux and detect the absence of valves; ascending phlebography is used to assess and detect the distribution of the collector systems, perforators, and degree of aplasia or hypoplasia of the deep system. Some patients with the Klippel-Trenaunay syndrome have a large venous capacitance, so ascending phlebography must be performed in 2 phases: the first with the superficial system compressed by elastic bandages and the second without compression. The deep system is visualized during the first phase. Compression prevents the misinterpretation of deep venous hypoplasia/ aplasia by blocking the superficial system and allowing the deep veins to fill preferentially.

Imaging of the Skeleton and Soft Tissues
Both spiral CT and MRI are used to assess the extent of a venous malformation. MRI augments the diagnosis of large vein atresia and shows the localization of abnormal venous collectors and the degree of enlargement of an extremity and clearly displays the distribution of the malformation in the soft tissues.525 Sequences of T2 weighing with second echo-enhanced venous ímaging and are useful in demonstrating intrathoracic hemangiomas. TI sequences show the subcutaneous and intramuscular distribution of a venous malformation. Plain radiographs can be used to evaluate the degree of osteolysis and shortening or enlargement of large bones in some predominantly venous malformations.

Lymphatic Imaging
Lymphoscintigraphy with tagged albumin or "Tc-labeled colloids can be used to determine involvement of the lymphatic system in congenital malformations and other lymphatic disorders. Isotope lymphoscintigraphy lacks the anatomic detail of lymphangiography, but it provides specific information about lymph flow and its abnormalities. There may be patterns of delayed transport, skin backflow, or lymphatic disruption.

Hematological Studies
Patients who have CVI as a result of valve destruction that complicates prior venous thrombosis may have an underlying thrombotic risk. This is usually due to activated protein C resistance, but other abnormalities of the coagulation system may also be present. These include protein C, protein S, and antithrombin III deficiency or the presence of lupus antico-agulant. Patients with a family history of CVI and multiple previous spontaneous venous thrombotic episodes or pulmonary embolism should be tested for these conditions.526
Thrombocytopenia and bleeding disorders are often part of the clinical picture in hemangiomatosis (Kasabach-Merritt syndrome), so a complete hematological and fibrinolytic profile is necessary in these cases.

Tissue Biopsy
Malignant degeneration is a potential outcome in large chronic leg ulcers. Biopsy samples obtained from affected areas may be essential for diagnosis. Echondroma and malignant degeneration of hemangiomas are frequent in the Maffucci syndrome.


Appendix
Complete List of Authors:
A.N. Nicolaides (Chairman and IUA representatíve; UK); L. Abenhaim (Canada); H. Akeson (Sweden); G.B. Agus (Italy); C. Allegra (Secretary; Italy); G.M. Andreozzi (Italy); P. Balas (Greece); F. Becker (France); G. Belcaro (Italy); G.G. Belz (Germany); J. Bergan (United States); D. Bergqvist (Sweden); V. Blazek (Germany); H. Boccalon (France); M.R. Boisseau (France); E. Bouskela (Brazil); P. Carpentier (France); L. Castellani (France); D. Christopoulos (Greece); D. Cleraent (Belgium); P. Coleridge-Smith (UK); A. Cornu-Thenard (France); M.C. Dalsing (United States): A. Davies (UK); M. De Castro Silva (Brazil); K. Delis (UK); T. El-Atrozy (Egypt); B. Eklof (United States); E.A. Enrici (Argentina); K. Esato (Japan); B. Fagrell (Sweden); J. Fareed (United States); J. Fernandes e Fernandes (ESVS representative; Portugal); D. Fitzgerald (Ireland); J. Fletcher (Australia); U. Franzeck (Switzerland); G. Geroulakos (UK); P. Gloviczki (United States); M. Griffin (UK); J. Gruss (Germany); R. Greenhalgh (UK); J. Hobbs (CDER Trust representative; UK): U. Hoffmann (Germany); S. Hoshino (Japan); E.A. Hussain (Egypt): V. Ibegbuna (UK); G. Jantet (UIP representative; France); E. Kalodiki (Associate Secretary; UK); L. Killewich (United States); R. Kistner (AVF representative; United States); X. Kurz (Belgium); N. Labropoulos (Associate Secretary; United States); R. Lacour (Argentina); A. Lechter (Colombia); J. Leal-Monedero (Spain); A. Lennox (Australia); L. Levien (South Africa); E.M. Masuda (United States); G. McMullin (Australia); M. Meissner (United States); G. Moneta (United States); K Myers (Australia); R. Naga (Egypt); P. Neglen (United States): L. Norgren (ESVS representative; Sweden); S. Novo (IASACO representative; Italy); T. O'Donnell (United States); A. O'Shaughnessey (Ireland); H. Partsch (Austria); M.R. Perrin (France); A. Pietravallo (Argentina); R. Poblete Silva (Chile); S. Raju (United States); N. Rich (United States); GT Richardson (Australia); H. Rieger (IUA representative; Germany); C.V. Ruckley (UK); S. Salas Flores (Chile); R. Samson (United States): U. Schultz-Ehrenberg (Germany): A. Scuderi (Brazil): J. Scurr (UIP representative; UK); H. Shigematsu (Japan): R. Simkin (Argentina); S. Simonian (United States); G. Stansby (UK); E. Strandness (United States); A. Strano (IASACO representative; Italy); D. Sumner (United States); J. Struckman (Denmark); G. Szendro (Israel); O. Thulesius (Sweden); J. Ulloa (Colombia); M. Vayssairat (France); M. Vandendreissche (UK); P. Vanhoutte (France); A. Van Rij (New Zealand); M. Veller (South Africa); L. Villavicencio (AVF representative; United States); P. Walker (Australia); L. Willows (UK); Th. Wupperman (Germany); Y. Yasaki (Japan); and P. Zamboni (Italy).

Acknowledgments
This consensus document was supported by educational grants from the Institute de Recherches Internationales Servier and the Cardiovascular Disease Educational and Research Trust (CDERT). The authors are grateful to the members and staff of these societies and organizations for their support that made the development of this document possible. We are also grateful to Anne Taft, Jennifer Sano, Susan Francis, and Elizabeth Thornton for their administrative and secretarial help.


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