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Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound
Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound Patrick Bastos Metzger, MD,a Fabio Henrique Rossi, MD, PhD,a Antônio Massamitsu Kambara, MD, PhD,b Nilo Mitsuru Izukawa, MD, PhD,a Mohamed Hassan Saleh, MD, PhD,c Ibraim M. F. Pinto, MD, PhD,b Jorge Eduardo Amorim, MD, PhD,d and Patricia E. Thorpe, MD, FSIR,e São Paulo-SP, Brazil; and Phoenix, Ariz Objective: The purpose of this study was to determine the sonographic criteria for diagnosis of iliac venous outflow obstruction by assessing the correlation of this method with intravascular ultrasound (IVUS) in patients with advanced chronic venous insufficiency (CVI). Methods: The evaluation included 15 patients (30 limbs; age, 49.4 % 10.7 years; 1 man) with initial CVI symptoms (Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] classification, CEAP1-2) in group I (GI) and 51 patients (102 limbs; age, 50.53 % 14.5 years; 6 men) with advanced CVI symptoms (CEAP3-6) in group II (GII). Patients from both groups were matched by gender, age, and race. The Venous Clinical Severity Score was considered. All patients underwent structured interviews and duplex ultrasound (DU) examination, measuring the flow phasicity, the femoral volume flows and velocities, and the velocity and obstruction ratios in the iliac vein. The reflux multisegment score was analyzed in both groups. Three independent observers evaluated individuals in GI. GII patients were submitted to IVUS, in which the area of the impaired venous segments was obtained and compared with the DU results and then grouped into three categories: obstructions <50%, obstructions between 50% and 79%, and obstructions $80%.
Results: The predominant clinical severity CEAP class was C1 in 24 of 30 limbs (80%) in GI and C3 in 54 of 102 limbs (52.9%) in GII. Reflux was severe (reflux multisegment score $3) in 3 of 30 limbs (10%) in GI and in 45 of 102 limbs (44.1%) in GII (P < .001). There was a moderately high agreement between DU and IVUS findings when they were grouped into three categories (k [ 0.598; P < .001) and high agreement when they were grouped into two categories (obstructions <50% and $50%; k [ 0.784; P < .001). The best cutoff points and their correlation with IVUS were 0.9 for the velocity index (r [ L0.634; P < .001), 0.7 for the flow index (r [ L0.623; P < .001), 0.5 for the obstruction ratio (r [ 0.750; P < .001), and 2.5 for the velocity ratio (r [ 0.790; P < .001). Absence of flow phasicity was observed in 62.5% of patients with obstructions $80%. An ultrasound algorithm was created using the measures and the described cutoff points with accuracy of 86.7% for detecting significant obstructions ($50%) with high agreement (k [ 0.73; P < .001). Conclusions: DU presented high agreement with IVUS for detection of obstructions $50%. The velocity ratio in obstructions $2.5 is the best criterion for detection of significant venous outflow obstructions in iliac veins. (J Vasc Surg: Venous and Lym Dis 2016;4:18-27.)
Treatment of chronic venous insufficiency (CVI) is based on the relief of reflux and obstruction.1 However, it has been recognized that obstruction alone or in conjunction with varicose veins may cause symptoms in a small subset of patients with CVI and post-thrombotic limbs2 or in
those with primary disease, such as iliac vein compression syndrome (IVCS).3 Approximately 50% to 60% of the patients with left-sided iliofemoral deep venous thrombosis (DVT) have extrinsic iliac vein compression.4 After 5 years, the remaining obstruction causes venous claudication in 44% and venous ulcer in 15% of the patients.5,6 Duplex ultrasound (DU) is the first test in the investigation of iliac venous outflow obstruction (IVOO). DU offers a significant advantage as it is a noninvasive, cheap, and easily repeatable test compared with other techniques. Despite this advantage, experienced sonographers cannot adequately visualize the iliac veins in at least 20% of the cases.7,8 Currently, there are no criteria for determining significant venous iliac obstructions with DU. The inaccuracy of single planar transfemoral venography in the delineation of IVOO has been increasingly recognized. Intravascular ultrasound (IVUS) is currently an imaging modality capable of delineating the venous wall architecture and precisely measuring the lumen diameter and area.9,10 Therefore, the purpose of this study was to determine the sonographic criteria for diagnosis of IVOO by assessing
From the Department of Vascular Surgery,a Department of Radiology,b and Department of Cardiology,c Instituto Dante Pazzanese de Cardiologia, São Paulo-SP; the Department of Vascular Surgery, Escola Paulista de Medicina, São Paulo-SPd; and the Department of Vascular Interventional Radiology, Arizona Heart Hospital, Phoenix.e This study was funded by FAPESP (Fundação de Amparo a Pesquisa do Estado de São Paulo; grant no. 2012/01021-9). Clinical Trial registration: NCT02240914. Author conflict of interest: none. Correspondence: Patrick Bastos Metzger, MD, Instituto Dante Pazzanese de Cardiologia, Doutor Dante Pazzanese Ave 500, Vila Mariana, São Paulo-SP, Brazil 04012-909 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvsv.2015.07.002
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the correlation of this method with IVUS in patients with advanced CVI. METHODS After approval of the Institutional Review Board, we analyzed two groups of patients from February 2013 to August 2014. Group I (GI) included 18 patients with initial CVI symptoms (Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] classification, CEAP C1-2). Group II (GII) included 58 patients with advanced CVI symptoms (CEAP C3-6) with complaints assessed by a pain score >5 on the visual analog scale,11 submitted to clinical treatment (phlebotonics and elastic compression) for at least 1 year with no relief of symptoms. The Venous Clinical Severity Score was assessed in GII patients.12 The number of investigated patients corresponds to 28% of the patients who underwent evaluation for CVI by the authors during the study period. Patients with nonvenous causes of limb symptoms were not included. The patient’s informed consent was obtained. Limbs were classified according to the revised CEAP classification.13 In GI, at least one limb had CEAP C1-2 classification. All 18 initial patients (36 limbs) in GI were evaluated by at least two expert examiners to exclude patients with suspected iliac venous obstruction lesions at DU. When there was mismatch between the two examiners, a third senior examiner performed the test. Three patients were excluded after this sonographic analysis because iliac vein obstructions >50% were found by two independent examiners; 15 patients (30 limbs) were included in GI. In GII, at least one limb had CEAP C3-6 classification. All 58 initial patients (116 limbs) in GII were assessed for their clinical and demographic characteristics. Two patients were excluded because of morbid obesity (body mass index >40 kg/m2), three because of renal insufficiency (creatinine clearance <30 mL/min/1.73 m2), and two because of concomitant chronic lower limb ischemia; 51 patients (102 limbs) were included in GII. All patients were submitted to DU, venography, and IVUS. Two different examiners blinded to each other performed these tests. Venous DU. Veins were imaged with different transducers on the basis of their depth using Toshiba ultrasound equipment (Aplio XV; Toshiba, Tochigi, Japan) with linear transducers of 10 to 13 MHz and curved transducers of 3 to 5 MHz. All patients underwent intestinal preparation with 6 hours of fasting and dimethicone administration 24 hours before the test for better visualization of the iliac
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veins. As described by Labropoulos et al,8 compression of the vein by the transducer was avoided by applying low pressure on the skin or by using an ultrasonic window through which the vein compression did not occur. The angle of insonation was set at 60 degrees, and the sample volume was parallel to the flow channel. The color gain was adjusted to a level at which flow was shown into the lumen without saturating the wall of the vein and the surrounding tissues. The color box was set at the best possible angle and was kept very small to allow the best frame rate. The pulse repetition frequency was kept at low levels, <1500 Hz in normal vein segments, and was increased in areas with stenosis. The B mode was set to show an anechoic lumen with the focus placed on the far wall.8 Reduction of the vein diameter was also measured by planimetry comparing the smallest lumen with the normal lumen. The luminal reduction was measured on B mode and color in the longitudinal and transverse views. The velocity measurements were taken before and through the area of obstruction.8 The volume flow measurements were calculated on the basis of the area of the vessel and the volume of one venous flow waveform in each common femoral vein. The characteristics of the waveform were analyzed. Obstructions in the iliac veins $50% were defined as significant lesions8 and obstructions $80% as critical lesions.14 The sonographic parameters considered suggestive of the presence of significant iliac venous obstruction were venous femoral velocity index (VI) #0.9, venous femoral flow index (FI) #0.6,15 venous iliac obstruction ratio (OR) $0.5,16 venous iliac velocity ratio (VR) $2.0,8 and monophasic waveform in the femoral venous flow (without respiratory variation)17 (Table I; Fig 1). The obstruction degree was then classified in three different categories: category 1, 0% to 49%; category 2, 50% to 79%; and category 3, $80% (Table II). After that, the test was performed with the patient in the upright position to evaluate the presence of obstruction or reflux in the superficial venous system (reflux time $0.5 second) and in the deep venous system ($1 second) and the venous reflux in the perforating system ($0.35 second) in the lower limbs.18 Refluxes in each limb were categorized according to the reflux multisegment score (RMS)19; a score of 1 each was given to reflux in the great saphenous vein above and below the knee, small saphenous vein, perforators, femoral vein, profunda femoris (deep femoral) vein, and popliteal vein. The total reflux score for
Table I. Calculation for each sonographic parameter regarding the degree of obstruction Sonographic parameters
Formula used to measure the obstruction
Venous femoral VI Venous femoral FI Venous iliac VR Venous iliac OR Monophasic waveform
Maximum velocity in ipsilateral femoral vein/maximum velocity in contralateral femoral vein Ipsilateral femoral vein volume flow/contralateral femoral vein volume flow Maximum through-obstruction velocity/maximum preobstruction velocity 1 (smaller diameter of the luminal obstruction/larger distal venous diameter) Present or absent
FI, Flow index; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
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Fig 1. Sonographic parameters of the duplex ultrasound (DU) examination. A, Me asurement of the obstruction ratio (OR) in color mode. B, Measurement of the OR in B mode. C, Site of the velocity ratio (VR) measurement. D, Measurement of the velocity index (VI). E and F, Measurement of the flow index (FI) and evaluation of the venous flow phasicity.
each individual limb was calculated (with a maximum score of 7). Thereafter, we categorized each limb as presenting moderate reflux (RMS <3) or severe reflux (RMS >3). IVUS. Bilateral lower limb venous access (femoral or popliteal) was performed using anatomic landmarks. First, vein anatomy and obstruction zones were evaluated with multiplanar digital subtraction venography. After that, bilateral IVUS was performed in all cases in both limbs, regardless of the venous DU and venographic findings. The IVUS system Sonicath Ultra 6, 6F (Boston Scientific,
Maple Grove, Minn) was inserted into the venous segment through the appropriately sized sheath. Images were obtained with catheter pullback from the infrarenal cava to the femoral veins to assess the venous size, degree of stenosis, and intraluminal thrombosis. The morphology of the stenosis and the presence of intraluminal webs were recorded. Both the diameter and the area reduction were measured. The precise percentage stenosis and area reduction were calculated. With the built-in software program, the areas of obstruction were measured at the maximum
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Table II. Vascular and intravascular sonographic classification regarding the degree of obstruction in the iliac veins Categories Category 1: 0%-49%
Category 2: 50%-79%
Category 3: $80%
Sonographic parameters OR < 0.5 and FI $ 0.6 and VI $ 0.9 and VR < 2.0 and Venous flow with respiratory variation OR $ 0.5 and/or FI < 0.6 and/or VI < 0.9 and/or VR $ 2.0 and/or Monophasic waveform OR $ 0.8 and Monophasic waveform Associated with FI < 0.6 and/or VI < 0.9 and/or VR $ 2.0
IVUS measurements 100 (100 A1/A2) ¼ 0%-49%
100 (100 A1/A2) ¼ 50%-79%
100 (100 A1/A2) ¼ 80%-100%
FI, Flow index; IVUS, intravascular ultrasound; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
compression point and at the healthy vein below the stenosis. Neglén and Raju10 recognized that the irregular shape of the iliac vein makes the precise measurement of its diameter difficult and preconize the area measurements to be more precise. In this study, the degree of obstruction was registered according to the following formula: 100 (100 A1/A2), where A1 is area at the point of maximum compression and A2 is area at the common iliac vein bifurcation (Fig 2). As already described, when the entire iliac vein was affected, the area in the stenotic segment was compared
with the contralateral vein if it appeared to be free from obstruction. If both iliac veins were affected, the area was compared with the normal iliac vein area of 150 mm2 (r ¼ 6.5 mm).10 The percentage of iliac vein compression or obstruction was then qualitatively classified in three categories: category 1, 0% to 49%; category 2, 50% to 79%; and category 3, $80% (Table II). Statistical analysis. Clinical and complementary evaluations were entered prospectively into an electronic medical record program. Individual data are given as mean and standard deviation, unless otherwise indicated. Continuous
Fig 2. Assessment of the left common iliac vein (CIV) stenosis with intravascular ultrasound (IVUS). A, Area at the site of the stenosis (A1). B, Area at the common iliac vein bifurcation (A2). a, Right common iliac artery.
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variables were analyzed by t-test or nonparametric Wilcoxon rank test for paired and unpaired data, depending on their normality; the Fisher exact test was used for category variables. The Spearman correlation coefficient was used to compare each sonographic parameter and the grade of obstruction by IVUS, with 95% confidence interval. Performance of each sonographic parameter in diagnosing the presence of IVOO was evaluated by the receiver operating characteristic curve and the area under the curve. Selection of the cutoff point was determined by the best value of sensitivity and specificity. The degree of agreement on the presence of venous obstruction by IVUS and DU was evaluated by the k index. The commercially available SPSS program 19.0 (IBM Corp, Armonk, NY) was used for statistical analysis. Results are reported using P values. A P value < .05 was considered statistically significant. Calculation of sample size and power of the study. The estimated proportion of venous obstruction was based on Marston et al.14 We used the prevalence of about 23% of iliac venous obstruction in the general population with CVI and estimated a proportion of 37% in the studied population. Applying the Wilcoxon-Mann-Whitney test for a standardized difference of 1.0 and 95% power, we estimated the total sample size of 64 limbs, 32 in each group. RESULTS Most of the patients in GI and GII were female (93.3% vs 88.2%; P ¼ .543), white (60% vs 56.9%; P ¼ .593), and with average age of 49.4 6 10.7 years vs 50.53 6 14.5 years, respectively (P ¼ .2). There were no differences among comorbidities between the groups. There was no previous DVT report in GI, whereas in GII, there was previous DVT in 10 of 51 (19.6%). The CEAP clinical classification was 80% C1 and 20% C2 in GI; in GII, the classification was 52.9% C3, 20.6% C4, 8.8% C5, and 17.6% C6. The Venous Clinical Severity Score mean was 14.3 6 6.7. At RMS evaluation,19 it was noted that most limbs (23 of 30; 76.7%) showed no reflux in GI, whereas in GII, only 26 of 102 (25.5%; P < .001) showed no reflux. The scoring ranged from 1 to 3 in GI and from 1 to 7 in GII. We observed a significant difference among patients with severe reflux in GI and GII (10% vs 44.1%; P < .001).
In GII, 10 of 102 iliac veins (9.8%) were occluded at venography. As for the classification of the degree of obstruction, 51 of 102 limbs (50%) were category 1, 27 of 102 (26.5%) were category 2, and 24 of 102 (23.5%) were category 3. The locations of these significant lesions were as follows: 34 of 102 (33.3%) in the left iliac vein; 13 of 102 (12.7%) in the right iliac vein; and 4 of 102 (3.9%) in the external iliac veins. The left to right ratio was 2.4:1. The descriptive variables of the sonographic parameter measures in GI and GII are shown in Tables III and IV. Only the left limbs were considered in the VI and FI analysis. There was a statistically significant difference among the categories of each sonographic parameter in GII (P < .001). At the intercategory comparison, there was no statistical difference between categories 2 and 3 in VI and FI (P ¼ .594 and P ¼ .164; Fig 3, A and B). Therefore, VI and FI discriminate obstructions $ 50%. The sonographic parameters for VR and OR discriminated obstructions $50% and obstructions $80% because the mean 6 standard deviation was statistically different in both categories (Fig 3, C and D). The monophasic waveforms were present in limbs in category 2 and category 3 (7.7% vs 62.5%; P < .001). Therefore, the presence of monophasic waveform discriminates obstructions $80% (Table IV). Data of each cutoff point of the DU parameters were analyzed. The best cutoff points and their receiver operating characteristic curve are shown in Table V and in Fig 4. Their correlations with IVUS are shown in Table VI. The VR had a better (high) correlation with IVUS than the other sonographic parameters did. There was a moderately high agreement between the DU and the IVUS findings when they were grouped into three categories (k ¼ 0.598; P < .001) and a high agreement when they were grouped into two categories (obstructions <50% and $50%; k ¼ 0.784; P < .001). Therefore, DU is better at discriminating significant obstructions than critical obstructions. A sonographic algorithm was developed with the best cutoff points. First, the phasicity of the femoral venous flow was evaluated. If a monophasic waveform was observed, the iliac vein was categorized as presenting obstruction $80%. After that, VI and FI were measured. If both indexes are normal, the iliac vein does not have a significant obstruction. If one or both of these parameters are altered, it is mandatory to
Table III. Descriptive variables in group I (GI) GI (N ¼ 30) Sonographic parameters
Mean 6 SD
Median (min-max value)
IQR (25%-75%)
VI (n ¼ 15) FI (n ¼ 15) OR VR Phasicity
0.99 0.95 0.10 1.21
6 6 6 6
1 (0.78-1.1) 0.97 (0.6-1.14) 0.09 (0.27-0.47) 1.14 (22.8-43.0) 100% present
0.96-1.07 0.88-1.08 0.01-0.21 0.87-1.69
0.08 0.15 0.16 0.22
FI, Flow index; IQR, interquartile range; n, number of lower limbs; OR, obstruction ratio; SD, standard deviation; VI, velocity index; VR, velocity ratio.
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Table IV. Descriptive variables in group II (GII) Parameters VI Category 1 Category 2 Category 3 FI Category 1 Category 2 Category 3 OR Category 1 Category 2 Category 3 VR Category 1 Category 2 Category 3 Monophasic waveform Category 1 Category 2 Category 3
Mean 6 SD
95% CI
1.17 6 0.51 0.75 6 0.23 0.67 6 0.25
0.9-1.46 0.65-0.86 0.53-0.83
1.15 6 0.62 0.76 6 0.45 0.56 6 0.27
Median (min-max value)
IQR (25%-75%)
P
1.00 (0.77-2.57) 0.80 (0.34-1.35) 0.71 (0.17-1.2)
0.92-1.09 0.59-0.90 0.52-0.81
<.001
0.81-1.5 0.56-0.97 0.39-0.71
1.00 (0.62-3.08) 0.62 (0.37-2.0) 0.54 (0.1-1.09)
0.76-1.39 0.50-0.83 0.39-0.57
<.001
0.12 6 0.22 0.47 6 0.23 0.71 6 0.22
0.06-0.18 0.04-0.56 0.61-0.81
0.12 (0.36 to 0.59) 0.54 (0.02 to 0.81) 0.65 (0.34-1.0)
0.02 to 0.3 0.40-0.62 0.54-1
<.001
1.15 6 0.28 2.53 6 0.99 3.38 6 0.91
1.05-1.25 2.13-2.93 2.88-3.88
1.05 (0.66-2.45) 2.60 (0.93-5.42) 3.21 (1.48-5.22)
0.97-1.20 1.53-3.15 3.12-3.89
<.001 <.001
100% absent 2 of 26 limbs (7.7%) 15 of 24 limbs (62.5%)
CI, Confidence interval; FI, flow index; IQR, interquartile range; OR, obstruction ratio; SD, standard deviation; VI, velocity index; VR, velocity ratio.
perform the VR analysis in both sides of the iliac veins because this parameter has the best correlation with the degree of obstruction by IVUS. If the VR is <2.5, the iliac vein does not have a significant obstruction. However, if this parameter is $2.5, the iliac vein is categorized as having an obstruction
$50% (Fig 5). When an appropriate view of the iliac veins is not possible, another diagnostic method should be considered. With this algorithm, it is possible to detect significant obstructions with a sensitivity of 92.4% and accuracy of
Fig 3. A-D, Box plot of each sonographic parameter divided into three categories by intravascular ultrasound (IVUS) in group II (GII). Intercategory analysis.
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Table V. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the cutoff points of the duplex ultrasound (DU) algorithm Parameters
Cutoff point
Sensitivity, %
Specificity, %
PPV, %
NPV, %
Accuracy, %
Category
VI FI VR OR Phasicity Algorithm
0.9 0.7 2.5 0.5 Absent
87.9 78.8 75.6 75.0 62.5 92.4
86.7 86.7 100 96.0 97.4 80.0
79.5 77.7 100 91.7 93.4 73.1
92.4 87.4 87.5 86.7 81.6 94.7
87.5 58.3 89 85.7 89.1 86.7
3 1 (2 þ 3)
FI, Flow index; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
86.7% and with k ¼ 0.730 (high agreement). For detection of critical lesions, the accuracy and k index dropped to 79.6% and 0.655, respectively (Table V). DISCUSSION Venous disease is a highly prevalent and disabling disorder.1 IVCS has been increasingly recognized as an important etiologic factor in CVI. It can cause disabling symptoms of CVI20 and venous hypertension, such as edema, leg heaviness, skin lipodermatosclerosis, pain, varicose veins, and ulcerations.21 Venographic studies suggest that the incidence
of extrinsic compressive lesions may be even more pervasive than the incidence of intrinsic lesions.10 Recent invasive imaging data22 indicate that the compression of the left iliac vein at the arterial crossover point may be present in 66% of the general population without any venous symptoms. In the past, single planar transfemoral venography was considered the “gold standard,” but this technique has been considered inaccurate in delineation of IVOO.9 The extent and severity of the obstructive lesion appear to be worse in IVUS results compared with venographic findings, and even severe obstructions may go undetected.23,24
Fig 4. A-D, Receiver operating characteristic (ROC) curves of each sonographic parameter. AUC, Area under the curve.
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Table VI. Correlation between the indexes and relations of the sonographic parameters and the categories of obstruction by intravascular ultrasound (IVUS) Parameters VI FI VR OR
Statistical analysis r value P value 95% CI r value P value 95% CI r value P value 95% CI r value P value 95% CI
0.634 <.001 0.758 to 0.478 0.623 <.001 0.737 to 0.623 0.790 <.001 0.698-0.849 0.750 <.001 0.657-0.818
CI, Confidence interval; FI, flow index; OR, obstruction ratio; r, Spearman correlation coefficient; VI, velocity index; VR, velocity ratio.
Injection of contrast dye can hide details such as intraluminal webs. On average, it underestimates the degree of stenosis by 30%.10 Currently, there is no well-established noninvasive screening study. The standard test for diagnosis of lower limb DVT and CVI is DU imaging because it is easy to perform and noninvasive. However, imaging of the pelvic veins is technically difficult and generally not sensitive enough to detect nonocclusive thrombosis and intraluminal defects within the iliac vein.7 Therefore, the obstruction component is rarely investigated in clinical practice today because the main tool for diagnosis is DU, which can fail in its diagnosis in 20% of the cases even when it is performed by experienced professionals.7,8 For this reason, we compared five
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sonographic parameters with the standard method (IVUS) to improve detection of the obstructive venous iliac lesion with a noninvasive screening method. Reflux is considered the dominant pathologic change in CVI.21 Raju et al19 found a prevalence of deep venous reflux in 33% of the analyzed limbs, and severe reflux was present in 308 of 528 limbs (59%). In this study, there was 25.5% reflux in the deep venous system in GII, whereas no reflux in the deep venous system was observed in GI. GII had 45 of 102 limbs (44.1%) with severe reflux, constituting a significant difference among the groups. It is important to consider the presence of an obstruction in all patients with symptomatic CVI, even those with apparent venous reflux.19 We found that 50% of the studied limbs have an iliac vein obstruction of at least 50% and that 23.5% presented an at least 80% obstruction when verified by IVUS. This percentage would be even higher if we considered only CEAP C3-6 studied limbs. Raju and Neglén21 found that IVUS-detectable lesions are present in >90% of patients with advanced CVI. This evidences the high prevalence of obstructions in the iliac veins and the importance of IVCS screening in patients with highly advanced CVI. The relation among velocities in the femoral veins to the passage of the blood flow in an unimpeded system must be equal to 1 (equal velocities), as we observed in GI (Table I). In obstructive blood flow conditions, this index is <1 in the affected side. In our study, when evaluating the VI in the left leg and comparing it to the right leg on expiration, we obtained the value of 0.9 as the best cutoff point. Among the sonographic parameters, FI was the least correlated with the IVUS results. This index is rarely
Fig 5. Ultrasonographic algorithm for detection of venous iliac obstructions. C2, Category 2; C3, category 3; CEAP, Clinical class, Etiology, Anatomy, and Pathophysiology.
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studied in the literature.15,25 Initially, we used a cutoff value of 0.615; however, this cutoff point has low sensitivity (60.6%). The best cutoff value obtained was 0.7 with 78.8% sensitivity to discriminate significant obstructions. Monophasic waveforms result when the transmission of the fluctuating intrathoracic pressures to distal venous structures is dampened. The loss of phasic variation may be due to (1) an iliac nonocclusive thrombus, (2) extrinsic compression, (3) intrinsic luminal narrowing, and (4) other causes, such as cardiac factors.17 Lin et al,17 in a retrospective study of 124 limbs with monophasic waveforms in the femoral vein, found that an iliac venous thrombosis was the most common cause (38%). There was no discernible explanation for the loss of phasic variation in 36% of the cases. In our study, the monophasic waveform was present in 62.5% of the limbs categorized as having an obstruction >80% and in only 7.7% (two limbs) categorized as having an obstruction of 50% to 79%. The cause of the monophasic waveform in 10 of 17 limbs (58.8%) was iliac vein occlusive disease, followed by extrinsic compression (35.3%) and intrinsic narrowing (5.9%). Labropoulos et al8 in 2007 investigated the central venous obstruction with DU and defined VR as the best diagnostic criterion. These authors studied 37 patients with 41 central venous obstructions. This study population was heterogeneous. Obstructions were located in the iliac veins in only 11 cases (26.8%). Initially, the authors used the VR cutoff point of 2.0 to determine obstructions $50%, but they considered 2.5 the best cutoff point for detection of significant venous lesions. Using this VR value, they reported only two false-positive test results, whereas the number of false-positive results increased to four when a VR value of 2.0 was used. Our experience shows results similar to those of Labropoulos et al.8 We initially used a VR of 2.0 to estimate significant obstructions. We noted that when using this relation, we obtained 78% sensitivity, 94% specificity, 88.4% positive predictive value, and 87.9% negative predictive value. Using the cutoff point of 2.5, we observed a slight reduction in sensitivity to 76%, with an improvement of specificity and positive predictive value to 100%, with 87.5% negative predictive value, thus reducing the number of false-positive test results. Our study population consisted of patients with advanced CVI, and the study was directed to the detection of iliac vein obstructions; therefore, we had a more homogeneous population than in the previous study. In this study, DU had a high agreement with IVUS for detection of significant obstructions using the studied sonographic parameters. Clinically, the presence of an obstruction >50% in symptomatic limbs is a criterion for endovascular treatment. An ultrasound algorithm was developed for this purpose. Use of this algorithm will allow all vascular surgeons and radiologists to diagnose significant IVOO with elevated sensitivity and accuracy rates with a noninvasive screening method. This approach can reduce the time to diagnose and to treat this disorder. The study was limited by its transverse design and by the difficulty in acquiring vascular abdominal images with DU
because most of the patients had an increased body mass index and high abdominal waist circumference, requiring adequate intestinal preparation to obtain a favorable acoustic window. In addition, acquisition of such images is also hampered by the high compliance of the venous system during the different phases of the respiratory cycle. This can be changed not only by the patient’s volemic status but also by the transducer pressure exerted during the test. In a small subset of patients with bilateral IVOO, normal VI and FI in both sides can generate false-negative results. It is a limitation of the algorithm. CONCLUSIONS DU presented high agreement with IVUS for detection of significant iliac venous obstructions with the use of the sonographic parameters. The VR in obstructions $2.5 is the best criterion for detection of significant venous obstructions in iliac veins. AUTHOR CONTRIBUTIONS Conception and design: PM, NI Analysis and interpretation: PM Data collection: PM, FR, AK, MS Writing the article: PM Critical revision of the article: PM, FR, AK, NI, MS, IP, JA, PT Final approval of the article: PM, FR, AK, NI, MS, IP, JA, PT Statistical analysis: PM Obtained funding: FR Overall responsibility: PM REFERENCES 1. Nicolaides AN; Cardiovascular Disease Educational and Research Trust; European Society of Vascular Surgery; The International Angiology Scientific Activity Congress Organization; International Union of Angiology; Union Internationale de Phlebologie at the Abbaye des Vaux de Cernay. Investigation of chronic venous insufficiency: a consensus statement (France, March 5-9, 1997). Circulation 2000;102:E126-63. 2. Palma EC, Esperon R. Treatment of the post-thrombophlebitic syndrome by means of internal saphenous transplants. Bol Soc Cir Urug 1959;30:115-25. 3. Taheri SA, Williams J, Powell S, Cullen J, Peer R, Nowakowski P, et al. Iliocaval compression syndrome. Am J Surg 1987;154:169-72. 4. Mickley V, Schwagierek R, Rilinger N, Görich J, Sunder-Plassmann L. Left iliac venous thrombosis caused by venous spur: treatment with thrombectomy and stent implantation. J Vasc Surg 1998;28:492-7. 5. Akesson H, Brudin L, Dahlström JA, Eklof B, Ohlin P, Plate G. Venous function assessed during a 5 year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 1990;4:43-8. 6. Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004;239:118-26. 7. Cronan JJ. Venous thromboembolic disease: the role of US. Radiology 1993;186:619-30. 8. Labropoulos N, Borge M, Pierce K, Pappas PJ. Criteria for defining significant central vein stenosis with duplex ultrasound. J Vasc Surg 2007;46:101-7. 9. Raju S. Best management options for chronic iliac vein stenosis and occlusion. J Vasc Surg 2013;57:1163-9. 10. Neglén P, Raju S. Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 2002;35:694-700.
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11. Huskisson EC, Jones J, Scott PJ. Application of visual-analogue scales to the measurement of functional capacity. Rheumatol Rehabil 1976;15:185-7. 12. Vasquez MA, Munschauer CE. Revised venous clinical severity score: a facile measurement of outcomes in venous disease. Phlebology 2012;27(Suppl 1):119-29. 13. Eklof B, Rutherford RB, Bergan JJ, Carpentier PH, Gloviczki P, Kistner RL, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004;40:1248-52. 14. Marston W, Fish D, Unger J, Keagy B. Incidence of and risk factors for iliocaval venous obstruction in patients with active or healed venous leg ulcers. J Vasc Surg 2011;53:1303-8. 15. Ogawa T, Lurie F, Kistner RL, Eklof B, Tabrah FL. Reproducibility of ultrasound scan in the assessment of volume flow in the veins of the lower extremities. J Vasc Surg 2002;35:527-31. 16. O guzkurt L, Ozkan U, Tercan F, Koç Z. Ultrasonographic diagnosis of iliac vein compression (May-Thurner) syndrome. Diagn Interv Radiol 2007;13:152-5. 17. Lin EP, Bhatt S, Rubens D, Dogra VS. The importance of monophasic Doppler waveforms in the common femoral vein: a retrospective study. J Ultrasound Med 2007;26:885-91. 18. Labropoulos N, Tiongson J, Pryor L, Tassiopoulos AK, Kang SS, Ashraf Mansour M, et al. Definition of venous reflux in lower-extremity veins. J Vasc Surg 2003;38:793-8.
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19. Raju S, Darcey R, Neglén P. Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg 2010;51:401-8. 20. Rabe E, Pannier F. Societal costs of chronic venous disease in CEAP C4, C5, C6 disease. Phlebology 2010;25(Suppl 1):64-7. 21. Raju S, Neglén P. High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 2006;44:136-44. 22. Kibbe MR, Ujiki M, Goodwin AL, Eskandari M, Yao J, Matsumura J. Iliac vein compression in an asymptomatic patient population. J Vasc Surg 2004;39:937-43. 23. Neglén P, Raju S. Balloon dilation and stenting of chronic iliac vein obstruction: technical aspects and early clinical outcome. J Endovasc Ther 2000;7:79-91. 24. Neglén P. Endovascular surgery in the treatment of chronic primary and post-thrombotic iliac vein obstruction. Eur J Vasc Endovasc Surg 2000;20:560-71. 25. Pannucci CJ, Henke PK, Cederna PS, Strachn SM, Brown SL, Moote MJ, et al. The effect of increased hip flexion using stirrups on lower-extremity venous flow: a prospective observational study. Am J Surg 2011;202:427-32.
Submitted May 8, 2015; accepted Jul 13, 2015.
Results: The predominant clinical severity CEAP class was C1 in 24 of 30 limbs (80%) in GI and C3 in 54 of 102 limbs (52.9%) in GII. Reflux was severe (reflux multisegment score $3) in 3 of 30 limbs (10%) in GI and in 45 of 102 limbs (44.1%) in GII (P < .001). There was a moderately high agreement between DU and IVUS findings when they were grouped into three categories (k [ 0.598; P < .001) and high agreement when they were grouped into two categories (obstructions <50% and $50%; k [ 0.784; P < .001). The best cutoff points and their correlation with IVUS were 0.9 for the velocity index (r [ L0.634; P < .001), 0.7 for the flow index (r [ L0.623; P < .001), 0.5 for the obstruction ratio (r [ 0.750; P < .001), and 2.5 for the velocity ratio (r [ 0.790; P < .001). Absence of flow phasicity was observed in 62.5% of patients with obstructions $80%. An ultrasound algorithm was created using the measures and the described cutoff points with accuracy of 86.7% for detecting significant obstructions ($50%) with high agreement (k [ 0.73; P < .001). Conclusions: DU presented high agreement with IVUS for detection of obstructions $50%. The velocity ratio in obstructions $2.5 is the best criterion for detection of significant venous outflow obstructions in iliac veins. (J Vasc Surg: Venous and Lym Dis 2016;4:18-27.)
Treatment of chronic venous insufficiency (CVI) is based on the relief of reflux and obstruction.1 However, it has been recognized that obstruction alone or in conjunction with varicose veins may cause symptoms in a small subset of patients with CVI and post-thrombotic limbs2 or in
those with primary disease, such as iliac vein compression syndrome (IVCS).3 Approximately 50% to 60% of the patients with left-sided iliofemoral deep venous thrombosis (DVT) have extrinsic iliac vein compression.4 After 5 years, the remaining obstruction causes venous claudication in 44% and venous ulcer in 15% of the patients.5,6 Duplex ultrasound (DU) is the first test in the investigation of iliac venous outflow obstruction (IVOO). DU offers a significant advantage as it is a noninvasive, cheap, and easily repeatable test compared with other techniques. Despite this advantage, experienced sonographers cannot adequately visualize the iliac veins in at least 20% of the cases.7,8 Currently, there are no criteria for determining significant venous iliac obstructions with DU. The inaccuracy of single planar transfemoral venography in the delineation of IVOO has been increasingly recognized. Intravascular ultrasound (IVUS) is currently an imaging modality capable of delineating the venous wall architecture and precisely measuring the lumen diameter and area.9,10 Therefore, the purpose of this study was to determine the sonographic criteria for diagnosis of IVOO by assessing
From the Department of Vascular Surgery,a Department of Radiology,b and Department of Cardiology,c Instituto Dante Pazzanese de Cardiologia, São Paulo-SP; the Department of Vascular Surgery, Escola Paulista de Medicina, São Paulo-SPd; and the Department of Vascular Interventional Radiology, Arizona Heart Hospital, Phoenix.e This study was funded by FAPESP (Fundação de Amparo a Pesquisa do Estado de São Paulo; grant no. 2012/01021-9). Clinical Trial registration: NCT02240914. Author conflict of interest: none. Correspondence: Patrick Bastos Metzger, MD, Instituto Dante Pazzanese de Cardiologia, Doutor Dante Pazzanese Ave 500, Vila Mariana, São Paulo-SP, Brazil 04012-909 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvsv.2015.07.002
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the correlation of this method with IVUS in patients with advanced CVI. METHODS After approval of the Institutional Review Board, we analyzed two groups of patients from February 2013 to August 2014. Group I (GI) included 18 patients with initial CVI symptoms (Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] classification, CEAP C1-2). Group II (GII) included 58 patients with advanced CVI symptoms (CEAP C3-6) with complaints assessed by a pain score >5 on the visual analog scale,11 submitted to clinical treatment (phlebotonics and elastic compression) for at least 1 year with no relief of symptoms. The Venous Clinical Severity Score was assessed in GII patients.12 The number of investigated patients corresponds to 28% of the patients who underwent evaluation for CVI by the authors during the study period. Patients with nonvenous causes of limb symptoms were not included. The patient’s informed consent was obtained. Limbs were classified according to the revised CEAP classification.13 In GI, at least one limb had CEAP C1-2 classification. All 18 initial patients (36 limbs) in GI were evaluated by at least two expert examiners to exclude patients with suspected iliac venous obstruction lesions at DU. When there was mismatch between the two examiners, a third senior examiner performed the test. Three patients were excluded after this sonographic analysis because iliac vein obstructions >50% were found by two independent examiners; 15 patients (30 limbs) were included in GI. In GII, at least one limb had CEAP C3-6 classification. All 58 initial patients (116 limbs) in GII were assessed for their clinical and demographic characteristics. Two patients were excluded because of morbid obesity (body mass index >40 kg/m2), three because of renal insufficiency (creatinine clearance <30 mL/min/1.73 m2), and two because of concomitant chronic lower limb ischemia; 51 patients (102 limbs) were included in GII. All patients were submitted to DU, venography, and IVUS. Two different examiners blinded to each other performed these tests. Venous DU. Veins were imaged with different transducers on the basis of their depth using Toshiba ultrasound equipment (Aplio XV; Toshiba, Tochigi, Japan) with linear transducers of 10 to 13 MHz and curved transducers of 3 to 5 MHz. All patients underwent intestinal preparation with 6 hours of fasting and dimethicone administration 24 hours before the test for better visualization of the iliac
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veins. As described by Labropoulos et al,8 compression of the vein by the transducer was avoided by applying low pressure on the skin or by using an ultrasonic window through which the vein compression did not occur. The angle of insonation was set at 60 degrees, and the sample volume was parallel to the flow channel. The color gain was adjusted to a level at which flow was shown into the lumen without saturating the wall of the vein and the surrounding tissues. The color box was set at the best possible angle and was kept very small to allow the best frame rate. The pulse repetition frequency was kept at low levels, <1500 Hz in normal vein segments, and was increased in areas with stenosis. The B mode was set to show an anechoic lumen with the focus placed on the far wall.8 Reduction of the vein diameter was also measured by planimetry comparing the smallest lumen with the normal lumen. The luminal reduction was measured on B mode and color in the longitudinal and transverse views. The velocity measurements were taken before and through the area of obstruction.8 The volume flow measurements were calculated on the basis of the area of the vessel and the volume of one venous flow waveform in each common femoral vein. The characteristics of the waveform were analyzed. Obstructions in the iliac veins $50% were defined as significant lesions8 and obstructions $80% as critical lesions.14 The sonographic parameters considered suggestive of the presence of significant iliac venous obstruction were venous femoral velocity index (VI) #0.9, venous femoral flow index (FI) #0.6,15 venous iliac obstruction ratio (OR) $0.5,16 venous iliac velocity ratio (VR) $2.0,8 and monophasic waveform in the femoral venous flow (without respiratory variation)17 (Table I; Fig 1). The obstruction degree was then classified in three different categories: category 1, 0% to 49%; category 2, 50% to 79%; and category 3, $80% (Table II). After that, the test was performed with the patient in the upright position to evaluate the presence of obstruction or reflux in the superficial venous system (reflux time $0.5 second) and in the deep venous system ($1 second) and the venous reflux in the perforating system ($0.35 second) in the lower limbs.18 Refluxes in each limb were categorized according to the reflux multisegment score (RMS)19; a score of 1 each was given to reflux in the great saphenous vein above and below the knee, small saphenous vein, perforators, femoral vein, profunda femoris (deep femoral) vein, and popliteal vein. The total reflux score for
Table I. Calculation for each sonographic parameter regarding the degree of obstruction Sonographic parameters
Formula used to measure the obstruction
Venous femoral VI Venous femoral FI Venous iliac VR Venous iliac OR Monophasic waveform
Maximum velocity in ipsilateral femoral vein/maximum velocity in contralateral femoral vein Ipsilateral femoral vein volume flow/contralateral femoral vein volume flow Maximum through-obstruction velocity/maximum preobstruction velocity 1 (smaller diameter of the luminal obstruction/larger distal venous diameter) Present or absent
FI, Flow index; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
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Fig 1. Sonographic parameters of the duplex ultrasound (DU) examination. A, Me asurement of the obstruction ratio (OR) in color mode. B, Measurement of the OR in B mode. C, Site of the velocity ratio (VR) measurement. D, Measurement of the velocity index (VI). E and F, Measurement of the flow index (FI) and evaluation of the venous flow phasicity.
each individual limb was calculated (with a maximum score of 7). Thereafter, we categorized each limb as presenting moderate reflux (RMS <3) or severe reflux (RMS >3). IVUS. Bilateral lower limb venous access (femoral or popliteal) was performed using anatomic landmarks. First, vein anatomy and obstruction zones were evaluated with multiplanar digital subtraction venography. After that, bilateral IVUS was performed in all cases in both limbs, regardless of the venous DU and venographic findings. The IVUS system Sonicath Ultra 6, 6F (Boston Scientific,
Maple Grove, Minn) was inserted into the venous segment through the appropriately sized sheath. Images were obtained with catheter pullback from the infrarenal cava to the femoral veins to assess the venous size, degree of stenosis, and intraluminal thrombosis. The morphology of the stenosis and the presence of intraluminal webs were recorded. Both the diameter and the area reduction were measured. The precise percentage stenosis and area reduction were calculated. With the built-in software program, the areas of obstruction were measured at the maximum
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Table II. Vascular and intravascular sonographic classification regarding the degree of obstruction in the iliac veins Categories Category 1: 0%-49%
Category 2: 50%-79%
Category 3: $80%
Sonographic parameters OR < 0.5 and FI $ 0.6 and VI $ 0.9 and VR < 2.0 and Venous flow with respiratory variation OR $ 0.5 and/or FI < 0.6 and/or VI < 0.9 and/or VR $ 2.0 and/or Monophasic waveform OR $ 0.8 and Monophasic waveform Associated with FI < 0.6 and/or VI < 0.9 and/or VR $ 2.0
IVUS measurements 100 (100 A1/A2) ¼ 0%-49%
100 (100 A1/A2) ¼ 50%-79%
100 (100 A1/A2) ¼ 80%-100%
FI, Flow index; IVUS, intravascular ultrasound; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
compression point and at the healthy vein below the stenosis. Neglén and Raju10 recognized that the irregular shape of the iliac vein makes the precise measurement of its diameter difficult and preconize the area measurements to be more precise. In this study, the degree of obstruction was registered according to the following formula: 100 (100 A1/A2), where A1 is area at the point of maximum compression and A2 is area at the common iliac vein bifurcation (Fig 2). As already described, when the entire iliac vein was affected, the area in the stenotic segment was compared
with the contralateral vein if it appeared to be free from obstruction. If both iliac veins were affected, the area was compared with the normal iliac vein area of 150 mm2 (r ¼ 6.5 mm).10 The percentage of iliac vein compression or obstruction was then qualitatively classified in three categories: category 1, 0% to 49%; category 2, 50% to 79%; and category 3, $80% (Table II). Statistical analysis. Clinical and complementary evaluations were entered prospectively into an electronic medical record program. Individual data are given as mean and standard deviation, unless otherwise indicated. Continuous
Fig 2. Assessment of the left common iliac vein (CIV) stenosis with intravascular ultrasound (IVUS). A, Area at the site of the stenosis (A1). B, Area at the common iliac vein bifurcation (A2). a, Right common iliac artery.
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variables were analyzed by t-test or nonparametric Wilcoxon rank test for paired and unpaired data, depending on their normality; the Fisher exact test was used for category variables. The Spearman correlation coefficient was used to compare each sonographic parameter and the grade of obstruction by IVUS, with 95% confidence interval. Performance of each sonographic parameter in diagnosing the presence of IVOO was evaluated by the receiver operating characteristic curve and the area under the curve. Selection of the cutoff point was determined by the best value of sensitivity and specificity. The degree of agreement on the presence of venous obstruction by IVUS and DU was evaluated by the k index. The commercially available SPSS program 19.0 (IBM Corp, Armonk, NY) was used for statistical analysis. Results are reported using P values. A P value < .05 was considered statistically significant. Calculation of sample size and power of the study. The estimated proportion of venous obstruction was based on Marston et al.14 We used the prevalence of about 23% of iliac venous obstruction in the general population with CVI and estimated a proportion of 37% in the studied population. Applying the Wilcoxon-Mann-Whitney test for a standardized difference of 1.0 and 95% power, we estimated the total sample size of 64 limbs, 32 in each group. RESULTS Most of the patients in GI and GII were female (93.3% vs 88.2%; P ¼ .543), white (60% vs 56.9%; P ¼ .593), and with average age of 49.4 6 10.7 years vs 50.53 6 14.5 years, respectively (P ¼ .2). There were no differences among comorbidities between the groups. There was no previous DVT report in GI, whereas in GII, there was previous DVT in 10 of 51 (19.6%). The CEAP clinical classification was 80% C1 and 20% C2 in GI; in GII, the classification was 52.9% C3, 20.6% C4, 8.8% C5, and 17.6% C6. The Venous Clinical Severity Score mean was 14.3 6 6.7. At RMS evaluation,19 it was noted that most limbs (23 of 30; 76.7%) showed no reflux in GI, whereas in GII, only 26 of 102 (25.5%; P < .001) showed no reflux. The scoring ranged from 1 to 3 in GI and from 1 to 7 in GII. We observed a significant difference among patients with severe reflux in GI and GII (10% vs 44.1%; P < .001).
In GII, 10 of 102 iliac veins (9.8%) were occluded at venography. As for the classification of the degree of obstruction, 51 of 102 limbs (50%) were category 1, 27 of 102 (26.5%) were category 2, and 24 of 102 (23.5%) were category 3. The locations of these significant lesions were as follows: 34 of 102 (33.3%) in the left iliac vein; 13 of 102 (12.7%) in the right iliac vein; and 4 of 102 (3.9%) in the external iliac veins. The left to right ratio was 2.4:1. The descriptive variables of the sonographic parameter measures in GI and GII are shown in Tables III and IV. Only the left limbs were considered in the VI and FI analysis. There was a statistically significant difference among the categories of each sonographic parameter in GII (P < .001). At the intercategory comparison, there was no statistical difference between categories 2 and 3 in VI and FI (P ¼ .594 and P ¼ .164; Fig 3, A and B). Therefore, VI and FI discriminate obstructions $ 50%. The sonographic parameters for VR and OR discriminated obstructions $50% and obstructions $80% because the mean 6 standard deviation was statistically different in both categories (Fig 3, C and D). The monophasic waveforms were present in limbs in category 2 and category 3 (7.7% vs 62.5%; P < .001). Therefore, the presence of monophasic waveform discriminates obstructions $80% (Table IV). Data of each cutoff point of the DU parameters were analyzed. The best cutoff points and their receiver operating characteristic curve are shown in Table V and in Fig 4. Their correlations with IVUS are shown in Table VI. The VR had a better (high) correlation with IVUS than the other sonographic parameters did. There was a moderately high agreement between the DU and the IVUS findings when they were grouped into three categories (k ¼ 0.598; P < .001) and a high agreement when they were grouped into two categories (obstructions <50% and $50%; k ¼ 0.784; P < .001). Therefore, DU is better at discriminating significant obstructions than critical obstructions. A sonographic algorithm was developed with the best cutoff points. First, the phasicity of the femoral venous flow was evaluated. If a monophasic waveform was observed, the iliac vein was categorized as presenting obstruction $80%. After that, VI and FI were measured. If both indexes are normal, the iliac vein does not have a significant obstruction. If one or both of these parameters are altered, it is mandatory to
Table III. Descriptive variables in group I (GI) GI (N ¼ 30) Sonographic parameters
Mean 6 SD
Median (min-max value)
IQR (25%-75%)
VI (n ¼ 15) FI (n ¼ 15) OR VR Phasicity
0.99 0.95 0.10 1.21
6 6 6 6
1 (0.78-1.1) 0.97 (0.6-1.14) 0.09 (0.27-0.47) 1.14 (22.8-43.0) 100% present
0.96-1.07 0.88-1.08 0.01-0.21 0.87-1.69
0.08 0.15 0.16 0.22
FI, Flow index; IQR, interquartile range; n, number of lower limbs; OR, obstruction ratio; SD, standard deviation; VI, velocity index; VR, velocity ratio.
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Table IV. Descriptive variables in group II (GII) Parameters VI Category 1 Category 2 Category 3 FI Category 1 Category 2 Category 3 OR Category 1 Category 2 Category 3 VR Category 1 Category 2 Category 3 Monophasic waveform Category 1 Category 2 Category 3
Mean 6 SD
95% CI
1.17 6 0.51 0.75 6 0.23 0.67 6 0.25
0.9-1.46 0.65-0.86 0.53-0.83
1.15 6 0.62 0.76 6 0.45 0.56 6 0.27
Median (min-max value)
IQR (25%-75%)
P
1.00 (0.77-2.57) 0.80 (0.34-1.35) 0.71 (0.17-1.2)
0.92-1.09 0.59-0.90 0.52-0.81
<.001
0.81-1.5 0.56-0.97 0.39-0.71
1.00 (0.62-3.08) 0.62 (0.37-2.0) 0.54 (0.1-1.09)
0.76-1.39 0.50-0.83 0.39-0.57
<.001
0.12 6 0.22 0.47 6 0.23 0.71 6 0.22
0.06-0.18 0.04-0.56 0.61-0.81
0.12 (0.36 to 0.59) 0.54 (0.02 to 0.81) 0.65 (0.34-1.0)
0.02 to 0.3 0.40-0.62 0.54-1
<.001
1.15 6 0.28 2.53 6 0.99 3.38 6 0.91
1.05-1.25 2.13-2.93 2.88-3.88
1.05 (0.66-2.45) 2.60 (0.93-5.42) 3.21 (1.48-5.22)
0.97-1.20 1.53-3.15 3.12-3.89
<.001 <.001
100% absent 2 of 26 limbs (7.7%) 15 of 24 limbs (62.5%)
CI, Confidence interval; FI, flow index; IQR, interquartile range; OR, obstruction ratio; SD, standard deviation; VI, velocity index; VR, velocity ratio.
perform the VR analysis in both sides of the iliac veins because this parameter has the best correlation with the degree of obstruction by IVUS. If the VR is <2.5, the iliac vein does not have a significant obstruction. However, if this parameter is $2.5, the iliac vein is categorized as having an obstruction
$50% (Fig 5). When an appropriate view of the iliac veins is not possible, another diagnostic method should be considered. With this algorithm, it is possible to detect significant obstructions with a sensitivity of 92.4% and accuracy of
Fig 3. A-D, Box plot of each sonographic parameter divided into three categories by intravascular ultrasound (IVUS) in group II (GII). Intercategory analysis.
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Table V. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the cutoff points of the duplex ultrasound (DU) algorithm Parameters
Cutoff point
Sensitivity, %
Specificity, %
PPV, %
NPV, %
Accuracy, %
Category
VI FI VR OR Phasicity Algorithm
0.9 0.7 2.5 0.5 Absent
87.9 78.8 75.6 75.0 62.5 92.4
86.7 86.7 100 96.0 97.4 80.0
79.5 77.7 100 91.7 93.4 73.1
92.4 87.4 87.5 86.7 81.6 94.7
87.5 58.3 89 85.7 89.1 86.7
3 1 (2 þ 3)
FI, Flow index; OR, obstruction ratio; VI, velocity index; VR, velocity ratio.
86.7% and with k ¼ 0.730 (high agreement). For detection of critical lesions, the accuracy and k index dropped to 79.6% and 0.655, respectively (Table V). DISCUSSION Venous disease is a highly prevalent and disabling disorder.1 IVCS has been increasingly recognized as an important etiologic factor in CVI. It can cause disabling symptoms of CVI20 and venous hypertension, such as edema, leg heaviness, skin lipodermatosclerosis, pain, varicose veins, and ulcerations.21 Venographic studies suggest that the incidence
of extrinsic compressive lesions may be even more pervasive than the incidence of intrinsic lesions.10 Recent invasive imaging data22 indicate that the compression of the left iliac vein at the arterial crossover point may be present in 66% of the general population without any venous symptoms. In the past, single planar transfemoral venography was considered the “gold standard,” but this technique has been considered inaccurate in delineation of IVOO.9 The extent and severity of the obstructive lesion appear to be worse in IVUS results compared with venographic findings, and even severe obstructions may go undetected.23,24
Fig 4. A-D, Receiver operating characteristic (ROC) curves of each sonographic parameter. AUC, Area under the curve.
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Table VI. Correlation between the indexes and relations of the sonographic parameters and the categories of obstruction by intravascular ultrasound (IVUS) Parameters VI FI VR OR
Statistical analysis r value P value 95% CI r value P value 95% CI r value P value 95% CI r value P value 95% CI
0.634 <.001 0.758 to 0.478 0.623 <.001 0.737 to 0.623 0.790 <.001 0.698-0.849 0.750 <.001 0.657-0.818
CI, Confidence interval; FI, flow index; OR, obstruction ratio; r, Spearman correlation coefficient; VI, velocity index; VR, velocity ratio.
Injection of contrast dye can hide details such as intraluminal webs. On average, it underestimates the degree of stenosis by 30%.10 Currently, there is no well-established noninvasive screening study. The standard test for diagnosis of lower limb DVT and CVI is DU imaging because it is easy to perform and noninvasive. However, imaging of the pelvic veins is technically difficult and generally not sensitive enough to detect nonocclusive thrombosis and intraluminal defects within the iliac vein.7 Therefore, the obstruction component is rarely investigated in clinical practice today because the main tool for diagnosis is DU, which can fail in its diagnosis in 20% of the cases even when it is performed by experienced professionals.7,8 For this reason, we compared five
Metzger et al 25
sonographic parameters with the standard method (IVUS) to improve detection of the obstructive venous iliac lesion with a noninvasive screening method. Reflux is considered the dominant pathologic change in CVI.21 Raju et al19 found a prevalence of deep venous reflux in 33% of the analyzed limbs, and severe reflux was present in 308 of 528 limbs (59%). In this study, there was 25.5% reflux in the deep venous system in GII, whereas no reflux in the deep venous system was observed in GI. GII had 45 of 102 limbs (44.1%) with severe reflux, constituting a significant difference among the groups. It is important to consider the presence of an obstruction in all patients with symptomatic CVI, even those with apparent venous reflux.19 We found that 50% of the studied limbs have an iliac vein obstruction of at least 50% and that 23.5% presented an at least 80% obstruction when verified by IVUS. This percentage would be even higher if we considered only CEAP C3-6 studied limbs. Raju and Neglén21 found that IVUS-detectable lesions are present in >90% of patients with advanced CVI. This evidences the high prevalence of obstructions in the iliac veins and the importance of IVCS screening in patients with highly advanced CVI. The relation among velocities in the femoral veins to the passage of the blood flow in an unimpeded system must be equal to 1 (equal velocities), as we observed in GI (Table I). In obstructive blood flow conditions, this index is <1 in the affected side. In our study, when evaluating the VI in the left leg and comparing it to the right leg on expiration, we obtained the value of 0.9 as the best cutoff point. Among the sonographic parameters, FI was the least correlated with the IVUS results. This index is rarely
Fig 5. Ultrasonographic algorithm for detection of venous iliac obstructions. C2, Category 2; C3, category 3; CEAP, Clinical class, Etiology, Anatomy, and Pathophysiology.
26 Metzger et al
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS January 2016
studied in the literature.15,25 Initially, we used a cutoff value of 0.615; however, this cutoff point has low sensitivity (60.6%). The best cutoff value obtained was 0.7 with 78.8% sensitivity to discriminate significant obstructions. Monophasic waveforms result when the transmission of the fluctuating intrathoracic pressures to distal venous structures is dampened. The loss of phasic variation may be due to (1) an iliac nonocclusive thrombus, (2) extrinsic compression, (3) intrinsic luminal narrowing, and (4) other causes, such as cardiac factors.17 Lin et al,17 in a retrospective study of 124 limbs with monophasic waveforms in the femoral vein, found that an iliac venous thrombosis was the most common cause (38%). There was no discernible explanation for the loss of phasic variation in 36% of the cases. In our study, the monophasic waveform was present in 62.5% of the limbs categorized as having an obstruction >80% and in only 7.7% (two limbs) categorized as having an obstruction of 50% to 79%. The cause of the monophasic waveform in 10 of 17 limbs (58.8%) was iliac vein occlusive disease, followed by extrinsic compression (35.3%) and intrinsic narrowing (5.9%). Labropoulos et al8 in 2007 investigated the central venous obstruction with DU and defined VR as the best diagnostic criterion. These authors studied 37 patients with 41 central venous obstructions. This study population was heterogeneous. Obstructions were located in the iliac veins in only 11 cases (26.8%). Initially, the authors used the VR cutoff point of 2.0 to determine obstructions $50%, but they considered 2.5 the best cutoff point for detection of significant venous lesions. Using this VR value, they reported only two false-positive test results, whereas the number of false-positive results increased to four when a VR value of 2.0 was used. Our experience shows results similar to those of Labropoulos et al.8 We initially used a VR of 2.0 to estimate significant obstructions. We noted that when using this relation, we obtained 78% sensitivity, 94% specificity, 88.4% positive predictive value, and 87.9% negative predictive value. Using the cutoff point of 2.5, we observed a slight reduction in sensitivity to 76%, with an improvement of specificity and positive predictive value to 100%, with 87.5% negative predictive value, thus reducing the number of false-positive test results. Our study population consisted of patients with advanced CVI, and the study was directed to the detection of iliac vein obstructions; therefore, we had a more homogeneous population than in the previous study. In this study, DU had a high agreement with IVUS for detection of significant obstructions using the studied sonographic parameters. Clinically, the presence of an obstruction >50% in symptomatic limbs is a criterion for endovascular treatment. An ultrasound algorithm was developed for this purpose. Use of this algorithm will allow all vascular surgeons and radiologists to diagnose significant IVOO with elevated sensitivity and accuracy rates with a noninvasive screening method. This approach can reduce the time to diagnose and to treat this disorder. The study was limited by its transverse design and by the difficulty in acquiring vascular abdominal images with DU
because most of the patients had an increased body mass index and high abdominal waist circumference, requiring adequate intestinal preparation to obtain a favorable acoustic window. In addition, acquisition of such images is also hampered by the high compliance of the venous system during the different phases of the respiratory cycle. This can be changed not only by the patient’s volemic status but also by the transducer pressure exerted during the test. In a small subset of patients with bilateral IVOO, normal VI and FI in both sides can generate false-negative results. It is a limitation of the algorithm. CONCLUSIONS DU presented high agreement with IVUS for detection of significant iliac venous obstructions with the use of the sonographic parameters. The VR in obstructions $2.5 is the best criterion for detection of significant venous obstructions in iliac veins. AUTHOR CONTRIBUTIONS Conception and design: PM, NI Analysis and interpretation: PM Data collection: PM, FR, AK, MS Writing the article: PM Critical revision of the article: PM, FR, AK, NI, MS, IP, JA, PT Final approval of the article: PM, FR, AK, NI, MS, IP, JA, PT Statistical analysis: PM Obtained funding: FR Overall responsibility: PM REFERENCES 1. Nicolaides AN; Cardiovascular Disease Educational and Research Trust; European Society of Vascular Surgery; The International Angiology Scientific Activity Congress Organization; International Union of Angiology; Union Internationale de Phlebologie at the Abbaye des Vaux de Cernay. Investigation of chronic venous insufficiency: a consensus statement (France, March 5-9, 1997). Circulation 2000;102:E126-63. 2. Palma EC, Esperon R. Treatment of the post-thrombophlebitic syndrome by means of internal saphenous transplants. Bol Soc Cir Urug 1959;30:115-25. 3. Taheri SA, Williams J, Powell S, Cullen J, Peer R, Nowakowski P, et al. Iliocaval compression syndrome. Am J Surg 1987;154:169-72. 4. Mickley V, Schwagierek R, Rilinger N, Görich J, Sunder-Plassmann L. Left iliac venous thrombosis caused by venous spur: treatment with thrombectomy and stent implantation. J Vasc Surg 1998;28:492-7. 5. Akesson H, Brudin L, Dahlström JA, Eklof B, Ohlin P, Plate G. Venous function assessed during a 5 year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 1990;4:43-8. 6. Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004;239:118-26. 7. Cronan JJ. Venous thromboembolic disease: the role of US. Radiology 1993;186:619-30. 8. Labropoulos N, Borge M, Pierce K, Pappas PJ. Criteria for defining significant central vein stenosis with duplex ultrasound. J Vasc Surg 2007;46:101-7. 9. Raju S. Best management options for chronic iliac vein stenosis and occlusion. J Vasc Surg 2013;57:1163-9. 10. Neglén P, Raju S. Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 2002;35:694-700.
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11. Huskisson EC, Jones J, Scott PJ. Application of visual-analogue scales to the measurement of functional capacity. Rheumatol Rehabil 1976;15:185-7. 12. Vasquez MA, Munschauer CE. Revised venous clinical severity score: a facile measurement of outcomes in venous disease. Phlebology 2012;27(Suppl 1):119-29. 13. Eklof B, Rutherford RB, Bergan JJ, Carpentier PH, Gloviczki P, Kistner RL, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004;40:1248-52. 14. Marston W, Fish D, Unger J, Keagy B. Incidence of and risk factors for iliocaval venous obstruction in patients with active or healed venous leg ulcers. J Vasc Surg 2011;53:1303-8. 15. Ogawa T, Lurie F, Kistner RL, Eklof B, Tabrah FL. Reproducibility of ultrasound scan in the assessment of volume flow in the veins of the lower extremities. J Vasc Surg 2002;35:527-31. 16. O guzkurt L, Ozkan U, Tercan F, Koç Z. Ultrasonographic diagnosis of iliac vein compression (May-Thurner) syndrome. Diagn Interv Radiol 2007;13:152-5. 17. Lin EP, Bhatt S, Rubens D, Dogra VS. The importance of monophasic Doppler waveforms in the common femoral vein: a retrospective study. J Ultrasound Med 2007;26:885-91. 18. Labropoulos N, Tiongson J, Pryor L, Tassiopoulos AK, Kang SS, Ashraf Mansour M, et al. Definition of venous reflux in lower-extremity veins. J Vasc Surg 2003;38:793-8.
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Submitted May 8, 2015; accepted Jul 13, 2015.