The Emerging Role of BIomarkers and Bio-Impedance

Clin Chem Lab Med 2012;50(12):2093–2105 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/cclm-2012-0289
Review
The emerging role of biomarkers and bio-impedance in
evaluating hydration status in patients with acute heart failure
Salvatore Di Somma1,
*, Silvia Navarin1
,
Stefania Giordano1
, Francesco Spadini1
,
Giuseppe Lippi2
, Gianfranco Cervellin3
,
Bryan V. Dieffenbach4
and Alan S. Maisel4
1
Department of Medical-Surgery Sciences and Translational
Medicine, Post Graduate School of Emergency Medicine,
Sapienza University, Sant’Andrea Hospital, Rome, Italy
2
Laboratory of Clinical Chemistry and Hematology,
Academic Hospital Parma, Italy
3
Emergency Department, Academic Hospital of Parma,
Parma, Italy
4
Division of Cardiology, University of California San Diego,
San Diego Veterans Healthcare System, San Diego, CA, USA
Abstract
The quantitative and qualitative estimation of total body fluid
content has proven to be crucial for both diagnosis and prog-
nosis assessment in patients with heart failure. The aim of
this review is to summarize the current techniques for assess-
ing body hydration status as well as the principal biomarkers
associated with acute heart failure (AHF). Although clinical
history, physical examination and classical imaging tech-
niques (e.g., standard radiography and echocardiography)
still represent the cornerstones, novel and promising tools,
such as biomarkers and bio-electrical impedance are achiev-
ing an emerging role in clinical practice for the assessment
of total body fluid content. In the acute setting, the leading
advantages of these innovative methods over device are rep-
resented by the much lower invasiveness and the reasonable
costs, coupled with an easier and faster application. This arti-
cle is mainly focused on AHF patients, not only because the
overall prevalence of this disease is dramatically increasing
worldwide, but also because it is well-known that their fluid
overload has a remarkable diagnostic and prognostic signifi-
cance. It is thereby conceivable that the bio-electrical vector
analysis (BIVA) coupled with laboratory biomarkers might
achieve much success in AHF patient management in the
future, especially for assisting diagnosis, risk stratification,
and therapeutic decision-making.
Keywords: acute heart failure; bio-impedance; biomarkers;
hydration status; total body water.
Introduction
The total body water (TBW) in the healthy population is esti-
mated to be approximately 60% of the body weight, and is
supposed to change during life because it is influenced by
age, amount of fat tissues as well as hormonal homeostasis.
Although there is a continuous shift of body fluids through-
out the cells, they are operatively divided into two compart-
ments, intracellular and extracellular. The intracellular fluid
is defined as the water contained within the cell membranes
and represents nearly two-thirds of TBW. The remaining one-
third is the extracellular compartment that is further divided
into interstitial fluid and intravascular fluid (1) (Figure 1). The
TBW is constantly adjusted by some important homeostatic
mechanisms including the balance between water intake and
water loss through renal and gastrointestinal output, breathing
and sweating (2). The estimation of TBW content is impor-
tant in the prognostic assessment of critically ill patients and
should be considered a vital parameter coupled with blood
pressure, heart and respiratory rates, oxygen saturation and
temperature.
The accurate and fast assessment of total fluid balance in
critical patients, along with a standard and reliable means for
its evaluation, has always been challenging for physicians
working in the acute care setting. The current gold standard
(i.e., isotope dilution) is not used in everyday clinical prac-
tice and is even more difficult to apply when an emergency
clinical decision is required (3). Several approaches have
been used to estimate the hydration status of patients, includ-
ing history and physical examination, laboratory testing and
imaging techniques (3). The clinical experience has provided
unquestionable evidence that fluid overload reflects the wors-
ening of clinical conditions in a variety of severe disorders,
such as heart failure (HF), chronic kidney diseases (CKD),
and liver cirrhosis (4). Moreover, the invasive catheterization
of heart and great vessels only reflects the circulating volume
of total fluid content and not the TBW.
*Corresponding author: Prof. Salvatore Di Somma, MD, PhD,
Department of Medical-Surgery Sciences and Translational
Medicine, Post Graduate School of Emergency Medicine, Sapienza
University, Sant’Andrea Hospital, Via di Grottarossa,
1035/1039 00189 Rome, Italy
Phone: +39 6 33775581/+39 6 33775592,
Fax: +39 6 33775890, E-mail: salvatore.disomma@uniroma.it
Received May 8, 2012; accepted July 22, 2012;
previously published online September 19, 2012
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2094 Di Somma et al.: Biomarkers and bio-impedance in acute heart failure
In this important scenario, several studies have investigated
and have further confirmed the emerging role of biomarkers,
such as natriuretic peptides (NPs) (5), assisted by bio-imped-
ance vector analysis (BIVA) in the management of congestion
due to increased TBW content in the setting of chronic heart
failure (CHF) or acute heart failure (AHF) patients (6, 7).
The aim of this review is thereby to provide some insights
on the currently used non-invasive methods for hydration
assessment and to describe the appealing results obtained
with the various bio-electrical impedance methods coupled
with some laboratory parameters in AHF patients, since they
represent the most common and evident example of hyperhy-
dration status among critical diseases (7).
Classical methods
In this section, we aim to examine the classic, non-invasive
techniques and biomarkers for hydration assessment in
patients primarily affected by AHF.
History assessment
The patient’s history at presentation has been proven useful
in the assessment of hydration status in a variety of clinical
scenarios. The presence of orthopnea and paroxysmal noc-
turnal dyspnea (PND) are two hallmark symptoms associated
with the diagnosis of fluid overload secondary to AHF. When
evaluated more closely in a study of 52 patients with estab-
lished left ventricular dysfunction, Butman et al. (8) showed
that only 50% presented with orthopnea and 35% with PND.
In a meta-analysis of over 22 studies on the diagnosis of CHF
performed by Wang et al. (9) it was shown that the pooled
sensitivities and specificities of common symptoms between
the studies yielded only modest values for the diagnosis or
exclusion of HF. The presence of PND or orthopnea in the his-
tory yielded sensitivities of 41% and 50%, respectively, while
providing more useful specificities of 84% and 77%, respec-
tively. These data suggest that when used as criteria for the
diagnosis of body fluid congestion secondary to AHF, classic
elements of the history may be unable to provide meaningful
information to the physician.
The physical examination
The physical examination provides important information
on the clinical status of the patients. Several studies have
assessed the efficacy of the physical exam in diagnosis of vol-
ume overload, using decompensated HF as a positive control
for the disease. Elevations in jugular venous pressure (JVP)
and rales have been proven to be inconsistent diagnostic tests
for HF, displaying sensitivities between 37% and 70%, and
24% and 66%, respectively, yet may still provide useful infor-
mation regarding the severity of disease (8–11). In patients
with congestive HF studied in the RESOLVD trial, peripheral
edema (Figure 1) was present in 21% of patients with AHF
and in only 10% of patients who were free of events (12).
This suggests that clinically evident peripheral edema is only
present in a minority of patients that have decompensated,
and thereby does not sufficiently reflect the hydration status
of the patient. Other studies have assessed the presence of a
third heart sound (S3) as an informative finding in the diagno-
sis of acutely decompensated HF. Unfortunately, the presence
of an S3 also fails to adequately support a diagnosis of HF
Figure 1 Non-invasive methods to assess hydration status.

Di Somma et al.: Biomarkers and bio-impedance in acute heart failure 2095
and fluid overload, with prevalence between 36% and 55% in
decompensated patients (9–12). Overall, the reliability of the
physical exam in detecting volume overload is questionable
(9, 13). Stevenson et al. (14) showed that the evaluation of all
volume overload characteristics by means of the presence of
a positive physical exam (including evidence of JVD, rales
and/or edema) had a rather limited sensitivity (i.e., 58%) in
patients with diagnosed HF and volume overload (PCWP >22
mm Hg).
Standard radiography
Chest radiography is also frequently used to identify the pre-
sence of volume overload in the acutely ill patient (Figure 1).
Gao et al. (15) recently showed that chest radiography can be
a useful tool for identifying elevated intravascular volumes
in peritoneal dialysis patients before treatment, by using the
cardiothoracic ratio and the vascular pedicle width. However,
chest radiography lacks accuracy in the diagnosis of decom-
pensated HF. In a study analyzing hospitalization rates in
86,376 HF patients from the Acute Decompensated Heart
Failure Registry (ADHERE), it was found that the frequency
of patient admission with a negative chest radiography was
greater than that of patients with a positive chest radiography,
23.3% vs. 13.0% (16). Although radiography is performed on
many patients presenting to the ED with decompensated HF,
it is still unclear whether the test would provide correct and
appropriate diagnostic information. An important chest radio-
graphy parameter is, however, the vascular pedicle width,
since its evaluation shows a statistically significant difference
(p<0.0004) in AHF patients as compared with healthy con-
trols (6).
Echocardiography
The European Society of Cardiology (ESC) (17) and the
American College of Cardiology/American HeartAssociation
(ACC/AHA) guidelines (18) clearly state that echocardio-
graphy represents “the single most useful diagnostic test in
the evaluation of patients with HF”. Echocardiography is a
non-invasive surrogate which can provide hemodynamic
data, such as stroke volume and cardiac output. The estima-
tion of pulmonary artery pressure requires the presence of
tricuspid valve regurgitation for mean and diastolic pres-
sure as well as an accurate estimate of right atrial pressure
and thus of circulatory volume content. Echocardiography
also evaluates the diastolic function, and its dysfunction is
classified according to severity. Mild diastolic dysfunction
is characterized by a decrease in early diastolic flow velo-
city (E wave) and a greater reliance on atrial contraction (A
wave) to fill the left ventricle (E/A<1). Moderate diastolic
dysfunction presents as increasing left atrial pressure at the
onset of diastole and increases in early diastolic flow velocity
to a level near that of normal filling (E/A 1 to 1.5). Severe
diastolic dysfunction occurs when left atrial pressure is fur-
ther elevated, so that early diastolic flow is very rapid and
left atrial and left ventricle pressures equalize quickly during
early diastole (E/A>2). According to the American Society
of Echocardiography (ASE) guidelines, the ejection fraction
(EF) measured with the 2D method is considered abnormal
if <55% (18). An important part of echocardiography is the
evaluation of Inferior Vena Cava (IVC), because it is con-
sidered as a surrogate circulatory volume (Figure 1). The use
of IVC sonography has increased markedly as a method for
determining volume status, especially with the advent of por-
table, handheld ultrasound devices. The assessment is based
on the measurement of the changes in vena cava diameter with
inspiration and expiration, with the maximum IVC diameter
occurring with increases in thoracic pressure during expira-
tion. In a study of 35 CKD patients before and after hemodi-
alysis, the IVC diameter decreased in parallel with reductions
of blood volume after hemodialysis (19). A similar study on
blood donors before and after donation of 450 mL of blood
also showed changes in IVC diameter measurements after
volume removal. Mean changes in diameter ranged from 17.4
to 11.9 mm on expiration (p<0.0001), and from 13.3 to 8.13
mm on inspiration (p<0.0001) (20). These findings demon-
strate an effective role for IVC sonography in the detection of
mild changes in volume state. It is noteworthy, however, that
echocardiographic assessment is of great utility in the evalua-
tion of vascular fluid content in patients with AHF, but cannot
provide reliable information on TBW content.
Thoracic ultrasound
Thoracic ultrasound (TUS) is a relatively new imaging tech-
nique used for identifying interstitial and/or alveolar edema
in volume overloaded patients, especially those with CHF
(Figure 1). TUS depends on the identification of sonographic
artifact called “B-lines” or lung comets. These findings
were first described in 1997 by Lichtenstein and colleagues
(21). Liteplo et al. (22) found similar results in a study of
100 patients in the Emergency Thoracic Ultrasound in the
Differentiation of the Etiology of Shortness of Breath Study
(ETUDES), where it was shown that a positive TUS displayed
a likelihood ratio for the diagnosis of CHF of 3.88 (99% CI
1.55–9.73), whereas a negative TUS had a negative likeli-
hood ratio of 0.5 (99% CI 0.30–0.82). These results suggest
that TUS alone is effective for diagnosing volume overload
secondary to CHF in patients presenting to the ED with short-
ness of breath.
Isotopic tracers of water – the gold standard for
TBW measurement
Isotopic tracers of water represent the “gold standard” for
TBW measurement (23, 24). These radioisotope assays uti-
lize structural similarity between radioisotope (D2
O, 3
H2
O,
H2
18
O) and water to estimate the TBW after sufficient time
for balance. After equilibration, samples are collected and
radioisotopes are measured by mass spectrometry. TBW esti-
mation can then be accurately performed based on the atom
percentage of the radioisotope compared with water in the
sample (25). Although the test is very effective for assessing
the fluid volume in a patient with abnormal homeostasis, it

is unfortunately impractical given the time (often more than
6 h) required for equilibration (26, 27). Therefore, accurate,
and even more importantly, practical measures of hydration
status are still necessary for the evaluation of patients in a
timely manner.
Laboratory biomarkers
The Biomarkers Definitions Working Group of the National
Institute of Health (NIH) has reliably defined a biological
marker, better known as “biomarker”, as a “…characteris-
tic that is objectively measured and evaluated as an indica-
tor of normal biologic processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention” (28).
According to this definition, biomarkers are now used in a
kaleidoscope of clinical conditions in the ED, including diag-
nosis (29) and prognostic assessment (30) of acute myocardial
infarction, diagnosis of acute renal injury (31), acute pancrea-
titis (32), pre-eclampsia (33), stroke (34), CHF assessment
(35) and AHF (Table 1).
Serum blood indices are commonly used for assessment of
hydration status abnormalities in AHF patients. Changes in
serum sodium concentrations and their associations with dis-
eases including abnormal fluid homeostasis are accurate tools
for assessing hydration status. Decreased serum osmolarity
is a common finding in patients with CHF. In these patients,
the heart becomes unable to pump blood forward effectively,
thus leading to activation of neurohormonal mechanisms
that result in increased serum renin activity and downstream
aldosterone secretion (36). The resultant effect is that these
patients develop hyponatremia secondary to unequal and
pathologic retention of water compared to salt. Hyponatremia
can also be used as a metric for disease status. A study of 66
chronic CHF patients with hyponatremia showed that those
with neurohormonal hyperactivation required more diuretic
(i.e, furosemide) than those without the electrolyte abnorma-
lity in order to recompensate (37). Severe hyponatremia is
also associated with worse prognosis in HF patients, and this
parameter is currently included in the guidelines as an indica-
tor of high mortality outcome for these patients (38).
Changes in hematocrit may also be effective measures of
hydration status, especially elevations with decreased blood
volume. Although postural variations can affect the hemato-
crit value, changes in hematocrit are expected in the context
of net water gain or loss (39). However, mild to moderate
decreases in the water volume are not easily detected by
blood indices (40).
Uric acid levels >9.8 mg/dL(>585 μmol/L) have been asso-
ciated with a worse outcome in HF patients. Hyperuricemia
reflects increased activity of the xanthine oxidase pathway
that causes oxidative stress and impair nitric oxide (NO) pro-
duction, thus worsening cardiovascular condition (41).
The accuracy of brain natriuretic peptide (BNP) in the
diagnosis, monitoring, and prognostic stratification of AHF
has been unquestionably established in a variety of interna-
tional trials (42, 43). BNP is the active hormone, composed
of 32 amino acids, while N-Terminal pro-brain natriuretic
peptide (NT-Pro BNP) is the inactive form, composed of 76
amino acids. They are both produced by the heart in response
to volume and pressure overload, and their increase is propor-
tional to systolic and diastolic dysfunction. In patients with
acute dyspnea the cut-off value for BNP (1-32) are tradition-
ally established at <100 pg/mL (NT-Pro BNP <400 pg/mL)
to rule out HF, and >400 pg/mL (NT-Pro BNP>2000 pg/mL)
to confirm HF. Values between 100 and 400 pg/mL (between
400 and 2000 pg/mL for NT-Pro BNP) are considered in
the so-called “grey zone”, and require further scrutiny (42).
Limitations in using these NPs emerge in certain conditions
including renal dysfunction, obesity and atrial fibrillation.
Pro-B-type natriuretic peptide 1-108 (proBNP 1-108) is the
108-amino acid prohormone that is cleaved to the 32-amino
acids, biologically active brain natriuretic peptide (BNP1-32),
also known as B-type natriuretic peptide, and to the 76-amino
acids, biologically inactive N-terminal pro-B-type natriuretic
peptide (NTproBNP1-76). Recently, it has been shown that
ProBNP (1-108) circulates in the majority of healthy humans
in the general population and is a sensitive and specific bio-
marker for the detection of systolic dysfunction. The proBNP
(1-108) to NT-proBNP (1-76) ratio may provide insights into
altered proBNP (1-108) processing during HF progression,
providing important new insights into the biology of the BNP
system (44, 45).
The application of NPs in everyday practice carries, how-
ever, undisputed advantages for improving the clinical man-
agement of patients with AHF, in that they are useful aids for
stratifying the risk in the ED, predicting death and rehospitali-
zation, and guiding therapy (46, 47).
The role of mid-region pro-atrial natriuretic peptide
(MR-proANP) has also been investigated. In the diagnosis
of AHF a cut-off of 120 pmol/L has been proven to be as
accurate as BNP (1-32) (negligible accuracy difference of
0.9%). MR-proANP is considered particularly useful not only
in obese and intermediate BNP (1-32) levels patients (48) but
also in patients with impaired renal function as compared
with BNP (1-32) and NT-ProBNP (1-76) (49).
Recently, in addition to NPs, other interesting and prom-
ising biomarkers have proven useful in the management of
AHF, and a multimarker panel approach has been suggested
to detect different causes of acute dyspnea (50).
Latest results from the biomarkers in acute heart failure
(BACH) trial support the role of several innovative biomark-
ers, such as procalcitonin (PCT). PCT has been investigated
for the diagnosis of pneumonia in patients withAHF. Elevated
PCT (>0.21 ng/mL) is associated with a worse outcome when
antibiotic therapy is not established (p=0.046), while a low
PCT value (i.e., <0.05 ng/mL) is associated with a better out-
come if not treated with antibiotics (p=0.049) (51).
Another interesting result from the 15-center BACH trial
defines the mid-region pro-adrenomedullin (MR-proADM),
the precursor of the hypotensive adrenomedullin, an accurate
14-day mortality predictor. This is also confirmed by the area
under the curve (AUC) in receiver operating characteristics
(ROC) curve of MR-proADM (0.742) which is higher than
that of BNP (0.484) and NT-proBNP (0.586) (52). Another
promising biomarker is copeptin, the C-terminal part of the
vasopressin pro-hormone. It is an independent predictor for

Table 1 Summary of the main utility biomarkers in HF.
Biomarkers Diagnosis and physiopathology Adverse prognosis
Serum sodium (n.v.: 136–145 mmol/L)
AHF- RAA activation
<120 mmol/L
Serum creatinine (n.v.: 0.5–1.5 mg/dL)
Cardiorenal syndrome
>150 μmol/L
>1.5 mg/dL
Serum uric acid (n.v.: m 3.2–8.1 mg/100 mL; 2.2–7.1 mg/100 mL)
AHF- oxidative stress
>9.8 mg/dL
NPs (blood and serum):
• BNP
• NT-proBNP
• MR-proANP
v.n.: HF cut-off:
<100 pg/mL; >400 pg/mL
<400 pg/mL; >2000 pg/mL
<120 pmol/L; >120 pmol/L
AHF: left ventricle volume and pressure overload
(heart muscle stretching)
>1000 pg/mL
>5000 pg/mL
–
ST2 (serum) (n.v.: 1.75–34.3 U/mL)
AHF-overload
>10 ng/mL
PCT (serum) (cut-off: 0.05 ng/mL)
Infection in AHF
0.05–0.5 ng/mL local infection
0.5–2 ng/mL systemic infection
2–10 ng/mL SIRS – sepsis
>10 ng/mL sepsis
NGAL (serum and urine) (cut-off: 150 ng/mL seruma
; 130 ng/mL urinea
)
Cardiorenal syndrome
>100 ng/mLa
Copeptin (serum) (median 3.7 pmol/La
)
AHF-vascular alterations
>54.2 pmol/La
MR-proADM (serum) AHF-vascular alterations >2.15 nmol/La
ADMA (serum) AHF-oxidative stress a
a
Different trials use different cut-off. ADMA, asymmetric dimethylarginine; AHF, acute heart failure; BNP, brain natriuretic peptide; MR-
proADM, mid-region pro-adrenomedulin; MR-proANP, mid-region pro-atrial natriuretic peptide; NGAL, neutrophil gelatinase-associated
lipocalin; NT-proBNP, N-terminal pro-brain natriuretic peptide; PCT, procalcitonin; RAA, renine-angiotensin-aldosterone.
short-term (30 days) mortality, especially in patients with
AHF (p<0.0001). The prognostic value of copeptin (>54.2
pmol/L) has been evaluated alone and in association with
NT-proBNP and BNP, and their AUC were 0.83, 0.76 and
0.63, respectively (53). Finally, a subanalysis of the BACH
trial confirmed that MR-proADM and copeptin in combina-
tion have the best 14-day mortality prediction (AUC=0.818),
compared with all other markers (52).
A new and still not adequately investigated biomarker is
soluble ST2, which is involved in cardiac remodelling and
overload (54). An increase in ST2 above 10 ng/mL is consid-
ered a predictor of mortality in patients with AHF (p<0.001)
(55).
Due to the known, complex and multifaceted interplay
between heart and kidneys, AHF is often complicated by
acute kidney injury (AKI) in critical patients. This circum-
stance defines a high mortality condition, called cardiorenal
syndrome (56). Classically, an increase of serum creatinine
(>150 μmol/L) (16) is used to define renal injury, but it is only
marginally associated with the outcome (AUC of 0.57) (57).
Neutrophil gelatinase-associated lipocalin (NGAL) is a new
biomarker that might help risk stratification in AHF patients.
Although not absolutely specific for AKI (it is also produced
and released by neutrophils) (58), it is still an early marker
of AKI. A discharge value of NGAL >100 ng/mL, combined
with BNP values or even measured alone, has been proven
to be a powerful predictor of 30-day adverse outcomes (57).
Finally, a preliminary study has shown that increased plasma
levels of asymmetric dimethylarginine (ADMA) are strong
and independent predictor of short- and long-term mortality
in AHF patients (NYHA Class III/IV) with reduced EF (59).
Bio-impedance analysis (BIA)
Bio-electrical impedance is the term used to describe the
response of a living organism to an externally applied elec-
tric current by surface electrodes. It measures the opposition
to the flow of electric current throughout the tissues. Electric
current is administered by surface electrodes that need high
current (800 μA) and high voltage to decrease the instabil-
ity related to cutaneous impedance (10,000 Ω/cm2
) (60). This
impedance value, termed electrical impedance (Z), consists of
two components, resistance (R) and reactance (Xc). In terms
of impedance, the human body can be schematically consid-
ered as a system composed of several different conductors in
parallel, each of which opposes the passage of an alternating
current, which passes through two pathways: extracellular tis-
sue and intracellular membranes. Since extracellular (ECW)
and intracellular water (ICW) compartments contain ions,
they are electrically conductive. Thus, estimations of fluid
volume can be based on their impedance to electrical flow
as cell membranes may act as capacitors. The resistivity of
ECW ionic composition is close to that of saline, but the ICW
ionic composition depends on the type of cell and, as a result,
resistivity cannot be measured directly. For technical reasons,

impedance meters using surface electrodes are limited to a
frequency range of 5–1000 kHz, and the ECW and the TBW)
resistance must be calculated by extrapolation as proposed by
the Cole-Cole model (61).
In bio-impedance analysis (BIA) the angular component
of the polar coordinate representation, called the phase
angle (PA), is assessed. The principle of measurement is
based upon the fact that the condensers in the alternating
current circuit lead to a time delay Δt: the current maxi-
mum is in advance of the voltage maximum. PA represents
the measurement of this time delay between the periodic
signals of current and voltage, which vary sinusoidally at
the same frequency. It is calculated from resistance and
reactance according to the formula: PA=arc-tangent reac-
tance/resistance×180°/π. The PA might be an indicator of
cell membrane integrity as well as distribution of ICW
and ECW, and it can also be used to assess total cell mass
(62). Cox multivariate models have also been used to estab-
lish that PA may be considered a significant and indepen-
dent predictor of mortality in patients with liver cirrhosis
(p<0.01) (63).
However, it is important to consider that impedance mea-
surements are rooted in an approximation of the human body
as a sum of five interconnected cylinders (limbs and trunk).
This approximation is calculated from the length and perim-
eters of the limbs and the trunk through a dimensionless
shape factor (Kb) in the resistance–volume relationship for
a single cylinder. A value of 4.3 for Kb has been established
from statistical anatomical measurements in adults (64). It is
also noteworthy that there are several factors impacting BIA
including height, weight, position of the body and limbs,
intense physical activity before BIA measurements, infection,
dermatological conditions, ambient temperature and non-ad-
herence of electrodes (65–68).
In 1871, Thomasset et al. (69) performed the initial study
assessing the electrical properties of tissues to measure imped-
ance using two frequencies of 1 kHz and 100 kHz through two
subcutaneously inserted needles. Using the Cole-Cole model,
he could then estimate the ECW and TBW volumes. Since
then, tetra-polar BIA has been widely investigated in medical
research as a tool for assessing body composition. Its use has
gradually expanded from estimation of body composition in
healthy individuals to embrace the assessment of fluid vol-
ume and distribution in various patient populations.
Single-frequency whole-body BIA (SF-WBIA) and bio-
electrical impedance spectroscopy (BIS)
The whole-body BIA (WBIA) uses four surface electrodes,
two placed on the wrist and two on the ankle, at the distal
metacarpals and metatarsals, respectively, with the subject
supine. A low-level alternating current is administered at
either single (50 kHz) or multiple frequencies (e.g., 1, 5, 50,
200, 500 and 2000 kHz), and then whole-body Z, R and Xc
are measured. These variables are adjusted for height and
then combined with various physical and demographic vari-
ables (body weight, age, gender, etc), into regression models
to predict volume status.
In 1983, Nyboer et al. (70) used the four-surface electrode
WBIA technique, initially presented by Hoffer in 1969, to
assess body composition in 144 subjects. A significant cor-
relation was observed between body fat mass (r=0.860),
TBW (r=0.947) and lean body weight (r=0.934) with the
whole-body impedance and the hydrostatic weighing, which
is another method for measuring the body mass density. It
is based on Archimedes’ principle and is performed during
forced exhalation with residual lung volume (70). By 1986,
the WBIA was accurately described and validated by Kushner
(71), for assessing TBW by BIA and deuterium-isotope dilu-
tion in 58 subjects. He found a significant correlation (r=0.99)
between BIA, weight and deuterium-dilution space.
In 1990, BIS was introduced by Xitron as a new method
to measure both ECW and ICW volumes using Hanai’s mix-
ture conductivity theory for concentrated disperse systems in
evaluating dielectric dispersion due to interfacial polarization
(72, 73).
The BIS device, which is able to assess TBW and differen-
tiate between ECW and ICW (TBW-ICW), uses low and high
frequencies of 5 kHz–2 MHz and extrapolates resistance val-
ues of extracellular and intracellular fluids, respectively, with
the Cole-Cole model. From these resistance values, extra- and
intra-cellular resistivities are derived with the Hanai model.
There is now consolidated evidence that the whole-body
technique, as compared with reference methods, can lead to
inaccurate assessment of body composition in some circum-
stances. In 54 patients with end stage renal disease, TBW
measurements derived by deuterium dilution and WBIA
showed no significant difference (mean difference=–1.221 L,
p=0.12) between the two methods in estimating fluid status.
Unfortunately, WBIA lacked consistency across all patient
populations and significantly overestimated fluid status in
obese patients (mean=–6.789 L, p=0.001) (74). In 2003, Sun
et al. developed a gender-specific, age- and race-combined
equation with the use of a multi-component model including
densitometry, isotope dilution and dual-X-ray absorptiometry
(DXA). A sample of 1829 patients aged from 12 to 94 years
old were studied and their body composition was assessed by
SF-WBIA. The final equation, validated by prediction of sum
of squares (PRESS) statistics, showed the utility of WBIA in
epidemiologic studies (75).
Segmental BIA (SBIA)
Segmental BIA (SBIA) has been developed as a practical
alternative to WBIA. It is a four-electrode bio-impedance
device with contact (tactile) electrodes that measure imped-
ance in the upper (arm-to-arm) or the lower (leg-to-leg) body
of a standing subject (76–79). The main assumptions of this
measurement technique are that conductor volume is equally
distributed in the upper and lower body, segmental imped-
ance values are proportional to whole-body impedance and
whole-body resistance can be derived by the sum of segmen-
tal resistances (80, 81). Interestingly, the segmental imped-
ance technique may be used for personal monitoring of body
composition because it does not require the presence of an
operator. Another type of segmental bio-electrical impedance

uses eight electrodes, four of which are placed in the handles
of the machine (in contact with the thumbs and palms) and
the other four in the foot scale pads, in contact with the balls
of feet and heels. These machines operate at either single or
multiple frequencies while the subject stands. A recent study
on 112 AHF patients used a segmental multi-frequency bio-
electrical analysis to estimate the 6-month prognostic value of
pre-discharge edema index, a derived surrogate for hydration
status, and established that an edema index >0.390 (i.e., the
cut-off value) represents a significant HF-related predictor of
re-hospitalization (p=0.04) (82).
WBIA vs. SBIA
The clinical application of segmental BIA was assessed for
determining fluid accumulation in 30 patients undergoing
abdominal surgery. ECW distribution changes (ΔECW) were
monitored preoperatively (before the induction of anesthesia)
and postoperatively (after recovery from anesthesia). The
ΔECW was estimated by the multi-frequency whole-body
device and as a sum of five body segments. The most sig-
nificant resistance decrease was found in the trunk where the
fluid composition contributes minimally to the whole body
resistance. It was thus concluded that segmental multi-fre-
quency bio-electrical impedance analysis provides ΔECW
assessment better then the whole-body technique in patients
with non-homogeneous fluid distribution (83). Although BIA
cannot be considered as an individual reference tool, newer
studies have warranted its broader application in combination
with other techniques.
Bio-electrical impedance vector analysis (BIVA)
BIVA can be considered an integrated component of BIA
measurement, and is a simple and quick method for assessing
fluid status and body cell mass (84). It can also be used as
a quality control measure for correct analysis of BIA results
(85).
BIVA is a non-invasive technique to estimate body com-
position by bio-electrical impedance measurements, R, Xc
and Z (86, 87). All biological structures have a specific resis-
tance, defined as the strength of opposition by a tissue to the
electric current flow (7). Fat-free tissues and fluids are good
conductors because they offer a low resistance to the electric
current flow, while bone and fat tissues are bad conductors
because they are electrically resistant. Therefore, the resis-
tance is inversely related with the TBW, thus representing an
indirect measure of the amount of body fluid. The measured
reactance is dependent upon the presence of inductors and/
or electrolytic capacitors. Since all cell membranes act like
a small capacitor, reactance can be considered as an indirect
measure of cell membrane activity and integrity, and is pro-
portional to body mass (66, 88).
The BIVA technique was developed at the University of
Padua (Italy) (7). The machine uses an alternating current
flux of 800 μA and an operating frequency of 50 kHz. The
results are visualized in two ways, as a vector or as a BIVA-
derived hydration percentage. The first method includes a
direct impedance plot which measures R and Xc, as a bi-vari-
ate vector in a normogram (85). Reference values adjusted
for age, body mass index (BMI), and gender are plotted as
so-called tolerance ellipses in the same coordinate system.
Three tolerance ellipses are distinguished, corresponding to
the 50th, 75th and 95th vector percentile of the healthy refer-
ence population (86). The major axis of this ellipse indexes
hydration status and the minor axis reflects tissue mass.
The second method involves a scale called the Hydrograph
(or Hydrogram), which expresses the state of hydration as
a percentage. This value is calculated by an independently
determined equation that uses the two components of BIVA,
R and Xc. A normal value is 73.3% with tolerance between
72.7% and 74.3%, corresponding to the 50th percentile (7)
(Figure 1).
Regarding interpretation of values, the length of Z vector
is inversely related to fluid volume, whereas the PA offers
insight into the relative distribution of fluids. A fundamen-
tal outcome of several studies is the delineation of the 75%
tolerance ellipse as the indicator of the boundary of normal
tissue hydration. Vectors outside the upper pole of the 75%
ellipse indicate dehydration, whereas others outside the 75%
confidence ellipse of the lower pole are characteristic of fluid
overload or overhydration. Thus, short vectors with a small
PA are associated with edema, whereas longer ones with an
increased PA indicate dehydration (86, 89, 90). Moreover,
vectors above or below the minor axis (meaning upper-left
or lower right half of ellipses) are associated with more or
less cell mass in soft tissue, respectively, with extremes along
the minor axis. As previously discussed, the normal BIVA-
derived hydration values for the hydrograph are comprised
between 72.7% and 74.3%, values above or below such rela-
tive thresholds indicate a state of hyperhydration (wet) and
dehydration (dry) (91). These two classes can be further sub-
divided into mild, moderate or severe volume abnormalities
(92).
The BIVA technique is very handy and can be used at the
bedside, with the patient supine with inferior limbs at 45° and
superior limbs abducted at 30° to avoid skin contacts with the
trunk (66). Four skin electrodes are applied, two on the wrist
and two on the ipsilateral ankle. A minimal inter-electrode
distance of 5 cm has been recommended to prevent interac-
tion between electrodes. The subject is laid recumbent on a
non-conductive surface. Free fluid in thorax and abdomen
(lung congestion, pleural effusion, ascites, urine, food) does
not affect the impedance values measured by this technique
(6).
Despite being relatively new, BIVA is becoming recog-
nized as a superior method for TBW content assessment (93).
Clinical studies have been carried out in hospitalized patients
with severe renal diseases to assess the utility of BIVA in
assessing volume status. Studies involving uremic patients,
compared to healthy controls, showed significantly shorter
vectors with smaller PAs. As discussed above, shorter vectors
(low impedance) are associated with hyperhydration. These
vectors then lengthened after dialysis, showing the ability
of BIVA to detect significant changes of fluid status after

dialysis. Changes in the volume of fluid removed significantly
correlated with changes in vector components (p<0.001 in
men, p=0.03 in women). Vectors of unstable (e.g., adverse
outcomes) compared to stable hemodialysis patients were sig-
nificantly different. It was also found that vectors of unstable
patients were longer with smaller PAs, and these differences
persisted after hemodialysis (89). Similar findings were found
in patients treated with peritoneal dialysis, before and after
fluid removal (86).
New application fields are emerging in critical care. In
intensive care unit patients, the central venous pressure (CVP)
was correlated with impedance measured by BIVA. CVP
values are significantly and inversely correlated with indi-
vidual impedance vector components (r2
=0.28 and 0.27 with
resistance and reactance, respectively), and with both vector
components together (r2
=0.31). Specifically, CVP values>12
mm Hg were associated with shorter impedance vectors (out-
side the lower pole of the 75% reference ellipse) in 93% of
patients, thus indicating fluid overload. Conversely, CVP val-
ues <3 mm Hg were associated with long impedance vectors
(outside the upper pole of the 75% reference ellipse) in only
10% of patients, indicating tissue dehydration. The progres-
sive increase of CVP values was associated with shorter and
down-sloping impedance vectors on the R-Xc graph (94).
The role of BIVA coupled with TUS has shown its effec-
tiveness in discriminating cardiac and non-cardiac acute
dyspnea patients presenting in ED (69% sensitivity, 79%
specificity) (95).
Future directions in managing AHF patients
using biomarkers plus BIVA
The BIVA evaluation is an appealing perspective when applied
in patients in the acute setting with congestive HF because of
specific fluid overload. A study by Di Somma et al. (6), shows
that BIVA data in decompensated AHF patients at admission
to the ED are statistically different as compared with controls
(p<0.0007). AHF patients had a significantly higher value of
hydration status (77±4) as compared with controls (73±2).
Sequential BIVAmeasurements inAHF patients showed reduc-
tion of congestion due to diuretic treatment.Asignificant corre-
lation with events (death or re-hospitalization) at 3 months was
also observed in patients with average hydration values >80%.
It was also demonstrated that combined use of BIVA and BNP
may improve the management of AHF patients in ED when
compared to BNP alone, thus allowing a faster and much more
accurate triage. BIVA helped distinguish cardiogenic dysp-
nea from non-cardiogenic causes and – in combination with
BNP – was also useful for management of AHF patients, since
both measures were helpful to guide emergency physician’s
decisions about diuretic therapy (e.g., preventing overuse).
Valle et al. (91) found that the combination of BNP and
BIVA measurements could prevent unnecessary aggressive
diuretic therapy, thereby reducing the level of renal compli-
cations. BIVA-BNP guided management during hospitaliza-
tion for HF was associated with lower events after discharge,
independent of other prognostic variables (91).
The evaluation of total body fluid has a great utility also in
patients with cardiorenal syndrome, and its use in combina-
tion with other parameters (e.g., in a multimarker approach)
has been proposed as a new model of management of ED
patients with cardiorenal syndrome (96).
According to the large number of studies available in the
scientific literature, the role of impedance is becoming more
and more predominant for the assessment of hydration sta-
tus. Characteristics, such as quick and simple use, non-inva-
siveness and low cost would make this device appealing and
potentially useful in a kaleidoscope of medical fields. BIVA
seems to be more accurate and more reliable when compared
with other impedance techniques (Figure 1). Further tri-
als with larger patient populations are obviously needed to
express a definitive consensus on the clinical effectiveness of
BIVA, as well as for identifying those clinical settings where
it can be more advantageous.
The use of BIVAin guiding the treatment of various disease
states has not been adequately studied. It would be interesting
to standardize BIVA employment in AHF patients, in combi-
nation with biomarkers, to guide a proper and correct diuretic
therapy. Preliminary data from studies that have monitored
the variations of BIVA values in volume overloaded patients
has already shown its utility in guiding diuretic treatment, but
more clinical evidence is necessary to create BIVA/diuretic
guidelines. Another promising application is related to the
emerging role of ultrafiltration in unloading CHF patients that
do not benefit from diuretic therapy. Regular use of BIVAplus
NPs might assist physicians to decide the amount of water
to remove, thus avoiding harmful consequences. Due to its
quick and easy use, BIVA should also be tested for its efficacy
in primary care setting as a means for monitoring congested
patients. This application could help primary care physicians
in the management of these patients, since exacerbations
may be detected sooner, avoiding severe worsening that may
require hospitalization.
BIVA alone is probably not the definitive answer to all
challenging questions about hydration status, but it seems to
be a useful and promising device for everyday use, especially
when coupled with biomarker measurement, because it is
accurate, non-invasive, cheap and easy to use in combination
with other techniques.
Conflict of interest statement
Authors’conflict of interest disclosure: The authors stated that there
are no conflicts of interest regarding the publication of this article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
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Prof. Salvatore Di Somma
(07/06/1953) graduated in
Medicine cum laude (Univer-
sity of Naples, 1978) and
postgraduated cum laude
both in Internal Medicine and
in Cardiology (University of
Naples, 1983 and 1987). He
began his university career
at the Department of Clinical
and Experimental Medicine
and as Assistant Professor –
Emergency Medicine and Cardioangiology – at the University
Federico II of Naples (1978–2001). He was research fellow
in cardiology at the University of Pavia (1989–1992) and was
Assistant Professor in the Cardiovascular Research Institute of
the Department of Medicine, New York Medical College, USA
(1994–1996). Now Prof. Di Somma is Associate Professor
of Medicine and Chairman of the Postgraduate School
of Emergency Medicine, II Medical School, La Sapienza
University of Rome. He is the Director of Emergency Medicine
in Sant’Andrea Hospital, Rome. Prof. Di Somma is author to
more than 400 papers in the field of Cardiology and Emergency
Medicine. He is the director of an international cooperation
team and reviewer for international medical journals.
Silvia Navarin born on
(01/08/1987) was born in
Rome and graduated from
Liceo Classico E. Montale
also in Rome (100/100). She
graduated from the Second
School of Medicine, La
Sapienza, University of Rome.
She has been a member of the
Italian Red Cross since 2006
as a first aid instructor, ambu-
lance operator, and she was the
Italian Red Cross delegate for
the international cooperation
work between Italy and Bosnia
Herzegovina (2008) and also at the international meeting in
Solferino (2009). She has been involved in medical practise and
researchprogramsintheEmergencyDepartmentofSant’Andrea
Hospital in Rome since 2009. She participated in a professional
exchange program of the International Federation of Medical
Students’AssociationattheDepartmentofEmergencyMedicine
in the University Clinical Centre Ljubljana in 2010. She won a 3
months international scholarship at the University of California,
San Diego and took part in a research project for her graduation
thesis in the Veterans Affair San Diego Healthcare System.

Stefania Giordano
(23/07/1987) was born in
Rome. She graduated from
Liceo Classico-Linguistico
Gaio Valerio Catullo in
2006, and she also gradu-
ated in the second School
of Medicine at La Sapienza
University of Rome. She
has been involved in medi-
cal practise and research
programs at the Emergency
Department of Sant’Andrea
Hospital in Rome since 2008. In 2011 she received a cer-
tificate of “Echography in the emergency department”. She
won a 3 months international scholarship at the University
of California, San Diego where she took part in a research
project for her graduation thesis at the Veterans Affairs San
Diego Healthcare System.
Francesco Spadini
(07/01/1976) was born in
Rome. He graduated from
Liceo Scientifico Statale
Louis Pasteur in 1994. From
1994 to 1997 he worked at
the Physics Department at La
Sapienza Rome University.
From 1997 to 2005 he worked
in the IT industry. He is cur-
rently studying at the Second
School of Medicine at La
Sapienza Rome University, where he is also collaborating on
various research projects.
Prof. Giuseppe Lippi is
the Director of the Clinical
Chemistry and Hematology
Laboratory of the Academic
Hospital of Parma and
Associate Professor of
Clinical Biochemistry and
Molecular Biology. He has
a degree in Medicine and
a specialization in Clinical
Biochemistry and Laboratory
Medicine. He currently
serves as Associate Editor of
Clinical Chemistry and Laboratory Medicine and Seminars
in Thrombosis of Hemostasis. He is also chairman of the sci-
entific division of the Italian Society of Clinical Biochemistry
and Molecular Biology (SIBioC), and member of the board
of the European Association of Clinical Chemistry (EFCC).
Prof. Lippi is author of more than 750 publications on inter-
national journals indexed in PubMed and Thomson, and in
more than 90% of them as main or senior author. His main
area of research includes preanalytical variability, analytical
and clinical validation of novel biomarkers, metabolism of
lipoproteins and relevant assay methods, diagnosis and man-
agement of disorders of hemostasis.
Prof. Cervellin Gianfranco
(30/06/1955) graduated in
Medicine in 1980. He com-
pleted his postgratuate stud-
ies in Geriatrics in 1984 and
in Cardiology in 1988 at the
University of Parma, Italy).
He has been the Director
of Emergency Medicine
in Azienda Ospedaliero,
University of Parma, Italy
since October 2005. In April
2006 he became the Professor of Emergency Medicine at the
University of Parma, Italy. He is author of approximately100
publications (66 available on PubMed), and some book
chapters.
Bryan Dieffenbach is cur-
rently a medical student at
the University of California,
San Diego (UCSD) School
of Medicine. Prior to medi-
cal school, he completed a
Master of Science degree at
UCSD studying the innate
immune response in rheu-
matoid arthritis. As an under-
graduate, he graduated with
honors from UCSD with a
degree in Biochemistry and
Cell Biology. He was also the
captain of the UCSD Men’s
Track and Field Team.

Dr. Alan Maisel attended
University of Michigan
Medical School and com-
pleted his cardiology training
attheUniversityofCalifornia,
San Diego. He is currently
Professor of Medicine at the
University and Director of
the Coronary Care Unit and
the Heart Failure Program at
the afﬁliated Veterans Affairs
Medical Center. He is con-
sidered one of the world’s
experts on cardiac biomark-
ers, and is given credit for ushering in the use of BNP levels
in clinical practice around the world. He has over 300 articles
in print and a large clinical and basic science laboratory. Dr.
Maisel is also a ﬁxture at the medical school, where he has
won countless teaching awards from medical students as well
as interns and residents. His yearly San Diego Biomarker
meeting is considered the most prestigious of its kind. He
is currently an Associate Editor of the Journal of American
College of Cardiology.

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