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Key Words did not occur in either group. Although the highest bi-
Citrate anticoagulation · Genius® dialysis · Acute renal carbonate levels were achieved during citrate anticoagu-
failure · Acid base · Electrolytes lation (p = 0.021 versus heparin) the acid base values
remained equilibrated in both groups. Filter longevity
was excellent and the targeted dialysis time was achieved
Abstract in all but 1 patient. Citrate anticoagulation was well tol-
Background: The Genius® dialysis system is a close loop erated with respect to cardiovascular hemodynamics.
dialysis batch system increasingly used as an intermit- Conclusions: Citrate anticoagulation can be safely and
tent hemodialysis device in intensive care units. The aim effectively performed during intermittent Genius® dialy-
of this study was to test the safety and feasibility of a sis. Calcium supplementation is not routinely required.
regional citrate anticoagulation protocol with respect to Copyright © 2004 S. Karger AG, Basel
www.karger.com www.karger.com/nec Tel. +49 30 450 514902, Fax +49 30 450 614137, E-Mail stanislao.morgera@charite.de
quently used anticoagulant but is associated with several The dialysate is composed of ultrapure water, providing a ster-
disadvantages such as life-threatening hemorrhagic com- ile and pyrogen-free dialysate. Electrolyte and bicarbonate concen-
trations can be individually composed according to the demands
plications or the induction of heparin-induced thrombo-
of the patient. Sterile, pre-packed bicarbonate and electrolyte con-
cytopenia type II [5–7]. In recent years, the regional an- centrates at various concentrations are commercially available. A
ticoagulation with sodium-citrate has gained popularity, double-sided roller pump simultaneously generates blood and di-
especially in patients with increased bleeding risks or sus- alysate flow in a ratio of 1: 1. Maximum blood flow is 300 ml/h,
pected thrombocytopenia type II. By virtue of chelating, minimum flow rate is 70 ml/h. Blood flow determines the overall
dialysis time that can range from 4 to 18 h. The arterial and venous
ionized calcium citrate is a very efficient anticoagulant. blood lines (Schlauchsystem-Set, Genius® 01, Fresenius Medical
Anticoagulation is exclusively confined to the extracorpo- Care AG) do not contain a bubble catcher or a venous drip cham-
real circulation. However, citrate anticoagulation has ber, respectively, thus avoiding air/blood contact areas and reduc-
some potential adverse effects such as metabolic alkalo- ing the thrombogenicity of the system.
sis, hypernatremia, hypo- and hypercalcemia. The spent fluid is drained at the bottom of the tank while fresh
dialysate comes from the top of the reservoir. Due to differences in
This study presents a citrate anticoagulation protocol temperature and fluid density, fresh and used dialysate do not mix
for the Genius® dialysis system. In a cross-over design, [8].
we compared a citrate anticoagulation protocol to that For this study a polysulfone membrane was used (F8 HPS, Fre-
using a standard heparin regime. We focused on the clin- senius Medical Care AG). Dialysate composition was as follows:
ical feasibility and the safety criteria, namely electrolytes, 1.00 mmol/l Ca, 0.5 mmol/l Mg, 140 mmol/l Na, 3 mmol/l potas-
sium, 35 mmol/l HCO3, 113 mmol/l Cl, 5.5 mmol/l glucose, and
acid-base values and cardiovascular hemodynamics. 0.067 mmol/l citrate. Hydrochloric acid (2.2 mmol/l) was used for
pH adjustment.
The vascular access was obtained by a double-lumen 12-french
Materials and Methods catheter inserted into either the internal jugular, femoral or subcla-
vian vein.
Study Design
The study was approved by the Ethical Committee on Human Citrate Anticoagulation Protocol
Research of the University Hospital Charité of Berlin and was in A 4% trisodium citrate solution (provided by the university
accordance with the Declaration of Helsinki. pharmacy, 100 ml containing sodium citrate 4.0 g, citric acid
Twenty-seven patients with acute renal failure were enrolled 34 mg in aqua ad inject.) was infused pre-filter at a initial rate of
into the study after written consent was obtained from either the 180 ml/h. Blood flow rate was 200 ml/min. Post-filter ionized cal-
patients or their relatives. Acute renal failure was based on one of cium levels were used to assess the adequacy of anticoagulation.
the following criteria: (1) fluid overload owing to inadequate urine Ionized calcium was measured by ion-selective electrodes (AVL
production despite administration of diuretic agents and mainte- 984-S Analysers, AVL Medical Instruments UK Ltd., Stone, UK).
nance of adequate blood pressure; (2) a rise in serum creatinine The citrate infusion was titrated to maintain the post-filter ion-
above 2.5 mg/dl (from normal baseline values) or a doubling of ized calcium level between 0.6 and 0.7 mmol/l. Post-filter ionized
the baseline creatinine value, and (3) serum potassium above calcium levels were obtained 15 min after treatment initiation
5.5 mmol/l due to oligoanuria. (T15), at the end of treatment (TE), and up to four times during the
In a cross-over design, patients were sequentially allocated to treatment. There was no routine calcium chloride supplementa-
the citrate anticoagulation protocol during the first study dialysis tion. For study purposes also pre-filter ionized calcium values were
session and the heparin anticoagulation during the following dialy- measured. Samples were taken from the arterial port.
sis session. Safety was determined on the basis of the changes in A diagram of the citrate anticoagulated Genius® dialysis system
blood electrolytes and acid-base homeostasis as well as cardiovas- is displayed in figure 1.
cular hemodynamics (blood pressure, heart rate). Effectiveness was
measured by a decrease in blood urea during dialysis and the clot- Heparin Anticoagulation
ting level of the hemofilter at the end of the dialysis session. A single bolus of 1,000 IU heparin (Liquemin; Hoffmann-La
In order to achieve a normal anticoagulation status all antico- Roche AG, Grenzach-Wyhlen, Germany) was given into the arte-
agulation therapy was suspended for at least 6 h prior to each di- rial port immediately after blood flow was initiated, followed by an
alysis session. individual patient-adjusted continuous heparin infusion. An acti-
vated clotting time (ACT) of 140–180 s was targeted. The initial
Genius® High-Flux Hemodialysis heparin infusion rate was 500 IE/h. The ACT was measured hour-
The Genius® dialysis system is a single-pass batch system (Fre- ly. Whole blood ACT was analyzed with a coagulometer (Sigma-
senius Medical Care, Bad Homburg, Germany). The dialysate des- Amelung, Lemgo, Germany) using kaolin as surface activator
ignated for one treatment session is stored in an air-free 75-liter (100 ng kaolin added to 0.3 ml whole blood).
glass tank. The dialysate is prepared immediately prior to the de-
sired dialysis session by the dialysis team. Once the tank is filled, Data Collection and Calculation
the system becomes highly mobile, allowing dialysis therapy to take Dialysis system pressure, blood flow and ultrafiltration rates
place almost anywhere. The use of a rechargeable battery enables were recorded hourly by the dialysis staff nurse. At the end of each
treatment even without a power supply. dialysis session, the nurse inspected the hemofilter for visible signs
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Karolinska Institutet, University Library
Citrate Anticoagulation with the Genius® Nephron Clin Pract 2004;98:c35–c40 c37
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Table 1. Electrolytes, acid-base values, urea and creatinine values during citrate and heparin dialysis with the Genius® system
Baseline values (T0) are compared to values obtained at the end of the dialysis session (TE).
beats/min for citrate dialysis and 135 8 29 mm Hg and Table 2. Coagulation parameters at baseline for citrate and heparin
84 8 17 beats/min for heparin dialysis. Corresponding dialysis
values at TE were 128 8 29 mm Hg and 87 8 17 beats/
Citrate Heparin p value
min for citrate and 129 8 30 mm Hg and 82 8 18 beats/ (n = 21) (n = 21)
min for heparin dialysis.
Prothrombin, % 182825 187824 0.475
Electrolytes and Acid-Base Balance Partial thromboplastin time, s 138811 13989 0.641
Thrombocytes, 106/µl 1958125 1978118 0.951
For both anticoagulation regimens, post-dialysis val- Hematocrit, % 12883 12982 0.320
ues for the electrolytes sodium, chloride and potassium Fibrinogen, mg/dl 4438173 4638148 0.841
were within the normal range. A significant treatment ef-
fect was detected for the magnesium levels during citrate
anticoagulation (significant decrease from baseline; p =
0.041). Total and ionized serum calcium levels remained
stable during citrate anticoagulation. The lowest ionized assay was normal in almost all patients. Five patients had
calcium level observed during citrate anticoagulation was thrombocyte dysfunction comparable to that induced by
0.98 mmol/l. aspirin (acetylic acid).
Blood pH, bicarbonate and base excess increased sig- The mean citrate infusion rate was 199 8 6 ml/h. Pre-
nificantly during both treatment modalities. The increase filter ionized calcium values were 0.18 8 0.05 mmol/l.
was slightly more pronounced during citrate anticoagula- Post-filter ionized calcium values during citrate antico-
tion. Final values for serum bicarbonate were greater with agulation were 0.67 8 0.07 mmol/l, and were thus with-
citrate as compared to heparin dialysis (p = 0.021). The in the desired range (0.6–0.7 mmol/l).
highest bicarbonate values observed were 29.1 mmol/l for In the heparin regime, a mean continuous heparin
citrate and 28.7 mmol/l for heparin anticoagulation. dose of 750 8 240 IU/h was achieved. The mean ACT
Electrolytes and acid base values before and at the end was 159 8 26 s. ACT values remained stable throughout
of the dialysis sessions are listed in table 1. the dialysis session. Figure 2 shows the ionized calcium
values and the ACT over time for both anticoagulation
Coagulation Status, Clotting Monitoring, Dialytic protocols.
Parameters and Filter Life Time Both dialysis sessions were comparable with respect to
The coagulation status was normal in all patients. Ta- blood flow rate and ultrafiltration rate. Both protocols
ble 2 shows baseline coagulation parameters for citrate achieved excellent filter longevity. Filter longevity did not
and heparin dialysis. The baseline thrombocyte function differ between citrate and heparin anticoagulation. Trans-
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Citrate Anticoagulation with the Genius® Nephron Clin Pract 2004;98:c35–c40 c39
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Systemic total calcium was not affected in our patients. dependent coagulation factor complexes. It has been
Hypercalcemia is well-known problem of citrate anti- shown that ionized calcium values of !0.5 mmol/l are
coagulation. It is often seen in patients with impaired necessary to achieve an anticoagulatory effect in the ex-
liver function [10, 11]. In these patients citrate metabo- tracorporeal circuit [12]. Most clinical trials targeted for
lization may be slowed down which may lead to citrate post-filter ionized calcium values below this threshold
accumulation, mainly as citrate-calcium complex. Also [13, 14]. In our study an ionized post-filter calcium value
magnesium may decline during citrate anticoagulation of around 0.6–0.7 mmol/l was targeted. We observed very
as, similar to calcium, magnesium chelates with citrate. good anticoagulatory effects. This phenomenon can only
In our study population a slight, but statistically signifi- be explained by the reduced thrombogenicity of the Ge-
cant, decline in systemic magnesium values was observed. nius® dialysis system compared to a standard hemodialy-
This may have been facilitated by the relatively low mag- sis device (avoiding blood/air contact areas and eliminat-
nesium content of the dialysate (0.5 mmol/l). Should ci- ing the venous drip chamber).
trate anticoagulation be used routinely, a supplementa- The simplicity of our citrate anticoagulation protocol
tion of magnesium will likely be necessary (either permits a safe implementation of this anticoagulation
increasing the Mg content in the dialysate or by intrave- protocol for a selected group of patients. Especially for
nous Mg administration). those patients with a high risk of bleeding or those with
Hypernatremia may occur due to the administration contraindications for the use of heparin, such as in hepa-
of high doses of sodium citrate. Hypernatremia was, how- rin-induced thrombocytopenia type II.
ever, not a problem in the present study. The use of a
dialysis fluid containing the relatively low sodium con-
centration of 135 mmol/l appropriately counteracted the
Acknowledgement
infusion of sodium with the citrate solution.
Citrate inhibits coagulation in a dose-dependent man- This study was supported by a grant from Fresenius Medical
ner which relies on a disturbed formation of the calcium- Care, Bad Homburg, Germany.
References
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