Varicose veins of the lower limb cause not only cosmetic problems but also unpleasant symptoms, including itching skin, pain, muscle cramps, swelling (oedema) and so on. Although surgical procedures, including stripping and high ligation, have been used to treat saphenous varicose veins, complications such as subcutaneous bleeding, nerve injury, postoperative pain or infection are common. Endovenous ablation, including endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), has replaced surgical treatment because of patient satisfaction with day surgery, less pain, and faster recovery [1]. In Japan, endovenous thermal ablation (ETA) for purposes other than cosmetic improvement is generally covered by national insurance, and guidelines regarding proper treatment were developed in 2019. The guidelines recommend that ETA be performed to improve clinical symptoms according to the CEAP classification [2]. Skin ulcers are classified as C5 (healed ulcer) or C6 (active ulcer) according to CEAP, and in general, surgical procedures for patients with ulcers are performed to improve them. Regarding the relationship between ulcers and venous functions, studies have indicated that the measurement of venous function obtained by air plethysmography (APG) is associated with the presence or absence and severity of skin ulcers [3,4]. Moreover, postoperative ulcer recurrence can be predicted using the APG index [5]. Regarding leg oedema, which is classified as C3 according to CEAP, few studies have explored the relationship between venous function measured by APG and oedema [6,7], and no study has focused on predicting improvements in postoperative leg oedema using an indicator of preoperative venous function. Recently, a multivariable analysis in a large-scale study indicated that the indicators obtained by APG show no statistical correlation with the severity of CEAP classification, especially between C1 and C4 [8], which might be the reason that there are few papers comparing venous function and clinical symptoms other than skin ulcers. In this study, we used a noninvasive venous pressure measurement device that we developed and evaluated the change in venous pressure before and after the procedure [9]. We also evaluated whether we could predict postoperative improvement in leg oedema by means of the change in circumferential diameter before versus after surgery. The device we used is a noninvasive controlled compression sonography device that can measure venous pressure without pain or the need for aseptic techniques within 3 to 4 seconds per measurement. As we described in our previous study, performing regression analysis with the pressure generated by a hydrostatic pressure generator and the measured pressure with our device yielded a significant regression equation (y=0.99x+3.13; p<0.001) and an extremely strong correlation (r²=1.00) [9].

Thirty-one limbs of 23 consecutive patients with various stages of chronic venous insufficiency who underwent the EVLA procedure between July 30, 2016, and July 11, 2017, in Chikugo City Hospital and agreed to participate in the study were evaluated. Patients confirmed to have severe gait disturbance were not recommended for the EVLA procedure at our hospital. Patients who had been taking medicine that may cause lower leg oedema as a side effect, such as calcium blocker and pregabalin, and continued to take the medicine after surgery were included in this study because, in the real world, a relatively high percentage of patients who are subjected to the ELVA procedure are taking these medicines. In this study, eight of the 23 patients (12 of 31 limbs) had been taking medication as described above. Patients with oedemagenic conditions such as cardiac, hepatic, and renal failure were excluded from the study. A 1470-nm diode laser (Ceralas E; Biolitec AG, Wien, Germany) and a commercial kit (ELVeS Radial kit; Biolitec AG) were used during the EVLA procedure. Patients with large saphenous venous regurgitation were included, while those having a combination of large and small saphenous venous regurgitation were excluded from this study. All insufficient perforators that we found with preoperative echography were excised using the Stab Avulsion technique, and the removal was confirmed by echography during the procedure. We evaluated venous pressure before and after surgery in all included patients using our noninvasive device, and the data were statistically analysed. The details regarding the venous pressure measurements are described below.

Venous Pressure Measurement

Using a noninvasive pressure measuring device, venous pressure was measured before EVLA and three months after the procedure. The pressure was measured in the large saphenous vein at 5 cm above the malleolus medialis with patients in a standing position. First, after a minute of standing rest, venous pressure was measured 3 times consecutively using our device within 12 seconds, and then, patients performed 10 tiptoe exercises at a rate of 1 per second, and the venous pressure after exercise was measured immediately 3 times consequently within 12 seconds. Because one venous measurement takes 3~4 seconds, three consecutive measurements take approximately 9~12 seconds. As a precaution to prevent measurement error caused by contractions of the calf muscle, patients supported themselves in the standing position by holding onto a supportive frame during the standing rest pressure measurement as described in a previous study [9]. Preoperative and postoperative measurements at standing rest and after exercise take 5 to 6 minutes, respectively, which is considerably less time than that needed for APG evaluation. The mean value of the 3 venous pressure measurements at standing rest is denoted by mST, and the preoperative and postoperative mST values are denoted by premST and postmST, respectively. Similarly, the mean value of the 3 venous pressure measurements immediately after tiptoe exercise is denoted by mEX, and preoperative and postoperative mEX values are denoted by premEX and postmEx, respectively. The resulting value of mEX divided by mST (mEX/mST) represents the index for venous pump function (IVPF). The value of IVPF before the procedure is denoted by pre-IVPF (?premEX/premST), and postoperative IVPF is denoted by post-IVPF (?post-mEX/post-mST). The values of all pressure measurements were concealed until the pressure of all patients was achieved and statistical analysis was conducted.

Circumferential Diameter

The circumferential diameter (CFD) of the ankle at 5 cm above the malleolus medialis was measured before and 3 months after the procedure. The CFD was measured by a different investigator, and the value was concealed until statistical analysis was conducted. The CFD measurements before and 3 months after the procedure are denoted pre-CFD and post-CFD, respectively. Diff-CFD represents the difference between the post-CFD and the pre-CFD. A positive diff-CFD value indicates postoperative worsening in leg oedema, and a negative value indicates postoperative improvement. DVI, deep venous insufficiency.

The following data were analysed using statistical methods.

• Mean premST and premEX values of all patients
• Mean postmST and postmEX values of all patients
• Mean premST and postmST values of all patients
• Mean premEX and postmEX values of all patients
• Mean pre-IVPF and post-IVPF values of all patients
• The relationship between pre-IVPF and diff-CFD
• ROC curve of the pre-IVPF and diff-CFD for the presence or absence of an increase in postoperative circumferential diameter
• Circumferential change in the groups classified by the threshold obtained by the ROC curve of pre-IVPF and diff-CFD

Statistical analysis was performed using EZR software (Version 1.32) [10]. All data are presented as the mean±standard deviation. The venous pressure, pump function and circumferential diameter data were checked for statistical normality using the Shapiro–Wilk test. The venous pressure data followed a normal distribution, and the IVPF and CFD data followed a nonnormal distribution. Thus, the data on venous pressure before and after surgery were compared using paired Student’s t test, and the correlation between mST and mEX before and after the procedure was analysed using an unpaired t test. The other data were compared using the Mann–Whitney U test. A P value <.05 was considered statistically significant.

Demographics And Clinical Characteristics of The Patients

We evaluated 31 limbs in 23 Japanese patients. The mean age of the patients was 70.2 ± 9.6 years. The percentage of females and the mean height of the patients were 90.5% and 153.2±8.0 cm, respectively. The included CEAP classifications were C2~C4a. Table 1 shows the demographics and clinical characteristics of the patients.

Table 1: Demographics and clinical characteristics of the patients.

Venous Pressure

The preoperative mean venous pressure of each patient in the standing position (premST) and after tiptoe exercise (premEX) are shown in Figure 1. The mean premST value was 73.6±7.1 mmHg, and the mean premEX value was 75.8±8.7 mmHg, with no statistically significant difference (p=0.156).

Figure 1: Preoperative mean venous pressure at the ankle joint.

Figure 2 shows the postoperative mean venous pressure of each patient in the standing position (post-mST) and after tiptoe exercise (post-mEX). The mean values of postmST and postmEX were 64.7±8.1 mmHg and 52.8±13.2 mmHg, respectively, with the postmEX value being significantly lower than the postmST value (p<0.01). In addition, the mean postmST and postmEX values were significantly lower than the premST and premEX values (p<0.01 and p<0.01, respectively).

Figure 2: Postoperative mean venous pressure at ankle joint.

Figure 3 presents the IVPF values of the patients before and after surgery. The mean pre-IVPF and post-IVPF values were 1.03±0.12 and 0.81±0.17, respectively, with the post-IVPF being significantly lower than the pre-IVFP (p<0.01). The percentage of patients with IVPF values that improved (decreased) after the procedure was 6.5%.

Figure 3: Index for venous pump function before and after surgery.

Circumferential diameter

Figure 4 depicts the results for circumferential pre-CFD, post-CFD and diff-CFD.

Figure 4: Change in the circumferential diameter before and after surgery.

The mean pre-CFD and post-CFD values were 22.3±2.5 cm and 22.4±3.1 cm, respectively.

The mean diff-CFD value was 0.1±1.21 cm.

There was no statistically significant difference between the mean pre-CFD value and post-CFD value (p=0.89).

Relation Between Pre-IVPF And Diff-CFD

Figure 5 shows the scatter plot of pre-IVPF and diff-CFD. When the pre-IVPF value was 1 or lower, diff-CFD was always 0 or lower. When the pre-IVPF value increases by 1.1 or more, the value of the diff-CFD tends to be large.

Figure 5: The relationship between the preoperative index for venous pump function and the difference in circumferential diameter before and after surgery.

Figure 6 shows the receiver operating characteristic curves of pre-IVPF and diff-CFD for the presence of a postoperative increase in the circumferential diameter. When the pre-IVPF cut-off value was 1.057, the area under the curve reached its maximum, with an AUC value of 0.92, a sensitivity of 0.864 and specificity of 0.889.

Figure 6: A receiver operating characteristic curve of pre-IVPF and diff-CFD regarding the presence or absence of an increase in postoperative circumferential diameter.

Circumferential Diameter of Subgroups Divided by Value of Pre-IVPF Cut-Off

Figure 7 presents the circumferential diameter of subgroups, which was divided by the 1.057 cut-off for pre-IVPF. In the group of patients with pre-IVPF values less than 1.057, the mean circumferential diameter before surgery was 21.8±1.4 cm, and the mean postoperative diameter was 21.4±1.4 cm. The postoperative diameter significantly decreased compared to the preoperative value (p=0.04). In the group of patients with pre-IVPF values of 1.057 or higher, the mean value of circumferential diameter before surgery was 23.2±3.7 cm, and the mean value after the procedure was 24.1±4.5 cm. The postoperative diameter tended to increase after the procedure (p=0.07).

Figure 7: The postoperative circumferential diameter of each group was divided by the preoperative index for venous pump function of 1.057.

Figure 8 presents the diff-CFD values before and after the procedure for each subgroup. The mean diff-CFD of the group of patients with pre-IVPF values less than 1.057 was -0.36±0.70 cm and that of the group of patients with pre-IVPF values 1.057 or higher was +0.92±1.52 cm. The group with pre-IVPF values of 1.057 or more had a significantly larger diff-CFD than the group with pre-IVPF values less than 1.057 (p=0.013).

Figure 8: Circumferential differences before and after surgery.

Ambulatory venous pressure (AMVP) is the gold standard for evaluating chronic venous function of the lower extremities, and various studies have focused on the changes in venous pressure associated with clinical symptoms or pathological conditions [11-13]. However, the method used for measurement requires invasive needle puncture, which is painful for patients. In 1987, Christopoulos et al. [14] introduced the APG as a noninvasive measurement approach that reflects the venous volume of the lower extremities, which is regarded as an indicator of venous function. Their paper and other papers revealed that the value of the residual volume fraction (RVF) obtained by the APG and the value of the AMVP show a linear correlation, and the value of the APG is useful as a noninvasive indicator of venous function [15,16]. Afterwards, the evaluation of venous function generally came to be measured by the APG, and various studies have been undertaken using this method [4,17,18]. In 2010, Park et al. revealed in a study involving 1756 limbs that APG parameters such as venous volume, venous filling index and RVF were improved after surgical procedures [19]. Thus, for the last few decades, venous function has been generally evaluated by the APG. Regarding skin ulcers, which were classified as C5 (healed venous ulcer) and C6 (active venous ulcer) in CEAP, papers have reported a strong correlation between the values obtained by APG and the presence of ulcers [3,4]. Moreover, prediction of the postoperative recurrence of ulcers is possible using APG [5]. On the other hand, for clinical symptoms other than skin ulcers, there are few papers exploring the relationship between each clinical symptom in the CEAP classification and the parameters of APG. Regarding leg oedema, which is C3 (oedema) in the CEAP classification, we found two papers evaluating the relationship between the parameters obtained by bioimpedance and APG indicators. One of the papers revealed that there was a statistically significant correlation between the bioimpedance parameter and the APG indicator, although the correlation coefficient between them was relatively low (p<0.001, r=0.34) [6]. Another study concluded that the parameter obtained by bioimpedance did not correlate with the parameters derived from APG [7]. Recently, in 2017, Raju et al. [20]. reported that the value obtained by the APG and the AMVP is nonlinear, and their conclusion was that APG and AMVP measure different parameters in different domains. After that, in 2019, they also reported in a detailed study of 8456 limbs in 4610 patients who the correlation between the RVF obtained by APG and postexercise venous pressure was weak (R?0.22), and the multiple regression analysis regarding the severity of CEAP classification and parameter of APG or AMVP revealed that the factor that indicates a good correlation with the CEAP classification is not the RVF of APG but AMBP [8]. In the study, RVF was significant only in C6 for CEAP classifications C0 to C6, with a P value of 0.03, although the AMVP showed statistically significant prediction for C2 through C6, with almost all significant P values <.05. Our new device can indicate the absolute value of venous pressure that is zero calibrated at atmospheric pressure and can noninvasively measure venous pressure within 3 to 4 seconds per measurement with no pain. Using the device, we detected statistically significant postoperative improvement in venous pressure and venous pump function as indicated by IVPF. Moreover, according to the results of this study, our device is likely to predict postoperative improvement and deterioration of lower limb oedema after ETA, which is difficult to achieve with APG. Hence, we think our device might be very useful for evaluating venous function and for the prediction of postoperative course after ETA therapy. As a next step, we studied the correlation between the severity of CEAP classification and venous function and obtained a good statistical correlation, as predicted in the study of Raju et al. [8]. We expect that our device is clinically very useful, although further prospective large-scale studies are needed.

The present study has some limitations. First, the number of limbs and patients was small, and multiple regression tests could not be performed to explore other elements that may affect venous pressure. Second, since our hospital was the first in our therapeutic area to start EVLA, a large number of patients in this study had not received treatment for a long time but were motivated to undergo minimally invasive treatment. The long period of morbidity might lead to different results being obtained relative to other studies focusing on patients with less severe cases.

Over the past few decades, venous function has been evaluated by APG because of its noninvasiveness. However, the multiple regression analysis in a recent large-scale study indicated that the severity of CEAP classification and parameter of APG indicated no statistical correlation, especially among patients with a CEAP classification of C0 to C4 [8]. On the other hand, our new noninvasive device can reflect venous pressure directly, which has been a standard parameter for CVI for a long time. Our system can indicate postoperative improvement in venous pressure and function in a fairly short time, and the value measured with our system can also clearly reflect symptoms of oedema (CEAP C3), which is difficult to ascertain with APG. Moreover, according to the results of this study, our device can predict postoperative improvement and deterioration of lower limb oedema after ETA, which is also difficult to achieve with APG. Therefore, there is a possibility that our device might be more useful to differentiate venous disease from other diseases or to check the severity of chronic venous insufficiency than APG, although further studies are needed to examine the full clinical usefulness of our device.

The authors appreciate Mrs. Chinako Taira and Hiroko Hironaka for their kind support.

None

The study protocol of this study was approved by the Ethics Committee of Chikugo City Hospital (approval number 2016-06), and all participants provided written informed consent to participate.

The funding source had no role in this study.

None

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