Local Echo-Free Space in a Limb with Lymphedema Represents Extracellular Fluid in the Entire Limb

Abstract

Background:

We previously reported that local subcutaneous echo-free space (SEFS) in the leg was stirringly correlated with extracellular fluid (ECF) status in the same part of the leg when assessed using bioelectrical impedance analysis (BIA). In this study, we examined whether local SEFS represents the ECF status in the entire limb.

Methods and Results:

In 51 legs and 40 arms with lymphedema (LE), subcutaneous tissue ultrasonography was performed to determine SEFS severity (range, 0–2). BIA was also performed to calculate the L-Dex^® score (LDS), which is a BIA-derived parameter to represent ECF status, for the arm and modified LDS (mLDS) for the leg (the right arm was used as a reference instead of the contralateral leg). SEFS severity in any part of the leg showed good correlation with mLDS, but that in the lateral lower calf showed the strongest correlation (ρ = 0.86). In contrast, only SEFS severity in the medial forearm showed good correlation with LDS (ρ = 0.74).

Conclusions:

Local SEFS may represent ECF status in the entire limb in both the leg and arm LE.

Introduction

The International Society of Lymphology has described a system to classify the severity of peripheral lymphedema (LE),¹ which is mainly based on the severity of symptoms such as edema, tissue fibrosis, and fat accumulation. Since all these symptoms are related to the skin and/or subcutaneous tissue, objective assessment of these tissues is useful to support the findings of physical examinations. Ultrasonography of the skin and subcutaneous tissue is one such assessment method. Ultrasonography using a ∼10 MHz-transducer is a noninvasive and inexpensive technique and is probably available in most clinics. We previously reported that this examination could aid in the differential diagnosis and assessment of treatment effects in extremity LE.^2,3 The finding of subcutaneous echo-free space (SEFS) in subcutaneous tissue ultrasonography suggests the accumulation of fluid in the space between the superficial fasciae. Since local SEFS correlates well with the local extracellular fluid (ECF) status,⁴ and since ECF seems to accumulate in the thigh and calf at a certain ratio when assessed using bioimpedance analysis (BIA),⁵ it may be hypothesized that local SEFS can be used to estimate ECF status in the entire lower limb. To test this hypothesis, in the current study, we tried to correlate SEFSs in various parts of the leg with the ECF status in the entire leg determined using BIA. Furthermore, we tried to perform the same analysis for arm LE to determine whether the hypothesis was true in the case of the arm as well.

Materials and Methods

This study was approved by the Institutional Review Board of Yamaguchi University Hospital (Ube, Yamaguchi, Japan). All participants provided signed, informed consent before enrollment. We studied 51 legs with LE in 45 patients (age range, 40–88 years; median age, 68 years) and 40 arms with LE in 40 patients (age range, 51–79 years; median age, 71 years), all of whom visited our clinic between April 2016 and March 2017. Patient characteristics are summarized in Table 1.

Table 1.

Subject Characteristics

	Arm LE (N = 40)	Leg LE (N = 45)
Age and median (range), years	71 (51–79)	68 (40–88)
Gender, male:female	2:38	7:38
Edema laterality, unilateral:bilateral	40:0	39:6

Tested extremities	N = 40	N = 51
Diagnosis	Primary 0	Primary 1
	Secondary 40	Secondary 50
	Stage I 4	Stage I 1
	II 36	II 48
	III 0	III 3

LE, lymphedema.

A bioimpedance spectrometer (U-400; Impedimed Ltd., Brisbane, Australia) was used for BIA. For 3 minutes before the measurements, as the manufacturer recommended, the participants lay supine in a room maintained at 25°C, and specially designed electrodes were then attached in the standard equipotential arrangement. All measurements were completed within a few minutes. For arm LE, the impedance in the affected arm was normalized to that in the contralateral normal arm, to obtain the L-Dex^® score (LDS). The basis of the L-Dex measure is to compare ECF resistance (Re) of the affected limb with that of the contralateral normal limb. The ratio is then compared with a normal population, and LE defined as a ratio more than three standard deviation greater than the mean and normalized.^6,7 For leg LE, the impedance in an affected leg was normalized to that in the right arm instead of the contralateral leg, to obtain the modified LDS (mLDS), as we previously recommended for assessing bilateral LE.⁸ Because the impedance ratio (IR), that is, the ratio of intracellular fluid (ICF) resistance (Ri) to Re, was used to represent ECF status in a previous study,⁴ this parameter was also correlated with ECF status in the entire limb.

Immediately following BIA, a B-mode scan of the subcutaneous tissue was recorded using an ultrasound system (LOGIQ S6; GE Healthcare, Little Chalfont, Buckinghamshire, United Kingdom) with an 8- to 12-MHz linear transducer. The leg was scanned at eight points (upper, lower, medial, and lateral thigh and leg) and the arm was scanned at four points (medial, lateral, upper arm, and forearm) as reported previously.^9,10 Then, the SEFS was graded as follows: grade 0, no echo-free space; grade 1, horizontally oriented echo-free space (at <45° to the skin) only; and grade 2, vertically oriented echo-free space (at ≥45° to the skin) bridging the horizontally oriented spaces.⁴

Statistical analyses

Results are expressed as median (range) unless otherwise indicated. The Spearman rank correlation was used to test the relation between LDS/mLDSs, IR, and SEFS grades in each part of the arm or leg. To test the differences in LDS/mLDSs among the arms or legs with or without SEFS, the Kruskal–Wallis test was used; the Mann–Whitney U-test was used for multiple comparisons. Statistical analyses were performed using JMP 11.0 (SAS Institute, Cary, NC). A p-value <0.05 was considered significant.

Results

The correlation between mLDS and SEFSs in various parts of the leg is shown in Figure 1A. SEFS in any part of the leg showed good correlation with mLDS, although SEFS in the lateral lower calf showed the strongest correlation with mLDS (ρ = 0.86). mLDS for each SEFS grade in this part was as follows: 24 (2–43) for SEFS 0, 54 (26–115) for SEFS 1, and 112 (41–268) for SEFS 2. IR did not show any such correlations for any part of the leg (Fig. 1B).

FIG. 1.

(A) Correlation between modified L-Dex^® score and local SEFS grades in legs with LE. (B) Correlation between IR and local SEFS grades in legs with LE. IR, impedance ratio; LE, lymphedema; SEFS, subcutaneous echo-free space.

The correlation between LDS and SEFSs in various parts of the arm is shown in Figure 2A. No correlation was found between SEFS and LDS in the upper arm, in contrast to the leg. SEFS in the medial forearm showed the strongest correlation with LDS (ρ = 0.74). The LDS for each SEFS grade in the medial forearm was as follows: 10 (2 to 28) for SEFS 0, 26 (−1 to 108) for SEFS 1, and 86 (53 to 104) for SEFS 2. IR did not show any such correlations for any part of the arm (Fig. 1B).

FIG. 2.

(A) Correlation between L-Dex score and local SEFS grades in arms with LE, (B) Correlation between IR and local SEFS grades in arms with LE.

SEFS was absent in the entire leg in 16 legs (31%) and only in the calf in 6 legs (12%). The mLDS in these groups was similar (22 [2–43] and 25 [17–40], respectively) and significantly lower than that in the legs, in which SEFS was found in both the thigh and calf (90 [26–268]) (Fig. 3). In 1 of the 16 legs without SEFS (6%), the mLDS exceeded 37, which is the tentative upper limit of the normal range for mLDS.⁸ SEFS was absent in the entire arm in 13 arms (33%) and only in the forearm in 3 arms (8%). The LDS in these groups was similar (11 [2–25] and 10 [4–27], respectively) and was significantly lower than that in the arms, in which SEFS was present in both the upper arm and forearm (26 [−1 to 108]). In 7 of the 13 arms without SEFS (54%), the LDS exceeded 10, which is the upper limit of the normal range for LDS.^6,11

FIG. 3.

Modified L-Dex score in leg LE and L-Dex score in arm LE with various SEFS conditions. (−), SEFS 0 in all parts; (+), SEFS 1 or 2 in any part; UA, upper arm; FA, forearm; ^†p < 0.05 versus thigh (−) calf (−), ^‡p < 0.05 versus UA (−) FA (−).

Discussion

In the present study, we found that local SEFS, particularly in the lateral lower calf for leg LE and medial forearm for arm LE accurately represented the ECF status in the entire limb when assessed using mLDS or LDS. The results suggest that estimating edema severity in the entire leg by examining SEFS in a specific local area is justified and may be useful in daily medical practices where BIA is not available.

We previously reported that mLDS reflects the ECF status in the entire limb better than IR does,⁸ and this was reconfirmed in the current study. However, the LDS/mLDS value for SEFS 0 requires some consideration. We previously reported that slight but significant abnormal ECF accumulation might be present in SEFS 0.⁴ The present study reconfirmed these findings, particularly in the arm, in that SEFS 0 does not necessarily mean absence of abnormal ECF accumulation. The reason for this phenomenon is currently unclear.

Unlike in other types of edema, in which SEFS is observed in a graduated manner from the bottom to the top of the leg according to gravity,² in LE, SEFS can be found only in the proximal part of the limb, that is, the thigh or the upper arm, and no SEFS is found in the calf or forearm, correspondingly. Judging from the current results, however, these SEFSs in the proximal part of the limb had a lower impact on the ECF status in the entire limb than SEFSs in the distal part of the limb did.

Limitations

Since this study was a single-center study and included a limited number of subjects, reaching a definite conclusion may be difficult. The simplification in the classification of echo-free spaces is derived from our personal experience and it is not supported by pathological basis, and therefore it requires further validation. Although we hypothesized that the vertical space acted as bridges between horizontal spaces, it might be upraised space which was originally running horizontally. Reevaluation of inter- and intraobserver differences in identifying SEFSs as well as definition of the normal range of mLDS may also be necessary. In addition, although the patients lay in the supine position for 3 minutes before BIA, so the shift in plasma caused by postural change could stabilize, the shift in the interstitial fluid during this period and the additional time taken for measurements might not be negligible. Echo-free space may be seen more frequently around the ankle. Although we do not scan and classify echo-free space in this area routinely because the standardization is difficult, it might represent whole-leg edema better. These issues must be considered in future studies.

Conclusion

Our findings show that SEFS in the lower lateral calf in patients with leg LE as well as SEFS in the medial forearm in patients with arm LE may represent the ECF status in the entire limb.

Footnotes

Acknowledgment

None.

Author Disclosure Statement

No competing financial interests exist.

References

International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lymphology, 2013; 46:1–11.

Suehiro

, Morikage

, Yamashita

, et al. Differentiation of functional venous insufficiency and leg lymphedema complicated by functional venous insufficiency using subcutaneous tissue ultrasonography. J Vasc Surg Venous Lymphat Disord, 2017; 5:96–104.

Suehiro

, Morikage

, Murakami

, et al. A study of increase in leg volume during complex physical therapy for leg lymphedema using subcutaneous tissue ultrasonography. J Vasc Surg Venous Lymphat Disord, 2015; 3:295–302.

Suehiro

, Morikage

, Yamashita

, et al. Correlation between the severity of subcutaneous echo-free space and the amount of extracellular fluid determined by bioelectrical impedance analysis of leg edema. Lymphat Res Biol, 2017; 15:172–176.

Suehiro

, Morikage

, Yamashita

, et al. Distribution of extracellular fluid in legs with venous edema and lymphedema. Lymphat Res Biol, 2016; 14:156–161.

Ward

, Dylke

, Czerniec

, Isenring

, Kilbreath

. Confirmation of the reference impedance ratios used for assessment of breast cancer-related lymphedema by bioelectrical impedance spectroscopy. Lymphat Res Biol, 2011; 9:47–51.

Ward

, Dylke

, Czerniec

, Isenring

, Kilbreath

. Reference ranges for assessment of unilateral lymphedema in legs by bioelectrical impedance spectroscopy. Lymphat Res Biol, 2011; 9:43–46.

Suehiro

, Morikage

, Harada

, et al. Application of the L-Dex Score for the assessment of bilateral leg edema. Lymphat Res Biol, 2017; March 27, 2017. [Epub ahead of print].

Suehiro

, Morikage

, Murakami

, Yamashita

, Samura

, Hamano

. Significance of ultrasound examination of skin and subcutaneous tissue in secondary lower extremity lymphedema. Ann Vasc Dis, 2013; 6:180–188.

10.

Suehiro

, Morikage

, Yamashita

, et al. Skin and subcutaneous tissue ultrasonography features in breast cancer-related lymphedema. Ann Vasc Dis, 2016; 9:312–316.

11.

Czerniec

, Ward

, Refshauge

, et al. Assessment of breast cancer-related arm lymphedema—comparison of physical measurement methods and self-report. Cancer Invest, 2010; 28:54–62.