Long-term continuous renal replacement therapy and anticoagulation with citrate in critically ill patients with severe liver dysfunction
Klingele et al. Critical Care
Long-term continuous renal replacement therapy and anticoagulation with citrate in critically ill patients with severe liver dysfunction
Matthias Klingele 0 1 2 3
Theresa Stadler 1 3
Danilo Fliser 1 3
Timo Speer 1 3
Heinrich V. Groesdonk 4
Alexander Raddatz 4
0 Departments of Nephrology and Internal Medicine , Hochtaunus-Kliniken, Zeppelinstrasse 20, D-61352 Bad Homburg , Germany
1 Department of Internal Medicine - Nephrology and Hypertension, Saarland University Medical Centre , Homburg/Saar , Germany
2 Departments of Nephrology and Internal Medicine, Hochtaunus-Kliniken , 61250 Usingen , Germany
3 Department of Internal Medicine - Nephrology and Hypertension, Saarland University Medical Centre , Homburg/Saar , Germany
4 Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Saarland University Medical Centre , Homburg/Saar , Germany
Background: As of 2009, anticoagulation with citrate was standard practice in continuous renal replacement therapy (CRRT) for critically ill patients at the University Medical Centre of Saarland, Germany. Partial hepatic metabolism of citrate means accumulation may occur during CRRT in critically ill patients with impaired liver function. The aim of this study was to evaluate the actual influence of hepatic function on citrate-associated complications during long-term CRRT. Methods: In a retrospective study conducted between January 2009 and November 2012, all cases of dialysis therapy performed in the interdisciplinary surgical intensive care unit were analysed. Inclusion criteria were CRRT and regional anticoagulation with citrate, pronounced liver dysfunction, and pathologically reduced indocyanine green plasma disappearance rate (ICG-PDR). Results: A total of 1339 CRRTs were performed in 69 critically ill patients with liver failure. At admission, the mean Model for End-stage Liver Disease score was 19.2, and the mean ICG-PDR was 9.8%. Eight patients were treated with liver replacement therapy, and 30 underwent transplants. The mortality rate was 40%. The mean duration of dialysis was 19.4 days, and the circuit patency was 62.2 h. Accumulation of citrate was detected indirectly by total serum calcium/ionised serum calcium (tCa/iCa) ratio > 2.4. This was noted in 16 patients (23.2%). Dialysis had not to be discontinued for metabolic disorder or accumulation of citrate in any case. In 26% of cases, metabolic alkalosis occurred with pH > 7.5. Interestingly, no correlation between citrate accumulation and liver function parameters was detected. Moreover, most standard laboratory liver function parameters showed poor predictive capabilities for accumulation of citrate. Conclusions: Our findings indicate that extra-hepatic metabolism of citrate seems to exist, avoiding in most cases citrate accumulation in critically ill patients despite impaired liver function. Because the citric acid cycle is oxygendependent, disturbed microcirculation would result in inadequate citrate metabolism. Raising the tCa/iCa ratio would therefore be an indicator of severity of illness and mortality rather than of liver failure. However, further studies are warranted for confirmation.
CRRT; Anticoagulation; Citrate; Critically ill; Liver; Accumulation
Acute renal failure requiring dialysis is a common
complication in critically ill patients in intensive care units
]. In order to perform renal replacement
therapy (RRT), adequate anticoagulation is necessary.
Heparin is often used for this purpose . However, the
bleeding risk may be elevated in critically ill patients,
especially in the context of surgery or patients with
hepatic impairment. Regional anticoagulation with citrate
lowers the risk of bleeding complications and therefore
appears to be advantageous in these patients [
Admitted citrate is half-eliminated during dialysis. The residual
half of citrate does return to the patient. Citrate
metabolism is oxygen-dependent via the citric acid cycle and
therefore mainly in organs with high amounts of
mitochondria, such as the liver, kidney or muscle [
]. In the
literature, citrate metabolism is described as being
dependent mainly on liver function [
]. Thus, regional
anticoagulation with citrate is considered critical in cases
of liver dysfunction with respect to the potential risk of
citrate accumulation resulting in metabolic disorders,
including shifts in calcium balance . Because of these
potential side effects, regional anticoagulation with
citrate is often avoided in patients with hepatic
insufficiency and mostly excluded in studies investigating
regional anticoagulation with citrate [
]. To this day,
there is still little knowledge about the actual incidence
of citrate-associated complications in patients with
impaired liver function. Moreover, the existing rare studies
describe only short periods of dialysis [
about continuous renal replacement therapy (CRRT) of
longer duration with citrate anticoagulation in critically
ill patients with hepatic insufficiency is not available.
This study had three aims: to evaluate the proportion of
critically ill patients with severe hepatic insufficiency
developing citrate-associated complications during CRRT, to
investigate the actual influence of hepatic impairment and
duration of CRRT on the development of these
citrateassociated complications, and finally to identify predicting
factors for citrate-associated complications in critically ill
patients with impaired liver function.
Since January 2009, regional anticoagulation with citrate is
routinely used for RRT in all ICUs at the Saarland
University Medical Centre. From that time until November 2012,
all dialysis cases in the interdisciplinary surgical ICU were
analysed. The ethics committee of the medical association
evaluated this retrospective study of anonymised data and
voted that no ethical approval or consent to participate
was needed (ethics vote of the Ethik-Kommission der
Aerztekammer des Saarlandes [211/11]).
Inclusion criteria were CRRT and anticoagulation with
citrate, pre-existing severe liver dysfunction, and/or
developing acute liver failure during the clinical course in
the ICU. Patients with known cirrhosis, elevated
bilirubin or ammonia, and/or reduced synthesis parameters
(e.g., prothrombin time [expressed as Quick value],
cholinesterase [CHE], albumin) were considered as showing
chronic and/or acute liver dysfunction. Because
indocyanine green plasma disappearance rate (ICG-PDR) is a
widely accepted parameter for clinical assessment of
liver function and is normally > 18%/minute [
only patients in whom ICG-PDR had been performed
were included. Unfortunately, ICG-PDR was not
determined systematically in all patients with signs of liver
dysfunction. Primary endpoints were metabolic disorders
due to citrate.
The aim of this study was to investigate the influence of
liver function on the metabolism of citrate during
longterm continuous venovenous haemodialysis (CVVHD) in
critically ill patients. We therefore focus on data
characterising our study population regarding pre-existing liver
disease, severity of illness and outcome parameters.
All clinical data were obtained by assessing patient
medical records. Laboratory parameters taken for
clinical monitoring were processed within the central
laboratory of the Saarland University Medical Centre.
Owing to the retrospective study design, not all
laboratory data were available at all time points desired for this
During the study period, Simplified Acute Physiology
Score II (SAPS II) and Therapeutic Intervention Scoring
System score were automatically determined every day.
At this time point, the more often used Sepsis-related
Organ Failure Assessment score was not automatically
or routinely determined.
CRRT and anticoagulation with citrate
CRRT was performed with multifiltrate CiCa dialysate
(Fresenius Medical Care, Bad Homburg, Germany) as
part of the regional citrate anticoagulation (RCA).
Postfilter-ionised calcium levels were used for
anticoagulation monitoring. The concentration of post-filter-ionised
calcium (iCa) was reduced to 0.25–0.35 mmol/L by
chelation with citrate as described by Calatzis and
]. Post-filter-ionised calcium levels were
measured three times within the first 2 h after initiation
of CRRT. After achieving stable iCa within the target
range, post-filter levels of iCa were measured at least
four times per day. Calcium was added before the blood
was returned into the patient’s circulation to achieve a
level within the normal range (2.2–2.6 mmol/L). Serum
levels of albumin-corrected total serum calcium (tCa)
were measured at least once per day.
CVVHD was the only renal replacement modality
used. All CRRTs were started according to our standard
protocol: Initial blood flow was 100 ml/minute, dialysate
flow was 2000 ml/h, citrate solution was infused
prefilter at an initial rate of 4.0 mmol/L blood, and calcium
was substituted with 1.7 mmol/L dialysate. In patients
with a body weight > 80 kg, flow rates of blood and
dialysate were likewise increased as target dialysis dose
was > 25 ml/kg/h.
In case of accumulation of citrate, in a first step,
dialysate flow was increased by 20–25%. In a second step, blood
flow was reduced by 10–20%, if possible with respect to
the body weight (minimal blood flow, 1 ml/minute/kg
body weight) and target dialysis dose. The last step for
correction was a further increase in dialysate flow.
The Molecular Adsorbents Recirculation System
(MARS; Baxter, Unterschleißheim, Germany) is an
extracorporeal liver dialysis system. It is a further
development of albumin dialysis. The first step consists of
albumin dialysis of the patient’s blood, whereby toxins
are bound to the albumin in the dialysate circuit. In a
second step, the albumin-containing dialysate is
regenerated for recirculation. For this purpose, albumin-bound
toxins are eliminated using an adsorber and by a second
In three of eight patients receiving liver replacement
therapy, standard CVVHD with RCA was discontinued
for the duration of MARS therapy. Furthermore, during
MARS therapy, a different dialysis machine was used for
liver dialysis (PRISMAFLEX system; Baxter). In addition,
heparin was used for anticoagulation of the
extracorporeal circuit according to the operating manual of the
PRISMAFLEX system used.
Metabolic complications of anticoagulation with citrate
For anticoagulation with citrate we used trisodium
citrate (sodium citrate 4%; Fresenius Kabi, Bad
Homburg, Germany). Because this contains an increased
supply of sodium, we used multiBic (Fresenius Medical
Care), a dialysate solution with a reduced degree of
sodium, to avoid hypernatremia.
Accumulation of citrate and metabolic alkalosis are
the main metabolic disorders described in the context of
anticoagulation with citrate. Increased citrate plasma
levels were detected by calculating the total tCa to iCa
ratio (tCa/iCa) as described by Hetzel and colleagues
]. A tCa/iCa ratio > 2.4 was considered a sign of
accumulation of citrate.
The metabolism of 1 mol of citrate results in 3 mol of
bicarbonate (HCO3−). Therefore, we used dialysate
solutions with reduced HCO3− content of 20 mmol/L
(multiBic) to avoid development of metabolic alkalosis. Serum
level of HCO3−, base excess, respiratory status (blood gas
analysis) and pH value were determined at the same
time points as iCa, at least four times per day. A blood
pH value > 7.5 was considered as alkalosis.
Continuous variables are expressed as the mean ± SD.
Categorical variables are given as relative and absolute
frequencies unless otherwise stated. The association
between continuous variables was assessed by Spearman’s
rank correlation testing.
To assess the influence of the laboratory variables on
the development of accumulation of citrate or alkalosis,
logistic and linear regression models were used. None of
these complications was used as the reference category in
the logistic regression. The predictive value of laboratory
markers of liver function on the development of
accumulation of citrate or alkalosis was assessed using ROC
analysis. Statistical analysis was carried out using IBM SPSS
version 20 software (IBM, Armonk, NY, USA).
Between January 2009 and November 2012, a total of
378 patients underwent CRRT during the study period.
Of these, 87 patients had acute or chronic liver
dysfunction. Because ICG-PDR was not determined
systematically, 69 patients were eligible for inclusion in this
analysis (as shown in Fig. 1), resulting in a total of 1339
dialysis days of CRRT. The mean duration of CRRT was
19.4 days (SD, ±22.9; range, 1–105) (Table 1).
Most patients had pre-existing liver disease with a
mean bilirubin at admission of 7.1 (SD, ±10.4; range,
0.2–41.6), mean ICG-PDR < 10% and mean Model for
End-stage Liver Disease (MELD) score of 19.7. During
the dialysis period, the average maximum serum level of
bilirubin was 15.6 ± 11.4 mg/dl. Liver replacement
therapy was performed in eight patients. Thirty patients
received liver transplants. Because the aim of this study
was to investigate the influence of liver function on the
metabolism of citrate during long-term CRRT, the main
focus was liver function at the beginning and during the
course of dialysis, as shown in Table 2.
At admission, most patients showed impaired renal
function, and three patients were on chronic dialysis
before admission (Table 2). The indications for dialysis
were mainly hypervolaemia (46.4%), uraemia (43.5%) or
hyperkalaemia (5.8%). The mean dialysis period was 19.4
days (SD, ±22.9).
Anticoagulation with citrate
Regional anticoagulation with citrate was used in 99.1% of
all 1339 CRRTs during the study period. All patients
started as described in the “Methods” section with standard
flow rates. In 40.6% of all patients and 48.5% of all dialysis
performed, exclusively standard flow rates of blood and
dialysate were applied during the whole duration of CRRT
without a need for change owing to metabolic disorders. In
three of eight patients receiving MARS for liver
replacement therapy, anticoagulation was performed with heparin
and not with citrate during this treatment period.
The effective mean blood flow was 96 ml/minute
(SD, ±9; range, 80–138), and the mean dialysate flow
was 2188 ml/h (SD, ±452; range, 1200–3600),
resulting in an effective dialysis dose of 28.9 ml/h/kg.
Sufficient anticoagulation was achieved with a mean
dose of citrate of 4.0 mmol/L blood (SD, ±0.3; range,
3.4–4.7), resulting in a mean iCa of 0.30 mmol/L
(SD, ±0.03; range, 0.12–0.38) in the extracorporeal
circuit. The effectiveness of anticoagulation yielded a
mean longevity of circuit filters of 62.2 h (SD, ±11.2;
range, 24–72). To restore physiological serum levels
of calcium, mean calcium substitution of 1.6 mmol/L
dialysate (SD, ±0.3; range, 0.6–2.2) was given.
Metabolic disorder due to anticoagulation with citrate
The occurrence of metabolic complications in this study
compared with what would have been expected in
patients with impaired liver function undergoing CRRT
with RCA is shown in Fig. 2. In 16 patients (23.2%), a
ratio of tCa/iCa > 2.4 occurred during CRRT, indicating
accumulation of citrate. Mean tCa during the dialysis
period was 2.54 ± 0.17 mmol/L. In nine patients, tCa
was > 2.7 mmol/L. The highest serum calcium level of
tCa measured was 3.7 mmol/L in one patient at 1 day.
At any time clinical complications occurred due to
hyper- or hypocalciemia. Hypercalcaemia or
accumulation of citrate did not require that RCA be stopped in
Mean HCO3− was 25.8 ± 4.4 mmol/L during the dialysis
period. Metabolic alkalosis occurred in 17 patients (24.6%).
Maximal HCO3− ranged from 19 to 46 mmol/L,
accompanied by a mean base excess of 7.7. Adequate modification of
CRRT resolved hypercalcaemia or alkalosis.
Factors influencing accumulation of citrate
Comparing the 16 patients showing signs of citrate
accumulation with the remaining 53 patients, we found
Male sex, n (%)
Cirrhosis, n (%)
Hepatitis B or C, n (%)
Alcoholic cirrhosis, n (%)
Hepatocellular carcinoma, n (%)
Others, n (%)
MELD score at admission
Severity of illness
Pre-existing liver disease (double appointment is possible)
Maximum SAPS II score during stay at hospital
Maximum TISS score during stay at hospital
Sepsis during dialysis period, n (%)
Mechanical ventilation during stay in ICU, n (%)
Duration of ventilation, h
Length of stay in hospital, days
Length of stay in ICU, days
Abbreviations: BMI Body mass index, ICU Intensive care unit, MELD Model
for End-stage Liver Disease, SAPS II Simplified Acute Physiology Score II,
TISS Therapeutic Intervention Scoring System
Results are shown as mean ± SD or as the number of patients and
corresponding percentage with respect to all 69 patients
that MELD score at the start of dialysis was higher
(33.1 ± 4.2 versus 28.8 ± 5.0; p = 0.001), Quick value
was lower (41.2 ± 23.6 versus 57.1 ± 19.3; p = 0.004),
duration of dialysis was shorter (11.6 ± 8.6 versus 22.1 ± 26.3;
p = 0.014) and dose of citrate per litre of blood was higher
(4.2 ± 0.6 versus 4.0 ± 0.6; p = 0.025). MARS for liver
replacement therapy had no impact on accumulation of
citrate, as shown in Table 3.
In correlation analysis only MELD score and
prothrombin time (Quick value) at the start of dialysis
showed a weak correlation (0.303 and −0.387,
respectively; p = 0.001). In a binary logistic regression model
only prothrombin time showed a small impact on the
accumulation of citrate. A reduction of 1% in Quick
value resulted in an elevation of 0.004 of the tCa/iCa
ratio. In ROC analysis the predictive capacity of hepatic
parameters (bilirubin, CHE, prothrombin time [Quick
value] and ICG-PDR), the dose of citrate and the ICU
length of stay for the accumulation of citrate were
tested. The resulting AUCs were 0.253 to 0.662,
Factors influencing development of alkalosis
Comparing the 17 patients showing signs of alkalosis with
the remaining 52 patients, the Quick value was higher
(74.0 ± 11.7 versus 56.4 ± 18.8; p = 0.000), the ICG-PDR
was higher (13.4 ± 5.6 versus 9.0 ± 6.2; p = 0.029), the
dose of citrate per litre of blood was lower (3.8 ± 0.2
versus 4.1 ± 0.3; p = 0.000), the flow of dialysate was
lower (1935 ± 267 versus 2270 ± 470 ml/h; p = 0.001) and
mortality was lower (35.3% versus 65.4%; p = 0.029).
In correlation analysis ICG-PDR and prothrombin
time (Quick value) showed a weak correlation with the
development of alkalosis (0.348 and 0.427; p = 0.029 and
0.000, respectively). In a binary logistic regression model
only prothrombin time (Quick value) and ICG-PDR
showed a weak impact on the development of alkalosis
(0.072 and −0.003, respectively). In ROC analysis the
predictive capacity of hepatic parameters (bilirubin,
CHE, prothrombin time [Quick value] and ICG-PDR)
for the development of alkalosis was tested. Only
prothrombin time and ICG-PCR showed AUCs above 0.70
(0.785 and 0.736, respectively).
In this retrospective evaluation, we demonstrate that in
critically ill patients with severe hepatic dysfunction,
regional anticoagulation with citrate for CRRT is possible,
even for long-term dialysis. Although patients showed
pronounced impaired liver function, citrate
accumulation occurred in only one of four patients and was far
less dramatic than expected.
Abbreviations: CRRT Continuous renal replacement therapy, iCa Ionised serum calcium, ICG-PDR Indocyanine green plasma disappearance rate, ICU Intensive care
unit, MELD Model for End-stage Liver Disease, n.s. Not significant, SAPS II Simplified Acute Physiology Score II, tCa/iCa Total serum calcium/ionised serum calcium
Results are shown as mean ± SD
Under physiological conditions, citrate is metabolised
by the liver and to a lesser extent by the skeletal muscle
]. Therefore, RCA is considered as contraindicated in
cases of impaired liver function resulting in
accumulation of citrate [
]. Increased citrate plasma
levels are indirectly detected, as described by Hetzel
and colleagues [
], through an increasing ratio of total
serum calcium (tCa/iCa). The limit of this ratio varies
in the literature from 2.1 to ≥ 2.5 [
physiological conditions, tCa ranges from 2.2 to 2.6
mmol/L and iCa ranges from 0.90 to 1.20 mmol/L. The
resulting ratio (tCa/iCa) ranges from 1.8 to 2.4. Thus, a
tCa/iCa ratio > 2.4 was considered a sign of
accumulation of citrate. This threshold was also previously
chosen by Link and colleagues [
]. Although all
patients included showed pronounced impaired liver
function, in almost half of these patients any aspect of
metabolic or electrolyte disturbance occurred, and only
one of four had signs of citrate accumulation.
Furthermore, slight changes in the dialysate and blood flows
mostly allowed correction of looming signs of
metabolic disorders. These results are in contrast to the
conventional wisdom in the literature. However, there is
anecdotal evidence that the use of citrate in patients with
impaired liver function would be possible [
3, 22, 23
note, some studies have reported RCA after liver
]. However, liver function normally
improves after transplant. Furthermore, the described mean
dialysis periods were quite short at 5–8 days [
In assessing metabolic complications of citrate
anticoagulation, in particular the duration of dialysis is of
central importance because in prolonged CRRT high
cumulative doses of citrate are administered. However,
in the literature, only short dialysis periods are
3, 8, 23–26
]. The recently published liver
citrate anticoagulation threshold (L-CAT) trial
convincingly showed the safety of CRRT-RCA in patients with
severely impaired liver function . Of note, the
reported observation period included the first 72 h of
CRRT-RCA treatment. In contrast, we report the whole
duration of CRRT-RCA; the mean duration of the
dialysis period was 19 days, resulting in high cumulative
doses of citrate.
Taken together, hepatic function seems not to be
exclusively or predominantly responsible for citrate
metabolism. We therefore hypothesise that in
critically ill patients with impaired liver function a part of
citrate metabolism is shifted into muscle cells or any
other cells. This also would explain why the duration
of dialysis with consecutive high cumulative doses of
citrate does not result in accumulation and
Theoretically, smaller doses of citrate would also
reduce the cumulative dose during long-term dialysis and
RCA with citrate. However, adequate anticoagulation is
an essential requirement to ensure the patency of the
dialysis circuit. Therefore, mean circuit lifespan is an
indirect indicator of the effectiveness of anticoagulation.
RCA circuit lifespans up to 48 h and more have been
14, 25, 27, 28
]. In our study mean circuit
patency was 62.2 h, confirming adequate anticoagulation
over time. Thus, despite high cumulative doses of citrate
during a mean dialysis period of 19 days, citrate
accumulation occurred in only 23% of patients.
Metabolism of administrated citrate can induce
metabolic alkalosis. Under physiological conditions citrate is
cleared by the citric acid cycle (tricarboxylic acid cycle),
resulting in 3 mmol of NaHCO3− per 1 mmol of
trisodium citrate [
]. In the literature the incidence of
alkalosis during RCA with citrate is reported in 23–55% of
]. Different citrate formulations and
HCO3− concentrations of the dialysate or replacement
solutions may partially explain these different incidences
of alkalosis. However, the occurrence of alkalosis also
depends on rapid metabolism of citrate. This is thought
to be dependent mainly on liver function . In
onefourth of patients in our study, metabolic alkalosis
occurred, in line with other reported incidences. Of note,
in contrast to studies reporting on alkalosis, all of our
included patients had severely impaired liver function.
We interpret this fact as a further indication of our
former described hypothesis that an adequate citrate
metabolism must be possible also outside the liver.
In the literature, citrate metabolism is primarily
associated with hepatic function. Therefore, baseline liver
function parameters should be predictive regarding citrate
accumulation during CRRT with RCA. However, most
standard laboratory liver function parameters showed
poor predictive capabilities [
3, 6, 26
]. This raises the
question whether impaired hepatic function is really the main
reason for accumulation of citrate. This poor prediction of
citrate accumulation by parameters of liver function
appears to be a further indication that an effective
extrahepatic metabolism of citrate seems to exist. Our results are
consistent with the recently published study by Slowinski
and colleagues [
]. However, the reported observation
period of CRRT was 3 days (first 72 h of CRRT). Thus,
comparability with our study is limited.
Because in all cells citrate can be metabolised within
the Cori cycle (tricarboxylic acid cycle), we hypothesise
that an impaired perfusion on the microvascular and
cellular levels is critical to the metabolism of citrate.
This hypothesis is supported by the observations of
Schultheiss and colleagues, who described a baseline
serum lactate level ≥ 3.4 mmol/L as a predictor of
citrate accumulation [
], and of Link and colleagues, who
showed that in patients with signs of citrate
accumulation, mean arterial blood pressure was lower and dose
of norepinephrine was higher than in those without
citrate accumulation [
]. This hypothesis has also been
suggested by recent studies, some of them pointing at
] or, more specifically, at lactate
kinetics during treatment [
] as a useful predictor for
citrate accumulation. Disturbed microvascular
circulation could also cause altered hepatic function, resulting
in an association of impaired liver function and citrate
accumulation. This hypothesis would also explain why
in the literature inconsistent results exist concerning
liver function and accumulation of citrate. Moreover, a
correlation was described between the tCa/iCa ratio
and hepatic clearance measured by the ICG-PDR and
multi-organ dysfunction measured by SAPS II score
during CRRT-RCA [
]. On the basis of our data, we
cannot prove the hypothesis that shock and disturbed
microcirculation are mainly responsible for disturbed
citrate metabolism. However, patients developing
citrate accumulation had a higher need for vasopressor
therapy and showed lower ICG-PDR. In addition,
reduced ICG-PDR is not only a sign of impaired liver
function but also was recently shown to be correlated
with impaired hepatic perfusion [
The retrospective design of this study limits the
meaningfulness of our hypothesis. The number of included
patients is quite small. This could result in bias despite
the long dialysis period and the high number of dialysis.
Furthermore, ICG-PDR is not available in all centres and
was not performed in all patients in our centre. Because
the duration of MARS results in discontinuity of the
load with citrate, this may have an impact on metabolic
complications. Not all laboratory data are available in all
patients at all time points desired for this evaluation.
Our findings may serve to somewhat dispel the notions
that RCA is contraindicated in critically ill patients with
impaired liver function. Citrate metabolism seems not to
be restricted to the liver. Therefore, liver failure in
patients treated by CRRT with RCA does not automatically
result in accumulation of citrate. However, caution and
close monitoring of metabolic disorders are needed
because wrong management of RCA can result in
serious adverse effects in critically ill patients with
impaired liver function. Further studies are warranted to
confirm our findings.
BMI: Body mass index; CHE: Cholinesterase; CKD-EPI: Chronic Kidney Disease
Epidemiology Collaboration equation; CRRT: Continuous renal replacement
therapy; CRRT-RCA: Continuous renal replacement therapy with regional
citrate anticoagulation; CVVHD: Continuous venovenous haemodialysis;
eGFR: Estimated glomerular filtration rate; HCO3−: Bicarbonate;
ICGPDR: Indocyanine green plasma disappearance rate; ICU: Intensive care unit;
L-CAT: Liver citrate anticoagulation threshold; MARS: Molecular Adsorbents
Recirculation System; MELD: Model for End-stage Liver Disease; n.s.: Not
significant; RCA: Regional citrate anticoagulation; RRT: Renal replacement
therapy; SAPS II: Simplified Acute Physiology Score II; tCa/iCa: Total serum
calcium/ionised serum calcium; TISS: Therapeutic Intervention Scoring
No financial support was received for this study.
Availability of data and materials
Not applicable in this retrospective evaluation of clinical data.
MK designed the study. MK, TSp, DF, HVG and AR were responsible for
medical care. TSt, MK and TSp performed analysis of clinical data and
interpreted the data. TSt and MK wrote the manuscript. All authors discussed
the results and implications and commented on the manuscript at all stages.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable; see the Methods section of the main text.
Consent for publication
Not applicable; see the Methods section of the main text.
MK received speaker fees from Baxter, Fresenius Medical Care and
Cytosorbents, DF received honoraria from Fresenius Medical Care. The other
authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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