Citrate vs. acetate dialysate on intradialytic heparin dose: A double blind randomized crossover study


Leung, K.C.W.; Tai, D.J.; Ravani, P.; Quinn, R.R.; Scott-Douglas, N.; MacRae, J.M.

Hemodialysis International 20(4): 537-547

2016


Introduction Citrate containing dialysate has a calcium-binding anticoagulant effect compared to standard acetic acid containing dialysate. We performed a randomized, double-blind, crossover trial in maintenance HD patients to determine if citrate dialysate ("citrate") safely allows for a lower cumulative heparin dose ("heparin dose"). Methods Intradialytic heparin was adjusted to the minimum during a 2-week run-in phase. Patients remaining on heparin at the end of the run-in phase were then randomized to two weeks of HD with acetate dialysate ("acetate") followed by two weeks of citrate (sequence 1) or two weeks of citrate followed by two weeks of acetate (sequence 2). We estimated a minimum of 14 patients are required to show a 30% reduction in heparin dose per HD session with citrate compared with acetate. Twenty-five patients entered the run-in phase, 20 were randomized, and 19 completed the study. Findings The mean heparin dose was reduced by 19% (656 units, 95% CI -174 to -1139 units, P = 0.011) in the acetate group, and 30% (1046 units 95% CI -498 to 1594 units, P < 0.001) in the citrate group. There was no difference in the mean heparin dose reduction between the two dialysates (P > 0.05). The intradialytic ionized calcium in the citrate group was lowered by 0.10 mmol/L (95% CI 0.07 to 0.14 mmol/L, P < 0.001), and remained unchanged in the acetate group. Discussion Although citrate is a safe alternative to acetate, it does not result in additional heparin dose reduction.

Hemodialysis
International
2016;
20(4):537-547
Citrate
vs.
acetate
dialysate
on
intradialytic
heparin
dose:
A
double
blind
randomized
crossover
study
Kelvin
C.
W.
LEUNG,
1
Davina
J.
TAI,
2
Pietro
RAVANI,
1
Rob
R.
QUINN,
1
Nairne
SCOTT-DOUGLAS,
1
Jennifer
M.
MACRAE
1
'
3
'Cumming
School
of
Medicine,
University
of
Calgary;
2
Cumming
School
of
Medicine,
University
of
Saskatchewan;
3
Department
of
Cardiac
Sciences,
University
of
Calgary
Abstract
Introduction
Citrate
containing
dialysate
has
a
calcium-binding
anticoagulant
effect
compared
to
standard
acetic
acid
containing
dialysate.
We
performed
a
randomized,
double-blind,
crossover
trial
in
maintenance
HD
patients
to
determine
if
citrate
dialysate
("citrate")
safely
allows
for
a
lower
cumulative
heparin
dose
("heparin
dose").
Methods
Intradialytic
heparin
was
adjusted
to
the
mini-
mum
during
a
2-week
run-in
phase.
Patients
remaining
on
heparin
at
the
end
of
the
run-in
phase
were
then
randomized
to
two
weeks
of
HD
with
acetate
dialysate
("acetate")
followed
by
two
weeks
of
citrate
(sequence
1)
or
two
weeks
of
citrate
followed
by
two
weeks
of
acetate
(sequence
2).
We
estimated
a
minimum
of
14
patients
are
required
to
show
a
30%
reduction
in
heparin
dose
per
HD
session
with
citrate
compared
with
acetate.
Twenty-five
patients
entered
the
run-in
phase,
20
were
randomized,
and
19
completed
the
study.
Findings
The
mean
heparin
dose
was
reduced
by
19%
(656
units,
95%
CI
-174
to
-1139
units,
P=
0.011)
in
the
acetate
group,
and
30%
(1046
units
95%
CI
-498
to
1594
units,
P
<
0.001)
in
the
citrate
group.
There
was
no
difference
in
the
mean
hepa-
rin
dose
reduction
between
the
two
dialysates
(P>
0.05).
The
intradialytic
ionized
calcium
in
the
citrate
group
was
lowered
by
0.10
mmol/L
(95%
CI
0.07
to
0.14
mmol/L,
P<
0.001),
and
remained
unchanged
in
the
acetate
group.
Discussion
Although
citrate
is
a
safe
alternative
to
acetate,
it
does
not
result
in
additional
heparin
dose
reduction.
Key
words:
Citrate
dialysate,
hemodialysis,
heparin
reduction,
randomized
crossover
INTRODUCTION
Hemodialysis
(HD)
dialysate
is
prepared
from
the
mixture
of
acid
buffer
and
base
concentrates
to
prevent
electrolyte
precipitation.
Acetic
acid
or
acetate
is
the
most
commonly
used
acid
buffer
that
is
mixed
with
bicarbonate
and
Correspondence
to:
J.
M.
MacRae,
MD,
MSc,
Foothills
Medi-
cal
Centre,
C210,
1403-29
Street
NW,
Calgary,
AB
T2N
2T9,
Canada.
E-mail:
Jennifer.macrae@albertahealthservices.ca
Conflict
of
Interest:
The
authors
have
no
conflicts
of
interest.
Disclosure
of
grants
or
other
funding:
This
study
was
funded
by
the
Division
of
Nephrology,
University
of
Calgary.
The
results
presented
in
this
manuscript
has
not
been
previ-
ously
published
in
whole
or
part
except
in
abstract
format.
©
2016
International
Society
for
Hemodialysis
DOI:10.1111/hdi.12433
treated
water
to
form
the
final
dialysate.
1-3
Exposure
of
blood
to
the
extracorporeal
HD
circuit
activates
the
clot-
ting
cascade
and
can
reduce
HD
efficiency.
4
Anticoagulation,
commonly
unfractionated
heparin,
is
often
required
to
prevent
clotting
of
the
HD
circuit.
Unfortunately,
heparin
is
associated
with
an
increased
risk
of
bleeding,
5-7
heparin-induced
thrombocytope-
nia,
8-10
hyperkalemia,
13
hypertriglyceridemia,
12
and
met-
abolic
bone
disease.'
3
Citrate
based
dialysate
("citrate")
containing
approxi-
mately
one-fifth
the
concentration
of
citric
acid
used
in
regional
citrate
anticoagulation
is
an
alternative
to
the
tra-
ditional
acetate
buffer.
1-3
Previous
studies
have
suggested
that
citrate
reduces
clotting
in
the
dialyzer
and
increases
537
Excluded
(n=50)
Not
on
Heparin
or
contraindications
to
Heparin
(n=26)
Warfarin
Therapy
(n=1)
Known
coagulopathy
Dysfunctional
Dialysis
Catheter
or
Vascular
Access
(n=1)
Planned
Vascular
Access
surgery
during
study
Planned
change
in
renal
replacement
modality
during
study
(n=2)
High
Calcium
Dialysate
Active
medical
issues
(n=1)
Unable
to
provide
Consent
(n=8)
Declined
(n=11)
Excluded
(n=5)
Achieved
Heparin
Free
Dialysis
(n=5)
Enro
llme
n
t
rN
ro
Leung
et
al.
Assessed
for
eligibility
(n=75)
Run-in
phase
4
weeks
Heparin
Dose
Reduced
and
Optimized
Baseline
Heparin
Dose
Recorded
(n=25)
Randomization
(n=20)
Sequence
1
Allocated
to
Acetate
Dialysate
Hemodialysis,
2
week
(n=10)
Sequence
2
Allocated
to
Citrate
Dialysate
Hemodialysis,
2
weeks
(n=10)
Discontinued
Intervention
(Consent
Withdrawn)
(n=1)
Discontinued
Intervention
(n=0)
Washout
68h
Sequence
2
Allocated
to
Acetate
Dialysate
Hemodialysis,
2
week
(n=10)
Discontinued
Intervention
(n=0)
Sequence
1
Allocated
to
Citrate
Dialysate
Hemodialysis.
2
weeks
(n=9)
Discontinued
Intervention
(n=0)
V
Analyzed
(n=20)
Excluded
from
analysis
(n=0)
Figure
1
Participant
flowchart.
538
Hemodialysis
International
2016;
20(4):537-547
Citrate
vs.
acetate
dialysate
dialysis
efficiency
and
dialyzer
reuse.
3
'
34
'
35
The
low
con-
centration
of
citrate
provides
some
anticoagulant
proper-
ties
by
binding
calcium
and
preventing
calcium-
dependent
activation
of
the
coagulation
pathway,
4
which
may
reduce
the
need
for
intradialytic
heparin
without
concerns
of
hypernatremia,
alkalosis,
or
hypocalcemia.
3
6-1
9
In
this
study,
we
determine
if
citrate
allows
for
a
reduction
in
cumulative
heparin
dose
("heparin
dose")
during
HD
compared
with
acetate-based
dialysate
("acetate").
METHODS
Overview
We
performed
a
randomized,
double-blind,
crossover
trial
in
maintenance
HD
patients
between
November
2011
and
December
2012
in
three
centers
in
Calgary,
Alberta,
Canada.
The
University
of
Calgary
Conjoint
Health
Research
Ethics
Board
approved
the
study
and
it
was
conducted
in
accordance
with
the
Helsinki
Declara-
tion
(clinicaltrials.gov:
NCT01466959).
Study
population
Patients
over
18
years
of
age
and
receiving
HD
at
least
thrice
weekly
for
at
least
3
months
were
eligible.
Exclu-
sion
criteria
included:
a
contraindication
to
heparin,
heparin-free
HD,
clotting
disorder,
high
calcium
dialysate,
warfarin
therapy,
medically
unstable,
recent
history
of
vascular
access,
or
central
venous
catheter
dysfunction
(blood
flow
consistently
less
than
300
mUmin
and/or
fre-
quent
use
of
thrombolytic),
a
planned
vascular
access
conversion
or
procedure
during
the
study,
a
planned
renal
transplant
or
conversion
of
renal
replacement
modality
during
the
study,
or
inability
to
provide
informed
consent.
Study
protocol
The
original
design
of
the
study
was
previously
described.
Eligible
patients
underwent
a
2
week
run-in
phase
where
the
intradialytic
heparin
dose
was
adjusted
using
a
standard
protocol
based
on
a
visual
dialyzer/
venous
chamber
clotting
score
21
at
the
end
of
each
HD
session
by
a
single
trained
research
nurse
to
achieve
the
minimum
heparin
dose
(Appendix
I).
The
heparin
dose
during
the
last
HD
session
of
the
run-in
phase
was
used
as
the
baseline
heparin
dose
for
each
patient.
Patients
who
remained
on
heparin
at
the
end
of
the
run-in
phase
were
randomized
in
a
crossover
fashion
to
either
two
weeks
of
acetate
followed
by
two
weeks
of
citrate
(sequence
1),
or
two
weeks
of
citrate
followed
by
two
weeks
of
acetate
(sequence
2;
Figure
1).
Each
patient
underwent
a
68-hour
washout
period
prior
to
crossing
over.
Each
study
phase
started
with
the
baseline
heparin
dose
and
adjusted
with
the
heparin
reduction
protocol
every
HD
session
(Appendix
I).
We
performed
a
computer-generated
randomized
number
list,
with
allocation
concealed
in
opaque
enve-
lopes.
Acetate
and
citrate
dialysate
were
prepared
in
iden-
tical
packaging
by
the
manufacturer
to
ensure
blinded
treatment.
All
patients
were
dialyzed
with
single-use,
Rexeed
series
wet-dialyzers
(Asahi
Kasei
Medical,
Tokyo,
Japan)
with
the
Phoenix
HD
System
(Gambro,
Lund,
Sweden)
thrice
weekly.
HD
prescriptions
were
standardized
using
blood
flow
rates
of
300-400
mUmin,
dialysate
flow
rates
500
mUmin,
dialysate
temperatures
of
0.5°C
less
than
the
patient's
pre-HD
temperature,
dialysate
calcium
of
1.25
mmol/L
and
dialysate
sodium
of
137
mmol/L
unless
otherwise
prescribed.
Individual
target
weight
was
opti-
mized
at
study
start.
The
control
dialysate,
acetate,
con-
tained
4.0
mEq/L
of
acetic
acid
and
the
intervention
dialysate,
citrate,
contained
2.4
mEq/L
of
citric
acid
(both
from
Chief
Medical,
Calgary,
Alberta,
Canada).
Study
endpoints
The
primary
outcome
was
the
reduction
in
the
heparin
dose
per
HD
session
with
citrate
compared
with
acetate.
The
heparin
dose
in
units
per
session
was
calculated
from
the
sum
of
the
initial
heparin
bolus
and
the
total
hourly
heparin
(hourly
heparin
infusion
rate
multiplied
by
the
time)
in
HD
each
session,
and
was
determined
from
the
HD
session
run
sheets.
The
heparin
dose
from
the
last
two
HD
sessions
of
each
study
phase
were
averaged
and
used
to
calculate
the
change
from
the
baseline
heparin
dose.
Secondary
outcomes
included:
the
effect
of
citrate
com-
pared
with
acetate
on
systematic
anticoagulation
(pro-
thrombin
time
[PT]/international
normalized
ratio
[INR]
and
activated
partial
thromboplastin
time
[aPTT]),
meta-
bolic
parameters
(serum
calcium,
magnesium,
and
bicar-
bonate),
systematic
inflammation
(beta-2-microglobulin
[B2M],
C-reactive
protein
[CRP]),
hemodynamic
stability
(intradialytic
hypotension
[IDH],
corrected
QT
interval,
blood
pressure,
heart
rate),
dialysis
adequacy
(single
pool
Kt/V),
bleeding
events,
bleeding
time,
and
the
visual
clot-
ting
score.
Hemodialysis
International
2016;
20(4):537-547
539
Leung
et
al.
Data
collection
Baseline
patient
characteristics
(age,
gender,
race,
HD
vin-
tage),
medical
comorbidities,
etiology
of
ESRD,
and
HD
prescription
(dialyzer,
dialysate
composition,
temperature,
blood
and
dialysate
flow
rates,
target
weight,
and
anticoa-
gulation
parameters)
were
extracted
from
the
HD
patient
charts
and
the
Southern
Alberta
Renal
Program
database.
22
The
systolic
blood
pressure
(SBP),
diastolic
blood
pres-
sure
(DBP),
and
heart
rate
were
measured
and
recorded
by
the
HD
nurses
pre
and
post
HD,
and
every
30
minutes
during
the
HD
session.
The
number
of
HD
sessions
com-
plicated
by
IDH
was
recorded.
IDH
was
defined
as
a
drop
in
the
SBP
by
>20
mmHg
to
<100
mmHg
with
patient
symptoms
or
nursing/physician
intervention.
If
the
patient's
pre-HD
SBP
was
<100
mmHg,
then
IDH
was
defined
as
a
drop
in
SBP
>10
mmHg
with
patient
symp-
toms
or
nursing/physician
intervention.
An
electrocardio-
gram
was
performed
at
the
end
of
the
run-in
phase
(baseline),
as
well
as
pre-
and
post-HD
during
the
last
HD
session
of
each
study
phase.
Serum
total
calcium,
ionized
calcium
(iCa),
albumin,
magnesium,
bicarbonate,
urea,
PT/INR,
aPTT,
B2M,
and
CRP
were
collected
at
the
beginning
of
the
first
HD
ses-
sion
after
randomization,
and
drawn
again
both
pre
and
post
HD
for
the
last
HD
sessions
of
each
study
phase.
Ion-
ized
calcium
was
drawn
pre-
and
post-HD
during
the
first
and
last
HD
session
of
each
study
phase.
Sample
size
calculation
Previously
published
data
demonstrated
that
the
heparin
dose
is
reduced
by
30-55%
with
the
use
of
citrate.
23
Locally,
we
determined
that
the
mean
heparin
dose
is
3000
units
(standard
deviation
of
900
units)
per
HD
ses-
sion
in
85%
of
the
HD
population
in
Calgary.
Based
on
this,
and
taking
into
account
a
30%
dropout
rate,
we
esti-
mated
that
20
patients
would
be
required
to
demonstrate
a
30%
decrease
in
heparin
dose
with
citrate
compared
to
acetate
(alpha
0.05,
power
80%).
Statistical
analysis
Baseline
characteristics
are
presented
as
means
and
95%
confidence
intervals
(CI),
or
medians
and
interquartile
range
(IQR).
The
primary
outcome
was
analyzed
using
a
mixed
model
regression
with
citrate
or
acetate
as
the
main
exposure
and
the
subjects
as
random
effects,
the
baseline
heparin
dose
as
a
covariate,
and
the
final
heparin
dose
(average
of
the
last
two
values)
as
the
outcome.
Carry-over
effect
was
assessed
by
comparing
the
randomization
order
Table
1
Baseline
characteristics
Overall
(n
=
20)
Age
(Years)
median
(IQR)
59
(19.5)
Male
n
(%)
13
(65%)
HD
Vintage
(months)
median
(IQR)
37.6
(34.2)
Etiology
of
ESRD
Diabetes,
n
(%)
6
(30%)
Hypertension,
n
(%)
10
(50%)
GN,
n
(%)
2
(10%)
Obstructive,
n
(%)
1
(5%)
Other,
n
(%)
1
(5%)
Comorbidities
Diabetes,
n
(%)
12
(60%)
Hypertension,
n
(%)
17
(85%)
CAD,
n
(%)
7
(35%)
CVA/TIA,
n
(%)
2
(10%)
PVD,
n
(%)
3
(15%)
Vascular
access
AVF,
n
(%)
17
(85%)
CVC,
n
(%)
3
(15%)
IQR
=
interquartile
range;
HD
=
hemodialysis;
ESRD
=
end
stage
renal
disease;
GN
=
glomerulonephritis;
CAD
=
coronary
artery
disease;
CVAMA
=
cerebral
vascular
accident/transient
ischemic
attack;
PVD
=
peripheral
vascular
disease;
AVF
=
arteriovenous
fistula;
CVC
=
central
venous
catheter.
and
session
interaction
terms
prior
to
direct
comparison
of
the
two
dialysates.
Secondary
outcomes
were
compared
with
either
chi-square
or
the
Students'
t
test.
All
statistical
analysis
was
performed
with
Stata
Statistical
Software
Ver-
sion
13
(College
Station,
Texas,
USA).
RESULTS
Study
participants
Seventy-five
patients
were
screened;
25
were
eligible
and
enrolled
(Figure
1).
During
the
run-in
phase,
5
patients
achieved
heparin-free
HD
and
were
excluded
from
ran-
domization.
The
remaining
20
patients
were
randomized
(10
randomized
to
sequence
1
[acetate
then
citrate],
and
10
to
sequence
2
[citrate
then
acetate])
and
analyzed.
After
randomization,
one
patient
(randomized
to
sequence
1)
electively
withdrew.
Nineteen
patients
com-
pleted
both
study
phases.
Table
1
shows
the
baseline
characteristics
of
the
study
patients.
The
median
age
was
59
years
(interquartile
range
[IQR]
19.5
years),
65%
were
male,
and
the
median
HD
vintage
was
37.6
months
(IQR
34.2
months).
Most
patients
used
an
arteriovenous
fistula
as
their
vascular
access.
540
Hemodialysis
International
2016;
20(4):537-547
ar
c
9
0
Citrate
vs.
acetate
dialysate
Run-In
Phase
I
Acetate
III
Citrate
Figure
2
Cumulative
heparin
dose
during
study.
Reduction
in
cumulative
heparin
dose
during
run-in
phase
The
mean
heparin
dose
was
3575
units
(95%
confi-
dence
interval
[CI]
3056
to
4094
units)
at
the
begin-
ning
of
the
run-in
phase
for
all
25
patients
(Table
2).
At
the
end
of
the
run
in
phase,
including
5
patients
who
achieved
heparin
free
status,
the
mean
heparin
dose
was
2666
units
(95%
CI
1804
to
3528
units),
a
significant
reduction
of
25%
(-909
units,
[95%
CI
—1543
to
—2755
units],
P
=
0.007;
Table
2).
Of
the
20
randomized
patients
the
mean
heparin
dose
at
the
start
and
end
of
the
run-in
phase
was
3799
units
(95%
CI
3203-4394
units),
and
3333
units
(95%
CI
2500
to
4165
units),
respectively
(heparin
dose
reduction
12%,
[
—466
units,
95%
CI
—1101
to
168
units,
P
=
0.141];
Table
2,
Figures
2
and
3).
c
Vo-
Cry
a,
a
a
cry
a
ma
d
Nc
,
ra
Qo
m
)
Run-In
Phase
Acetate
Citrate
Figure
3
Decrease
in
heparin
dose
during
study.
Primary
outcome:
Cumulative
heparin
dose
with
acetate
vs
citrate
Patients
receiving
acetate
during
the
study
phase
had
a
mean
heparin
dose
of
3450
units
(95%
CI
2650
to
4249
units)
at
the
baseline
and
2794
units
(95%
CI
1781
to
3807
units)
at
the
end
of
the
phase;
a
mean
heparin
dose
reduction
of
19%
(-656
units,
95%
CI
—174
to
—1139
units,
P
=
0.011).
Patients
receiving
citrate
had
a
mean
heparin
dose
of
3445
units
(95%
CI
2643
to
4247
units)
at
baseline
and
2399
units
(95%
CI
1230
to
3567
units)
at
the
end
of
the
study
phase;
a
mean
heparin
dose
reduc-
tion
of
30%
(-1046
units,
95%
CI
—498
to
—1594
units,
P
<
0.001).
The
baseline
heparin
dose,
determined
at
the
end
of
the
run-in
phase
for
the
two
treatment
inter-
ventions
differ
due
to
one
participant
electively
withdraw-
ing
after
randomization;
resulting
in
a
5
units
difference
in
the
baseline
heparin
dose.
In
multivariate
regression
analysis,
after
adjustments
for
baseline
demographics,
dialysis
vintage,
comorbidities,
study
sequence,
and
baseline
heparin
dose,
citrate
use
was
not
associated
with
an
additional
reduction
in
the
heparin
dose
compared
with
acetate
(P
>
0.05).
Secondary
outcomes
Metabolic
analysis
Metabolic
outcomes
are
shown
in
Table
3.
With
acetate,
there
was
no
difference
in
the
mean
intradialytic
(post-
minus
pre-HD)
iCa
(P
=
0.655).
The
use
of
citrate
resulted
in
0.10
mmol/L
reduction
in
the
mean
intradia-
lytic
iCa
(95%
CI
0.07-0.14
mmol/L,
P
<
0.001).
The
mean
intradialytic
change
in
iCa
was
significantly
lower
with
citrate
compared
to
acetate
(delta-iCa
0.11
mmol/L
[95%
CI
0.06-0.16
mmol/L],
P
<
0.001).
Although,
the
mean
intradialytic
(postminus
pre-HD)
corrected
serum
calcium,
magnesium,
and
beta-2-microglobulin
were
reduced
in
both
interventions,
there
was
no
significant
difference
in
the
degree
of
reduction
between
them.
The
serum
bicarbonate
significantly
increased
postdialysis
for
both
citrasate
and
acetate
with
no
difference
detected
between
the
two
interventions.
There
were
no
intradia-
lytic
changes
in
C-reactive
protein
and
anticoagulation
variables
for
both
intervention
and
no
difference
between
them.
There
was
no
difference
in
the
single
pooled
Kt/V
between
interventions.
Hemodynamic
and
safety
analysis
Hemodynamic
and
safety
results
are
shown
in
Table
4.
There
were
no
differences
in
the
pre-
and
post-SBP
and
Q
r
o„
,1,
Hemodialysis
International
2016;
20(4):537-547
541
Leung
et
al.
Table
2
Change
in
cumulative
heparin
dose
through
study
phase
Start
of
Phase
End
of
Phase
Mean
Change
in
Mean
CHD,
units
Mean
CHD,
units
CHD,
units
Group
(95%
CI)
(95%
CI)
(95%
CI)
P
value
P
value
*
Run
in
(n
=
25)
3575
(3056
to
4094)
2666
(1804
to
3528)
—909
(-1543
to
—2755)
0.007
Run
in
(n
=
20)
a
3799
(3203
to
4394)
3333
(2500
to
4165)
—466
(-1101
to
168)
0.141
Acetate
(n
=
20)
3450
(2650
to
4249)
2794
(1781
to
3807)
—656
(-174
to
—1139)
0.011 0.271
Citrasate
(n
=
20)
3445
(2643
to
4247)
2399
(1230
to
3567)
—1046
(-498
to
—1594)
<0.001
'Randomized
patients
only
(excluded
patients
achieving
heparin
free
HD
during
the
run-in
period).
CHD
=
cumulative
heparin
dose;
CI
=
confidence
interval.
*Comparing
mean
change
in
CHD
in
acetate
vs
citrate
groups.
intradialytic
change
in
SBP
(pre
minus
post)
between
the
interventions.
The
mean
intradialytic
SBP
was
reduced
by
8
mmHg
(95%
CI
4-11
mmHg,
P
<
0.001)
with
acetate;
and
by
7
mmHg
(95%
CI
2-11
mmHg,
P
=
0.008)
with
citrate
(mean
difference
delta
SBP
—1
mmHg,
95%
CI
—7
to
5,
P
=
0.705).
Similarly,
the
mean
intradialytic
DBP
did
not
differ
between
acetate
(P
=
0.055)
or
citrate
(P
=
0.291).
The
mean
intradialytic
heart
rate
and
cor-
rected
QT
interval
remained
consistent
with
both
inter-
ventions.
Proportion
of
HD
sessions
affected
by
IDH
did
not
differ,
occurring
in
45%
with
acetate
and
44%
with
citrate
(P
=
0.853).
The
frequency
of
IDH
per
HD
session
did
not
differ:
0.62/session
with
acetate
and
0.67/session
with
citrate
(P
=
0.627).
The
access
hold
times
did
not
differ
between
acetate
and
citrate
(5.94
and
5.65
minutes,
respectively,
P
=
0.601).
There
were
no
HD
systems
lost
due
to
clotting
in
either
phase
during
the
study.
There
were
4
and
17
adverse
events
with
acetate
and
citrate
respectively
(P
=
0.005).
Adverse
events
with
acetate
consisted
of
two
episodes
of
angina,
one
epi-
sode
of
prolonged
vascular
access
hold
time,
and
an
episode
of
IDH
related
syncope
which
resolved
with
saline
infusion.
With
citrate,
the
majority
of
adverse
events
(11
of
17)
were
related
to
asymptomatic
hypo-
calcemia,
in
addition
to
three
episodes
of
prolonged
vascular
access
hold
time,
two
episodes
of
angina,
and
one
conjunctival/subconjunctival
bleed.
There
were
one
serious
adverse
events
with
citrate
(acute
coronary
syndrome
during
the
interdialytic
period)
and
none
with
acetate
(P
=
1.000).
DISCUSSION
To
our
knowledge,
this
is
the
first
randomized
study
to
explore
the
effect
of
citrate
vs.
acetate
dialysate
on
the
cumulative
heparin
dose
in
maintenance
HD
patients.
During
our
run-in
phase,
our
heparin
reduction
proto-
col
led
to
a
25%
or
909
unit
reduction
in
the
heparin
dose.
There
was
a
significant
decrease
in
heparin
dose
by
30%
with
citrate
and
an
unanticipated
decrease
in
heparin
dose
of
19%
with
acetate
likely
reflecting
the
underlying
heparin
reduction
protocol.
Thus,
the
decrease
in
heparin
dose
was
not
significantly
different
with
citrate
use
as
compared
to
acetate.
Nonetheless,
we
have
demonstrated
that
citrate
is
a
safe
alternative
to
acetate,
with
no
considerable
differences
in
hemody-
namic,
metabolic,
bleeding
parameters,
and
serious
adverse
events
despite
a
decrease
in
the
intradialytic
ionized
calcium
with
citrate.
The
use
of
citrate
to
reduce
systematic
anticoagulation
has
been
assessed
in
only
two
prospective
studies.
In
the
first
study
by
Sands
et
a1,
36
277
HD
patients
requiring
bolus
heparin
were
enrolled
into
four
sequential
2-week
periods
of
acetate
with
the
standard
heparin
bolus
fol-
lowed
by
citrate
with
sequential
heparin
bolus
reductions.
The
primary
outcome
of
single-pooled
Kt/V
remained
sta-
ble
without
an
increase
in
clotted
dialysis
circuits,
sug-
gests
that
citrate
use
allows
for
lowering
of
the
bolus
heparin
dose.
16
This
study
differs
from
ours
in
that
only
the
bolus
heparin
dose
was
measured,
potentially
missing
the
hourly
heparin
dose.
Second,
there
was
no
attempt
to
reduce
the
heparin
in
the
acetate
sessions,
resulting
in
dif-
ferential
treatment.
Similarly,
there
was
no
run-in
phase
or
a
systematic
method
of
reducing
the
bolus
heparin
to
ensure
that
patients
are
dialyzing
at
the
minimum
heparin
dose.
Thus
patients
not
being
dialyzed
at
the
lowest
hepa-
rin
dose
receiving
citrate
may
tolerate
a
reduced
heparin
dose
without
a
decrease
in
single-pooled
Kt/V
when
com-
pared
to
acetate.
In
the
second
study by
Rocha
et
a1,
24
30
HD
patients
were treated
in
a
randomized
crossover
fashion
with
either
acetate
with
usual
heparin
or
citrate
with
a
30%
reduced
heparin.
The
study
did
not
find
any
difference
in
dialyzer
reuse/survival,
dialysis
adequacy,
and
completed
542
Hemodialysis
International
2016;
20(4):537-547
H
em
od
i
al
ysi
s
I
nt
ern
ati
on
al
2
01
6
;
2
0
(053
7
-54
7
Table
3
Metabolic
analysis
Category
Group
Pre
(95%
CO
Post
(95%
CO
Post-Pre
(95%
CO
P
value
AD
delta-CD
delta
(95%
CO
value
Ionized
calcium
Acetate
1.15
(1.13-1.17)
1.16
(1.13-1.18)
0.01
(-0.02
to
0.04)
0.655
-0.11
(-0.16
to
-0.06)
<0.001
(mmol/L)
Citrate
1.13
(1.09
-1.16)
1.02
(1.00
-1.05)
-0.10
(-0.14
to
-0.07)
<0.001
Corrected
calcium
Acetate
3.14
(2.88
-3.39)
2.53
(2.19
-2.87)
-0.60
(-0.86
to
-0.35)
<0.001
-0.14
(-0.51
to
0.23)
0.452
(mmol/L)
Citrate
3.13
(2.87-3.38)
2.66
(2.35-2.97)
-0.46
(-0.75
to
-0.17)
0.004
Magnesium
Acetate
0.89
(0.82-0.97)
0.76
(0.73-0.80)
-0.13
(-0.18
to
-0.07)
<0.001
-0.03
(-0.10
to
0.04)
0.348
(mmol/L)
Citrate
0.84
(0.78
-0.90)
0.74
(0.72
-0.77)
-0.10
(-0.14
to
-0.05)
<0.001
Bicarbonate
Acetate
23.85
(22.56-25.12)
28.58
(26.65-30.51)
4.74
(3.02-6.45)
<0.001
-0.26
(-2.50
to
1.98)
0.814
(mmol/L)
Citrate
25.00
(23.60-26.40)
30.00
(27.84-32.16)
5.00
(3.43-6.57)
<0.001
B2M
(mg/L)
Acetate
17.60
(14.17-21.03)
5.25
(4.56-5.94)
-12.35
(-15.26
to
-9.44)
<0.001
0.56
(-3.10
to
4.22)
0.757
Citrate
18.75
(15.43-22.08)
5.83
(4.70-6.97)
-12.92
(-15.26
to
10.58)
<0.001
CRP
(mg/L)
Acetate
3.56
(2.56
-4.56)
3.81
(2.75
-4.86)
0.24
(-0.02
to
0.51)
0.067
0.09
(-0.29
to
0.47)
0.638
Citrate
3.42
(1.85-4.98)
3.57
(2.05-5.09)
0.16
(-0.14
to
0.45)
0.280
PTT
(seconds)
Acetate
29
(26-32)
31
(29-34)
3
(0-6)
0.074
0
(-5
to
4)
0.858
Citrate
28
(26-29)
31
(28-33)
3
(0-6)
0.054
PT/INR
Acetate
0.95
(0.92-0.99)
0.95
(0.02-0.98)
0.00
(-0.03
to
0.02)
0.666
-0.14
(-0.40
to
0.11)
0.262
Citrate
0.96
(0.93-0.99)
1.1
(0.83-1.27)
0.14
(-0.13
to
0.41)
0.295
Kt./V
Acetate
1.32
(1.27-1.38)
0.02
(-0.06
to
0.10)
0.575
Citrate
1.30
(1.25-1.36)
B2M
=
beta-2-microglobulin;
CRP
=
C-reactive
protein;
PTT
=
partial
thromboplastin
time;
PT/INR
=
prothrombin/international
normalized
ratios.
Ol
usi
q
uIp
al
up
ou
SA
a1
S110
H
em
od
i
al
ysi
s
I
ntern
ati
on
al
2
01
6
;
2
0
(4
)
:53
7
-54
7
Table
4
Hemodynamic
and
adverse
events
Category
Group
Pre
Post
(95%
CO
(95%
CO
Post—Pre
(95%
CO
P
value
AD
delta-CD
delta
(95%
CO
P
value
Heart
Rate
(BPM)
Acetate
73
(69
to
77)
74
(70
to
78)
1
(-3
to
5)
0.612
0
(-2
to
4)
0.872
Citrate
74
(71
to
77)
76
(71
to
80)
1
(-3
to
5)
0.462
SBP
(mm
Hg)
Acetate
135
(132
to
138)
128
(125
to
130)
—8
(-11
to
—4)
<0.001
—1
(-7
to
5)
0.705
Citrate
134
(131
to
137)
127
(124
to
131)
—7
(-11
to
—2)
0.008
DBP
Hg)
Acetate
75
(73
to
77)
73
(71
to
75)
—2
(-4
to
0)
0.055
—1
(-4
to
3)
0.767
Citrate
74
(71
to
76)
72
(70
to
75)
—2
(-5
to
1)
0.291
QTc
(milliseconds)
Acetate
434
(419
to
449)
445
(430
to
461)
11
(6
to
16)
<0.001
—7
(-21
to
7)
0.311
Citrate
446
(417
to
474)
464
(436
to
492)
18
(4
to
32)
0.014
Access
Hold
Times
(minutes)
Acetate
5.94
(5.32
to
6.36)
0.19
(-0.53
to
0.92)
0.601
Citrate
5.65
(5.13
to
6.16)
IDH
(Frequency)
a
Acetate
0.62
(0.47
to
0.76)
—0.05
(-0.27
to
0.16)
0.627
Citrate
0.67
(0.51
to
0.83)
IDH
(Proportion)
b
Acetate
0.45
(0.36
to
0.54)
0.01
(-0.11
to
0.14)
0.853
Citrate
0.44
(0.35
to
0.53)
BPM
=
beats
per
minute,
mm
Hg
=
millimeter
mercury,
SBP
=
systolic
blood
pressure,
DBP
=
diastolic
blood
pressure,
QTc
=
corrected
QT
interval,
IDH
=
intradialytic
hypotension.
'Frequency
defined
as
number
of
episodes
of
IDH
per
HD
session.
b
Proportion
defined
as
proportion
of
HD
sessions
complicated
by
IDH.
Ui
Citrate
vs.
acetate
dialysate
HD
sessions.
24
Similar
to
the
Sands
et
al
study,
the
two
interventions
are
treated
differently
with
the
heparin
reduction
applied
to
only
those
receiving
citrate.
This
study
also
lacked
a
run-in
phase
and
systematic
heparin
reduction,
meaning,
patients
are
not
receiving
the
lowest
possible
heparin
dose
prior
to
randomization
and,
there-
fore,
potentially
able
to
tolerate
further
heparin
reductions.
Citrate
hemodynamic
safety
and
anticoagulation
parameters
was
studied
by
Gabutti
et
al.
25
Twenty
patients
were
randomized
to
alternating
weeks
of
ace-
tate
or
citrate
for
5
weeks.
The
mean
SBP,
DBP,
and
peripheral
resistances
were
statistically
lower
with
citrate,
however,
clinical
relevance
was
unclear.
Similar
to
our
study,
the
use
of
citrate
resulted
in
a
significant
reduction
in
postdialysis
serum
iCa
of
0.08
mmol/L
that
was
ablated
with
dialysate
calcium
supplementa-
tion.
Systemic
coagulation
parameters
including
thrombin-antithrombin
complexes
and
prothrombin
fragments
were
no
different
between
the
groups.
25
Our
findings
with
citrate
are
consistent
with
the
coagula-
tion
parameters
seen
in
this
study.
There
are
a
few
possible
explanations
as
to
why
the
results
of
our
study
differ
from
the
published
literature.
One
may
be
that
our
results
are
truly
negative,
and
the
use
of
citrate
does
not
result
in
less
heparin
use.
Alterna-
tively,
our
study
may
have
failed
to
detect
a
true
reduction
of
heparin
dose
with
our
small
sample
size.
We
antici-
pated
and
demonstrated
a
reduction
of
30%
in
heparin
dose
with
citrate
based
on
a
previously
published
abstract,
23
however,
when
the
heparin
reduction
protocol
was
applied
equally
to
both
citrate
and
acetate,
this
resulted
in
an
unanticipated
19%
reduction
in
the
acetate
group.
As
previous
studies
did
not
systematically
reduce
heparin
in
both
acetate
and
citrate
groups
this
may
have
resulted
in
relative
overestimation
of
the
clinical
reduction
in
heparin
dose
and
underestimation
of
our
sample
size.
Lastly,
our
patients
may
have
not
reached
the
minimum
heparin
dose
prior
to
randomization,
resulting
in
further
heparin
decreases
during
the
study
thus
nullifying
the
effect
of
citrate
use.
Our
study
is
also
limited
by
including
only
those
with
well-functioning
vascular
accesses,
without
contraindica-
tions
to
heparin,
and
not
on
systemic
anticoagulation.
Thus,
patients
who
may
derive
the
most
benefit
from
citrate
were
excluded
from
our
study.
Furthermore,
the
generalizability
of
the
study
findings
may
be
limited
by
the
high
prevalence
of
fistula
since
patients
with
catheters
may
have
difficulty
with
using
less
heparin
due
to
cathe-
ter
dysfunction.
Study
strengths
include
the
use
of
randomization,
dou-
ble
blind
protocol,
and
an
adequately
powered
study
based
on
previously
published
data.
In
addition,
our
study
included
both
a
run-in
phase
to
reduce
the
patient's
cumulative
heparin
using
an
objective
dialyzer
clotting
score.
Our
results
have
clinical
and
research
implications.
After
controlling
for
excess
intradialytic
heparin
with
the
use
of
a
standardized
heparin
reduction
protocol,
the
use
of
citrate
did
not
result
in
additional
heparin
reduction.
Although
citrate
use
did
not
promote
hemo-
dynamic
instability,
the
need
to
monitor
ionized
cal-
cium
limits
the
use
of
citrate
to
patients
that
cannot
tolerate
acetate
or
to
HD
programs
that
reuse
dialyzers.
As
the
practice
of
dialyzer
reuse
has
largely
fallen
out
of
practice
in
North
America,
this
limits
the
applicabil-
ity
of
the
citrate
related
literature
in
this
field.
26
'
27
Fur-
thermore,
the
increased
cost
of
citrate
may
further
limit
is
use.
Future
studies
should
focus
on
minimizing
the
use
of
heparin
prior
to
trial
start
to
isolate
the
anti-
coagulation
effect
of
citrate.
Our
findings
suggest
that
the
estimated
30%
reduction
in
heparin
dose
with
citrate
is
an
overestimate
of
its
effectiveness.
In
conclusion,
we
found
that
when
compared
to
ace-
tate,
the
use
of
citrate
did
not
lead
to
a
significant
reduc-
tion
in
heparin
dose.
Citrate
however
is
a
safe
alternative
to
acetate,
which
despite
a
drop
in
ionized
calcium,
did
not
lead
to
increased
hemodynamic
instability.
Larger
studies
are
needed
to
determine
optimal
intradialytic
anti-
coagulation
strategies.
ACKNOWLEDGMENTS
We
would
like
to
acknowledge
the
hemodialysis
patients
and
nurses
for
their
support
of
this
project.
Manuscript
received
January
2016;
revised
March
2016.
REFERENCES
1
Ahmad
S,
Callan
R,
Cole
JJ,
Blagg
CR.
Dialysate
made
from
dry
chemicals
using
citric
acid
increases
dialysis
dose.
Am
J
Kidney
Dis.
2000;
35:493-499.
2
Apsner
R,
Buchmayer
H,
Gruber
D,
Sunder-
Plassmann
G.
Citrate
for
long-term
hemodialysis:
Prospective
study
of
1,009
consecutive
high-flux
treatments
in
59
patients.
Am
J
kidney
Dis.
2005;
45:
557-564.
3
Pinnick
R
V,
Wiegmann
TB,
Diederich
DA.
Regional
citrate
anticoagulation
for
hemodialysis
in
the
patient
Hemodialysis
International
2016;
20(4):537-547
545
Leung
et
al.
at
high
risk
for
bleeding.
N
Engl
J
Med.
1983;
308:
258-261.
4
Shen
JI,
Winkelmayer
WC.
Use
and
safety
of
unfrac-
tionated
heparin
for
anticoagulation
during
mainte-
nance
hemodialysis.
Am
J
Kidney
Dis.
2012;
60:
473-486.
5
Wasse
H,
Gillen
DL,
Ball
AM
et
al.
Risk
factors
for
upper
gastrointestinal
bleeding
among
end-stage
renal
disease
patients.
Kidney
Int.
2003;
64:1455-1461.
6
Chachati
A,
Godon
JP.
Effect
of
haemodialysis
on
upper
gastrointestinal
tract
pathology
in
patients
with
chronic
renal
failure.
Nephrol
Dial
Transplant.
1987;
1:
233-237.
7
Yang
J-Y,
Lee
T-C,
Montez-Rath
ME
et
al.
Trends
in
acute
nonvariceal
upper
gastrointestinal
bleeding
in
dialysis
patients.
J
Am
Soc
Nephrol
2012;
23:
495-506.
8
Hutchison
C
a,
Dasgupta
I.
National
survey
of
heparin-induced
thrombocytopenia
in
the
haemodialy-
sis
population
of
the
UK
population.
Nephrol
Dial
Transplant.
2007;
22:1680-1684.
9
Yamamoto
5,
Koide
M,
Matsuo
M
et
al.
Heparin-
induced
thrombocytopenia
in
hemodialysis
patients.
Am
J
Kidney
Dis.
1996;
28:82-85.
10
Chang
JJ,
Parikh
CR.
When
heparin
causes
thrombo-
sis:
Significance,
recognition,
and
management
of
heparin-induced
thrombocytopenia
in
dialysis
patients.
Semin
Dial.
2006;
19:
297-304.
11
Hottelart
C,
Achard
JM,
Moriniere
P,
Zoghbi
F,
Dieval
J,
Fournier
A.
Heparin-induced
hyperkalemia
in
chronic
hemodialysis
patients:
Comparison
of
low
molecular
weight
and
unfractionated
heparin.
Artif
Organs.
1998;
22:614-617.
12
Nasstrom
B,
Olivecrona
G,
Olivecrona
T,
Stegmayr
BG.
Lipoprotein
lipase
during
heparin
infusion:
Lower
activity
in
hemodialysis
patients.
Scand
J
Clin
Lab
Invest.
2003;
63:45-54.
13
Lai
KN,
Ho
K,
Cheung
RC
et
al.
Effect
of
low
molecu-
lar
weight
heparin
on
bone
metabolism
and
hyperlip-
idemia
in
patients
on
maintenance
hemodialysis.
Int
J
Artif
Organs.
2001;
24:447-455.
14
Kossmann
RJ,
Gonzales
A,
Callan
R,
Ahmad
S.
Increased
efficiency
of
hemodialysis
with
citrate
dialy-
sate:
A
prospective
controlled
study.
Clin
J
Am
Soc
Nephrol.
2009;
4:1459-1464.
15
Ahmad
5,
Callan
R,
Cole
J,
Blagg
C.
Increased
dialyzer
reuse
with
citrate
dialysate.
Hemodialysis
Int.
2005;
9:
264-267.
16
Sands
JJ,
Kotanko
P,
Segal
JH
et
al.
Effects
of
citrate
acid
concentrate
(citrasaten
on
heparin
N
require-
ments
and
hemodialysis
adequacy:
A
multicenter,
pro-
spective
noninferiority
trial.
Blood
Purif.
2012;
33:
199-204.
17
Gabutti
L,
Bianchi
G,
Soldini
D,
Marone
C,
Burnier
M.
Haemodynamic
consequences
of
changing
bicarbonate
and
calcium
concentrations
in
haemodialysis
fluids.
Nephrol
Dial
Transplant.
2009;
24:973-981.
18
Tu
A,
Ahmad
S.
Heparin-free
hemodialysis
with
citrate-containing
dialysate
in
intensive
care
patients.
Dial
Transplant.
2000;
29:620-624.
19
Cointault
0,
Kamar
N,
Bories
P
et
al.
Regional
citrate
anticoagulation
in
continuous
venovenous
haemodiafil-
tration
using
commercial
solutions.
Nephrol
Dial
Trans-
plant.
2004;
19:171-178.
20
Tai
DJ,
Leung
K,
Ravani
P
et
al.
The
effect
of
citrate
dialysate
on
intradialytic
heparin
dose
in
haemodialysis
patients:
study
design
of
a
randomised
controlled
trial.
BMC
Nephrol.
2015;
16:147.
21
Sagedal
5,
Hartmann
A,
Osnes
K
et
al.
Intermittent
saline
flushes
during
haemodialysis
do
not
alleviate
coagulation
and
clot
formation
in
stable
patients
receiving
reduced
doses
of
dalteparin.
Nephrol
Dial
Transplant.
2006;
21:444-449.
22
Manns
BJ,
Mortis
GP,
Taub
KJ,
McLaughlin
K,
Donaldson
C,
Ghali
WA.
The
Southern
Alberta
renal
program
database:
A
prototype
for
patient
management
and
research
initiatives.
Clin
Invest
Med.
2001;
24:164-
170.
23
Ahmad
5,
Callan
R,
Kossmann
RJ.
Heparin
reduction
with
citrate
dialysate
[abstract].
Nephrol
Dial
Transplant.
2006;
21(Suppl
4).
24
Rocha
AD,
Padua
VC,
Oliveira
E
et
al.
Effects
of
citrate-enriched
bicarbonate
based
dialysate
on
anti-
coagulation
and
dialyzer
reuse
in
maintenance
hemodialysis
patients.
Hemodialysis
Int.
2014;18:
467-472.
25
Gabutti
L,
Lucchini
B,
Marone
C,
Alberio
L,
Burnier
M.
Citrate-
vs.
acetate-based
dialysate
in
bicarbonate
haemodialysis:
Consequences
on
haemodynamics,
coagulation,
acid-base
status,
and
electrolytes.
BMC
Nephrol.
2009;
10:7.
26
Upadhyay
A,
Sosa
MA,
Jaber
BL.
Single-use
versus
reusable
dialyzers:
The
known
unknowns.
Clin
J
Am
Soc
Nephrol.
2007;
2:1079-1086.
27
Lacson
E,
Lazarus
JM.
Dialyzer
best
practice:
Single
use
or
reuse?
Semin
Dial.
2006;
19:120-128.
APPENDIX
I:
VISUAL
CLOTTING
SCORE
AND
HEPARIN
ADJUSTMENT
PROTOCOL
Visual
Clotting
Score
(dialyzer/venous
chamber
appear-
ance
at
the
end
of
each
HD
session)
0
=Clear
1
=
Few
strands/small
clot
2
=
1
/
2
clotted
3
=
3
/
4
clotted
(able
to
return
blood)
4
=
Clotted
completely
(unable
to
return
blood)
546
Hemodialysis
International
2016;
20(4):537-547
Citrate
vs.
acetate
dialysate
Heparin
dose
adjustment
for
next
HD
Visual
Clotting
Score
session
0/1
Decrease
boost by
200
units
and
decrease
running
dose
by
200
units/hour
2
Increase
boost
by
200
units
and
increase
running
dose
by
200
units/hour
and
maintain
this
new
heparin
dose
3
Increase
boost
by
300
units
and
increase
running
dose
by
300
units/hour
4
Increase
boost
by
400
units
and
increase
running
dose
by
400
units/hour
Bleeding
from
access
Heparin
dose
adjustment
site
post-dialysis
Unusually
prolonged
Turn
off
heparin
30
minutes
earlier
than
usual
for
the
patient
and
decrease
running
dose
by
200
units/hour
This
maintenance
dose
is
obtained
by
achieving
a
clot-
ting
score
of
2
and
then
increasing
the
heparin
dose
by
200U
bolus
and
200U/h
infusion.
The
new
baseline
hep-
arin
dose
is
the
lowest
dose
achieved
without
clotting
(or
a
post
dialysis
score
of
<
2)
for
2
consistent
HD
runs.
Hemodialysis
International
2016;
20(4):537-547
547