The Chronic Volume Expansion

Published Date: 02 Nov 2017

apparent or occult, is a pervasive complication

in patients with end-stage renal

disease (ESRD) maintained on dialysis.

Even though the independent prognostic power of

volume overload remains scarcely defined in epidemiologic

studies, recent findings in a large multiethnic

cohort of American patients documented that fluid

accumulation between dialysis is a powerful predictor

of death and cardiovascular complications in this

population (1). There has been a quest for methods

aimed at estimating body fluids volume and for

personalizing fluids removal in ESRD (2,3). The

main issue for the achievement of dry weight by

dialysis is that volume subtraction should be tailored

to the individual patient’s hemodynamic tolerance

taking into full account cardiac performance, which is

very often compromised in ESRD patients (4,5).

Extravascular lung water (LW) is a relatively

small but fundamental component of body fluids

volume (6,7). This component represents the water

content of the lung interstitium that is strictly

dependent on the filling pressure of the left ventricle

(LV), that is, the hemodynamic parameter

considered as the golden standard for guiding fluids

therapy in critical care.

In recent years, the use of chest ultrasound (US)

to detect LW has received growing attention in

clinical research in intensive care patients (8) and in

patients with heart failure (9). In the presence of

excessive LW, the US beam is reflected by subpleural

thickened interlobular septa, a low impedance

structure surrounded by air with a high acoustic

mismatch. This US reflection generates hyperechoic

reverberation artifacts between thickened

septa and the overlying pleura that are defined as

"lung comets" (10). Lung comets represent the US

equivalent of Kerley B lines in standard chest

X-rays. These artifacts (Fig. 1) are easily detected

with standard US probes. Remarkably, lung comets

are strongly related to LV filling pressure (capillary

wedge pressure) and the measurement of LW by

US has been formally validated against a golden

standard technique such as the indicator thermodilution

method in a series of patients submitted to

cardiac catheterization (11). A recent proof-ofconcept

study aimed at testing the regression of

lung comets along with fluids removal was based

just on hemodialysis patients (12), and chest US is

increasingly applied to detect and monitor pulmonary

congestion in patients with chronic heart

failure (9) and to grade disease severity in acute

respiratory distress syndrome/acute lung injury (13). The aim of the present study is 3-fold: 1) to

estimate the feasibility of LW measurements by chest

US in hemodialysis patients and to determine the

prevalence of pulmonary congestion in these patients;

2) to investigate the relationship between LW, body

fluids volume status, and echocardiographic parameters

of cardiac performance; and 3) to study the effect

of standard ultrafiltration dialysis on LW.

METHODS

The study protocol conformed to the Declaration of

Helsinki and was approved by the local ethics

committee. All patients provided informed consent.

Patients. Between May 8 and July 7, 2009, we

invited, to take part into the study, all patients

undergoing chronic hemodialysis treatment and

those who initiated hemodialysis during this period

in the dialysis unit of our department (n _ 78).

Seventy-five patients (49 men and 26

women) accepted and were enrolled. Hemodialysis

patients were being treated

thrice weekly with standard bicarbonate

dialysis by cuprophan or semisynthetic

membranes. Forty-six patients were habitual

smokers (17 _ 13 cigarettes/day).

Sixty patients were on treatment with

erythropoietin. Forty-two patients were

being treated with various antihypertensive

drugs (26 on monotherapy with

angiotensin-converting enzyme inhibitors,

calcium channel blockers, beta-blockers,

angiotensin II receptor blockers, and other

antihypertensive drugs) and the remaining

16 patients were on double or triple therapy

with various combinations of these drugs.

Patients were classified as symptomatic or asymptomatic

on the basis of a slightly modified New

York Heart Association (NYHA) scale (14). Total

body water volume was estimated in each patient by

bioelectrical impedance analysis (BIA) by using a

standard apparatus (Akern BIA 101/S, Florence,

Italy) and the subject’s nutritional and hydration

status was interpreted in relationship to normative

data in the Italian general population (15).

Lung comets detection and lung comets score. A

standard (3.0-MHz) echocardiography probe

(Toshiba Nemio XG, Toshiba, Tokyo, Japan) was

used for the detection of lung comets. Examinations

were performed in the supine position. Scanning

of the anterior and lateral chest was performed

on both sides of the chest, from the second to the

fourth (on the right side to the fifth) intercostalspaces, at parasternal to mid-axillary lines, as previously

described (8). Lung comets were recorded in

each intercostal space and were defined as a hyperechoic,

coherent US bundle at narrow basis going

from the transducer to the limit of the screen (Fig.

1). These extended comets arise from the pleural

line and should be differentiated from short comets’

artifacts that may exist in other regions. Lung

comets starting from the pleural line can be either

localized or scattered to the whole lung and be

present as isolated or multiple artifacts (with a

distance _7 mm between 2 artifacts). The sum of

lung comets produces a score reflecting the extent of

LW accumulation (0 being no detectable lung

comet). More details are available in a 2-min movie

on YouTube (16). On the basis of this score, we

grouped patients into 3 categories of increasingly

severe pulmonary congestion (mild: _14 comets;

moderate: 14 to 30 comets; severe: _30 comets) as

described in detail elsewhere (17). All measurements

were made by an observer unaware of the

result of clinical and echocardiography data.

Echocardiography. Echocardiographic measurements

were obtained in each patient before and

after dialysis by a standard echocardiography instrument

(Toshiba Nemio XG). Details on the echocardiography

protocol followed in our unit were

previously described (18).

Reproducibility studies. The interobserver reproducibility

of comets scoring was assessed in a set of 24

consecutive patients. One of 2 observers is an expert

echocardiography technician who received specific

training on chest US, and the second observer is a

nephrology trainee with introductory level experience

in renal US who was trained by the technician

(in a 2-h practical session) to measure the lung score.

The reliability of comets score over time was investigated

in a series of 10 patients who maintained stable

(_1 kg) body weight over 2 to 4 weeks. To test the

agreement of comets scoring by different probes, these

measurements were recorded in random order with

the 3.5-mHz probe (a probe routinely applied for

renal sonography) and the standard echocardiography

(3.0-mHZ) probe in a series of 21 consecutive patients

and then read by a blind observer.

Statistical analysis. Data are expressed as mean _

SD, median, and interquartile range, or as percent

frequency, as appropriate. Comparisons among

groups were made by p value for linear trend (1-way

analysis of variance or chi-square test). Among

patients, comparisons were made by paired t test

(normally distributed data) or by Wilcoxon signed

rank test (non-normally distributed data). Correlations

between variables were investigated by Pearson

product moment correlation coefficient (r),

point-biserial correlation coefficient, or by Spearman

rank correlation coefficient (rho), as appropriate.

The agreement between continuous or discrete

data was tested by the Bland-Altman method and

by the concordance correlation coefficient, whereas

that between categorical variables was tested by

kappa statistics. Independent correlates of lung

comets score were identified by multiple linear

regression analysis. Significant independent correlates

of lung comets were identified by backward

elimination strategy (p out: 0.10). Data are expressed

as standardized regression coefficient (beta)

and p value. All calculations were made using a

standard statistical package (SPSS for Windows,

version 9.0.1, Chicago, Illinois).

RESULTS

All eligible patents (n _ 78) but 3 (1 patient with

severe mental handicap, 2 patients that refused to

take part for logistic reasons) agreed to participate

in the study. Thus, 75 patients (96%) were actually

enrolled. The demographic and clinical characteristics

of the study population are reported in Table 1.

Six patients had chronic obstructive pulmonary

disease, 1 patient had a previous diagnosis of

Wegener granulomatosis, and 46 were smokers.

Seventy-three patients were virtually anuric (24-h

diuresis, 0 to 250 ml/min), whereas the remaining

patients had a 24-h urine volume ranging from 550

to 750 ml/24 h. On average, pre-dialysis arterial

pressure was 138 _ 25/71 _ 12 mm Hg and

post-dialysis was 124 _ 28/68 _ 13 mm Hg.

Eleven patients (15%) had hypoalbuminemia (serum

albumin: _3.6 g/dl) and 36 presented mild to

moderate pedal edema before dialysis. Nineteen

(25%) patients had a NYHA score _3.

Pre-dialysis BIA. On the basis of individual’s plot in

the reactance/resistance nomogram, 24 patients

(32%) were classified as "overhydrated," 38 (51%) as

at normal hydration status, and 13 (17%) as hypohydrated.

Among patients with moderate to severe

heart failure (NYHA functional class III to IV, n _

19), 15 (79%) were overhydrated by BIA.

Chest US. Chest US examinations were successfully

completed in all cases (feasibility 100%). No data

were rejected. The time needed for the chest US

varied between 3 and 6 min (average: 4 min). Lung

comets score significantly reduced (p _ 0.001) after

dialysis (Fig. 2). The mean and the median number

of pre-dialysis lung comets (lung comets score) were

33 and 18, respectively. Lung comets score was _14

in 28 cases, 14 to 30 in 26 cases, and _30 in 21

cases. Overall, 47 of 75 patients (63%) had moderate

to severe pulmonary congestion (i.e., a lung

comets score _14) before dialysis. The score was

higher in patients with symptomatic heart failure

(NYHA functional class III to IV) than in patients

without symptoms of heart failure, but the vast

majority of asymptomatic patients (32 of 56, 57%)

had a score _14, indicating moderate to severe

pulmonary congestion. Patients with lung disease

(n _ 7) had a higher (median: 44, interquartile

range 21 to 56 vs. median: 17, interquartile range 12

to 30) score than those without (p _ 0.03).

On the basis of the pre-dialysis score, patients

were divided into 3 pre-specified categories denoting

increasingly severe LW accumulation (17) (no

or mild: _14 comets, moderate: 14 to 30 comets,

severe: _30 comets) (Table 1). Patients in the most

severe category were older, more frequently smokers,

with lower fractional urea clearance (Kt/V), and

with NYHA functional class III to IV heart failure

as compared to those in the other categories (Table

1). These associations were confirmed in correlation

analyses (Table 1, last column), which also showed

weak but significant relationships between lung

comets and pre-dialysis systolic pressure (inverse

association) and heart rate (direct association).

Lung comets score, BIA hydration status classification,

and echocardiographic parameters. The lung comets

score in patients identified as overhydrated by BIA

(median: 20, interquartile range 13 to 57) did not

significantly differ (p _ 0.35) from that in patients

with normal hydration status (median: 17, interquartile

range 17 to 22) or that in hypohydrated

patients (median: 15, interquartile range 7 to 45),

and as much as 50% of the 38 patients who were

normohydrated had a score indicating moderate to

severe pulmonary congestion. The score was closely

related to anatomical and functional echocardiographic

parameters (Table 2). Indeed patients in the

third lung comets category (_30 comets, severe

congestion) had higher left ventricular mass index,

left atrial volume, and left ventricular end-diastolic

volume (LVEDV) than those in other 3 categories.

Furthermore, patients in the third category displayed

compromised LV systolic function as denoted

by lower LV ejection fraction in comparison

to other groupings. Correlation analyses substantially

confirmed these categorical associations (Table

2, last column) and also revealed highly significant

relationships of pre-dialysis lung comets with

early left ventricular filling velocity (E), early filling

to early diastolic mitral annular velocity (E/E=)

ratio, pulmonary pressure, and LVEDV. The relationships

between lung comets and LV ejection

fraction, E/E= ratio, and left atrial volume were the

strongest among those considered in this study

(Fig. 3).

In a multiple regression model including standard

clinical correlates (p _ 0.10) of lung comets

score (age, smoking, Kt/V, systolic pressure and

heart rate, and NYHA functional classification) as

well as anatomical (LV mass index) and functional

(ejection fraction, left atrial volume, pulmonary

pressure, and E/E= ratio) echocardiographic parameters

of the left ventricle, results show only LV

ejection fraction to be an independent correlate of

the pre-dialysis score (beta _ –0.61, p _ 0.001).

Forcing serum albumin into the model did not

materially modify the link of the lung comets score

with LV ejection fraction.

Effect of dialysis on hydration status by BIA and on

lung comets. Body weight reduced from 66.7 _

18.0 kg pre-dialysis to 64.4 _ 17.4 kg after dialysis

(–3.4%, p _ 0.001). After dialysis, 7 out 24 patients

(29%) moved from the overhydration to the normohydration

or hypohydration area. The proportion

of patients with moderate to severe pulmonary

congestion fell from 47 (63%) to 23 (31%). The

association between the comets score and hydration

status by BIA improved after dialysis: among patients

who were normohydrated after dialysis (n _

25) only 4 (16%) had a score _14. Importantly

there was a high correlation between pre-dialysis

lung comets and the reduction in this score after

dialysis (Fig. 3). LVEDV fell from 116 _ 37 ml to

103 _ 32 ml after dialysis, as did left atrial volume

(from 14.1 _ 4.0 ml/m2.7 to 12.6 _ 3.6 ml/m2.7)

whereas LV ejection fraction remained unmodified

(57.4 _ 9.3% vs. 57.4 _ 9.5 %), denoting improved

LV performance. The decrease in lung comets after

dialysis was also strongly related with pre-dialysis

LV ejection fraction (r _ –0.55, p _ 0.001),

pre-dialysis E/E= ratio (r _ 0.38, p _ 0.001),

pre-dialysis left atrial volume (r _ 0.35, p _ 0.003),

pre-dialysis LVEDV (r _ 0.32, p _ 0.006), NYHA

functional class (r _ 0.32, p _ 0.005), pre-dialysis

LV end-diastolic diameter (r _ 0.31, p _ 0.007),

pre-dialysis LV mass index (r _ 0.29, p _ 0.01),

pre-dialysis pulmonary pressure (r _ 0.23, p _

0.05); however, it was largely independent of the

volume of fluids removed across dialysis or changes

in systolic and diastolic pressures or serum albumin

(p _ NS). Notably the strength of the association

between the post-dialysis lung comets score and LV

ejection fraction (r _ –0.59, p _ 0.001), left atrial

volume (r _ 0.30, p _ 0.01) and pulmonary

pressure (r _ 0.35, p _ 0.003) was of a degree

similar to that observed before dialysis (Fig. 3). In

the 7 patients with pre-existing pulmonary disease,

the decrease in lung comet score (from 44 [median]

to 18, –59%) did not significantly differ (p _ 0.09)

from that in patients without pulmonary disease

(from 17 to 9, –47%).

Reproducibility studies. The reproducibility of the

lung comets score over time in 10 stable patients

who maintained a pre-dialysis body weight within

_1 kg of the initial study was good in that the

difference between the 2 measurements was always

less than 2 SD of the average measurement (concordance

index _ 0.83, 95% confidence interval:

0.60 to 0.93) (Fig. 4). The agreement between the

expert and the naive observer was quite satisfactory:

in over 24 independent measurements, only in 2

cases did the between-observer difference exceed 2

SD, and in 1 of these cases (very high score), the

difference did not modify the categorization of

the severity of pulmonary congestion (severe in

both cases) (Fig. 4). Equally good was the reproducibility

of the comets score as measured with

the echocardiography probe (3.0 mHz) and the

standard renal probe (3.5 mHz) in that just in 1

case did the interprobe difference exceed 2 SD

(Fig. 4).

DISCUSSION

Chest US is a simple, easy to perform, and quick

technique that provides reproducible estimates of

LW in hemodialysis patients. By this technique,

LW is strikingly increased in the vast majority of

symptomatic and asymptomatic ESRD patients

and appears strongly associated with altered LV

performance but scarcely related with hydration

status before dialysis. Standard ultrafiltration dialysis

markedly reduces LW and improves LV performance

but fails to normalize this parameter in most

cases. Overall findings in this study indicate thatchest US gives reliable information that can be

potentially useful for complementing the characterization

of cardiac performance and body fluids

status in hemodialysis patients.

Fluids overload and pulmonary congestion in ESRD

and in heart failure. Accumulation of fluids in the

lung is the most concerning consequence of fluids

overload and pulmonary congestion, and congestive

heart failure is a notorious, frequent complication in

ESRD (19). The risk of pulmonary congestion due

to fluids overload is particularly high in the presence

of compromised LV function (20). In these cases,

even a minor degree of fluids excess may translate

into clinical symptoms of pulmonary congestion.

The joint effect of fluids excess and LV dysfunction

on pulmonary water is of paramount importance in

ESRD because about 30% of patients entering

chronic dialysis display frank symptoms of heart

failure (21) and because as much as 48% of asymptomatic

patients stabilized on dialysis have compromised

LV function (5). Pulmonary capillary wedge

pressure, which reflects LV filling pressure, is the

driving force determining fluids extravasation into

the lungs, a phenomenon that only occurs after

substantial fluids accumulation in patients without

heart disease (22) but even in the absence of fluids

retention in patients with LV failure (23).

LW and LV function in ESRD. Patients with ESRD

accumulate water in the lungs as their extracellular

volume expands (24,25). We found that chest US, a

technique with a very short learning curve that can

be performed by standard equipment, provides reproducible

estimates with good interobserver and

interprobe agreement. Importantly, our observations

in an inclusive population of ESRD patients, comprising

19 (25%) with NYHA functional class III to

IV heart failure, show that LW before dialysis is

highly dependent on LV function but largely independent

of total body water. The close, inverse association

betweenLWand ejection fraction, both before

and after dialysis, clearly points to LV dysfunction as

a main driver of pulmonary congestion.

Extending observations in patients with heart failure

(10), our study provides evidence that chest US

captures pulmonary congestion at a pre-clinical stage

in most patients. Indeed as many as 57% of asymptomatic

dialysis patients had moderate to severe congestion.

As in patients with heart failure, detection of

LW accumulation at a pre-clinical stage in dialysis

patients may represent an important clue for preventing

decompensated heart failure (23).

Study limitations. Although we specifically tested the

reproducibility of the lung comet score in dialysis

patients, the precision of US LW estimates in this

population remains unknown. Because the uremic

lung may have an altered water permeability (22,26),

the issue deserves further study in ESRD patients. Yet

the problem of precision of LW estimates appears to

be of greater relevance for mechanistic rather than for

outcome-oriented studies.

Our study is based on the dialysis population of a

single center in its entirety without any prejudicial

exclusion of patients. However, larger studies aimed

at assessing the prognostic value and the usefulness

of chest sonography in the clinical decision process

are needed to solidly establish the value of this

technique in ESRD.

CONCLUSIONS

Chest US is a reliable technique for estimating LW

in dialysis patients. Subclinical pulmonary congestion

is prevalent in asymptomatic and normohydrated

dialysis patients. Chest US may prove useful

in clinical practice to tailor ultrafiltration and drug

treatment to ESRD patients, an issue that will be

investigated in specifically designed observational

and interventional studies.