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Low cardiac output predicts development of
hepatorenal syndrome and survival in patients
with cirrhosis and ascites
A Krag, F Bendtsen, J H Henriksen, et al.
Gut 2010 59: 105-110 originally published online October 15, 2009
doi: 10.1136/gut.2009.180570
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Cirrhosis
Low cardiac output predicts development of
hepatorenal syndrome and survival in patients with
cirrhosis and ascites
A Krag,1,2 F Bendtsen,1 J H Henriksen,2 S Møller2
1
Department of
Gastroenterology, Hvidovre
Hospital, Faculty of Health
Sciences, University of
Copenhagen, Copenhagen,
Denmark; 2 Department of
Clinical Physiology, Hvidovre
Hospital, Faculty of Health
Sciences, University of
Copenhagen, Copenhagen,
Denmark
Correspondence to:
Dr A Krag, Department of
Medical Gastroenterology 439,
Hvidovre Hospital, DK-2650
Hvidovre, Denmark; aleksander.
[email protected]
Revised 27 August 2009
Accepted 29 August 2009
Published Online First
15 October 2009
ABSTRACT
Objectives: Recent studies suggest that cardiac
dysfunction precedes development of the hepatorenal
syndrome. In this follow-up study, we aimed to
investigate the relation between cardiac and renal
function in patients with cirrhosis and ascites and the
impact of cardiac systolic function on survival.
Patients and design: Twenty-four patients with cirrhosis
and ascites were included. Cardiac function was
investigated by gated myocardial perfusion imaging (MPI)
for assessment of cardiac index (CI) and cardiac volumes.
The renal function was assessed by determination of
glomerular filtration rate (GFR) and renal blood flow (RBF)
and the patients were followed up for 12 months.
Results: In patients with a CI below 1.5 l/min/m2 on MPI,
GFR was lower (39 (SD 24) vs 63 (SD 23) ml/min,
p = 0.03), RBF was lower (352 (SD 232) vs 561 (SD
229) ml/min, p = 0.06), and serum creatinine was higher
(130 (SD 46) vs 78 (SD 29) mmol/l, p,0.01). The number
of patients who developed hepatorenal syndrome type 1
within 3 months was higher in the group with low CI than
in the high CI group (43% vs 5%, p = 0.04). Patients with
the lowest CI (N = 8) had significantly poorer survival at
3, 9, and 12 months compared to those with a higher CI
(N = 16), p,0.05. In contrast, the Model for End-stage
Liver Disease (MELD) score failed to predict mortality in
these patients.
Conclusions: The development of renal failure and poor
outcome in patients with advanced cirrhosis and ascites
seem to be related to a cardiac systolic dysfunction. Other
parameters may be more important than MELD score to
predict prognosis.
Ascites occurs in about 50% of patients with
cirrhosis within 10 years after diagnosis and is
associated with a 50% mortality within 2 years.1 2
In many of these patients the renal function
deteriorates with the development of the hepatorenal syndrome. According to the peripheral arterial
vasodilation hypothesis, renal impairment and
hepatorenal syndrome develop in the setting of a
hyperdynamic circulation with severe arterial
underfilling due to progressive splanchnic arterial
vasodilation.1–4 However, it has recently been
shown that a cardiac dysfunction with reduction
of cardiac index (CI) precedes the hepatorenal
syndrome and accordingly a modified peripheral
arterial vasodilation hypothesis has been proposed.2 5–7 This hypothesis is mainly based on two
studies. The first study showed a decreased CI in
patients with spontaneous bacterial peritonitis
who developed renal failure during treatment.6
The second study identified CI as an independent
Gut 2010;59:105–110. doi:10.1136/gut.2009.180570
predictor of development of hepatorenal syndrome.5 The finding that a decreased cardiac
output has a role in the development of hepatorenal syndrome has some therapeutic implications.
Thus, improvement of the systolic cardiac function
could be part of the treatment strategy to improve
survival
of
the
hepatorenal
syndrome.
Approximately 60–80% of patients hospitalised
for heart failure have renal dysfunction, which is
associated with a significantly increased morbidity
and mortality.8 However, the presence of a cardiorenal relation, its pathophysiological background,
and clinical importance in patients with cirrhosis
and ascites needs to be further elucidated. The
primary aim of this study was therefore in patients
with advanced cirrhosis and ascites to assess the
relation between cardiac and renal function and
secondarily to asses the impact of cardiac systolic
function on survival.
PATIENTS AND METHODS
Twenty-four patients with alcoholic cirrhosis and
ascites without hepatorenal syndrome type 1
according to previous definitions of the
International Ascites Club were included in the
study.9 Nine patients, five of whom had serum
creatinine above 133 mmol/l, had refractory ascites
and 15 had non-refractory ascites according to
these criteria,9 12 were classified as Child B and 11
as Child C. Patients were in a stable condition:
none had gastrointestinal bleeding within the week
before the study, spontaneous bacterial peritonitis,
insulin-dependent diabetes, acute or chronic intrinsic renal or cardiovascular diseases, arterial hypertension, abnormal electrocardiogram or any acute
medical conditions such as infections or acute
heart or lung diseases. Furthermore, alcohol abstinence for 6 weeks was required. Pre-existing
cardiac diseases were excluded by a negative
history of arterial hypertension, cardiac or pulmonary diseases, a normal clinical examination and
a normal electrocardiogram (ECG). All had normal
baseline ECG, oxymetry and myocardial perfusion
imaging (MPI) without signs of ischaemia.
Diuretics and beta-blockers were discontinued
3 days before the investigations. None of the
patients were receiving any other drugs that could
interfere with cardiovascular system or nephrotoxic drugs. The patients were put on a sodiumrestricted diet of 60 mmol/day the last 72 h before
the investigations, and they were instructed orally
and given written information on sodium restriction by a dietician. All patients recruited were
hospitalised during the last 24 h prior to the study
105
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Cirrhosis
and the nutrition unit prepared their food with a 60 mmol/day
sodium diet. After the investigations the patients were followed
for 12 months or until death by regular clinical controls.
Patients were studied at 9:00 am after a 9 h fast. At 10:00 pm
the previous day, an oral dose of 300 mg of lithium carbonate
was administered. An oral water load of 200 ml of tap water
was given every half hour from 9:00 am to the end of the
clearance periods and the patients were in the supine position
throughout the investigation. A bladder catheter was placed
before the clearance periods to ensure correct urine sampling.
51
Cr-EDTA and 131I-hippuran were used to determine
glomerular filtration rate (GFR) and effective renal plasma flow
(ERPF).10–14 Renal blood flow = ERPF/(1 2 haematocrit).
Infusion of tracers was prepared in 60 ml isotonic saline with
16 MBq 51Cr-EDTA (GE-Healthcare, Hilleroed, Denmark) and
10 MBq 131I-hippuran (GE-Healthcare). At 9:00 am, a priming
dose of 8 ml of the 51Cr-EDTA and 131I-hippuran solution was
given as a rapid intravenous bolus injection together with 6.5
MBq 51Cr-EDTA, followed by a constant infusion of 8 ml/h
(Kivex P 300 pump; Kivex, Hoersholm, Denmark) for 3.5 h, in
total 10 MBq. After an equilibrium period of 2 h, blood samples
were drawn for analyses of plasma lithium, sodium, osmolality,
51
Cr-EDTA and 131I-hippuran. Blood sampling was immediately
followed by urine collection from the bladder catheter. Urine
volume was recorded and samples were assayed for lithium,
sodium, osmolality, 51Cr-EDTA and 131I-hippuran. A gamma
counter (Wallac 1480 WIZARD 3; Wallac, Turku, Finland)
assessed the radioactivity of 51Cr-EDTA and 131I-hippuran in the
samples. The samplings were repeated at 30 min intervals,
resulting in three clearance periods after equilibration. Blood
samples for plasma renin, serum aldosterone, proANP and pro
BNP substances were obtained after the second clearance period.
Plasma and urinary lithium concentrations were measured by
atomic absorption spectrophotometry (Perkin Elmer 2380;
Perkin Elmer, Wellesley, Massachusetts, USA). Sodium in
plasma and urine was measured by flame-emission photometry
(Perkin Elmer 2380).
Table 1 Demographic, clinical and biochemical data of 24 patients with
alcoholic cirrhosis and ascites with cardiac index above or below 1.5 l/
min/m2
n = 24
Age (years)
57 (8)
Gender (M/F)
14/10
Child–Pugh score
8.6 (1.9)
MELD score
10.5 (6.0)
Ascites/refractory
15/4/5
ascites/HRS-2
Spironolactone, mg/day
200 (400)
Furosemide, mg/day
80 (320)
Beta-blocker treatment (%)
38%
Plasma coagulation factors II,
0.59 (0.19)
VII, X, units (0.70–1.30) {
Serum sodium, mmol/l
136 (5)
(136–146) {
Serum creatinine, mmol/l;
95 (42)
(60–130){
Serum albumin, mmol/l;
449 (96)
(540–800){
Serum bilirubin, mmol/l
19 (73)
(4–22){
CI,1.5 (n = 8)
CI.1.5 (n = 16)
58 (6)
5/3
8.5 (1.3)
11.8 (6.6)
2/2/4
56 (9)
9/7
8.6 (2.2)
9.9 (5.8)
13/2/1
125 (400)
90 (120)
38%
0.66 (0.23)
200 (375)
60 (320)
31%
0.55 (0.16)
132 (10)
137 (3)
130 (46)
78 (30)*
415 (82)
467 (102)
18 (26)
21(69)
Results are given as mean (SD) or median (range).
*p,0.05, compared to CI,1.5 l/min/m2.
{Reference interval in parentheses.
CI, cardiac index; HRS-2, hepatorenal syndrome type 2; MELD, Model for End-stage
Liver Disease.
106
Clearance during the steady state was calculated by the
standard formula Cx = Ux6V/Px, where Cx = renal clearance of
substance x, Ux = concentration in urine of substance x, V =
urine flow rate, and Px = mean plasma concentration of
substance x in the clearance period. Lithium clearance is used
as a marker of proximal sodium reabsorption based on the
assumption that lithium is filtered freely across the glomerulus,
is reabsorbed in proportion to sodium and water in the proximal
tubules and that no reabsorption or secretion takes place in the
distal tubules.15–17 The excretion fraction of x is calculated as:
Cx/GFR.
Scintigraphic method
A gated myocardial scintigraphy with single photon emission
computed tomography (SPECT) was performed in all patients
after an overnight fast. Gated SPECT is considered an accurate
and reproducible method, which corresponds very well with
findings of magnetic resonance imaging.18 19 Studies on serial
reproducibility of gated SPECT-assessed ejection fraction in
patients with ischaemic heart disease have shown a mean
difference between two sequential measurements at rest of
0.09%, with a 95% limit of agreement (2 SDs) at 5.8%.18 The
nature of this method as a non-invasive, observer-independent
and reproducible method makes it an attractive investigational
tool. The patients were placed in the supine position 1 h before
the study. 99mTc-methoxy-isobutylisonitrile (99mTc-MIBI)
(Cardiolite) was used as perfusion tracer and infused intravenously in a dose of 600 MBq 0.5 h before data acquisition. A
low-energy, high-resolution collimator was used and the studies
were acquired in a 64664 matrix on a dual headed gamma
camera (Millenium VG Nuclear Imaging System; GE
Table 2 Haemodynamics, renal function and mortality in patients with
cardiac index above or below 1.5 l/min/m2
SV, ml
SVI, ml/m2
MAP, mmHg
HR, min21
AC, ml/mmHg
SVR, Newton s cm25
QTc, sK
Serum proANP, pg/ml
Serum proBNP, pg/ml
RBF, ml/min
GFR, ml/min
CNa, ml/min
FeNa, %
CLi, ml/min
log serum aldosterone, pmol/l
Plasma renin, pg/ml
Serum creatinin, mmol/l
Dead ,3 months
Hepatorenal syndrome type 1
,3 months
Dead ,9 months
Dead ,12 months
CI,1.5 n = 8
CI.1.5 n = 16
p Value
38 (9)
21.4 (4.7)
83.0 (15.0)
63 (10)
1.02 (0.34)
0.02924
(0.00808)
0.436 (0.029)
1874 (2818)
717 (4185)
352 (232)
39 (24)
0.31 (0.30)
0.005 (0.005)
8.0 (5.6)
3.21 (2.06)
86 (3996)
130 (46)
4/8
3/7*
55 (17)
30.5 (8.0)
89.9 (13.0)
77 (14)
1.12 (0.47)
0.01884
(0.00660)
0.429 (0.029)
1117 (2230)
602 (3681)
561 (229)
63 (23)
0.86 (0.80)
0.011 (0.009
15.4 (9.0)
2.66 (2.15)
20 (1207)
78 (29)
1/16
1/16
0.02
0.01
0.26
0.009
0.63
0.004
5/8
5/8
2/16
4/16
0.57
0.03
0.72
0.06
0.03
0.03
0.047
0.058
0.08
0.28
0.003
0.01
0.04
0.006
0.03
Results are given as mean (SD) or median (range).
*One patient died outside hospital.
AC, arterial compliance; CLi, lithium clearance; CNa, sodium clearance; FeNa, fractional
sodium excretion; GFR, glomerular filtration rate; HR, heart rate; MAP, mean arterial
pressure; Pro ANP, pro atrial natriuretic peptide; Pro BNP, pro brain natriuretic peptide;
QTc, QT interval corrected for heart rate; RBF, renal blood flow; SV, stroke volume;
SVI, stroke volume index; SVR, systemic vascular resistance.
Gut 2010;59:105–110. doi:10.1136/gut.2009.180570
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Cirrhosis
Healthcare, Milwaukee, Wisconsin, USA). The camera heads
were positioned in a 90u angle and the studies were acquired
with 30 projections in steps of 3u each of 25 s giving a total
acquisition time of 25 min. The zoom factor was set at 1.28. All
gates were reconstructed using filtered back-projection
(Butterworth filter). Gated data were analysed on a Xeleris
Functional Imaging Workstation (GE Healthcare, Milwaukee,
Wisconsin, USA) by the QGS programme (Quantitative
Gated SPECT, Cedar-Sinai Medical Center, Los Angeles,
California, USA).
The cardiac cycle was divided into 16 intervals (frames) to
obtain the highest temporal resolution and the gating was
triggered by the ECG signal. This allows evaluation of left
ventricular ejection fraction, end diastolic volume, end systolic
volume, stroke volume and left ventricular regional wall motion
and wall thickening.20 Furthermore, it improves the diagnostic
accuracy of perfusion imaging and the functional gated SPECT
data represent images of the left ventricular myocardium during
acquisition and not at the time of tracer injection.20 Cardiac
output was assessed as stroke volume 6 heart rate and cardiac
index (CI) = cardiac output/body surface area (Dubois formula).21 Mean arterial pressure (MAP) was calculated MAP =
systolic pressure + (diastolic pressure 6 2)/3. Arterial compliance was assessed as stroke volume/pulse-pressure (systolic
minus diastolic blood pressure) and the systemic vascular
resistance as MAP*80/cardiac output.
ECG was recorded by a conventional non-computerised
electrocardiogram (Siemens-Elema, Erlangen, Germany) to
evaluate conductive and possible ischaemic changes. The Q-T
interval was determined from the ECG (25–50 mm/s), as
described elsewhere.22
Blood samples for analyses of vasoactive hormones were
obtained from a cubital vein. The circulating plasma renin
concentration was determined by commercially available twosite immunoradiometric assay (DGR International, Hamburg,
Germany). Aldosterone was measured with a commercial kit,
DSL-8600 (Diagnostic Systems Laboratories, Webster, Texas,
USA). N-terminal pro ANP (1–30) was measured radioimmunologically with antiserum and calibrator material from
Peninsula Laboratories (Los Angeles, California, USA) and tracer
prepared in-house.
Statistics
Results are expressed as the mean with the SD or medians and
total range if non-normal distribution. Statistical analyses were
performed by the unpaired Student t test or the Mann–Whitney
test as appropriate. Correlations were performed by the Pearson
regression analysis. Survival is given in Kaplan–Meier survival
curves and differences analysed by the logrank test. All reported
p values are two-tailed, with values less than 0.05 considered
significant. The SPSS 10.1 statistical package was applied
throughout.
Patients were divided into two groups according to their CI to
separate those with the lowest CI, and compared with respect
to survival and cardiac and renal functions. The cut off to divide
the patients based on CI was pragmatically chosen to be 1.5 l/
min/m2, though supported by a study in heart failure that
linked CI below 1.5 to liver function abnormalities.23 CI is used
because cardiac output increases in proportion with body
surface area and individual values indexed by body surface area
are therefore more accurate in the comparison of individuals
with different body texture.24
RESULTS
Patient’s characteristics are given in table 1, both as pooled data
and according to CI group. Those with the lowest CI had higher
serum creatinine (p = 0.01) and borderline lower serum sodium
concentration (p = 0.06). Both the Model for End-stage Liver
Disease (MELD) score and the Child–Pugh score failed to separate
the two groups (table 1). Although there was a tendency towards
lower values of cardiac output in the nine patients with refractory
ascites this did not differ significantly from those without (1.7
(SD 0.8) vs 2.1 (SD 0.6) l/min/m2, p = 0.2).
Cardiac function
Low CI was due to chronotropic incompetence as reflected by a
relatively low heart rate p,0.01 and inotropic incompetence
reflected by a lower stroke volume, p = 0.02 (table 2). The group
Figure 1 Correlations between log aldosterone and glomerular filtration rate (GFR) and between mean arterial pressure (MAP) and glomerular filtration
rate with 95% confidence interval (n = 23, one patient failed GFR mesurements).
Gut 2010;59:105–110. doi:10.1136/gut.2009.180570
107
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Cirrhosis
Figure 2
Kaplan–Meier survival curves and logrank test on survival depending on cardiac index (CI) and mean arterial pressure (MAP).
of patients with low CI had higher systemic vascular resistance
(mean difference 0.01039 Newton s cm25, confidence interval
0.00374 to 0.01704 Newton s cm25, p = 0.004); however, arterial
compliance and MAP did not differ between the groups (table 2).
End diastolic volume (77 vs 51 ml, p = 0.06), end systolic
volume (21 vs 13 ml p = 0.23) ejection fraction, myocardial wall
motion, and wall thickening were not significantly different
between the groups.
Renal function
In patients with low CI, GFR was lower (mean difference
23 ml/min, confidence interval 2 to 46 ml/min, p = 0.03), and
renal blood flow lower (mean difference 209 ml/min, confidence interval 27 to 425 ml/min, p = 0.06) and serum
creatinine higher (p,0.01) than in patients with higher CI.
Sodium clearance (mean difference 0.48 ml/min, confidence
interval 0.06 to 0.89 ml/min, p = 0.03) and fractional sodium
excretion (p = 0.03) was lower in patients with low than those
with high CI. Lithium clearance was lower although this
difference did not reach statistical significance (table 2,
p = 0.058). GFR correlated with log serum aldosterone
(r = 20.55, p = 0.006) (fig 1a). GFR correlated with MAP
(r = 0.52, p = 0.01) (fig 1b). There was no linear correlation
between CI and GFR. There were no significant differences in
plasma noradrenaline or plasma renin between the two groups,
however plasma proANP concentrations were significantly
higher in the low CI group (p = 0.03) (table 2).
Survival
Patients with ascites and CI below 1.5 l/min/m2 (N = 8, CI 1.3
(SD 0.2) l/min/m2) had a poorer survival at 3, 9, and 12 months,
than those with a CI above 1.5 l/min/m2 (N = 16, CI = 2.3 (SD
0.6) l/min/m2), p,0.05 (fig 2a). Furthermore, patients with a
MAP below 80 mm Hg had a lower 12 months survival (fig 2b).
The number of patients who died from hepatorenal syndrome
type 1 within 3 months was significantly higher in the low CI
group than in the high CI group (43% (3/7) vs 6% (1/16),
p = 0.04). Patients with a cardiac output below the mean of
3.6 l/min had a borderline significant poorer 12 month survival
than those with a cardiac output above the mean level (logrank
test p = 0.059). The mean cardiac output (CO) did not separate
108
those with the lowest GFR (51 (SD 23) vs 64 (SD 28) ml/min,
p = 0.2; below vs above mean cardiac output). Among patients
with normal serum creatinine at baseline 11% (2/19) developed
hepatorenal syndrome type 1 and died within 3 months.
Among patients with a serum creatinine above upper normal
limit at baseline 80% (4/5) had a CI below 1.5 l/min/m2.
In subsequent analyses, we compared cardiac and renal
parameters in patients who died within 12 months (n = 9)
with survivors (N = 15) (table 3). CI was significantly higher in
survivors (mean difference 0.7 l/min/m2, confidence interval 0.2
to 1.2, p = 0.007) and heart rate was 17% higher (p = 0.04). All
renal function parameters were significantly impaired in nonsurvivors compared to survivors (table 3): renal blood flow was
36% lower (mean difference 208 ml/min, confidence interval 10
to 405, p = 0.05) and GFR was 37% lower (mean difference
23.1 ml/min, confidence interval 2.0 to 44.2, p = 0.03).
Although there was a tendency towards a higher MELD score
(13.1 vs 8.9, p = 0.10) and Child-Pugh score (9.3 vs 8.1, p = 0.14)
in patients with low CI, this difference did not reach statistical
difference.
DISCUSSION
This is the first study to describe the association between
cardiac and renal dysfunction and survival in patients with
advanced cirrhosis. Our data support the hypothesis that renal
and cardiac dysfunctions are closely related in cirrhosis. A
cardio-renal relation in cirrhosis is most likely the result of
chronic circulatory stress combined with more acute events,
such as bacterial translocation and systemic inflammatory
response, which trigger a systemic response. This may lead to
progression of a systolic failure with a decrease in CI, starting a
vicious circle in which the decreased CI leads to accentuated
arterial underfilling, decreased MAP and decreased renal
perfusion and perfusion pressure, resulting in deterioration of
the renal function, which further enhances cardiac and renal
deterioration.
In these patients with ascites but a relatively low MELD score
of 10.6 at mean (table 1), the MELD score failed to predict
mortality in contrast to CI. This suggests that other parameters
as CI may also be more important determinants and reflect
secondary organ dysfunction in advanced cirrhosis. Similar
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Table 3 Haemodynamics and renal function in patients dead within 12 months compared to survivors
CO, l/min
CI, l/min/m2
SV, ml
EF
EDV, ml
ESV, ml
MAP, mm Hg
HR, min21
AC, ml/mmHg
SVR, Newton s cm25
RBF, ml/min
GFR, ml/min
Vu, ml/min
COsm, ml/min
CLi, ml/min
CNa, ml/min
CH2O, ml/min
log serum aldosterone, pmol/l
Serum creatinine, mmol/l
Alive .12 months
Dead ,12 months
n = 15
n=9
4.1 (1.5)
2.3 (0.7)
30.0 (8.5)
76 (9)
74 (29)
19 (13)
91.5 (14.1)
77.0 (13.9)
1.10 (0.46)
0.02256 (0.00878)
569 (242)
63.8 (23.6)
2.42 (1.32)
2.01 (0.82)
15.7 (8.7)
0.80 (0.63)
0.41 (0.35)
2.67 (0.60)
81.5 (30.0)
2.8 (0.8)
1.6 (0.4)
23.5 (6.3)
79 (17)
59 (29)
17 (17)
81.0 (11.2)
65.6 (9.0)
1.07 (0.38)
0.02470 (0.00757)
362 (197)
40.8 (22.3)
0.83 (0.69)
1.30 (0.84)
8.4 (6.6)
0.27 (0.46)
20.46 (0.35)
3.40 (0.63)
118.7 (51.4)
p Value
0.01
0.007
0.07
0.63
0.26
0.64
0.07
0.04
0.88
0.27
0.05
0.03
0.005
0.06
0.055
0.04
0.006
0.01
0.03
Results are given as the mean (SD) or median (range).
AC, arterial compliance; CH2O, free water clearance; CI, cardiac index; CLi, lithium clearance; CNa, sodium clearance; CO, cardiac
output; COsm, osmolar clearance; EDV, end diastolic volume; EF, ejection fraction; ESV, end systolic volume; GFR, glomerular
filtration rate; HR, heart rate; MAP, mean arterial pressure; RBF, renal blood flow; SV, stroke volume; SVR, systemic vascular
resistance; Vu, urinary flow rate.
observations were reported in the studies by Ruiz-del-Arbol, in
which the baseline MELD and Child–Pugh scores did not differ
between the patients who developed hepato-renal syndrome
and those who did not.5 6 A relatively low heart rate is a main
factor responsible for the low CI. Treatment with beta-blockers
further decreases heart rate and CI may therefore have
deleterious effects on haemodynamics and renal function in
this group of patients and thereby influence survival negatively.
Future studies should therefore specifically look at this aspect
and beta-blockers should in the meanwhile be administered
cautiously in these patients.
This study has some limitations. Gated SPECT has not been
validated in cirrhosis. To validate gated SPECT in patients with
cirrhosis and due to the observation of rather low CI in all
patients, we compared it with magnetic resonance imaging
(MRI) in 20 other patients with cirrhosis. There was a close
linear correlation between the two modalities (r = 0.74,
p,0.0001); however, gated SPECT systematically underestimated CI by on the average 1.1 l/min/m2, 95% confidence
interval 0.85 to 1.37 in cirrhotic patients compared to MRI. This
is a problem regarding absolute values, but not in terms of
relative values or in separating those with the lowest CI. We
have no data on the variability relating to the size of the cardiac
index but in our opinion it should be small as compared with
the variability relating to the size of the cardiac volumes (ie,
lower number of counts/s). Smaller values of EDV and ESV are
associated with a higher variability but the variability of the SV
depends on the size of the volumes (number of counts/s) of
which the calculation of SV is based. Thus, the same SV based
on acquisition of larger volumes are associated with a lower
variability compared to a numerical identical SV based on
acquisition of smaller volumes.
The failing heart in cirrhosis appears to be a general dysfunction
comprising systolic and diastolic dysfunction and conductance
abnormalities partly as a result of prolonged exposure to activated
SNS, RAAS, endocanabinoids, inflammation and other systems
Gut 2010;59:105–110. doi:10.1136/gut.2009.180570
that interact with cardiac energy metabolism and physiology.25–28 In patients with heart failure, a similar cardio-renal
relation, with co-existence of cardiac and renal failure that
amplifies the progression of failure of the individual organs
have been described.29 30 Whether this condition is similar to
the pathophysiology in cirrhosis is unknown, but primary
heart failure and cardiomyopathy in cirrhosis share several
characteristics.31 32
From a pathophysiological point of view the key physiological
factor is effective arterial underfilling. It may induce or amplify
disturbances in the cardio-renal homeostasis and neurohumoral
integrity, which is a result of arterial vasodilation, relatively or
absolutely decreased CI and ultimately both as described in this
study. Albumin that expands central blood volume and
increases CI and MAP and thereby ameliorates arterial underfilling can prevent hepato-renal syndrome and reduce mortality
in spontaneous bacterial peritonitis and post paracentesis.33–35
The primary mechanisms responsible for deterioration of renal
function are renal hypoperfusion and impaired filtration, and
GFR in advanced cirrhosis is critically dependent on blood flow
and perfusion pressure.36 In this study we observed that GFR
was correlated to MAP and the activation of RAAS (fig 2).
Whether renal impairment is a direct consequence of low CI
cannot be ruled out in this paper, ie, we cannot exclude that
both low CI and low GFR are results of hypovolaemia.
Implications
A low CI seems to develop in parallel with renal impairment in
cirrhosis and ascites and may play an important role at this
stage of the disease. Therefore future treatments of hepato-renal
syndrome should aim not only at improving renal function but
also at preserving a sufficient CI. Vasoconstriction with
terlipressin is an important treatment in hepato-renal syndrome
which improves renal function,7 36 but this treatment decreases
CI.37 Some patients with hepato-renal syndrome type 1 already
have a decreased or relative low CI5 6 and a further decrease in
109
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Cirrhosis
the systemic blood flow and oxygen transport capacity may be
deleterious in some patients.
Beta-blockers decrease CI and in patients with ascites and low
CI they may potentially worsen haemodynamics and band
ligation may therefore be the preferred treatment as prophylaxis
against variceal bleeding.38 39 Studies in patients with decompensated cirrhosis and hepato-renal syndrome type 2 in whom
CI is monitored both with and without beta-blocker are highly
relevant.
In conclusion, our study demonstrates that in patients with
cirrhosis and ascites those with the lowest CI had the most
impaired renal function and the poorest survival. Hence, the
development of hepato-renal syndrome, and poor outcome in
these patients seem to be related to a cardiac systolic
dysfunction.
14.
Funding: This study was supported by grants from the Lundbeck Foundation and
Hvidovre Hospital Foundation for Liver Disease. AK received a grant from the University
of Copenhagen.
22.
Competing interests: None.
24.
Ethics approval: The Regional Medical Ethics Committee approved the study (KF 02–
059/04), which was carried out in accordance with the Helsinki Declaration II after
informed consent. No complications were encountered during the study.
25.
Provenance and peer review: Not commissioned; externally peer reviewed.
15.
16.
17.
18.
19.
20.
21.
23.
26.
27.
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