Respiratory changes in biometry of suprarenal inferior vena cava in patients with varicose veins of lower extremities

Abstract

Aim

This study examines respiratory biometry of inferior vena cava in patients with varicose veins of lower extremities.

Material and Methods

We performed retrospective analysis of clinical and ultrasound data of 67 patients with primary varicose veins.

Results

The largest expiratory (mean 16.2 mm, p-value 0.09) and inspiratory (mean 8.2 mm, p-value 0.02) inferior vena cava diameters were in C3 Clinical Etiological Anatomical Pathophysiological clinical class; the smallest expiratory diameters (mean 13.1 mm, p-value 0.5) were in C6 class; the smallest inspiratory diameters (mean 4.6 mm, intercept) were in C2 class. C2 class was associated with highest inferior vena cava collapsibility index (mean 68.2%, intercept); C6 class was associated with lowest collapsibility index (mean 48.3%, p-value 0.04).

Recurrent varices in comparison with previously untreated were associated with smaller inspiratory diameters of inferior vena cava (mean 4.4 mm, p-value 0.005), smaller expiratory diameters (mean 13.4 mm, p-value 0.06) and higher collapsibility index (mean 68.5%, p-value 0.005). Patients with recurrent and bilateral varicose veins had identical respiratory biometry of inferior vena cava.

Older age was associated with smaller inferior vena cava diameters (p-value <0.01).

Conclusion

Clinical presentation of varicose veins is associated with different respiratory biometry of suprarenal inferior vena cava. C6 clinical class in comparison with C2 clinical class is associated with lower central venous compliance possible due to the narrowing of inferior vena cava. Smaller inferior vena cava diameters and higher collapsibility index in recurrent subgroup in comparison with previously untreated can be a sign of the significantly altered pressure gradient between the systemic capillaries and the right heart and impaired peripheral venous return. Narrowing of inferior vena cava with age can be a sign of more profound changes in systemic venous return with age in patients with varicose veins in comparison to those without chronic venous disease.

Keywords

Inferior vena cava varicose veins venous compliance hydrostatic indifference point gravity

Introduction

Two main components contribute to a pressure measured anywhere within the cardiovascular system.^1–4 First dynamic component caused by the heart, thoracic pump and skeletal muscle activity^1–4 against the second static component caused by gravity^1–7 acting on the blood and fluid distribution in the body,^1–7 on the blood volume^1,2,8,9 and on the peripheral vascular resistance.^4,6 This concept of hemodynamics is also applicable to the assessment of the central venous pressure: according to previous studies, gravity-dependent peripheral venous pressure correlates positively with central venous pressure and it determines inferior vena cava (IVC) biometry;^{1,2,5,7,10–13} influences of the cardiac hemodynamics and respiration on the central venous pressure and IVC biometry were also previously described.^14–16 Thus, peripheral venous pressure, right heart filling pressure and respiratory pressure variations determine the central venous pressure and the IVC biometry in normal adult humans, where IVC is the place of interaction of these different intensities – indicator of the changes in systemic venous return.

Advanced stages of chronic venous disease or clinical classes C3-C6 in the Clinical Etiological Anatomical Pathophysiological classification (CEAP)^17,18 are associated with higher ambulatory venous pressure.^17,19–21 But associated with the disease changes in the central venous physiology that can potentially not only reflect, but also significantly alter peripheral venous physiology, remain unclear due to the lack of research works.

We conducted a retrospective analysis of ultrasound data of suprarenal IVC in a cohort of patients with symptomatic primary varicose veins of lower extremities^17,18 to determine the interactions between the central venous physiology and the clinical presentation of the disease – potential causes the impaired peripheral venous physiology.

Material and methods

Patient population

This study consisted of patients referred to us for treatment of varicose veins from 2017 to 2019 years. Inclusion criteria for retrospective data analysis were patients with symptomatic primary varicose veins of lower extremities in clinical classes C2–C6 CEAP classification. IVC ultrasound data were collected as a part of preoperative focused echocardiography in patients who chose general anesthesia for the treatment of varicose veins (surgery, endovenous laser ablation or a combination of both). Exclusion criteria were previously diagnosed or revealed during our clinical and ultrasound examination conditions that could significantly affect cardiac physiology and right atrial pressure.^14–16 Personal identifiers were not used in the analysis part of the evaluation.

Ultrasound examination

The first part of our ultrasound examination²² was the assessment in a physiological upright standing position of the superficial and deep venous systems of the legs. We used compression/release manoeuvre to find the venous incompetence. PW Doppler reflux time more than 0.5 s was determined as a cut-off value for incompetence in the superficial venous system and 1 s for the deep venous system (common femoral vein and popliteal vein). The second part was the assessment in supine position of the ilio-caval segment and then in slight left lateral decubitus position of the heart.

Natural movement of the diaphragm during inspiration results in caudal displacement of the IVC and, in effect, measurement of two different locations during expiration and inspiration,²³ especially by M-mode ultrasound. For this reason, IVC measurements were performed in following manner (Figure 1):

IVC was visualized by B-mode ultrasound with low frequency ultrasound probes in sub-xyphoid transabdominal long axis view;^14,23,24

all measurements were taken caudal to hepatic vein inlet or at least 3cm peripheral to the ostium of the right atrium, and cranial to renal veins or at least 1cm central to the right renal artery (Figure 1);

in this segment (hepatic vein inlet – right renal artery) during normal respiration (without sniff and special thoracic pump activation) were measured maximal expiratory and then at the same level the minimal inspiratory IVC diameters or the diameters from the anterior to posterior walls (inner edge to inner edge);

by the presence of the pulsatile activity of IVC by B-mode ultrasound, maximal expiratory IVC diameters and minimal inspiratory IVC diameters were measured.

Figure 1.

Maximal expiratory and minimal inspiratory IVC diameters by B-mode ultrasound. Male patient, 40 years old with recurrent varicose veins, C3 CEAP clinical class.

We calculated respiratory variability with percentage collapse of the IVC as the inferior vena cava collapsibility index (IVC CI): [(Maximum IVC diameter – Minimum IVC diameter)/Maximum IVC diameter] × 100.^23,24

Ultrasound data were assessed qualitative and quantitative retrospectively. Invalid data were excluded from the further analysis.

Statistical analysis

To find the interaction between ultrasound parameters and clinical predictors, we used simple linear regression analysis of the data set.

IVC diameters and IVC CI were considered as dependent continuous numeric variables – outcomes. CEAP clinical classes (intercept C2 clinical class), recurrence of varicose veins (previously untreated or recurrent) and side (bilateral or unilateral) were considered as independent categorical variables – predictors. We also analyzed the linear relationships between the dependent IVC biometry and CEAP clinical classes as continuous independent variables.

We merged C5 CEAP class with C4, because of the limited number of patients in C5 class. Recurrence included recurrent varices, residual varices and PREVAIT (PREsence of Varices (residual or recurrent) after InTervention).^17,25 The reasons of no treatment (untreated subgroup) were the first presentation (diagnosis) of the disease or previous patient's refusal of treatment.

To avoid the overfitting in our model, we assessed separately influences of CEAP clinical class, recurrence of varicose veins and side on ultrasound parameters.

Control for confounders was not achieved because, according to previous studies,^26,27 IVC biometry is independent of age, gender, height, weight and body mass index of the adult individual (without chronic venous disease). But, we assessed separately the influences of these independent variables on IVC biometry.

Cook's distance higher than 0.5 was considered as influential. The value of p < 0.05 (Pr(>|t|)) was considered as statistically significant. P-values were not corrected for multiple comparisons. For statistical analysis, we used R (Deducer – Java Gui for R. Version 1.7-9. R version 2.15).

Results

Valid data were available for 67 of 127 examined patients. 38 patients were excluded because of the invalid ultrasound data. 22 patients were excluded because of the relevant comorbidities that could significantly affect cardiac physiology and right atrial pressure.^14–16 The patients were adult Caucasian aged from 20 to 81 years (mean 55.4 years, 13.4 SD). 55% were females. 20 patients (30%) had comorbidities that could potentially influence right heart diastolic function:⁵ obesity grade I (body mass index 30.0–34.9 kg/m2) had 7 patients, 14 patients had treated (controlled) hypertension, 10 patients were current smokers, 3 patients had mild COPD, 5 patients had treated (controlled) diabetes, 2 patients had treated (controlled) hypothyroidism. Patients with deep venous reflux more than 1 s were not present in the data set. Influential outliers were not present in the data set.

We found following influences of clinical predictors on IVC biometry:

CEAP clinical class

The largest expiratory (mean 16.2 mm, p-value 0.09) and inspiratory (mean 8.2 mm p-value 0.02) IVC diameters were in C3 CEAP class; the smallest expiratory IVC diameters (mean 13.1 mm, p-value 0.5) were in C6 CEAP class; the smallest inspiratory diameters (mean 4.6 mm, intercept) were in C2 CEAP class.

C2 CEAP was associated with highest IVC CI (mean 68.2%, intercept); C6 CEAP was associated with lowest IVC CI (mean 48.3%, p-value 0.04).

Recurrence of varicose veins

Recurrent varices in comparison with previously untreated were associated with smaller inspiratory IVC diameters (mean 4.4 mm, p-value 0.005), smaller expiratory IVC diameters (mean 13.4 mm, p-value 0.06) and higher IVC CI (mean 68.5%, p-value 0.005).

Bilateral/unilateral varicose veins

Bilateral varices in comparison with unilateral were associated with smaller inspiratory IVC diameters (mean 5.7 mm, p-value 0.02), smaller expiratory IVC diameters (mean 14.2 mm, p-value 0.09) and higher IVC CI (mean 62.1%, p-value 0.02).

Tables 1 to 3 show the relationships between respiratory IVC biometry and clinical predictors.

Table 1.

Characteristics of expiratory IVC diameters stratified by CEAP clinical class, recurrence and side (unilateral/bilateral), and difference in age between the subgroups. Descriptive statistical analysis: mean (SD; n). And influences of CEAP clinical class, recurrence of varicose veins and side (unilateral/bilateral) on expiratory IVC diameters: p-values from regression analysis.

Clinical predictor	Age (years)	IVC expiratory (mm)	p^a
CEAP clinical class:			0.34^b
C2	54.6 (15.1, 21)	14.2 (4.6, 21)
C3	50,8 (13.4, 24)	16.2 (5.0, 24)	0.13
C4–5	62,1 (9,2, 9)	13.1 (3.6; 9)	0.6
C6	63.3 (11.0, 9)	13.1 (3.0; 9)	0.5
Recurrence
Untreated	52.3 (14.1, 41)	15.6 (4.3, 41)
Recurrent	60,7 (10.9, 25)	13.4 (4.6, 25)	0.06
Side:
Unilateral	51.4 (15.6, 26)	16.2 (5.0, 26)
Bilateral	58.0 (11.3, 41)	14.2 (4.3, 41)	0.09

IVC: inferior vena cava.

^ap-value. Influence of C3-C6 CEAP clinical classes in comparison with C2 on expiratory IVC diameter. Influence of recurrent varices in comparison with previously untreated on expiratory IVC diameter. Influence of bilateral varices in comparison with unilateral on expiratory IVC diameter.

^bp-value. Linear relationships between CEAP clinical classes and expiratory IVC diameters.

Table 2.

Characteristics of inspiratory IVC diameters stratified by CEAP clinical class, recurrence and side (unilateral/bilateral). Descriptive statistical analysis: mean (SD; n). And influences of CEAP clinical class, recurrence of varicose veins and side (unilateral/bilateral) on inspiratory IVC diameters: p-values from regression analysis.

Clinical predictor	IVC inspiratory (mm)	p^a
CEAP clinical class		0.28^b
C2	4.6 (3.6; 22)
C3	8.2 (7.0; 21)	0.02^c
C4–5	6,8 (4.4; 9)	0.28
C6	7.1 (4.1; 9)	0.23
Recurrence
Untreated	8.4 (6.1, 39)
Recurrent	4.4 (4.1, 24)	0.005^c
Side
Unilateral	9.2 (6.4, 24)
Bilateral	5.7 (5.0, 40)	0.02^c

IVC: inferior vena cava.

^ap-value. Influence of C3-C6 CEAP clinical classes in comparison with C2 on inspiratory IVC diameter. Influence of recurrent varices in comparison with previously untreated on inspiratory IVC diameter. Influence of bilateral varices in comparison with unilateral on inspiratory IVC diameter.

^bp-value. Linear relationships between CEAP clinical classes and inspiratory IVC diameters.

^cp-value regression analysis. <0.05 – by conventional criteria, this difference is statistically significant.

Table 3.

Characteristics of IVC collapsibility index stratified by CEAP clinical class, recurrence and side (unilateral/bilateral). Descriptive statistical analysis: mean (SD; n). And influences of CEAP clinical class, recurrence of varicose veins and side (unilateral/bilateral) on IVC collapsibility index: p-values from regression analysis.

Clinical predictor	IVC CI (%)	p^a
CEAP clinical class		0.03^b,c
C2	68.2 (20.1; 21)
C3	54.9 (29,9; 21)	0.09
C4–5	50.2 (22.9; 9)	0.07
C6	48.3 (21.8; 9)	0.04^c
Recurrence
Untreated	49.4 (26.7; 39)
Recurrent	68.5 (21.4; 23)	0.005^c
Side
Unilateral	46.4 (26.8; 24)
Bilateral	62.1 (24.5; 39)	0.02^c

IVC: inferior vena cava; CI: collapsibility index.

^ap-value. Influence of C3-C6 CEAP clinical classes in comparison with C2 on IVC CI. Influence of recurrent varices in comparison with previously untreated on IVC CI. Influence of bilateral varices in comparison with unilateral on IVC CI.

^bp-value. Linear relationships between CEAP clinical classes and IVC CI.

^cp-value regression analysis. <0.05 – by conventional criteria, this difference is statistically significant.

Age

Discordant with previous studies on patients without chronic venous disease,^26,27 we found significant influence of age on IVC biometry: decrease in expiratory IVC diameters with age, p-value 0.006; decrease in inspiratory IVC diameters with age, p-value 0.01. IVC CI changes with age (tendency to increase) were statistically insignificant, p-value 0.07.

Gender and BMI

Concordant with previous studies,^26,27 we did not find significant influence of gender (p-values > 0.3) and BMI (p-values > 0.1) on IVC biometry.

Discussion

“Blood feels gravity”.⁹ Throughout evolution of mankind, gravity has constantly stressed the cardiovascular system by diminishing the venous return of blood to the heart.^1,3,5–7 Therefore, the effects of gravity on the cardiovascular system must be taken into account whenever a hemodynamic assessment is made,¹ especially the assessment of IVC. Because suprarenal IVC in normal adult humans is the place where hydrostatic and volume indifference points are located, where blood pressure and volume are not affected by gravity. I.e. venous pressure and volume are the same and independent of a posture (supine or upright) at the level of the indifference points.^1–3,5 The location of these points also dictates the filling gradient to the heart and determines IVC biometry,^1,3,5,13 where decrease in peripheral venous pressure is associated with the shift of both indifference points in a caudal direction (lower abdomen)^1,5,13 or towards the point where the venous system naturally loses the respiratory collapsibility. This results in decrease in central venous pressure and right heart filling^1,5,11–13 and increased respiratory IVC collapsibility. Increase in peripheral venous pressure is associated with the shift of both points in a cranial direction or to the heart^1,5,13 This results in increased central venous pressure, right heart filling^1,5,13 and decreased respiratory IVC collapsibility.

This concept of physiology of IVC venous return lead us to the following interpretations of the results:

CEAP clinical class

Lowest IVC CI in C6 CEAP clinical class can be a sign of higher venous pressure in comparison with C2 clinical class. Abnormalities in cardiac physiology that could significantly affect the right heart filling in our patients were excluded by the focused echocardiography and clinical examination. Thus, possible mechanism of the lower IVC compliance in C6 subgroup was significant non-cardiac shift of the indifference points to the heart^1,5,13 possible due to the narrowing of IVC (statistically insignificant smallest expiratory IVC diameters in C6 CEAP class).

Recurrence

Increased IVC collapsibility and smaller IVC diameters in recurrent subgroup can be a sign of preserved elasticity of the caval wall and a sign of the shift of hydrostatic and volume indifference points in caudal direction (lower abdomen),^1,5,11–13 or a sign of the significantly altered pressure gradient between the systemic capillaries and the right heart and impaired peripheral venous return.²² Possible underlying mechanisms of this finding in recurrent subgroup are significantly altered intraabdominal – IVC recoil pressure and/or distribution of IVC blood volume to lower pressure areas:²⁶ internal iliac,^28–30 lumbar³¹ and renal (gonadal) veins.^29,30,32 This can result in peripheral venous congestion and recurrence^28,30 of varicose veins of lower extremities.

Bilateral/unilateral varicose veins

Patients with recurrent and bilateral varicose veins had identical respiratory IVC biometry. Thus, possible underlying mechanisms are also identical.

Age

Older age was associated with smaller expiratory and inspiratory IVC diameters in patients with varicose veins in comparison to those without chronic venous disease.^26,27 This narrowing of IVC with age can be a potential sign/cause of more profound changes in systemic venous return with age in patients with chronic venous disease²² and a cause of increased rates of chronic venous disease in older population.¹⁷

BMI

We did not find significant influence of BMI on IVC biometry. Possible cause of this insignificance was small and relative homogenous by BMI valid data set. Patients with relevant obesity (BMI > 35 kg/m2) and underweight were not present in the data set. Thus, the influence of this factor on IVC biometry needs further investigations.

Practical standpoint and clinical consequences

Severe chronic venous disease and recurrence of varicose veins are associated with different suprarenal IVC biometry, different central venous compliance and also different right heart filling.²² These different patterns of the endpoint of systemic venous return can be a sign of different underlying pathophysiological mechanisms in these conditions,²² and thus, they may require different treatment strategies.

Superficial venous ablation and compression therapy are the main components of treatment for primary varicose veins and chronic venous disease. Based on the mentioned above concept of physiology of IVC venous return, these two methods of treatment may influence central venous physiology differently. Superficial venous ablation can improve peripheral venous physiology due to the elimination of peripheral venous reflux, potential decrease in peripheral venous pressure and thus, caudal shift of the indifference points.^{1,2,5,7,11–13} Compression therapy can improve peripheral venous physiology due to increase in peripheral extravascular and decrease in peripheral intravascular – extravascular recoil pressures resulting in the immediate cranial shift of the indifference points.^1,5,11,13

Based on these data, it is possible, that superficial venous ablation in patients with severe chronic venous disease can potentially not only improve the peripheral venous hypertension, but it can also cause the caudal shift of the elevated indifference points. This shift can potentially decrease the right heart filling and eliminate the negative influence of the impaired venous return on cardiac physiology – right heart diastolic dysfunction.²² Compression therapy may cause more cranial shift of the elevated in this cohort indifference points or the shift above the physiological level. It can potentially further increase the right heart filling and cause the worsening of the right heart diastolic function, especially in patients with previously diagnosed right heart diastolic dysfunction²² and at the beginning of the treatment or adaptation to the increased right heart filling (Table 4).

Table 4.

Characteristics and potential influence of treatment (compression therapy, superficial venous ablation) on venous return in patients with severe chronic venous disease.

Hemodynamic outcome	Without treatment	Compression therapy	Superficial venous ablation
Peripheral venous pressure	Increased	Decrease	Decrease
Indifference points	Cranial shift^a	Further cranial shift and then adaptation	Caudal shift
Central venous compliance	Decreased^a	Further decrease and then adaptation	Increase
Right heart filling	Increased²²	Further increase and then adaptation	Decrease or normalization
Right heart diastolic function	Impaired²²	More profound impairment and then adaptation	Improvement

^aAccording to this study.

Ablation of the superficial venous network in patients with recurrent varices can potentially improve the peripheral venous physiology. But it cannot shift the caudal displaced indifference points cranially. Thus, it cannot improve the altered pressure gradient between the systemic capillaries and the right heart – possible cause of recurrence of varicose veins. Compression therapy, based on these data, can shift the caudal displaced indifference points more cranial or the shift to the physiological level. This shift can potentially improve the pressure gradient between the systemic capillaries and the right heart (Table 5).

Table 5.

Characteristics and potential influence of treatment (compression therapy, superficial venous ablation) on venous return in patients with recurrent varicose veins.

Hemodynamic outcome	Without treatment	Compression therapy	Superficial venous ablation
Peripheral venous pressure	Increased or normal	Decrease	Decrease
Indifference points	Caudal shift^a	Cranial shift and then adaptation	Further caudal shift or no changes
Central venous compliance	Increased^a	Decrease and then adaptation	Further increase or no changes
Right heart filling	Normal²²	Increase and then adaptation	Normal
Right heart diastolic function	Preserved²²	Further preserved or impairment and then adaptation	Preserved

^aAccording to this study.

Further investigations are required to confirm these hypotheses.

Limitations

Our study has following limitations:

First, IVC biometry is influenced by many factors: comorbidities, pattern of respiration, hydration status, etc… To prevent confounding due to these factors, we used standardized approach to collect and analyze the data and we excluded the patients with comorbidities that could significantly affect the cardiac physiology with right atrial pressure. We did not instruct our patients to maintain a special hydration pattern. But, patients with conditions that could cause relevant hypo- or hypervolemia were not present in the data.

Second, all IVC measurements were taken from only one view – sub-xyphoid transabdominal long axis view in B-mode ultrasound or measurement from the anterior to posterior walls. Thus, the IVC diameters between lateral walls, changes in IVC cross-sectional area and characteristics of IVC flow velocities during respiration remain unknown.

Third, because of the frequently poor ultrasound image quality of this anatomic region, we had limited valid data set and “small rather heterogenous population”. Thus, influences of some clinical predictors (flow pattern, flow velocity, reflux origin, reflux extension, etc.) on IVC biometry remain unknown and require further investigations. But, results from this study can serve as preliminary data for further investigations.

Fourth, patients with secondary varicose veins and deep venous reflux more than 1 s were not present in the data set. These data were collected as binary variables (yes/no). Thus, the influences of the deep venous reflux and obstruction on IVC biometry remain unclear.

Fifth, our study was the retrospective analysis of the previously collected ultrasound and clinical data. Case-control study design was not possible. Thus, difference between the normal central venous physiology and those in chronic venous disease requires further investigations.

In conclusion

This study shows the characteristics of IVC biometry in different clinical presentation of varicose veins of lower extremities.

Clinical presentation of varicose veins is associated with different respiratory biometry of inferior vena cava.

C6 clinical class is associated with lower central venous compliance possible due to the narrowing of inferior vena cava.

Smaller inferior vena cava diameters and higher collapsibility index in recurrent subgroup in comparison with previously untreated can be a sign of the significantly altered pressure gradient between the systemic capillaries and the right heart and impaired peripheral venous return.

Narrowing of inferior vena cava with age can be a sign of more profound changes in systemic venous return with age in patients with varicose veins in comparison to those without chronic venous disease.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The study complies with the Declaration of Helsinki, and the research protocol was approved by the locally appointed ethics committee (Numbers: III/1/sja/ewa FF4/2019 and V/1/sja/kaa 2019-1401-evBO LAEK Hessen).

Guarantor

YR.

Contributorship

YR: ethical approval. YR and VR: data analysis, draft of the manuscript, literature search and editing of the manuscript.

Acknowledgement

The authors would like to thank department of vascular surgery 4th city clinical hospital (Minsk) for the academic sources. The authors would also like to thank the anonymous reviewers for all comments and suggestions.

ORCID iDs

Yury Rusinovich

Volha Rusinovich

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