Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00718289 |
| Other study ID # |
012008 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
July 16, 2008 |
| Last updated |
July 17, 2008 |
| Start date |
March 2007 |
| Est. completion date |
November 2007 |
Study information
| Verified date |
July 2008 |
| Source |
Ospedale Regionale di Locarno |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Switzerland: Swissmedic |
| Study type |
Interventional
|
Clinical Trial Summary
Background:
A concentrate for bicarbonate haemodialysis acidified with citrate instead of acetate has
been marketed in the recent years. The small amount of citrate used (one-fifth of the
concentration adopted in regional anticoagulation) protects against intradialyser clotting,
minimally affecting the calcium concentration. The aim of this study is to compare the
impact of a citrate- and acetate-based dialysate on systemic haemodynamics, coagulation,
acid-base status, calcium balance and dialysis efficiency.
Methods:
In 25 patients, 375 dialysis sessions, we will compare acetate (A) with citrate dialysate
with (C+) or without (C) calcium supplementation (0.25mmol/L) in a randomized single blind
cross-over study. Systemic haemodynamics will be evaluated using pulse wave analysis
systems. Coagulation, acid-base status, calcium balance and dialysis efficiency will be
assessed using standard biochemical markers.
Description:
Introduction:
A concentrate for bicarbonate haemodialysis acidified with citric instead of the less
physiologic acetic acid has been successfully implemented in the United States in the past 7
years [1-3]. Contrarily to traditional regional citrate anticoagulation, the small amount of
citrate used in the acid concentrate (0.8 mmol/L only; about one-fifth of the concentration
necessary to achieve anticoagulation [1,4,5]) affects the calcium concentration and the
locally enhanced coagulation activation in a limited way, resulting in approximately 10%
reduction in post-dialysis ionized calcium and in no measurable systemic anticoagulation
[1]. The absence of significant systemic repercussions is related to both, the low amount of
citrate used but also the rapid conversion of citrate into bicarbonate taking place in the
liver and muscles and determining a higher post-dialysis bicarbonataemia [1,6,7]. Despite
the rapid citrate clearance, the local consequences of removing calcium from the blood
clotting cascade has measurable positive effects on the dialyser life-span in the "reuse"
modality and on the dialysis quality quantified by urea Kt/V [1,3]. The improvement in urea
clearance was correlated to a postulated favourable effect on dialyser fibre permeability
mediated by the intra-dialyser anticoagulants properties of citrate [1,3,8]. Considering the
importance of limiting the biocompatibility related coagulation activation taking place in
the extracorporeal circuit [9-17], disposing of a simple way to inhibit it without affecting
the systemic coagulation and the bleeding risk [18] is very promising.
Even if thousands of patients have been treated in the recent years with haemodialysis
fluids based on citric instead of acetic acid, the haemodynamic tolerance (the reduction in
ionized calcium concentration and the increase in bicarbonateamia could both result in a
lower intra-dialytic blood pressure [19-25]) and the amount of systemic coagulation
activation related to each one of the modalities, were not investigated.
The aim of this randomized, controlled, single blind, cross-over study in single-use
dialyser bicarbonate haemodialysis, is to detail the consequences on systemic haemodynamics,
coagulation activation, acid-base status, calcium balance and dialysis efficiency of using
citric instead of acetic acid in the haemodialysis fluids.
Methods and patients:
Twenty-five chronic haemodialysis patients (15 male and 10 female), dialysed 3 to 4 hours
three times a week, clinically stable and without intercurrent illnesses, will be enrolled
in the study. Using a single blind, cross-over design, the patients will be randomized in
the two arms of the study beginning by either the traditional acetic acid (modality A) or
the citric acid dialysate (modality C). In the following 3 weeks the modality will be weekly
switched to the alternative one. Finally, with the intention to compensate the reduction in
serum calcium induced by the citrate binding, both study arms will be completed with a week
using a citric acid dialysate with a calcium supplementation of 0.25 mmol/L (modality C+).
The haemodialyses will be performed using a 4008 H machine, equipped with a cartridge of
bicarbonate Bibag©, and a high flux single use polysulfone membrane, all from Fresenius
Medical Care (Bad Homburg, Germany). The prescribed dialyser effective surface area,
dialysis fluid conductibility, temperature and composition (with the exception of acetate
[3.0 mmol/L in A and 0.3 in C and C+], citrate [0 mmol/L in A and 0.8 in C and C+] and
calcium [1.25 and 1.50 mmol/L in A and C and 1.50 and 1.75 in C+]), and effective blood flow
will be recorded at the enrolment in the study, and left unchanged for the following 5
weeks. The medications of the patients (including phosphate binders) will also be left
unchanged.
Serum BUN, creatinine, potassium, phosphate, calcium and whole blood pH, bicarbonate, and
ionized calcium will be measured at the beginning and at the end of the third dialysis
session of each week. Ionized and total calcium will also be measured at the beginning and
at the end of the first dialysis session of each week. The prothrombin fragments 1+2 (F1+2)
and thrombin-antithrombin complexes (TAT) will be determined at the beginning and at the end
of the third dialysis session of each week [26]. Blood samples will be taken from the
arterial limb of the shunt.
Systolic and diastolic blood pressures and heart rate will be measured before starting every
session, and then repeated at 30 min interval throughout the dialysis with an automated
Blood Pressure Monitor 4008 (Fresenius Medical Care, Bad Homburg, Germany) integrated in the
dialysis machine. Stroke volumes (integrated mean of the flow waveform between the current
upstroke and the dicrotic notch) and peripheral resistances (ratio of mean arterial pressure
to stroke volume multiplied by heart rate) will be evaluated between 5 and 10 minutes after
starting the session and then every 45 minutes using a finger beat-to-beat monitor
Finometer© (Finapres Medical Systems BV, Arnhem, The Netherlands). The use of isotonic
saline (100-200 ml) infusions to treat symptomatic hypotension or symptoms related to
intravascular hypovolaemia will be registered.
Kt/V will be calculated using a second generation single-pool Daugirdas formula (Kt/V =
-ln(R-0.03) + [(4-3.5 x R) x (UF/W)] where R = post-dialysis BUN/pre-dialysis BUN, UF = net
ultrafiltration and W = weight).
The citrate accumulation during dialysis will be estimated calculating the calcium gap =
│post-predialysis total calcium│- │post-predialysis ionized calcium│[6]. The value of 0.2
mmol/L will be used as a cut-off to divide the patients in rapid (< 0.2 mmol/L) and slow (≥
0.2 mmol/L) metabolizers.
Results will be expressed as mean ± SD. Statistical analyses will be performed using a
statistical software package (SPSS 12.0; SPSS Inc., Chicago, IL, USA). Comparisons between
laboratory and haemodynamic parameters will be done first with an ANOVA followed if
significant by a paired t-test performed between the mean of the values obtained in each
patient with each modality. Haemodynamic parameters as a function of the dialysis time will
be compared using a trapezoidal estimation of the area under the curves followed by a
Wilcoxon Signed Ranks test. With the intention of ameliorating the understanding of the
haemodynamic changes, an evaluation of the maximum increase and decrease in each parameter
will be added to the data analysis (see Figure 2 for an explanation of the calculation
method). Percentages will be compared using a Fisher Exact test. In all cases, a P ≤ 0.05
will be considered statistically significant; P will be expressed as ns (not significant),
=0.05, <0.05, <0.01 and <0.001.
The protocol of the study has been approved by the local Ethical Committee. All the patients
will give written informed consent prior to enrolment in the study.
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