a b s t r a c t

Background: The Inferior vena cava parameters, including its diameter and collapsibility index have been evaluated for fluid status for over 30 years, but little is known about the impacts of patient characteristics on IVC parameters. The purpose of this study was to explore the relationships between individual patient character- istics and IVC parameters in healthy Chinese adult volunteers.

Methods: From February 2012 to May 2012, 216 healthy volunteers older than the age of 18 years were consec- utively enrolled in our study. The individual characteristics and presence or absence of hypertension of each par- ticipant were recorded. sonographic measurements of IVC and abdominal aorta diameter (Ao) were performed (DP-6900; Mindray, Shenzhen, China).

Results: Volunteers ranged in age from 18 to 84 years (43.7 +- 7.8 years), and 50.5% were males. In univariate analyses, maximum IVC diameter (IVC_max) was negatively correlated with age (years) (r = -0.171, P = .012) and positively correlated with sex (men) (r = 0.174, P = .01), height (centimeters) (r = 0.281, P b .001), and body surface area (square meters) (r = 0.173, P = .011). The IVC/Ao index was negatively correlated with age (years) (r = -0.326, P b .001), waist circumference (centimeters) (r = -0.176, P = .01), body mass index (r = - 0.173, P = .011), and hypertension (r = -0.186, P = .006). None of the patient characteristics were sig- nificantly correlated with percentage collapse of the IVC. Height (centimeters) was the sole significant predictor of IVC_max (R² = 0.079, P b .001). Age (years) and body mass index (kilogram/square meter) were independent predictors of the IVC/Ao index (R² = 0.123; P b .001 and P = .046, respectively).

Conclusions: The percentage collapse of IVC and the IVC_max are not substantially influenced by patient character- istics. In contrast, the IVC/Ao index is more susceptible to patient characteristics than IVC.

(C) 2015

1. Introduction

Many different conditions can cause hypovolemia in patients who are receiving emergency care, including blood loss, vomiting, diarrhea, urorrhagia, vasodilatation, transudation of fluid into the extravascular compartment, increased insensible fluid loss, and decreased oral intake. Early detection and correction of hypovolemia may limit and/or reverse tissue hypoxia and improve patient outcomes [1]. However, multiple studies have demonstrated that approximately 50% of hemodynamically unstable patients respond to a fluid challenge [2]. In contrast, overzealous resuscitation can lead to increased morbidity and mortality [3,4],

? Funds: none.

?? Conflict of interests: All authors declare that they have no any conflict of interests.

* Corresponding author at: Department of the General Intensive Care Unit, Dongguan Hospital Affiliated to Medical College of Jinan University, No. 154 Humendadao Road, Humen Town, Dongguan 523905, Guangdong, China. Tel.: +86 13509000999; fax: +86

0769 85010107.

E-mail address: [email protected] (D. Jiang).

especially in cases of altered pulmonary vascular permeability [5]. There- fore, optimizing volume status is an essential task for emergency care.

The inferior vena cava is a high-capacitance vessel that carries approximately 80% of the venous return to the right atrium. The IVC route is purely abdominal, and it is subject to intra-abdominal pressure [6], right atrial pressure [7], and intravascular volume [8]. Because sono- graphic assessment of IVC diameter is noninvasive, facilitates rapid di- agnosis, and is relatively low cost, this approach is emerging as a useful tool in the assessment of volume status in critically ill patients [9]. Some hospital centers now use IVC ultrasound (US) instead of cen- tral venous pressure in early goal-directed therapy for sepsis protocols. It has been shown that the IVC parameters including its diameter and collapsibility index vary greatly between individuals [10,11]. How- ever, accurate data on the effects of individual patient characteristics such as age, body mass index (BMI), and body surface area (BSA) on IVC parameters are lacking. Masugata et al [12] reported an age- related reduction in maximum IVC diameter (IVC_max) and an increase in the Respiratory variation of IVC, but the participants in their study were older patients (67 +- 15 years; range, 17-94 years), and 63% of

http://dx.doi.org/10.1016/j.ajem.2015.06.047

0735-6757/(C) 2015

them had a history of hypertension. They may not have been represen- tative of a healthy population. In addition, an ideal tool for measuring volume status should have an established normal reference range. How- ever, to our knowledge, the data available on the normal sonographic values of IVC are sparse [10,13,14]. A study conducted by Rein et al

[10] in 1982 enrolled only 10 healthy subjects and has been cited 19

times since 2006.

To mitigate the effects of individual characteristics on IVC diameter and its use as a diagnostic test, Kosiak et al [15] introduced a new tool to evaluate volume status in children and young adults, the IVC diame- ter/aorta diameter (IVC/Ao) index. The authors reported that the IVC/Ao index was superior to IVC diameter for predicting volume status [15]. However, there has been little subsequent investigation of the utility of the index in evaluating volume status in either children or adults [16]. The aims of the present study were to (1) establish reference ranges for the sonographic measurement of IVC parameters and the IVC/Ao index and (2) assess the effects of individual characteristics on IVC pa-

rameters in healthy Chinese adult volunteers.

1. Material and methods
   1. Study design

This was a cross-sectional descriptive US study conducted in our hospital. Our institutional ethical committee approved the study proto- col without requiring participant consent forms; however, the oral con- sent of participants was required and obtained.

Study setting and population

From February 2012 to May 2012, we enrolled 228 physically active, healthy volunteers older than the age of 18 years into this study. The volunteers were residents of China who were visiting the Department of US for routine comprehensive health checkups during the study en- rollment period. Exclusion criteria included age younger than 18 years, history of symptomatic cardiovascular or cerebrovascular disease, pregnancy, cirrhosis, ascites, moderate-to-severe tricuspid insufficien- cy, and a BMI above 35 kg/m². The volunteers received no remuneration for their participation.

We initially recruited 228 volunteers for this study. We exclud- ed 12 volunteers from the study because their IVC could not be ad- equately visualized.

Study protocol

inferior vena cava diameter, abdomi”>At the study site, Trained nurses asked volunteers their age, sex, and if they had a history of hypertension. Each subject wore light clothes without shoes during anthropometric measurements. Waist circumfer- ence was measured midway between the lower rib and the Iliac crest. Blood pressure was measured after 5 minutes of rest on 2 occasions 30 minutes apart using a random zero mercury sphygmomanometer on the right arm with the participant in a seated position. Hypertension was defined as systolic blood pressure greater than or equal to 140 mm Hg and/or diastolic blood pressure greater than or equal to 90 mm Hg at 2 different times and/or having a history of hypertension. The calcula- tion of the BMI was based on the formula BMI = weight (kilograms)/ (height [meters])². Body surface area was calculated using the DuBois formula: BSA = (weight, 0.425 x height, 0.725) x 0.007184.

To achieve equivalent fluid status, volunteers were required to fast for a minimum of 8 hours before the morning US examination. The IVC diameter measurements were performed with the participant in the supine position during quiet passive respiration. The measurements were collected using a Portable US machine (DP-6900; Mindray, Shenzhen, China) with a 3.6-MHz phased array cardiac transducer. The evaluations were performed by 1 radiologist, YF, who has 6 years of experience in cardiovascular US. The probe was placed in the

subxiphoid location, and the sagittal section of the IVC was imaged. The IVC diameter was measured approximately 2 cm distal to the IVC- hepatic vein junction, where the anterior and posterior walls of the IVC are visible and parallel to each other (Figure). All images were re- corded in 6-second B-mode (gray scale) video clips to ensure that the images captured the full range of respiratory variation and the maximal and minimal IVC diameters rather than an oblique view of the IVC. The maximum and minimum IVC dimensions were obtained by measuring the vein lumen during a regular breathing cycle from one interior wall to the opposite interior wall. The abdominal Ao was measured in a sim- ilar manner during systole, 5 to 10 mm above the celiac trunk, from one interior wall to the opposite interior wall. The percentage collapse of the IVC (?DIVC) was calculated using the following equation:

([IVC_max in millimeters - minimum IVC diameter in millimeters]/

IVC_max in millimeters) x 100 [17].

The IVC/Ao index was calculated as (IVC_max in millimeters/Ao diam- eter in millimeters) x 100 [15].

Data analysis

Data were expressed as means +- SD (2 SD range) or as proportions. The distributions of the continuous variables were evaluated for nor- mality through histograms and 1-sample Kolmogorov-Smirnov tests. For the latter, P N .05 indicated a normal distribution. Pearson coeffi- cients were obtained from correlation tests between continuous vari- ables, with transformations used before analysis as necessary. To assess the independent effects of the explored variables on IVC_max, min- imum IVC diameter, ?DIVC, diameter of the abdominal aorta, and the IVC/Ao index, we used Multivariate linear regression models with a for- ward stepwise inclusion strategy. F statistics with P = .05 as the criteri- on level were used to identify variables retained in the model. All statistical analyses were performed using Statistical Package for Social Sciences version 19.0 (SPSS, Inc, Chicago, IL). All the reported P values are 2 tailed, with those b.05 considered to be statistically significant.

1. Results
   1. Demographic data

The measured individual characteristics of the 216 volunteers are shown in Table 1. The mean age was 43.7 +- 7.8 years, the mean height was 163.3 +- 7.9 cm, the mean weight was 59.0 +- 9.9 kg, and the mean waist circumference was 76.9 +- 8.7 cm (mean +- SD). The mean BMI and BSA were 22.1 +- 3.1 kg/m² and 1.6 +- 0.2 m², respectively (mean +- SD).

Inferior vena cava diameter, abdominal Ao, ?DIVC, and the IVC/Ao index

A summary of the minimum and IVC_max, the abdominal Ao, ?DIVC, and the IVC/Ao index is provided in Table 2. The means of IVC_max, ?DIVC, abdominal Ao, and the IVC/Ao index were 14.9 +- 3.2 mm, 47.3% +- 8.9%, 17.8 +- 2.3 mm, and 0.8 +- 0.2, respectively (mean +- SD). The distribution of minimum IVC diameter was not normal (1- sample Kolmogorov-Smirnov test, P = .002); therefore, we report the median, which was 8.0 (6.0-9.9) mm. Square root transformation of minimum IVC diameter was performed to approach normality.

Table 3 shows the correlations between individual characteristics and IVC_max, minimum IVC diameter, ?DIVC, abdominal Ao, and the IVC/Ao index. All of the individual characteristics showed significant positive correlations with abdominal Ao, and none were correlated with ?DIVC. Maximum IVC diameter was negatively correlated with age (years) (r = -0.171, P = .012) and positively correlated with sex (men) (r = 0.174, P = .01), height (centimeters) (r = 0.281, P b

.001), and BSA (square meters) (r = 0.173, P = .011). Minimum IVC diameter was positively correlated with height (millimiters) (r = 0.176, P = .01) and negatively correlated with age (years) (r =

Figure. Longitudinal view of the IVC during inspiration and expiration through the liver.

-0.134, P = .049). The IVC/Ao index was negatively correlated with age (years) (r = -0.326, P b .001), waist circumference (centimeters) (r = -0.176, P = .01), BMI (r = -0.173, P = .011), and hypertension (r = -0.186, P = .006).

Table 4 shows the results of multiple linear regression analyses of IVC_max, minimum IVC diameter, abdominal Ao, and the IVC/Ao index with candidate individual characteristics. Height (centimeters) was the sole significant predictor of both IVC_max and minimum IVC diameter (r = 0.079, P b .001 and r = 0.031, P = .01, respectively). Age (years) and BSA (square meters) independently predicted diameter of the ab- dominal aorta (r = 0.256, P b .001 and P b .001, respectively). Age (years) and BMI (kilogram per square meter) were independent predic- tors of the IVC/Ao index (r = 0.123, P b .001 and P = .046, respectively).

1. Discussion

Our study explores the relationships between participant character- istics and sonographic measurements of IVC and abdominal Ao and the IVC/Ao index in physically active, healthy Chinese adult volunteers. Vol- unteers in the study were aged 18 to 84 years (43.7 +- 7.8 years). The percentages of men and women were similar (50.5% vs 49.5%, respec- tively). We found that ?DIVC was not influenced by any of the individ- ual characteristics investigated. In addition, the IVC/Ao index appeared to be more sensitive to individual characteristics than was IVC_max, al- though the R-squared value of the regression analysis of the IVC/Ao index was only 0.12, compared with the value of 0.08 for the regression analysis of IVC_max. However, none of the tested variables were useful for predicting IVC diameter or any of the other evaluated IVC parameters.

In the present study, the IVC/Ao index was more strongly influenced by individual characteristics than was IVC_max in adults. It appears that the correlations between the predictors and the IVC/Ao index were driven by Ao, which was more susceptible to individual characteristics than were any of the IVC parameters. Therefore, we conclude that the IVC/Ao index does not outperform the IVC parameters in predicting vol- ume status in adult patients.

Our study also establishes the reference ranges for IVC_max (8.5-21.3 mm), minimum IVC diameter (4-13.58 mm), ?DIVC (29.5%-65.1%),

Table 1

Demographic characteristics of the study volunteers (n = 216)

Age (y) 43.7+-14.8

18-44 (%) 116 (53.7)

abdominal Ao (13.2-22.4 mm), and the IVC/Ao index (0.4-1.2) in healthy Chinese adults.

Our results are generally in agreement with several previous surveys that have found that IVC diameter varies greatly between individuals and is not substantially influenced by individual characteristics [10,11]. In contrast to our findings, Masugata et al [12] found that age was ac- companied by an increase in ?DIVC in Japanese people in 2010. The au- thors suggest that low right atrial pressure and decreased IVC compliance in the elderly may have led to their results. However, there were no data available in their study to support this interpreta- tion. Our study was based on healthy Chinese volunteers with an aver- age age of 43.7 +- 7.8 years (range, 18-84 years), whereas their study consisted of elderly Japanese patients with an average age of 66.6 +-

14.7 years. In addition, the prevalence of hypertension in our study was lower than that in their study (19% vs 63%). Therefore, our results are less likely than theirs to be affected by disease and likely more accu- rately indicate the influence of age on IVC size in Healthy adults. In con- trast, Krumpe et al [18] demonstrated that aging is associated with an increase in the resting values of right atrial pressure, pulmonary artery pressure, and wedge pressure. Furthermore, elderly subjects breathe with smaller tidal volumes than do younger adults at rest [18], which may also decrease ?DIVC in the elderly.

Our study found that age was negatively correlated with IVC_max, which is similar to the result in a description of the specific study. How- ever, we also found that age was negatively correlated with height (cen- timeters) (r = -0.267, P b .001). Multiple Linear regression analysis showed that height (centimeters) was the sole independent predictor of IVC_max.

Interestingly, Kathuria et al [19] found a statistically significant pos- itive correlation between age and IVC diameter in healthy pediatric pa- tients. However, the relationship between IVC diameter and other individual characteristics, such as height and weight was not evaluated in the study. There remains a need to further study the relationships be- tween IVC diameter and individual characteristics in children.

Limitations

There are some limitations to our study. First, the volunteers en- rolled in our study were physically active, healthy residents who were

Table 2

Sonographic measurement of the IVC and abdominal aorta parameters

45-59 (%) >= 60 (%)	63 (29.2) 37 (17.1)	Parameters	Mean +- SD
Male (%)	110 (50.5)	IVCmax (mm)	14.9 +- 3.2
Height (cm)	163.3 +- 7.9	Median (IQR) IVCmin (mm)	8.0 (6.0-9.9)
Weight (kg)	59.0 +- 9.9	?DIVC (%)	47.3 +- 8.9
Waist circumference (cm)	76.9 +- 8.7	Ao (mm)	17.8 +- 2.3
Hypertension (%)	41 (19)	The “IVC/Ao index”	0.8 +- 0.2
BMI (kg/m2)	22.1 +- 3.1	The IVC/BSA (mm/m2)	9.2 +- 2.0

BSA (m²) 1.6 +- 0.2

Abbreviations: IQR, interquartile range; IVC_min, minimum IVC diameter.

Values are expressed in mean +- SD or the number of subjects (percent of the total). All values are the mean +- SD, median (interquartile range).

Table 3

Correlation between the IVC_max, minimum IVC diameter, ?DIVC, abdominal aorta, and the “IVC/Ao index” with individual characteristics

Variable IVC_max IVC_min ?DIVC Ao The “IVC/Ao index”

	r	P		r	P		r	P		r	P		r	P
Age (y)	-0.171	.012		-0.134	.049		0.22	.752		0.347	b.001		-0.326	b.001
Sex (female, 0; men, 1)	0.174	.01		0.113	.097		0.013	.852		0.196	.004		0.04	.564
Height (cm)	0.281	b.001		0.176	.01		0.037	.587		0.253	b.001		0.093	.172
Weight (kg)	0.093	.174		0.074	.276		-0.037	.584		0.307	b.001		-0.088	.199
Waist circumference (cm)	-0.064	.35		-0.011	.877		-0.092	.177		0.242	b.001		-0.176	.01
BMI (kg/m2)	-0.082	.23		-0.029	.669		-0.075	.275		0.201	.003		-0.173	.011
BSA (m2)	0.173	.011		0.12	.08		-0.013	.853		0.598	b.001		-0.029	.668
Hypertension (no, 0; yes, 1)	-0.121	.076		-0.093	.075		0.025	.709		0.192	.005		-0.186	.006

Square root transformation of minimum IVC diameter was performed to improve normality.

Table 4

Multiple linear regression analysis of the association of the IVC_max, minimum IVC diameter, abdominal aorta, and the “IVC/Ao index” with candidate individual characteristics

Parameter	Variable	Coefficient	P	r
The IVCmax	Height (cm)	0.112 (0.061 to 0.164)	b.001	0.079
The IVCmin	Height (cm)	0.054 (0.013 to 0.095)	.01	0.031
Ao	Age (y) BSA (m2)	0.062 (0.044 to 0.081) 5.504 (3.766 to 7.243)	b.001 b.001	0.256
The “IVC/Ao index”	Age (y) BMI (kg/m2)	-0.004 (-0.006 to -0.003) -0.009 (-0.017 to -0.0002)	b.001 .046	0.123

Square root transformation of minimum IVC diameter was performed to improve normality.

visiting the Department of US for routine comprehensive health checkups. There may be some selection bias. Second, although partici- pants with moderate-to-severe tricuspid insufficiency were excluded from our study, mild tricuspid insufficiency was not recorded or ana- lyzed. Third, our study is only a cross-sectional study. A prospective co- hort study should be performed to confirm the relationship between participant height and IVC diameter.

1. Conclusion

We conclude that height is an independent predictor of IVC_max. However, height only explained a small percentage (7.9%) of the vari- ance in IVC_max. Similarly, age (years) and BMI (kilogram per square meter) were independent determinants of the IVC/Ao index, but, to- gether, they explained only a small percentage (12.3%) of the variance in the IVC/Ao index. The values of the IVC parameters and Ao varied greatly among individuals but were not substantially influenced by par- ticipant characteristics.

It appears that the correlations of predictors with the IVC/Ao index were driven by Ao, which was more susceptible to individual character- istics than were any of the IVC parameters. Therefore, we conclude that the IVC/Ao index did not perform better than the IVC parameters in predicting volume status for adult patients.

Acknowledgments

The authors appreciate all attending physicians working in our hos- pital for providing their full support for this study.

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