Acid-Base Disorders and Regional

Citrate Anticoagulation with Continuous 30

Renal Replacement Therapy

C. Ichai, H. Quintard, and L. Velly

30.1 Introduction

Citrate delivery with continuous renal replacement therapy (CRRT) enables ­provision
of real regional anticoagulation. Several meta-analyses have strongly confirmed that
regional citrate anticoagulation (RCA) is more efficient (longer circuit lifespan) and
safer (lower bleeding risk) than heparin [1–3]. Besides these beneficial effects, three
recent high-quality randomized controlled trials (RCTs) have demonstrated that met-
abolic complications are now uncommon, transient and easily preventable when
RCA is implemented using a formalized strategy [4–6]. Therefore, RCA is now rec-
ommended as the first choice for anticoagulation during CRRT [7, 8].
In this chapter, we summarize current knowledge on the interaction between
CRRT and citrate metabolism and its consequences in terms of acid-base adverse
effects. The final paragraph provides some practical management approaches aimed
at preventing and treating these effects appropriately at the bedside.

C. Ichai (*)
Polyvalent Intensive Care Unit, Hôpital Pasteur 2, University Hospital of Nice,
University Côte D’Azur, Nice, France
e-mail: ichai@unice.fr
H. Quintard
Polyvalent Intensive Care Unit, Hôpital Pasteur 2, University Hospital of Nice,
University Côte D’Azur, Nice, France
UMR 7275 CNRS, Valbonne, France
L. Velly
Department of Anesthesiology and Critical Care Medicine, Institut de Neuroscience de la
Timone (INT), University Hospital La Timone, Aix Marseille University, Marseille, France

© Springer Nature Switzerland AG 2019 383

J.-L. Vincent (ed.), Annual Update in Intensive Care and Emergency
Medicine 2019, Annual Update in Intensive Care and Emergency Medicine,
https://doi.org/10.1007/978-3-030-06067-1_30
384 C. Ichai et al.

30.2 Citrate in CRRT: General Considerations

Understanding the pharmacokinetics of citrate is essential to comprehend the devel-

opment of acid-base disorders related to RCA during CRRT. Most commercialized
citrate solutions exclusively contain trisodium citrate to provide a prolonged effect.
Under physiological conditions, trisodium citrate is converted into citric acid within
30 min. This latter enters the tricarboxylic acid cycle and is finally metabolized into
CO2, H2O and ATP through the mitochondrial oxidative phosphorylation pathway
[9–11]. This reaction is mainly performed by the liver and to a lesser extent by
skeletal muscle and the renal cortex. Citrate metabolism is characterized by a short
systemic half-life of 5 min. This saturable reaction can be impaired and reduced in
case of liver failure and in all conditions associated with an altered Kreb’s cycle or
mitochondrial oxidation caused by hypoxia or toxics. The major role of the liver in
citrate metabolism has been confirmed by Kramer et al. [10]. These authors reported
a substantial altered citrate metabolism, which was characterized by a 50% reduc-
tion in total body clearance in patients with compared to those without cirrhosis.
Trisodium citrate acts by chelating calcium, which is a major element of the
coagulation cascade. Briefly, 2 trisodium molecules react with 3 molecules of cal-
cium to produce a citrate-calcium (Cit-Ca++) complex while releasing 6 molecules
of sodium (Fig. 30.1). With usual doses of RRT, approximately 60% of these com-
plexes are removed through the filter regardless of the convective or diffuse modal-
ity. However, because of its close relationship with the effluent rate (ultrafiltration/
dialysate), this amount can vary. The remaining Ca++ released from the non-removed

2 TRISODIUM CITRATE 1 CITRATE-CALCIUM complex

H H H H
O O
OH C C OH C C
O-Na+ O O-
O
C C C C
H H
O-Na+ O Ca++
O O
C 3 Ca ++ C C
C

H O-Na+ H O-
Hypocalcemia
Ca++
H H H H
O O-
Hypernatremia
OH C C OH C C
+
-
O Na + 6 Na O
O O
C C C C
H H
O-Na+ O-
O O
C C C C
Ca++
H O-Na+ H O-

Fig. 30.1 Trisodium citrate and calcium chelation. Two molecules of trisodium citrate are
­converted into one complex of citrate-calcium leading to a simultaneous systemic ionized hypocal-
cemia (fixation of 3 molecules of ionized calcium) and hypernatremia (release of 6 molecules of
sodium)
30 Acid-Base Disorders and Regional Citrate Anticoagulation with Continuous… 385

Cit-Ca++ induces a partial systemic ionized calcium (iCa++) return in the total cal-
cium blood pool. Therefore, blood calcium supplementation is needed to compen-
sate for losses through the filter [9, 11, 12].

30.3 Acid-base Disorders and RCA

The Stewart approach is now accepted as the more comprehensive concept to pre-
cisely identify and quantify complex acid-base disorders [13–16]. Briefly, the
Stewart concept assumes that the pH depends on three independent variables:
PaCO2, strong ion difference (SID) and weak anions (albuminate, phosphate) [17].
Any modification of one of these parameters causes pH variations. Accordingly,
hypercapnia causes respiratory acidosis (and conversely). Metabolic abnormalities
are the consequences of changes in SID or weak acids. In these situations, the abso-
lute rule of electroneutrality, i.e., the equilibrium between positive (cations) and
negative (anions) charges, lead to acidosis or alkalosis. As a consequence, any
reduction in SID is responsible for a metabolic acidosis by decreasing bicarbonate
concentration. An increase in any strong anion (hyperlactatemia, hyperketonemia)
or decrease in strong cation (hyponatremia) induces a reduction in SID and, in turn,
a metabolic acidosis (and conversely). Finally, changes in weak acid concentration
represent the second cause of metabolic acid-base disturbances. Physiological weak
acids are albuminate− and phosphate− while citrate− is an exogenous weak metabo-
lizable anion. Elevation in weak acids is responsible for metabolic acidosis (hyper-
phosphatemia or hyperalbuminemia). In the absence of acid base disorders, the
normal value of PaCO2 is 40 mmHg, of SID is 39 meq/L (Fig. 30.2). Trisodium
citrate can cause complex and various acid base disorders, depending on citrate load
and a patient’s capacity to metabolize it.
During RCA, metabolic acidosis may be the consequence of two different mech-
anisms which must be identified to deliver the appropriate treatment. First, meta-
bolic acidosis caused by citrate accumulation occurs when citrate metabolism is
impaired leading to hypercitratemia. As previously mentioned, the increase in the
negatively charged citrate− leads to a decrease in bicarbonate concentration (the
main plasma buffer) to maintain electroneutrality and creates metabolic acidosis. In
this situation, the SID is normal and the cause of the problem is hypercitratemia
(Figs. 30.3a and 30.4a). However, other anions, especially strong metabolizable
anions (lactate) can participate partly to the development of metabolic acidosis. The
presence of such anions is identified by a reduction in the SID and an increase in the
strong ion gap (difference between the apparent and the effective SID), which indi-
cates the presence of excessive strong metabolizable anion (Figs. 30.3b and 30.4b).
Hyperlactatemia is frequently associated with hypercitratemia [18]. Finally, meta-
bolic alkalosis related to hypoalbuminemia can counteract or minimize the acidify-
ing effect of hypercitratemia or hyperlactatemia, and lead to an incorrect
interpretation in case of normal pH.
Because the level of citratemia is not routinely available in clinical practice,
citrate accumulation must be suspected and recognized from indirect warning
386 C. Ichai et al.

Acidotic effect Alkalotic effect

a b
39 meq/L cations anions
SID
40 mmHg

PaCO2
Cl-
40 g/L
Alb
Na+

0.8 mmol/L
Phosph
HCO3- eSID

+
Alb-
K
HCO3- Alb- 14 meq/L Ca
++ Phosph-
Mg
++
UA- aSID SIG
24 meq/L pH Phosph- 1.8 meq/L
7.40

Fig. 30.2 Schematic representation of the acid base equilibrium in physiological conditions
according to the Stewart concept. (a) The three independent variables of the pH value: PaCO2,
strong ion difference (SID) and weak acids (albuminate [Alb−] and phosphate [phosph−]).
Hypercapnia causes respiratory acidosis (and conversely). Regardless of the specific cause, any
reduction in SID or elevation in weak acid, is responsible for metabolic acidosis (and conversely).
Normocapnia (40 mmHg) associated with a normal albumin (40 g/L), phosphate (0.8 mmol/L) and
SID (39 meq/L) leads to an acid-base equilibrium within normal range. (b) Schematic representa-
tion of plasma electroneutrality with the major cations (positive charges) and anions (negative
charges). The effective SID (eSID) is calculated using the following formula: eSID = (HCO3− + albu-
minate− + phosphate−) = 39 meq/L; the apparent SID (aSID) = (Na+ + K+ + Ca++ + Mg++) − (Cl−)
= 45 meq/L. The strong ion gap (SIG), which is the difference between the aSID and the eSID,
indicates the presence of unmeasured strong anions (UA; normal value = 5–8 meq/L)

signs. The most popular of these is the increased total to ionized calcium ratio
(Catot/iCa++) above 2.5: Catot increases due to the accumulation of Cit-Ca++ com-
plexes while iCa++ remains low and protein-bound calcium unchanged (Fig. 30.5)
[19]. The Catot/iCa++ ratio is closely correlated with citrate plasma level and a cut-
off >2.5 mmol/L appears accurate to predict citrate accumulation [18–20].
Persistent ionized hypocalcemia, despite a progressive increase in calcium sup-
plementation, seems to be the most sensitive and earliest sign of citrate accumula-
tion. A trend towards abnormal values is probably a good and early marker of
citrate accumulation rather than an absolute cut-off. Finally, hyperlactatemia is an
interesting surrogate marker of altered citrate metabolism due to an impaired
Krebs’ cycle [18, 21, 22].
Second, metabolic acidosis caused by insufficient trisodium citrate delivery
occurs when the amount of citrate is low (low blood flow) with respect to the amount
of Cit-Ca++ removed (high ultrafiltration or dialysate flow). With such a setup, the
30 Acid-Base Disorders and Regional Citrate Anticoagulation with Continuous… 387

a b c
Acidotic effect Acidotic effect Alkalotic effect

39 meq/L Hypernatremia
SID SID High
40 mmHg 40 mmHg SID
40 mmHg
PaCO2 PaCO2
PaCO2
40 g/L
40 g/L
Alb 40 g/L
Alb
Alb
Citrate
Citrate
0.8 mmol/L 0.8 mmol/L 0.8 mmol/L
Phosph Phosph Phosph

HCO3- Alb- HCO3- Alb- HCO3- Alb-

pH Phosph- pH Phosph- pH Phosph-

Metabolic acidosis caused Metabolic acidosis caused Metabolic alkalosis caused

by hypercitratemia by hyperlactatemia by excessive citrate delivery

Fig. 30.3 Regional citrate anticoagulation-related metabolic acid base disorders according to the
Stewart concept. (a) Because citrate is a weak metabolizable anion, hypercitratemia (citrate accu-
mulation) causes metabolic acidosis (low pH and bicarbonate values) providing there is no change
in other weak acids, PaCO2 or strong ion difference (SID). (b) Because lactate is a strong metabo-
lizable anion, hyperlactatemia causes metabolic acidosis by decreasing the SID (high pH and
bicarbonate values) providing there is no change in weak acids or PaCO2. (c) Because sodium is a
strong non-metabolizable cation, hypernatremia, which results from excessive citrate delivery and
metabolism, causes metabolic alkalosis by increasing the SID (low pH and bicarbonate level)
providing there are no changes in weak acids or PaCO2. Alb albumin; Alb− albuminate; Phosph
phosphorus; Phosph− phosphate

low citrate delivery associated with high citrate removal does not enable a sufficient
alkalinizing effect of citrate metabolism. Contrary to what happens with citrate
accumulation, metabolic acidosis is associated with normal citrate metabolism.
Metabolic alkalosis caused by trisodium citrate overload occurs when the amount
of trisodium citrate delivery is excessive or its filter clearance is insufficient while
the Cit-Ca++ complexes are normally metabolized. According to the Stewart con-
cept, when citrate is metabolized, the non-metabolizable cation, sodium, is simulta-
neously released and persists in the plasma. To maintain electroneutrality,
bicarbonate increases and in turn, the SID too, leading to metabolic alkalosis
(Figs. 30.3c and 30.4c) [13, 17]. However, because citrate produces H2O and CO2,
the final alkalinizing effect of trisodium citrate depend on the patient’s capacity to
excrete CO2. If there is altered CO2 elimination, the metabolic alkalosis can be
replaced by respiratory acidosis (hypercapnia).
In summary, RCA can be responsible for complex acid-base disorders. Citrate,
which is a weak acid, is the cause of metabolic acidosis essentially due to an impair-
ment in its metabolism, with citrate accumulation. The non-metabolizable cation,
sodium, which is released when trisodium citrate is metabolized, is responsible for
the development of metabolic alkalosis. This latter disorder indicates citrate
overload.
388 C. Ichai et al.

a b c
cations anions cations anions
cations anions

Cl- Cl-
Cl-

Na+ Na+ Na+

HCO3- HCO3-
HCO3-
Alb- eSID Alb- eSID
eSID
Phosph- Phosph- Alb-
K+ Citrate- K
+
Lactate aSID K+
-
Ca++ Ca
++
+ UA- SIG Ca
++
Phosph
Mg++ UA- aSID Mg++ Mg++ UA- aSID
Metabolic acidosis caused Metabolic acidosis caused Metabolic alkalosis caused
by hypercitratemia by hyperlactatemia by citrate metabolization

Fig. 30.4 Plasma electroneutrality during regional citrate anticoagulation (RCA)-related acid-­
base disorders. The effective strong ion difference (eSID) is calculated using the following for-
mula: eSID = (HCO3− + albuminate− + phosphate−); the apparent SID (aSID) = (Na+ + K+ + Ca++
+ Mg++) – (Cl−). Strong ion gap (SIG) = aSID − eSID. (a) Metabolic acidosis caused by hypercit-
ratemia (citrate accumulation). To maintain plasma electroneutrality, the accumulation of the weak
anion, citrate−, leads to a decrease in bicarbonate (the major plasma buffer) and pH. Neither eSID
nor aSID change as there is no change in strong cations or anions. (b) Metabolic acidosis caused
by hyperlactatemia. To maintain plasma electroneutrality, the accumulation of the strong anion,
lactate−, leads to a decrease in bicarbonate (the major plasma buffer) and pH. Consequently the
eSID decreases while the SIG increases indicating the presence of abnormal strong anions, in this
case, lactate−. (c) Metabolic alkalosis caused by trisodium citrate metabolism. Metabolism of
excessive trisodium delivery leads to the release of citrate, which disappears during metabolism,
and sodium, which is non-metabolizable and remains in the plasma. To maintain plasma electro-
neutrality, hypernatremia induces an increase in the eSID by increasing the bicarbonate negative
charges. As a result, plasma pH elevates. Phosph− phosphate; Alb− albuminate; UA− unmeasured
strong anions (lactate, ketone bodies)

30.4  ractical Management of Acid-base Disorders Related

P
to RCA

The reported incidence of RCA-related acid-base disorders varies in the literature

[21, 23–29]. Multiple reasons likely contribute to this large variability, including the
technique, the types of patients, the absence of appropriate setup and monitoring
and above all the absence of formalized protocols, expertise and training of the team
for this modality of anticoagulation [12, 30, 31]. The incidence of the syndrome of
citrate accumulation with metabolic acidosis is now rare (approximately 5% of
patients). A higher incidence was reported in patients with acute liver failure reach-
ing up to 12% [5, 19, 23, 25, 27]. More recently, studies performed in patients with
liver failure failed to demonstrate a greater risk of citrate accumulation provided a
30 Acid-Base Disorders and Regional Citrate Anticoagulation with Continuous… 389

3.5

2.5 Cit-Ca++
Cit-Ca++
Calcium (mmol/l)

2
Protein
bound Protein
Total calcium
1.5 Ca++ bound Protein
Ca++ Ratio bound Ratio
<2.5 Ca++ >2.5
1

0.5 iCa++

iCa++ iCa++
0
Physiological Citrate Citrate
condition overdose accumulation

Fig. 30.5 Distribution of total plasma calcium in physiological conditions and during regional
citrate anticoagulation with continuous renal replacement therapy. In physiological conditions,
50% of total plasma calcium (2.2–2.6 mmol/L) is distributed in an ionized form (iCa++ 1.1–
1.3 mmol/L), 10% in complexed form (0.05 mmol/L) and 40% in protein-bound form (0.95–
1.2 mmol/L). In citrate overdose, the presence of citrate-Ca++ complex (Cit-Ca++) is associated with
ionized hypocalcemia and usually with total hypocalcemia. The ratio of total calcium to iCa++
(Catot/iCa++) is <2.5 because protein Ca++ does not change. In citrate accumulation, the presence of
high levels of Cit-Ca++ with ionized hypocalcemia leads to an elevation of Catot/iCa++ to >2.5 as
protein Ca++ does not change

formal protocol was used with close monitoring by an expert trained team [21, 28].
However, it is difficult to really predict this risk as usual laboratory tests (bilirubine-
mia, transaminase levels) poorly reflect liver dysfunction. Hyperlactatemia
>3.4 mmol/L (and lactate kinetics) and a low prothrombin time (≤25%) seem to be
the most accurate indicators of citrate accumulation in patients with severe liver
dysfunction [21]. In these situations, patients also present with hyperlactatemic
metabolic acidosis before starting citrate delivery due to severe hemodynamic insta-
bility. Although rare, citrate accumulation develops within the first 24 h and resolves
rapidly with the appropriate treatment.
Metabolic alkalosis is the most common metabolic disorder caused by RCA dur-
ing CRRT. Its incidence can reach up to 50% of patients [23, 28, 29]. Usually, meta-
bolic alkalosis remains moderate without severe clinical consequences. It develops
later than metabolic acidosis, within 48–72 h. Schultheiß et al. [21] found that meta-
bolic acidosis was already present at baseline in 65% of patients with liver failure
receiving RCA; normalization of bicarbonate was obtained after 24 h in 60% of
cases but, after 72 h, metabolic alkalosis developed in 53% of patients.
390 C. Ichai et al.

30.4.1 Prevention of Acid-base Disorders Related to RCA

Three large RCTs have reported no differences in metabolic derangements, espe-

cially for acid-base adverse effects between RCA and heparin anticoagulation dur-
ing CRRT. Regardless of the precise modality, these disorders were uncommon,
transient and resolved early in experienced centers [4–6]. Two major recent meta-­
analyses confirmed that the incidence of metabolic alkalosis was comparable
between RCA and heparin [1, 3], while another reported an increased risk [2].
Indeed, it is not the acid-base disorders by themselves, but rather the resulting ion-
ized hypocalcemia, which is more frequently observed with RCA, that may cause
severe clinical complications. Nevertheless, these data must be interpreted with cau-
tion as patients at risk were not included.
The prevention of RCA-related complications is based on the implementation of
a proper technique including the choice of the most appropriate modality (dedicated
machines and fluids), and education and training of the healthcare professionals
involved in this management [30–32]. It is necessary to create an in-home formal
protocol that includes as a minimum the optimal setup of the devices, patient and
machine monitoring (especially the alarms) and regular evaluation of the quality of
the management. In these conditions, RCA can be performed with all continuous
diffuse and convective modalities with comparable efficiency and safety [9, 12, 31].
RCA requires a device equipped with a blood flow coupled to citrate delivery to
maintain a stable citrate concentration. However, such a control loop forces reduced
blood flows compared with heparin, to prevent excessive citrate delivery. Citrate
solution is delivered in the arterial line. A citratemia target between 3 and 4 mmol/L
provides effective anticoagulation with a minimal risk of bleeding. This objective is
obtained by measuring the postfilter iCa++ with a value of 0.25–0.35 mmol/L. Such
close monitoring is essential to prevent unplanned blocks of the circuit caused by
clotting and risks of bleeding [33, 34]. However, the accuracy of this measurement
is poor with large over- and underestimations according to the machine [35, 36].
Accordingly, it is strongly suggested that the targeted value of postfilter iCa++ should
be adjusted and personalized using the bedside blood gas analyzer. Losses of
Cit-Ca++ through the filter require calcium supplementation to be provided. Calcium
infusion is performed after the filter on the ‘venous’ line as close as possible to the
patient to avoid recalcification of the circuit. The target is to achieve physiological
values of 1.1–1.3 mmol/L. Ionized hypocalcemia represents the most serious meta-
bolic complication of RCA, affecting 12–18% of patients [37, 38]. Fortunately, the
incidence of severe hypocalcemia associated with shock or profound hypotensive
episodes remains low (2.5%). To prevent such a complication, it is recommended to
favor devices with a feedback control between the citrate and the calcium supple-
mentation pumps, to always normalize the patient’s iCa++ before starting RCA and
to monitor it closely during the therapy. Only specifically formulated dialysate and
substitution solutions are available and must be calcium-free, with low
30 Acid-Base Disorders and Regional Citrate Anticoagulation with Continuous… 391

concentrations of sodium and bicarbonate and high concentrations of chloride. This

is essential to counteract the development of metabolic alkalosis and hypernatremia
caused by the trisodium citrate solution. For similar reasons, it is preferable to favor
calcium chloride rather than calcium gluconate. Exclusive convective modalities
(continuous venovenous hemofiltration [CVVH]) are performed with low-­
concentration solutions (18 mmol/L of citrate) which lead to high predilution and
may reduce the capacity of clearance. Therefore, ultrafiltration must be used exclu-
sively in postdilution with a sufficient rate (20–25 mL/kg/h). Blood flow in CVVH
must not exceed 150–160 mL/min. The disadvantage of this strategy is that the
anticoagulation effect is coupled with the predilution volume, which partially deter-
mines the clearance. High trisodium citrate solution (140 mmoL/L) is required with
the diffusive modality (continuous venovenous hemodialysis [CVVHD]) to reach
the targeted concentration of citrate in the circuit while maintaining low blood flow
to prevent citrate overdose. Blood flow must be less than with CVVH at between 80
and 120 mL/min and dialysate rate between 1500 and 2000 mL/h. Thanks to the
dialysate solution, it is easily possible to modulate blood bicarbonate concentration
and to compensate metabolic acid base disorders. Consequently, RCA with CVVHD
cannot be performed in patients requiring high blood flows. As recommended with
heparin, it is mandatory to correctly interpret the pressure alarms and to check and
manage them appropriately.
RCA requires closer biological monitoring than when using heparin. Ionized
hypocalcemia is the most serious complication that can worsen patient outcomes.
To prevent it, it is crucial to measure baseline iCa++ and any initiation of RCA is
strictly prohibited before normalizing this value. Approximately 15–30 min from
the start of RCA, iCa++ must be checked, then hourly within the first 3 h and every
6 h in stable situations. Any new adjustment requires a new control measurement
approximately 30 min later. The calculation of Catot/iCa++ ratio is usually performed
daily, but close monitoring (3 times per day) is necessary in conditions at risk of
citrate accumulation. Baseline arterial blood gas and electrolyte (sodium, chloride,
potassium, magnesium and phosphate) measurements are needed followed by
repeated measurements every 6–8 h in stable situations. Hyperlactatemia and lack
of normalization of lactate levels may be a good early indicator of citrate accumula-
tion and must be checked regularly in patients at risk [18, 21]. An example of a
protocol indicating how to approach biological monitoring in patients receiving
RCA is summarized in Box 30.1.
In summary, all convective and diffusive modalities (CVVH, CVVHDF,
CVVHD) are comparable in terms of efficiency and safety enabling control of
citrate losses via the total effluent rate (ultrafiltration and/or dialysate rate). Despite
substantial improvements in simplicity, ergonomy and automation of devices, the
appropriate setting, close monitoring, and expertise of the healthcare team are
needed to elaborate a formalized protocol and prevent RCA-related adverse effects,
especially acid-base derangements.
392 C. Ichai et al.

Box 30.1: An Example of Patient and Filter Biological Monitoring During

Regional Citrate Anticoagulation

The patient (arterial samples) The circuit (postfilter samples)

Measure systemic iCa++ to adjust calcium Measure postfilter iCa++ to adjust
supplementation citrate concentration
• Baseline before starting • 15 min after starting
• 15–30 min after initiation and 30 min after • The 1 h after initiation
any adjustment • 30–60 min after any adjustment
• Every hour within the first 3 h • Every 6–8 h if postfilter iCa++ is
• Every 6 h if iCa++ is stable stable and in the target range
Measure total systemic calcium to calculate the
total calcium/iCa++ ratio
• Daily if stable
• Every 6–8 h in patients at risk of citrate
accumulation (medical prescription)
Arterial blood samples
• Blood gas (pH, bicarbonates, PaCO2), Na,
Cl, K, magnesium, and phosphate daily
Additional and more frequent measurements on
medical prescription

30.4.2 Treatment of Acid-base Disorders Related to RCA

30.4.2.1 Metabolic Acidosis Related to Citrate Accumulation

Citrate by itself is not toxic or dangerous except in cases of very high accumulation,
which may result in vasodilation. The real clinical risk is the development of sub-
stantial hypotension or shock caused by the resulting persistent severe systemic
ionized hypocalcemia. The two most frequent causes of citrate accumulation are a
violation of protocol or use in patients at risk [11, 24]. However, liver failure, shock
and some intoxications (metformin, cyclosporine, paracetamol) are not absolute
contraindications for RCA during CRRT provided closer than usual monitoring is
performed by an experienced team. In this condition, the risk of citrate accumula-
tion is negligible, easily suspected and rapidly treated [11, 21, 28, 39]. The sole real
treatment for citrate accumulation, especially with severe ionized hypocalcemia and
metabolic acidosis, is to stop citrate delivery while increasing Cit-Ca++ complex
clearance with a sufficient effluent rate (dialysate or ultrafiltration rate) and normal-
izing the systemic iCa++ value. The removal of citrate will lead to an ‘endogenous’
alkalization and a progressive restoration of a normal pH. If citrate accumulation
and metabolic acidosis are slight and caused by an incorrect circuit setup, an adjust-
ment consisting of a reduction in blood flow (to decrease citrate delivery) associated
with an increase in the effluent rate (to elevate citrate losses) can be cautiously
proposed aimed at a rapid normalization of metabolic disorders (Box 30.2).
30 Acid-Base Disorders and Regional Citrate Anticoagulation with Continuous… 393

Box 30.2: An Example of a Formalized Protocol to Prevent and Treat Metabolic

Complications

Metabolic Associated Corrective measures (associated with medical

abnormality abnormalities help & prescription)
Ionized hypocalcemia
• Before initiation • Hypotension • Infuse 1 amp i.v. of CaCl2 in central vein (or
2 amp i.v. of Ca gluconate in peripheral
vein) to normalize Ca++
• During • Hypotension
maintenance
– Line • Check the calcium infusion line
disconnection
– Citrate • Metabolic • Suggested if hypoCa++ persists despite
accumulation acidosis increasing supplementation (>130%)
• Confirm it by a Ca total/Ca++ ratio >2.5
• Stop citrate & continue CVVH/CVVHD
while increasing ultrafiltration/dialysate rate
Unexplained • Metabolic • Infuse 1 amp i.v. of CaCl2 in central vein (or
hypotension alkalosis 2 amp i.v. of Ca gluconate in peripheral vein)
Postfilter ionized • Reduce the citrate dose
hypocalcemia
CVVH continuous venovenous hemofiltration; CVVHD continuous venovenous hemodialysis;
i.v. intravenous

30.4.2.2 Metabolic Alkalosis Caused by Trisodium Citrate Overload

This disorder can be easily resolved by reducing the blood flow and in turn the
excessive citrate delivery and by increasing the effluent rate too (Box 30.2).

30.4.2.3  etabolic Acidosis Caused by Insufficient Trisodium

M
Citrate Delivery
This disorder is caused by an inappropriate circuit setup due to low citrate delivery with
low blood flow associated with too high citrate removal, especially with CVVHD. The
treatment consists of increasing blood flow and decreasing the dialysate rate.

30.5 Conclusion

RCA is now the preferred anticoagulation modality performed during CRRT. Despite
considerable effort to improve safety, ergonomy and simplicity of devices, RCA
remains a clinical challenge for healthcare professionals in critically ill patients.
Major complications consist of metabolic acidosis caused by citrate accumulation
and metabolic alkalosis caused by citrate overload. Citrate accumulation is usually
rare and potentially severe in case of simultaneous severe ionized hypocalcemia.
394 C. Ichai et al.

Metabolic alkalosis related to citrate overload is frequent but transient and easily
resolved. Such disturbances are essentially due to protocol violation or use in
patients at risk with inadequate monitoring. To prevent complications, formal pro-
tocols should be used that include all specificities in term of setup of devices, appro-
priate fluids, patient and circuit monitoring and an expert team should be created by
continuous education and training.

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