a b s t r a c t

Study objective: We aimed to determine the role of inferior vena cava diameter in making a differentiation between dyspnea of cardiac (acute heart failure [AHF]) and pulmonary origin. We also attempted to determine the best Sonographic method for the measurement of IVC diameter.

Methods: This prospective observational study was conducted at the intensive care unit of the emergency depart- ment of a training and research hospital. This study enrolled patients with the main symptom of dyspnea who were categorized into 2 groups, cardiac dyspnea and pulmonary dyspnea groups, based on the final diagnosis. All patients underwent sonographic measurement of minimum and maximum diameters of IVC, and the Caval index (CI) was calculated in both M-mode and B-mode. The sensitivity, specificity, and likelihood ratios (LR) of the IVC values for the differentiation of the 2 groups were calculated.

Results: This study included a total of 74 patients with a mean age of 72.8 years. Thirty-two patients had dyspnea of Cardiac origin, and 42 patients had dyspnea of pulmonary origin. The IVC diameter measured with B-mode during inspiration (B-mode i) was the most successful method for differentiation of the 2 groups. B-mode i values greater than 9 mm predicted dyspnea of cardiac origin with a sensitivity of 84.4% and a specificity of 92.9% (+LR: 11.8, LR: 0.16).

Conclusion: Sonographic assessment of the IVC diameter may be used as a rapid, readily, nonexpensive, complication-free, and reproducible technique for the differentiation of cardiac and pulmonary causes of dys- pnea. B-mode i measurement may be more successful in the differentiation of dyspnea compared with other IVC diameters and calculations.

(C) 2014

Introduction

Dyspnea is one of the leading causes of emergency department ad- missions [1]. A rapid diagnosis and an early, targeted therapy reduce mortality and morbidity [2]. Particularly, differentiating acute dyspnea due to Acute heart failure is important with regard to the need of a specific therapy for volume overload. Differentiation between car- diac dyspnea and pulmonary dyspnea (PD) is conventionally achieved by physical examination, blood tests, and chest x-ray [3,4]. However, these tests have moderate accuracy [5]. Moreover, absence of conges- tion in conventional imaging cannot rule out AHF [6,7]. Echocardio- graphic evaluation helps clinicians make the differentiation, but it

? Prior presentations: Preliminary data presented at the 1.International Critical Care and Emergency Medicine Congress, Istanbul, 2013.

* Corresponding author at: Department of Emergency Medicine, Haseki Training and Research Hospital, 34096 Istanbul, Turkey. Tel.: +90 5432222570.

E-mail address: [email protected] (A. Yamanoglu).

requires significant experience and training. Thus, various other labora- tory examinations and techniques have been developed for making an accurate differentiation of dyspnea. Brain natriuretic peptide has been developed and introduced into clinical practice for this pur- pose [8]. However, BNP has some limitations, such as having an inter- mediary gray zone, time requirement, and being dependent on age, sex, and renal function [9]. Thus, attempts to develop bedside tests or applications have continued. For example, jugular vein has been ultrasonographically assessed in an attempt to distinguish AHF from other etiologies of dyspnea; however, low specific results were obtain- ed [10]. Similarly, bedside ultrasonography has been used to measure Inferior vena cava diameter to differentiate AHF from other etiol- ogies of dyspnea. Some former studies have reported that BNP and IVC diameter were correlated, suggesting that IVC diameter could be used in the differentiation of dyspnea [11,12]. Unfortunately, despite obtaining successful results, there is a limited number of studies conducted for this purpose [13,14]. Furthermore, there are no studies that have specif- ically sought for best ultrasonography mode (B- or M-modes) for the

http://dx.doi.org/10.1016/j.ajem.2014.12.032

0735-6757/(C) 2014

differentiation of dyspnea or studies that have investigated whether the most useful IVC diameter for this purpose is the inspiratory (minimum), expiratory (maximum) diameter, or the caval index (CI).

The first aim of this study was to test whether IVC diameter was suit- able for differentiation of dyspnea of AHF or pulmonary origin. The sec- ond objective was to find out whether the most effective IVC diameter measurement for this purpose was the inspiratory (minimum), expira- tory (maximum) diameter, or the CI, all of which were measured both in M-mode and B-mode.

Methods

Study design and setting

This single-center prospective observational study was conducted at the intensive care unit of the emergency department of a training and research hospital in Turkey. It was approved by the hospital committee for training planning. All patients gave a written informed consent be- fore study entry.

This hospital’s emergency department annually serves 200000 pa- tients, of whom 5% to 10% require intensive care unit follow-up under monitorization. This study was conducted between December 1, 2012, and March 15, 2013.

Adult patients (N 18 years of age) of both sexes with the main com- plaint of dyspnea without antecedent trauma presenting to the emer- gency department within the specified time window were enrolled by the order of presentation. Patients with severe tricuspid regurgitation (TR), cardiac tamponade, aortic dissection, abdominal surgery within last 2 weeks, or patients who had cardiopulmonary arrest or been intubated and were pregnant were excluded from the study.

Study protocol

Methods of measurement

The IVC measurements were carried out by a single emergency med- icine resident. Before the measurements, a cardiology director provided the resident with 6 hours of theoretical training and 20 hours of practi- cal training.

The measurements were completed within 10 minutes of admission to the emergency department. The measurements were carried out while the patients had acute respiratory difficulty, and no intervention was done against dyspnea. The measurements were done with an USG device (Sonoscape, S6/S6 pro) using a 3.5-Mhz convex transducer

with the patients at 45? from the horizontal. A video recording was made from the subxiphoid region in a longitudinal plan for at least 3 re- spiratory cycles. The maximum expiratory IVC diameter on B-mode (B-mode e, Figure a) and the minimum inspiratory IVC diameter on B-mode (B-mode i, Figure b) were measured from these video record- ings. All measurements were done at a point 2 cm away from the IVC’s entry into the right atrium (RA). M-mode measurements were also made at a location 2 cm distal to IVC’s entry into the RA (Figure c). Both M-mode and B-mode measurements were repeated 3 times, and the arithmetical mean of 3 measurements was taken for analysis. The IVC collapsibility index was calculated as the formula (CI) = (IVCe - IVCi)/IVCe) x 100. All measurements were completed within less than 5 minutes.

Data collection and processing

The study data were collected in 3 categories. The first data collec- tion task was the IVC measurements that were completed at the initial admission after the primary physician assessed the patients. These mea- surements were completed by a single senior emergency department resident.

The second category of data was echocardiographic measurements. These were performed after stabilization of patients by the cardiologist in our team or an on-duty cardiologist at that time. Echocardiographic examination included minimum diameters of heart chambers, wall thicknesses, valvular functions, ventricular wall motion, and ventricular functions. The measurements were usually obtained within the first hour of admission, and they were reported and archived by the cardiol- ogist in our team.

The third data collection task was fulfilled by a senior emergency resident using the hospital automation system after completion of all di- agnostic and Therapeutic procedures. They included the laboratory re- sults, chest X-rays and/or computed tomography (at least one), consultation records, patient records about clinical course and treat- ment, and the results of the applied therapies.

Diagnosis method

After completion of the necessary tests for a definitive diagnosis, all data excluding IVC diameter values were merged and analyzed by an emergency department chief physician, an emergency medicine expert, a radiologist, a cardiologist, and 2 senior residents. The patients were di- agnosed according to the criteria listed on Table 1. The patients who have multiple causes of their dyspnea were excluded.

• B-Mode e b) B-Mode i c) M-Mode e, i

Figure. Inferior vena cava measurement methods.

Table 1

Final diagnosis method

Diagnoses Diagnoses methods

All patients Medical history, clinical examination, radiography

(for each patient at least 1 chest radiograph or

CT [n = 49]) read by radiologists, for each patient at least 1 echocardiography by cardiologist, at least 1 blood gas analysis, basic blood tests WBC, Hb, liver, heart, and renal function test) control radiography, and CT after or during treatment

Table 2

General characteristics of the subjects

PD group CD group

No. 42 32

Age 72.57 +- 11.10 74.09 +- 11.52

Female 11 (26.2%) 15 (46.9%)

Male 31 (73.8%) 17 (53.1%)

Medical history CHF + COPD 10 (23.8%) 14 (43.7%)

Only CHF 2 (4.7%) 12 (37.5%)

Only COPD 26 (61.9%) 5 (15.6%)

CDs (cardiogenic pulmonary edema) (n = 32)

PDs (n = 42)

Decompensated COPD (n = 19)

Cardiac function evaluation using echocardiography, BNP level, in accordance with the American

Heart Association treatment recommends, and control echocardiography

Decompensated COPD was confirmed by functional tests and radiography (without pneumonia, pulmonary edema, pneumothorax, pulmonary embolism, etc.).

Noninfiltrative simple bronchial infection was classified in this group. BNP for differential diagnosis (n = 11)

None 4 (9.5%) 1 (3.1%)

Diagnosis COPD-asthma AHF 32 (100%)

Exacerbation 26 (61%)

Pneumonia 14 (33%)

Pulmonary emboly 2 (4.8%) CHF, congestive heart failure.

statistical calculations. The results of IVC measurement (M-mod e, i, CI, B-mod e, i, CI), echocardiographic measurements (left atrium [LA]

Pneumonia (n = 14) Radiologic asymmetric images. Microorganism isolated

in blood or sputum. blood test results. Recovery after antibiotic therapy. BNP for differential diagnosis (n = 3)

Asthma attacks (n = 7) History and recovery with bronchodilator treatment

size, left ventricular [LV] size, right atrium [RA] size, right ventricular [RV] size, and ejection fraction [EF]), and BNP levels were compared be- tween the 2 groups. As presented on Table 3, all measurements except

Pulmonary emboli

(n = 2)

Pulmonary angiography

for the RV were significantly different between the 2 groups (P b

.001). The ROC curves were drawn to determine the ideal IVC values

Abbreviations: CT, computed tomography; WBC, white blood cell; Hb, hemoglobin.

Primary data analysis

The study data were analyzed in SPSS software package. In our study, none of the variables were normally distributed, and thus, non- parametric tests were used for analysis of continuous variables. Paired comparisons of the continuous variables were performed with Mann- Whitney U test; the Correlation analyses between continuous variables were performed using spearman correlation test. Chi-square test was used to compare the categorical variables across the groups. A P value less than .05 was considered statistically significant. receiver operating characteristic curves were drawn, and a cutoff value was calculat- ed for each variable to test the Discriminatory power of the continuous variables across the groups. Chi-square test was used to examine the power of these cutoff levels. Cross tables were used to calculate the sen- sitivity, specificity, and positive and negative predictive values.

Results

Characteristics of subjects

The study included a total of 101 patients who presented to our emergency department within the prespecified time window. Six (5.9%) of these patients were excluded from the study since they had in- adequate windows for IVC-USG, and 3 (2.97%) subjects were excluded for being unsuitable for transthoracic echocardiography. Of the remain- ing patients, 15 (14.85%) were excluded since transthoracic echocardi- ography detected severe tricuspid insufficiency in them. Three (2.97%) more patients were excluded from the study owing to inability to deter- mine the basic mechanism of dyspnea (exacerbation of chronic obstruc- tive pulmonary disease [COPD] plus AHF plus pneumonia, etc.). A total of 74 patients complying with the inclusion criteria were included in the final analysis. Among them, 26 (35.1%) were female and 48 (64.9%) were male. The demographic characteristics of the study popu- lation were listed on Table 2. The subjects were categorized into cardiac disease (CD) group (n = 32) and pulmonary disease (PD) group (n = 42) according to their dyspnea etiologies.

Main results

A total of 74 video tracks obtained from 74 patients, and 666 images obtained from these tracks (3 M-mode and 6 B-mode) were used for

to be used in the differentiation of the 2 groups. Among the 6 variables compared, B-mode i had the greatest area (0.876) under curve and the lowest standard error (0.045) (Table 4). B-mode i’s cutoff points on the ROC curve seen on Table 5 A and B summarizes the best cutoff values of 6 markers differentiating the 2 groups. It shows that B-mode i had the best sensitivity and specificity, and it was the strongest marker differen- tiating the 2 groups. We found that B-mode i that we expected to be higher in patients with heart failure was significantly correlated to LA diameter, LV diameter, and BNP level (r = 0.46, r = 0.40, and r = 0.43, respectively; P b .05 for all correlations).

Discussion

Making the differentiation of patients with the main symptom of dys- pnea in a rapid and noninvasive manner is an important goal for emer- gency physicians. In our study, we found a significant difference between the CD and PD groups with respect to IVC diameter (P b .001). This difference was evident for all 6 sonographic methods used in this study (Table 3). Table 5B shows the ideal cutoff numbers to be used in the differentiation of CD and PD. We noted that the cutoff levels found were able to differentiate the 2 groups at high sensitivity and specificity. Previous studies have advocated the exclusion of patients with severe TR from the study protocols owing to a larger-than-expected IVC diame- ter in such patients [15]. We therefore excluded 15 (14.7%) patients with severe TR. The percentage of the patients with severe TR was slightly higher than the number reported by Lorenzo et al (9.7%) [16]. This is

Table 3

Comparison of PD and CD groups according to their echocardiographic measurement re- sults and BNP values

PD (n = 42)		CD (n = 32)	P
BNP	75.65 +- 83.54	792.26 +- 575.49	.001?
EF% (Modified SImpson)	57.55 +- 10.83	44.75 +- 14.20	.001?
M-mode e	16.75 +-3.21	21.89 +- 4.95	.001?
M-mode i	5.76 +- 4.44	15.97 +- 7.07	.001?
M-mode CI	66.43 +- 19.69	30.29 +- 21.87	.001?
B-mode e	16.19 +- 3.37	21.00 +- 3.97	.001?
B-mode i	4.40 +- 4.05	14.34 +- 6.53	.001?
B-mode CI	73.73 +- 19.58	34.42 +- 24.02	.001?
LA diameter	38.65 +- 6.64	48.28 +- 8.87	.001?
LV diameter	47.56 +- 8.48	53.63 +- 9.53	.008?
RA	38.97 +- 9.63 (n = 24)	43.50 +- 5.78 (n = 15)	.005?
RV	26.40 +- 3.70 (n = 40)	26.79 +- 3.49 (n = 31)	.588

* P b .05, statistically significant.

Table 4

Area under the ROC curve of IVC measurements via B- and M-modes

Variables Area under the curve Standard error P Asymptotic 95%

confidence interval

				Alt	Ust
M-mode e	0.800	0.057	.001	0.689	0.911
M-mode i	0.863	0.048	.001	0.769	0.957
B-mode e	0.841	0.048	.001	0.746	0.935
B-mode i	0.876a	0.045a	.001	0.788a	0.964a
M-mode CI	0.858	0.047	.001	0.766	0.950
B-mode CI	0.864	0.046	.001	0.773	0.955

^a Most significant.

possibly because their patient population was 8 years younger than our population and half of our population had CD. The 2 groups differed with respect of sex distribution, with the PD group having a female per- centage of 26.2 and male percentage of 73.8. This is probably due to the fact that 85% of our PD patients had COPD, the prevalence of which is 2.4 times greater in men than women (20% vs 8.2%) in our country [17]. Thus, high rate of men in our PD group may be related to this.

We could perform our measurements with the patients lying at 45? from horizontal. Blehar et al similarly performed measurements with their patients having a primary complaint of dyspnea lying at 45? from horizontal [18]. Our measurements were performed via a widely used method recommended by ACEP, at a point 2 cm distal to the IVC’s entry into RA [19-22]. In addition, our measurements were obtained in both B-mode and M-mode, and intergroup comparisons were done between both the minimum and maximum diameters. We could not identify any other study comparing all possible longitudinal measure- ments the way we described.

The M-mode IVC measurements obtained in our study were shown on Table 3. Miller et al, who studied in M-mode and on similar groups to ours, made the following measurements in the AHF group that was the equivalent to our CD group: expiratory: 21.3 (19.2-23.3) mm, inspirato- ry: 17 (14.7-19.3) mm, and CI value: 22% (17-27). Their measurements in the non-AHF group that was the equivalent to our PD group were as follows: expiratory: 16.3 (15.2-17.5) mm, inspiratory: 7.2 (5.6-8.8) mm, and CI value: 59% (52-66). These results indicate that, when both groups are considered, maximum diameters are quite similar in both studies,

whereas their minimum diameter is slightly greater than ours, especial- ly in the non-AHF group. Not surprisingly, our CI values in both CD and PD groups were greater than their values in equivalent groups. This dif- ference is also reflected by the cutoff levels, with their ideal cutoff level being 33% and our cutoff level being 52%. To our opinion, these discor- dant results emerge from 2 basic causes. The first cause is that they did not exclude patients with severe TR. In our study, in both groups the patients with severe TR had higher inspiratory and expiratory diam- eters and a lower CI compared with the patients without. Failure to ex- clude patients with severe TR would have reduced the CI of the PD group, and this could have possibly approximated the results of the PD group to those of the CD group. This may be the reason of the lower cutoff levels reported by Blehar and Miller, who did not exclude subjects with severe TR [13,14]. The second cause is that Miller et al per- formed the measurements with their patients lying at 30? from horizon- tal. Although we studied a similar population, we could not place our patients in this position because they could not tolerate it due to dys- pnea. We could therefore perform our measurements with the patients lying at 45? from horizontal, which may have modified our results.

Among 6 parameters we analyzed, B-mode i had the greatest area under curve (0.87; 95% CI, 0.78-0.96) (Table 4). B-mode i may therefore be the most ideal method for differentiation of the 2 etiologies of dys- pnea. As shown on Table 5, the cutoff levels provided by the ROC curves were similar, and both methods had similar predictive values. Among all the values, a B-mode i value greater than 9 mm had the greatest pre- dictive value with a sensitivity of 84.4% and a specificity of 92.9%. In our study, the B-mode CI and the M-mode CI values are approximately 50%, a threshold that has also been accepted by previous studies for CI, and lower levels have been considered abnormal or high [23,24,21,25].

A BNP level of 400 pmg/mL has been recommended after the AHF di- agnosis. It has been suggested that BNP performs well in differentiating AHF from other causes of dyspnea [26]. Although the BNP level was

792.2 +- 575.4 in our CD group, it was 75.6 +- 83.5 in our PD group (P b .001). This significant difference indicates that our groups were ac- curately and effectively differentiated from each other.

Previous studies have reported greater LA, LV diameters and BNP level in patients with heart failure [11,12,27]. Likewise, our study re- vealed significantly greater LA, LV diameters, BNP level, and IVC diame- ter in the CD group than the PD group. The examination of the correlation between B-mode i value and BNP revealed a significant

Table 5

The most appropriate cutoff values for B-mode i (A) and all IVC measures (B) in differential diagnosis

	A: Cutoff values of B-mode i
	B-mode i cutoff points, mm		Sensitivity, %			Specificity, %
	N=0.39		100.0			2.4
	1.35		96.9			14.6
	2.10		93.8			34.1
	3.40		87.5			51.2
	5.45		84.4			73.2
	7.35		84.4			87.8
	8.10		84.4			90.2
	9.00		84.4			92.7
	10.25		78.1			92.7
	13.10		65.6			95.1
	18.30		34.4			97.6
	19.85		18.8			100.0
	23.30		06.3			100.0
	B: Best cutoff points of all IVC measures
	Cutoff point Sensitivity % (95% CI)	Specivity % (95% CI)	P	+ PPV % (95% CI)	- NPV % (95% CI)	+LR -LR
	M-mode e 19.40mm 81.3 (62.9-92.1)	85.4 (70.1-93.9)	.001	81.2 (62.9-92.1)	85.4 (70.1-93.9)	5.5 0.21
	M-mode i 10,75mm 84.4 (66.4-94.1)	92.7 (78.9-98.0)	.001	90.0 (72.3-97.3)	88.4 (74.1-95.6)	11.5 0.16
	M-mode CI 52.00% 84.4 (66.4-94.1)	85.7 (70.7-94.0)	.001	81.8 (63.9-92.3)	87.8 (72.9-95.4)	5.9 0.18
	B-mode e 18.30mm 81.3 (62.9-92.1)	73.8 (57.6-85.6)	.001	70.3 (52.8-83.5)	83.8 (67.3-93.2)	3.10 0.25
	B-mode i 9.00mm 84.4 (66.4-94.1)	92.7 (79.4-98.1)	.001	90.0 (72.3-97.3)	88.6 (74.6-95.7)	11.8 0.16
	B-mode CI 50.5% 84.4 (59.5-90.0)	90.5 (79.4-98.1)	.001	87.1 (70.6-97.1)	88.4 (70.5-93.1)	8.8 0.17

Abbreviation: LR, likelihood ratio.

correlation (r = 0.46; P b .006). Pudil et al, in an AHF population, found that among other parameters, IVC had the best correlation to BNP (r = 0.51; P b .01) [28]. Ramasubbu et al explored the echocardiographic changes during therapy and found the greatest correlation between IVC diameter and pulmonary capillary wedge pressure (r = 0.53; P b

.05) [29]. Pellicori et al reported that reduced systolic blood pressure, in- creased New York Heart Association functional class, serum urea level, IVC diameter, and tricuspid systolic gradient were significantly correlat- ed to a poor outcome [27]. The above information as a whole suggests that heart failure is closely correlated to IVC diameter. This information supports our hypothesis that IVC can be used for the differentiation and follow-up of AHF patients.

Some researchers led by Lichtenstein have advocated that lung ultra- sonography is able to differentiate between lung edema and other lung diseases such as pneumonia or COPD exacerbations [30-32]. Some other researchers have attempted to combine lung USG with IVC-USG and transthoracic echocardiography in an attempt to categorize dyspneic patients with a greater sensitivity and specificity [33,34]. Kajimoto et al, for instance, found that CI index had a sensitivity of 83% and a specificity of 81% for differentiation of PD and heart failure. The sensitivity was in- creased to 94% and the specificity to 91% when they combined IVC-USG and cardiac and lung USG [33]. Kimura et al attempted to predict the rates of mortality and morbidity as well as LVEF in a retrospective study where they combined some transthoracic echocardiography parameters (LA and LV), IVC-USG, and lung USG. They suggested that said method could be used with a sensitivity of 69% and a specificity of 91% [34]. The protocols of both studies required performance of transthoracic echocar- diography, lung USG, and IVC-USG, thus demanding more training, time, and experience. Performing all 3 USG examinations at the same time seems problematic in acute dyspnea, when time is golden. It is even more challenging to position dyspneic patients for these 3 ultrasono- graphic examinations. Moreover, many studies have reported that the B-lines used as marker in lung USG are not specific to pulmonary edema [35-37], questioning the reliability of these methods. Considering all of these factors, we are of the opinion that such a combination of dif- ferent methods is yet not suitable for use in Acute dyspneic patients in emergency department. We suggest that B-mode i, which was as success- ful as the combined methods, may be the ideal marker for use in the dif- ferentiation of patients with acute dyspnea in emergency department.

As a rapid, readily available, cheap, reproducible technique, IVC-USG

can be used to support the findings of physical examination in the dif- ferentiation of cardiac and pulmonary etiologies of dyspnea in emergen- cy department. B-mode i can perform better than other IVC diameters and calculations.

Limitations

This was a single-center study in which patient enrollment could not be done on a 7/24 basis. Rather, it was accomplished during the working and duty hours of the study team. These factors may limit the generaliz- ability of this study.

The physician performing the measurements was blind to all of the other results of the subjects. However, it was not possible to prevent some findings of physical examination (pretibial edema or anasarca edema, wheezing) from being noted by the performer. Moreover, B- mode and M-mode measurements were performed one after the other, and they may thus have affected each other. To minimize this in- teraction, the video recordings were completed first, followed by mak- ing measurements from these recordings.

Patients with severe TR were excluded from the study. Thus, this method offers no benefit for differentiation of patients with severe TR.

Conclusions

We suggest that IVC-USG is a rapid and simple method for determi- nation of preliminary diagnoses and guiding the initial therapy in

patients presenting with acute dyspnea. The reliability of IVC-USG for this indication should be confirmed by further large-scale studies in the future.

Acknowledgments

The authors appreciate all attending physicians working at the De- partment of Chest Diseases of our hospital for providing their full sup- port for this study.

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