Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

In-Depth Review

Regional Citrate Anticoagulation for RRTs in CriticallyIll Patients with AKI

Santo Morabito,* Valentina Pistolesi,* Luigi Tritapepe,† and Enrico Fiaccadori‡

AbstractHemorrhagic complications have been reported in up to 30% of critically ill patients with AKI undergoing RRTwith systemic anticoagulation. Because bleeding is associated with significantly increased mortality risk,strategies aimed at reducing hemorrhagic complications while maintaining extracorporeal circulation should beimplemented. Among the alternatives to systemic anticoagulation, regional citrate anticoagulation has beenshown to prolong circuit life while reducing the incidence of hemorrhagic complications and lowering transfusionneeds. For these reasons, the recently published Kidney Disease Improving Global Outcomes Clinical PracticeGuidelines for Acute Kidney Injury have recommended regional citrate anticoagulation as the preferredanticoagulation modality for continuous RRT in critically ill patients in whom it is not contraindicated. However,the use of regional citrate anticoagulation is still limited because of concerns related to the risk of metaboliccomplications, the complexity of the proposed protocols, and the need for customized solutions. The introductionof simplified anticoagulation protocols based on citrate and the development of dialysis monitors with integratedinfusion systems and dedicated software could lead to the wider use of regional citrate anticoagulation inupcoming years.

Clin J Am Soc Nephrol 9: 2173–2188, 2014. doi: 10.2215/CJN.01280214

IntroductionAlthough AKI is a well recognized high–bleeding riskcondition (1), the patency of the extracorporeal circuitfor RRT is usually maintained by the use of systemicanticoagulation with unfractionated heparin (2,3).However, a high incidence of hemorrhagic complica-tions has been documented in patients undergoingRRT in the intensive care unit (ICU), with wide var-iability (5%–30%) related to differences in patientpopulations and anticoagulation protocols (4–7).Thus, the choice of the anticoagulant strategy, possi-bly limited to the extracorporeal circuit (i.e., regionalanticoagulation), represents a key issue for safe andeffective RRT in AKI. Although RRT can be per-formed without anticoagulation (8–11), this approachincreases the risk of delivering low RRT doses in upto 30% of patients (12) because of shorter circuit life,increased downtime, and reduced filter performance(12–14).

A number of recent clinical studies has shownadvantages of regional citrate anticoagulation (RCA)compared with heparin in terms of prolonged circuitlife, reduced incidence of hemorrhagic complications,and lower transfusion needs (14–19). On the basis ofthese data, the 2012 Kidney Disease ImprovingGlobal Outcomes (KDIGO) Clinical Practice Guide-lines for Acute Kidney Injury recommend use ofRCA as the preferred anticoagulation modality forcontinuous RRT (CRRT) in patients without contra-indications for citrate, even in the absence of an in-creased bleeding risk or deranged coagulation (20). Inaddition, the same guidelines also recommend using

RCA rather than no anticoagulation in patients with ahigh risk of bleeding (20). These KDIGO guidelineswere also endorsed by the Canadian Society of Ne-phrology (21). However, issues remain regardingthe use of citrate for RRT in AKI, including a cleardefinition of potential contraindications to its use,heterogeneity of RCA protocols, optimal bedsidemonitoring, and cost.This review provides a critical overview of the use

of RCA in patients undergoing RRT for AKI. Themetabolism and kinetics of citrate will be discussedalong with the advantages and potential drawbacksof RCA in the clinical setting of AKI in the ICU.Moreover, the practical application of RCA for variousRRT modalities will be discussed in depth, includingfuture perspectives for simplification of RCA proto-cols.

RCA: Basic Principles and Citrate MetabolismCitrate, the anionic salt of citric acid, is available at

various concentrations of the trisodium salt. Citrateanticoagulates the extracorporeal circuit by chelatingionized calcium (10,11,22), the key cofactor of manysteps of the clotting cascade (23). Additional antihe-mostatic and anti-inflammatory activities of citratemay indirectly derive from its effects on blood cellcomponents, including reduced activation of whiteblood cells and platelets (24–29), and protective ef-fects against endothelial-cell inflammation and dys-function (30). Furthermore, citrate may be directlyinvolved as a signal molecule in several cellular

*Department ofNephrology andUrology,Hemodialysis Unitand †Department ofAnesthesiology andIntensive Care,Sapienza University,Rome, Italy; and‡Department ofClinical andExperimentalMedicine, Acute andChronic Renal FailureUnit, ParmaUniversity, Parma,Italy

Correspondence:Dr. Santo Morabito,Department ofNephrology andUrology, Umberto I,Policlinico di Roma,Sapienza University,Viale del Policlinico,155 00161 Rome,Italy. Email: [email protected]

www.cjasn.org Vol 9 December, 2014 Copyright © 2014 by the American Society of Nephrology 2173

mailto:[email protected]

mailto:[email protected]

processes related to inflammation and balance of oxidativespecies (31). On this basis, citrate may behave as a trueanti-inflammatory agent (10,18).Citrate is infused in the most proximal portion of the RRT

circuit at rates proportional to blood flow. The infusionrates also vary with the concentration of the citrate solutionused and the target blood citrate concentration (Figure 1)(11,22). The citrate infusion rate is titrated to maintain lowionized calcium levels in the extracorporeal circuit that aresufficient to achieve full blood anticoagulation (i.e., 0.3–0.4mmol/L) (11,22); this target is generally attained with acitrate level in the extracorporeal circuit of approximately3 mmol/L (Figure 1) (32). Because both citrate anion andtrisodium citrate complexes have low molecular weight(198 and 258, respectively), high sieving coefficients(0.85–1), and high diffusive/convective clearances, a sig-nificant quantity of the citrate anions and calcium-citratecomplexes is lost in the effluent fluid (33,34). As a result,calcium infusion is usually needed to replace calciumlosses and maintain systemic ionized calcium levelswithin the normal range (Figure 1). Although some re-ports suggest possible differences in the rapidity of cal-cium release from calcium chloride (CaCl2) comparedwith calcium gluconate (35), chemically equivalent dosesof these formulations produce equally rapid increases insystemic ionized calcium during the anhepatic stage ofliver transplantation (36). Thus, simple dissociation ratherthan hepatic metabolism is probably the main mecha-nism for the release of ionized calcium from both prep-arations (36). In practice, 10% CaCl2 and 10% calciumgluconate solutions provide 0.68 and 0.226 mmol/mlelemental calcium, respectively.

Specific clinical situations, such as severe rhabdomyol-ysis, can potentially complicate the management of serumionized calcium concentrations during RCA (22,37). Al-though hypocalcemia is a common complication in theearly phase of rhabdomyolysis, full correction of calciumlevels is not recommended because of potentially harmfuleffects of excessive calcium supplementation (e.g., tissuecalcium deposition and episodes of late hypercalcemia)(38). Thus, a lower than usual systemic ionized calciumlevel (0.9–1 mmol/L) should be considered a reasonabletarget while performing RCA CRRT in this clinical sce-nario (22,37).Because ionized magnesium is also chelated by citrate,

this cation is also removed by RRT. However, magnesiumis partially replaced with dialysate and/or replacementfluid; therefore, the need for supplementation is related toexchanged volumes and the magnesium concentration inCRRT solutions (22,39).The metabolic load of citrate is the difference between the

citrate infused into the extracorporeal circuit and theamount of citrate lost in the effluent. This citrate load israpidly metabolized through the aerobic pathways of theKrebs cycle (tricarboxylic acid cycle) in the liver and to alesser extent, the skeletal muscle and the kidney (11,22).Thus, the final whole-body citrate balance, which is themain determinant of systemic citrate levels, results fromthe difference between the citrate load and metabolic dis-posal. Although the metabolic clearance of citrate is re-duced and the half-life is prolonged in patients withliver disease (40), no major differences in citrate kineticshave been documented in patients with AKI comparedwith subjects with normal renal function (41).

Figure 1. | RCA in continuous RRT: basic principles. *Sampling for systemic ionized calcium is from the circuit arterial line or the patient’sarterial line (to avoid the effects of vascular access recirculation). Systemic total calcium can be measured from a central venous line. CVVH,continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration;Qb, blood flow rate; RCA, regional citrate anticoagulation.

2174 Clinical Journal of the American Society of Nephrology

The ensuing bicarbonate production from citrate metab-olism along with bicarbonate in replacement/dialysisfluids provides the buffer supply to the patient. Indeed,for each 1 mmol citrate metabolized in the Krebs cycle,3 mmol hydrogen ions are consumed, and 3 mmol bicar-bonate is generated (11,22). In citrate solutions containingcitric acid, 3 mmol hydrogen ions are generated from each1 mmol citric acid, counterbalancing the ensuing 3 mmolbicarbonate. Therefore, although the citric acid contained insome citrate solutions contributes to attaining the targetblood citrate concentration and extracorporeal circuit anti-coagulation, it should not be considered as a buffer source.Finally, citrate also represents a source of carbohydrate-

like energy, providing 0.59 kcal/mmol (10,42). Thus, withthe more commonly reported citrate protocols, whichprovide a citrate load of 11–20 mmol/h, the energy de-rived from citrate is approximately 150–280 kcal/24 h.Moreover, when anticoagulant citrate dextrose solutionA (ACD-A) is used, which contains 2.5% dextrose, an ad-ditional caloric load is derived from dextrose metabolism(0.73 kcal/mmol), therefore providing 350–600 kcal/24 h.Lastly, in RCA protocols using lactate-buffered CRRT solu-tions, an additional supply of energy (500–600 kcal/24 h)may be derived from lactate (0.33 kcal/mmol). Therefore,the energy delivered from RRT fluid components (bothanticoagulation and replacement fluid) should be takeninto account when calculating the nutritional needs of crit-ically ill patients undergoing RRT (10,42,43).

Citrate Accumulation Risk and RCA MonitoringCitrate accumulation represents the most common com-

plication of RCA, with a reported incidence of 0%–12% ofpatients depending on the RCA protocol used and the pa-tient case mix (14,16,18,19,44–51). Because hepatic clear-ance represents the main metabolic fate of endogenousand exogenous citrate, citrate metabolism may be signifi-cantly slowed in clinical conditions where liver function isimpaired, with a higher risk of citrate accumulation andconsequent acid-base and electrolyte complications. Inclinical conditions such as severe liver failure or septic/cardiogenic shock, impaired citrate metabolism may pre-vent bicarbonate generation from citrate, leading to nega-tive buffer balance and metabolic acidosis during RCARRT. Moreover, inadequate citrate metabolism may be as-sociated with a fall in ionized serum calcium levels as theresult of impaired calcium release from the calcium-citratecomplexes. As a consequence, progressively higher cal-cium infusion rates may be required to maintain the ion-ized calcium concentration within physiologic limits, andthere may be a disproportionate rise in both the total sys-temic calcium concentration and the total-to-ionized cal-cium ratio (the calcium ratio) (11,22,44,52). In clinicalpractice, because the calcium ratio is related to the bloodcitrate concentration, it is commonly accepted as an indi-rect index of citrate accumulation during RCA (45,48,53–55). A calcium ratio.2.5 is considered the critical thresholdfor increased risk of metabolic complications caused byimpaired citrate metabolism (54). However, it has beenreported that a lower cutoff of 2.1 seems to accurately pre-dict citrate overdose (systemic citrate concentration.1mmol/L) with high sensitivity and specificity (89% and

100%, respectively) (55). It should be recognized that thesuggested cutoff values for the calcium ratio were obtainedwithout any adjustment of total systemic calcium for serumalbumin.The suitability of the calcium ratio as a surrogate for

blood citrate accumulation has only been partially con-firmed (34,40). However, the measurement of blood orplasma citrate concentration is not widely available andgenerally cannot be obtained in a timely manner for rapidbedside clinical decision making. Thus, assessment of thecalcium ratio along with accurate monitoring of acid-basestatus, systemic ionized calcium levels, and changes in cal-cium substitution requirements is the most reasonable ap-proach for early detection of citrate accumulation. Closeattention to the early signs of citrate accumulation is man-datory in high-risk patients (21); in particular, because themain risk of citrate accumulation is a rapid fall in the sys-temic ionized calcium level, potentially resulting in seriouscomplications, such as hypotension and arrhythmias(10,52), the usual calcium monitoring intervals (4–6 hours)as well as the timing of the calcium ratio assessmentshould be shortened in patients who may have impairedcitrate metabolism (e.g., those with severe liver failure andtissue hypoperfusion). Despite these concerns, there is in-creasing evidence of the safety of RCA in patients withsevere liver failure/liver transplant with or without mo-lecular adsorbent recirculating system support (53,56–58)or severe septic shock with liver hypoperfusion (47). Inthese clinical settings, strategies for the prevention of cit-rate accumulation should be targeted to reduce the citrateload by decreasing citrate administration (lower bloodflow rates and higher ionized calcium targets) and/or in-creasing citrate clearance (higher convective and/or dif-fusive dialysis dose) (59). Moreover, because liberaladministration of citrate-containing blood products (i.e.,blood transfusions and fresh frozen plasma) may signifi-cantly increase the citrate metabolic load, this potentialsource of additional exogenous citrate should be takeninto account in any strategy aimed at preventing citrateaccumulation (59).Finally, because the value of conventional liver function

tests is poor at predicting metabolic clearance in critically illpatients with decompensated liver cirrhosis or acute liverfailure, it may be difficult to identify subjects at increasedrisk for citrate accumulation (53). Instead, a prothrombintime#26%, roughly corresponding to $33 seconds, andelevation of the serum lactate to $3.4 mmol/L seem tobe the best predictors of RCA-related metabolic complica-tions (53), serving as surrogates of the liver’s capacity forcitrate metabolism.

Solutions and Protocols for RCARCA was first described for intermittent hemodialysis

in the 1960s (60), and it was later applied to CRRT (61). Us-ing commercially available or pharmacy-made citrate so-lutions, which generally were not specifically intendedfor RRT use (i.e., ACD solutions), multiple RCA proto-cols were developed for different RRT modalities (14–19,46,47,49,50,61–67) (Table 1). The wide array of citratesolutions and dialysate/replacement fluids as well as thewidely changing operational parameters are associated

Clin J Am Soc Nephrol 9: 2173–2188, December, 2014 Regional Citrate Anticoagulation in Patients with AKI, Morabito et al. 2175

Tab

le1.

Characteristicsofthemainregional

citratean

tico

agulationprotoco

ls

Citrate

Solution

/RRT

Mod

ality

Blood

Flow

andCitrate

Infusion

Rates

Citrate

Solution

Dialysate

Rep

lacemen

tFluid

Referen

ce

Highco

ncentration

(hyp

ertonic

insodium)

Postdilu

tion

CVVH

Qb=

150–

300ml/min;

citrate=

38–77

ml/h

(38–

77mmol/h)

TSC

=10

00mmol/L;

Na+=30

00mmol/L

N/A

Low

sodium

(120

mmol/L);bu

ffer-free;

calcium-free

Mon

chietal.(15

)

Pred

ilution

CVVHDF

Qb=

150ml/min;citrate

150ml/h(16.9mmol/h

)ACD-A

:citrate=11

2.9

mmol/L(TSC

=2.2%

/citric

acid=0.8%

);Na+=22

4mmol/L

Low

sodium

(132

mmol/L);

lactate=

40mmol/L;calcium

containing

(1.25mmol/L)

Isoton

icsalin

e(N

a+=15

4mmol/L)

Gup

taetal.(10

3)

Postdilu

tion

CVVHDF

Qb=

125ml/min;

citrate=

190ml/h

(25.3mmol/h)

TSC

=13

3mmol/L;

Na+=39

9mmol/L

Low

sodium

(117

mmol/L);

buffer-free;

calcium-free

Low

sodium

(117

mmol/L);va

riab

lebicarbon

ate(33–

50mmol/Laccord

ingto

A-B

status

);calcium-free

Kutsog

iann

isetal.(16

)

Postdilu

tion

CVVH

Qb=

220ml/min;citrate

flow

rate

notreported

(targe

tcitratemia=3

mmol/L)

TSC

/citricacid=50

0mmol/L;N

a+=13

52mmol/L

N/A

Low

sodium

(109

.5mmol/L);bu

ffer-free

combine

dwith

abicarbon

ate-

buffered

solution

acco

rdingto

A-B

status;Ca2

+=1.81

mmol/L

Oudem

ans-va

nStraaten

etal.(18

)

CVVHD

Qb=

80–12

0ml/min;

citrate=

140–

205ml/h

(19–

27.9

mmol/h)

TSC

=13

6mmol/L;

Na+=40

8mmol/L

Low

sodium

(133

mmol/L);low

bicarbon

ate

(20mmol/L);

calcium-free

N/A

Morge

raetal.(46

)

CVVHD

Qb=

150–

200ml/min;

citrateflow

rate

not

reported(targe

tcitratem

ia=4mmol/

L)

TSC

=13

6mmol/L;

Na+=40

8mmol/L

Low

sodium

(133

mmol/L);low

bicarbon

ate

(20mmol/L);

calcium-free

N/A

Kalbetal.(49

)


Tab

le1.(Continued

)

Citrate

Solution

/RRT

Mod

ality

Blood

Flow

andCitrate

Infusion

Rates

Citrate

Solution

Dialysate

Rep

lacemen

tFluid

Referen

ce

Pred

ilution

CVVHDF

Qb=

120ml/min;

citrate=

700ml/h

(19.75

mmol/h)

ACD-A

–ba

seddilu

ted

citratesolution

=28

.22

mmol/L;N

a+=16

3.3

mmol/L;

bicarbon

ate=

30mmol/L

Low

sodium

(133

mmol/L);low

bicarbon

ate

(20mmol/L);

calcium-free

N/A

Mariano

etal.(47

)

CVVHD

Qb=

75–10

0ml/min;

citrate=

35–45

ml/h

(39.3–

50.6

mmol/h)

TSC

/citricacid=74

3/38

1mmol/L;

Na+=22

29mmol/L

Low

tostan

dardsodium

(129

–14

0mmol/L);

variab

lebicarbon

ate

(13.2–

34.3

mmol/L

accord

ingto

A-B

status

);calcium

containing

(1.75mmol/L)

N/A

Sane

retal.(57

)

SLED

Qb20

0ml/min;citrate

180ml/h(24.5

mmol/h)

TSC

=13

6mmol/L;

Na+=40

8mmol/L

Stan

darddialysate

(Gen

iussystem

;18

0–20

0ml/min);

calcium

containing

(1.0

mmol/L)

N/A

Morge

raetal.(10

5)

SLED

Qb=

250ml/min;

citrate=

231–

261ml/h

(31.4–

35.5

mmol/h)

TSC

=13

6mmol/L;

Na+=40

8mmol/L

Stan

dardsodium

and

bicarbon

atedialysate

(300

ml/min);

calcium-free

N/A

Clark

etal.(86

)

SLED-H

DF

Qb=

130ml/min;

citrate=

1350

ml/h

(38.1mmol/h)

ACD-A

–ba

seddilu

ted

citratesolution

=28

.22

mmol/L;N

a+=16

3.3

mmol/L;

bicarbon

ate=

30mmol/L

Low

sodium

(133

mmol/L);low

bicarbon

ate

(20mmol/L);

calcium-free

N/A

Mariano

etal.(47

)

SLED

Qb=

200ml/min;

citrate=

200–

400ml/h

(22.6–

45.2

mmol/h)

ACD-A

:citrate=11

2.9

mmol/L(TSC

=2.2%

/citric

acid=0.8%

);Na+=22

4mmol/L

Cocurrent

flow

stan

dard

dialysate

(300

ml/

min);calcium

containing

(1.25mmol/L)

N/A

Fiaccadorietal.(51

)

Low

concentration

(iso

tonic

insodium)

Pred

ilution

CVVHDF

Qb=

100–

150ml/min;

citrate=

1000

–20

00ml/h(18–

46mmol/h)

TSC

=18

or23

mmol/L

obtained

bydilu

ting

aTSC

4%citrate

solution

;Na+=14

0mmol/L

Stan

dardsodium

(140

mmol/L);low

bicarbon

ate

(25mmol/L);

calcium-free

N/A

Tolwan

ietal.(62

)


Tab

le1.(Continued

)

Citrate

Solution

/RRT

Mod

ality

Blood

Flow

andCitrate

Infusion

Rates

Citrate

Solution

Dialysate

Rep

lacemen

tFluid

Referen

ce

Pred

ilution

CVVH

Qb=

100–

200ml/min;

citrate=

2000

–40

00ml/h(26–

52mmol/h)

TSC

=13

mmol/L;

Na+=14

0mmol/L

N/A

N/A

Hetzeletal.(19

)

Pre-

andpo

stdilu

tion

CVVH

Qb=

130–

150ml/min;

citrate=

1560

–18

00ml/h(18.7–

21.6

mmol/h)

TSC

/citricacid=10

/2

mmol/L;N

a+=13

6mmol/L

N/A

Stan

dardsodium

(140

mmol/L);stan

dard

bicarbon

ate

(32mmol/L);calcium

containing

(1.75mmol/L)

Morab

itoetal.(14

)

Pred

ilution

CVVH

Qb=

150ml/min;

citrate=

2500

ml/h

(30mmol/h)

TSC

/citricacid=10

/2

mmol/L;N

a+=13

6mmol/L

N/A

N/A

Shum

etal.(64

)

Pred

ilution

CVVH

Qb=

180ml/min;

citrate=

2400

ml/h

(31.9mmol/h)

TSC

=13

.3mmol/L;

Na+=14

0mmol/L

N/A

N/A

Nurmoh

amed

etal.(50

)

Pre-

andpo

stdilu

tion

CVVHDF

Qb=

140ml/min;

citrate=

1000

ml/h

(18mmol/h)

TSC

=18

mmol/L;

Na+=14

0mmol/L

Stan

dardsodium

(140

mmol/L);stan

dard

bicarbon

ate

(30mmol/L);calcium

containing

(1.25mmol/L);

phosph

atecontaining

(HPO42

+=1.2

mmol/L)

Stan

dardsodium

(140

mmol/L);stan

dard

bicarbon

ate

(30mmol/L);calcium

containing

(1.25mmol/L);

phospha

tecontaining

(HPO

422=1.2

mmol/L)

Morab

itoetal.(66

)

The

defi

nition

sSL

ED

andSL

ED-H

DFha

vebe

enmaintaine

das

intheoriginal

articles;b

othtreatm

entm

odalitiesmay

beinclud

edun

der

theterm

prolon

gedinterm

ittent

RRT(PIR

RT).CVVH,

continuo

usve

nove

nous

hemofi

ltration

;CVVHDF,

continuo

usve

nove

nous

hemod

iafiltration

;CVVHD,con

tinu

ousve

nove

nous

hemod

ialysis;SL

ED,sus

tained

low-efficien

cydialysis;SL

ED-

HDF,

sustaine

dlow-efficien

cyhe

mod

iafiltration

;Qb,

bloo

dflow

rate;T

SC,trisodium

citrate;ACD-A

,anticoa

gulant

citratedextrosesolution

A;N

/A,n

otap

plicab

le.


with exposure of patients to different electrolyte andbuffer combinations, significantly affecting acid-base sta-tus and electrolyte balance during RCA (46,62,65,66).For the sake of simplicity, RCA solutions may be clas-

sified on the basis of citrate concentration as high- and low-concentration solutions, with high citrate concentrationscorresponding to hypertonicity with regard to sodium.

High-Concentration Citrate Solutions (Hypertonic inSodium)High-concentration citrate solutions are also known as

hypertonic citrate solutions because of their high sodiumcontent as trisodium citrate. Although the use of standardsodium concentration CRRT solutions has also been re-ported in RCA protocols adopting hypertonic citrate for-mulations (68,69), these solutions are usually combinedwith customized low-sodium dialysis/replacement fluidsto prevent hypernatremia. As long as a well designed pro-tocol is implemented, hypertonic citrate solutions can beused to perform RCA with all modalities of CRRT (Figure2, Table 1) (15,16,18,46,47,49). RCA protocols based on hy-pertonic citrate solutions use citrate as the primary buffer,regardless of CRRT modality. In the case of continuous

venovenous hemodialysis (CVVHD), a custom-made orcommercially available low-bicarbonate concentration di-alysate is commonly used to obtain a negative bicarbonatemass balance to compensate for the indirect bicarbonateload derived from citrate (46). Therefore, in these proto-cols, the optimization of acid-base status and prevention/treatment of metabolic alkalosis can be achieved by en-hancing the diffusive removal of citrate and bicarbonatethrough increased flow rates of a low-bicarbonate dialy-sate. Conversely, as in the case of metabolic acidosis, anincrease in the buffer supply to the patient can be achievedby increasing the citrate load throughout a parallel rise ofblood and citrate flow rates (46). This approach permitsflexibility in the management of acid-base status, but itmay result in the development of metabolic acidosis if ahigh dialysis dose is required (high diffusive removal ofbuffers related to the increase of low-bicarbonate dialysateflow rate) (46,49). A different approach, using pharmacy-made solutions, was adopted to perform RCA in continu-ous venovenous hemofiltration (CVVH). This approachused a very high-concentration citrate solution (500mmol/L) along with a variable bicarbonate concentrationin the replacement fluid (18). Specifically, a buffer-free

Figure 2. | Schematic representation of RCA for the different continuous RRT modalities. In protocols adopting high-concentration citratesolutions, the use of a low-sodiumdialysate and/or replacement fluid is generally required to prevent hypernatremia. In protocols adopting low-concentration citrate solutions, citrate acts as both an anticoagulant and a predilution replacement fluid, thus contributing to the total con-tinuous RRT dose. Sections A and C display RCA circuits in predilution-only CVVH and CVVHDmodalities, respectively. The dotted boxes inB andD indicate the possibility of using a calcium-free predilution replacement fluid alongwith a separate hypertonic citrate solution to obtainpredilution and postdilution CVVH or CVVHDF.


replacement solution was mixed in various proportionswith bicarbonate-buffered fluids to modulate the postdilu-tion buffer supply on the basis of clinical needs (18). A sim-ilar approach was described for continuous venovenoushemodiafiltration (CVVHDF), combining a hypertonic cit-rate solution with buffer-free dialysate and postdilution re-placement fluid with variable bicarbonate concentrations(33.3–50 mmol/L) (16).In an alternative approach, hypertonic ACD-A has been

used to prepare a custom-made replacement solution:ACD-A was diluted with a commercially available CRRTsolution, making a hypertonic citrate-containing predilu-tion replacement fluid (28.22 mmol/L citrate, 163.3 mmol/L Na, 77.2 mmol/L chloride, and 30 mmol/L NaHCO3

2),which was combined with a low-bicarbonate dialysate(20 mmol/L) to perform RCA in CVVHDF (47).

Low-Concentration Citrate Solutions (Isotonic in Sodium)In protocols using low-concentration citrate solutions, a

higher citrate flow rate is required to achieve the targetcitrate levels in the extracorporeal circuit. As a conse-quence, citrate acts as both an anticoagulant and a pre-dilution replacement fluid (citrate-buffered replacementsolutions), thus contributing significantly to the total di-alysis dose (Figure 2). The physiologic sodium content ofisotonic solutions allows RCA CVVH or RCA CVVHDFwithout the need of a low-sodium replacement fluid and/or dialysate (Table 1). In protocols using citrate-bufferedreplacement solutions, the buffer supply derives from cit-rate (predilution CVVH) or citrate and bicarbonate in var-ious proportions (predilution and postdilution CVVH andCVVHDF) in relation to the composition and the combi-nation of the solutions that are used (14,19,50,62,64–67). Asimplification on the basis of the use of solutions with anappropriately low citrate concentration allows RCA CRRTas CVVH in the predilution-only modality (19,50). Thisapproach has the advantage of allowing RCA despite theuse of CRRT equipment without a dedicated citrate infu-sion pump, but the downside is that the CRRT dose isintimately linked to the citrate dose (50). The buffer supplyto the patient is exclusively derived from citrate, makinghandling of acid-base status more difficult and potentiallyincreasing the risk of citrate accumulation when a highdialysis dose is used or in other specific clinical settings(50). The use of standard sodium and bicarbonate replace-ment fluids in addition to the citrate-buffered solutionprovides a simplified method for RCA CVVH when predi-lution and postdilution replacement fluids are used withoutrequiring customized CRRT solutions (14,67); a standard(66) or lower than usual bicarbonate (62) dialysate can beused to design an RCA CVVHDF protocol with the advan-tage of operating at lower filtration fractions (Table 1).

Safety and Efficacy of RCASeveral studies comparing citrate-based protocols with

heparin-based protocols have reported better filter survivaland/or fewer bleeding events during RCA (14–19). Twoseparate meta-analyses, including six randomized trialscomparing RCA with systemic anticoagulation with hep-arin, confirmed a significant decrease of bleeding events inthe citrate arm (70,71); however, they provided slightly

different results about filter survival. In particular, Zhangand Hongying (70) showed a significantly prolonged filterlife (mean difference.20 hours) and a highly significantreduction of bleeding risk with RCA (0.28 risk ratio com-pared with heparin). The meta-analysis of Wu et al. (71),which excluded one of six randomized controlled trialsfrom the analysis of filter life, confirmed the lower riskof bleeding with RCA without showing significant advan-tages in terms of circuit survival. Transfusion needs werealso reduced with the use of RCA (14,15,17). Comparedwith unfractioned heparin, RCA was associated with amarked reduction in transfusion requirements in 20 pa-tients treated with CVVH (0.2 versus 1.0 blood units/d,P,0.001) (15). More recently, in patients with high-bleedingrisk cardiac surgery switched to citrate from heparin or noanticoagulation at all, no bleeding complications were ob-served with RCA, and the transfusion rate was significantlylower compared with the other anticoagulation modalities(P,0.02) (14). In addition, RCA was associated with anincrease in platelet count and antithrombin-III activity,thus avoiding platelet concentrate administration andantithrombin-III supplementation (14). At the same time,RCA safely prolonged filter life in the absence of CRRT in-terruption for filter clotting, minimizing CRRT downtime(mean delivered dose around 95%) (14).No robust demonstration is currently available concern-

ing the possible positive effects of RCA on patient survival.In a large single-center randomized trial including 200critically ill patients on CRRT using nadroparin or citrateanticoagulation, RCA was associated with an unexpected15% absolute increase in 3-month survival, which was notcompletely explained by the lower incidence of bleeding(18). Post hoc analysis showed that RCA might be particu-larly beneficial in specific clinical conditions (e.g., surgery,sepsis, severe multiple organ dysfunction syndrome, andyounger age). To explain the survival benefit of RCA, thepreviously discussed interference of citrate with the acti-vation of the inflammatory cascade was suggested (18).However, although RCA was associated with prolongedcircuit patency and a marked reduction in bleeding com-plications, no survival benefit of citrate was shown in asubsequent multicenter randomized trial comparing un-fractioned heparin with RCA in 170 patients undergoingCVVH (19).

RCA in Prolonged Intermittent RRTSustained low-efficiency dialysis, also known as ex-

tended daily dialysis, is a prolonged intermittent RRT(PIRRT) usually lasting 8–12 hours that is increasinglyused in patients with AKI in the ICU (12,72–76). PIRRTis considered a hybrid RRT modality; it combines the mainadvantages of conventional intermittent forms of RRT (e.g.,standard hemodialysis equipment, online-produced dialy-sate, flexible scheduling, and lower costs) with those ofCRRT (e.g., better hemodynamic tolerance, excellent meta-bolic control, and gentle osmotic fluctuation and fluid re-moval capacity) (74,77–81).Despite shorter treatment duration, even with PIRRT,

anticoagulation of the extracorporeal circuit is often re-quired. The optimal strategy for anticoagulation duringPIRRT is still a matter of debate (13,82). Saline flushes


without a antihemostatic agent (81,83,84), unfractionedheparin (79,81,83,85), or prostacyclin (80) are among thedifferent options proposed thus far for the maintenance ofthe extracorporeal PIRRT circuit. Treatment interruptionbecause of circuit clotting is found in 26%–46% of caseswith saline flushes and 17%–26% of cases with standardheparin (500–1000 IU/h) (81,83,84). A 10% incidence ofcircuit interruption (one half for circuit coagulation) hasbeen reported when relatively low doses of epoprostenol,a synthetic analog of the antiaggregant and vasodilatoryprostacyclin PGI2, are used (80). In parallel to the expand-ing use of citrate as a regional anticoagulation method inCRRT, increasing interest has been devoted to the appli-cation of this anticoagulant strategy to PIRRT. Protocolsfor RCA have been proposed for PIRRT on the basis of theuse of different citrate solutions and the use of eitherCRRT or standard dialysis machines (86,87) (Table 1). Inone of these studies, in 30 patients undergoing 117 PIRRTsessions with citrate, treatment interruption caused by cir-cuit clotting never occurred, with an average treatmentduration of 6.7–7.3 h (86). However, the protocol requiredcalcium-free dialysis fluid and CaCl2 supplementation,with a stepwise titration protocol for both citrate and cal-cium administration (86). Recently, a simple RCA protocolfor PIRRT was proposed and validated in a single-institutionobservational study of 116 patients in the ICU with AKI whounderwent 807 PIRRT sessions (51). The protocol usedACD-A solution and standard dialysis equipment withmaintenance of blood calcium levels provided by calciumback-transport from calcium-containing dialysis fluid(1.25 mmol/L) (Figure 3). Interruptions of PIRRT caused

by impending/irreversible clotting were recorded in 19sessions (2.4%); blood restitution was complete in 98%of the cases. Major bleeding was observed in six patients(5.2% or 0.4 episodes per 100 person-days on PIRRT),with a hemorrhagic complication rate similar or even lowerto that reported in previous studies (4,5,70,71,88–91). Nocitrate accumulation was observed, even in patients withsevere liver dysfunction (51). Intravenous calcium for sys-temic hypocalcemia (ionized calcium levels,0.90 mmol/L)was needed during 28 treatment sessions (3.4%); however,in eight of 28 sessions, low ionized calcium was alreadypresent before starting PIRRT. Systemic coagulation of pa-tients remained unchanged, and metabolic/fluid controlwas easily achieved. These results suggest that simplifiedprotocols with commercially available citrate solutions al-low safe and effective RCA for PIRRT with limited labora-tory monitoring and without the need for systemic calciuminfusion in most patients.

RCA: Electrolyte Balance, Acid-Base Status, andEffects on Bone MetabolismDespite its recognized advantages, concerns about the

risk of electrolyte and acid-base disorders are probablyamong the main factors still precluding the more wide-spread use of RCA in critically ill patients undergoing RRT.Although reported issueswith citrate include hypernatremiaor hyponatremia, hypercalcemia or hypocalcemia, hyper-magnesemia or hypomagnesemia, and metabolic acidosis oralkalosis (Table 2), these complications are quite uncommonwhen strict adherence to the RCA protocol and accurate

Figure 3. | Schematic representation of a simplified regional citrate anticoagulation protocol for SLED using a calcium-containing dialysate.Detailed protocol is shown as supplemental material in ref. 51. *Sampling for systemic ionized calcium is from the circuit arterial line or thepatient’s arterial line (to avoid the effects of vascular access recirculation). Systemic total calcium can be measured from a central venous line.ACD-A, anticoagulant citrate dextrose solution A; SLED, sustained low-efficiency dialysis; Uf, ultrafiltration.


Table 2. Potential acid-base and electrolyte complications during regional citrate anticoagulation and preventive measures

Complication Mechanism Preventive Measures

Metabolic alkalosis Excessivebuffer load related tohighcitrate delivery to the patient(imbalance between citrateinfusion rate and citrate removalwith the effluent) and/orinadequate matching of RCAsolutions (citrate concentration,bicarbonate concentration indialysate/replacement fluid) inthe case of CRRT

Decrease citrate infusion rate byreducing blood flow and/orreducing target citrate dose (witha corresponding higher circuitionized calcium)

Increase citrate and bicarbonatelosses by increasing dialysate/replacement fluid flow rate

Reduce bicarbonate concentration inthe dialysate/replacement fluid

Remove or limit exogenous buffersources (acetate in total parenteralnutrition solutions and citrate-containing blood products)

Metabolic acidosis Inadequate buffer supply(imbalance between citrate/bicarbonate delivered to thepatient and citrate/bicarbonateremoved with the effluent)

After excluding inadequate citratemetabolism, increase citratedelivery to the patients byincreasing citrate infusion rateand/or increasing target citratedose, reduce citrate andbicarbonate losses by reducingdialysate/replacement fluid flowrate, or increase bicarbonateconcentration in the dialysate/replacement fluid or startbicarbonate supplementation bysystemic infusion

Inadequate citrate metabolism(i.e., severe liver failure and septicor cardiogenic shock with tissuehypoperfusion) preventingbicarbonate production

In the presence of signs of citrateaccumulation, reduce or stopcitrate infusion and/or increasecitrate lossby increasingdialysate/replacement fluid flow rate orswitch to a standard bicarbonatedialysate/replacement fluidand/or start bicarbonatesupplementation by systemicinfusion

Systemic ionized hypercalcemia Excessive calcium replacement Reduce calcium infusion rateSystemic ionized hypocalcemia Inadequate calcium replacement After excluding inadequate citrate

metabolism, increase calciuminfusion rate (check infusionpump to exclude technical issues)

Inadequate citrate metabolismpreventing calcium release fromcalcium-citrate complexes

In the presence of signs of citrateaccumulation, increase calciuminfusion rate and consider themeasures suggested for citrateaccumulation

Hypernatremia Use of high-concentrationtrisodium citrate solutionswithout adequate lowering ofsodium concentration in thedialysate/replacement fluid

Use a low-sodium dialysate/replacement fluid in protocolsbased on hypertonic citratesolutions

Hyponatremia Accidental omission of hypertoniccitrate solution in protocolsadopting hypotonicdialysate/replacement fluid(rarely observed)

Verify the correct matching of RCAsolutions

Hypomagnesemia Inadequate magnesiumreplacement

Increase magnesium replacement(check infusion pump to excludetechnical issues)

RCA, regional citrate anticoagulation; CRRT, continuous RRT.


monitoring of the procedure by an adequately trained staffare ensured (Table 3) (22,92).Hypernatremia represents a potential but rarely ob-

served complication related to the use of hypertonic solu-tions without low-sodium concentration dialysate and/orreplacement fluids (22,92). Calcium and magnesium imbal-ances are usually caused by effluent losses of both electro-lytes, mainly in the form of citrate complexes, not adequatelycounterbalanced by systemic supplementation (22,92).As previously discussed, alterations of ionized calciumlevels may also occur as a consequence of accumulation ofcalcium-citrate complexes in patients with impaired cit-rate metabolism. In this situation, increasing levels of totalserum calcium coexist with low systemic ionized calciumlevels, leading to high–calcium ratio values (10,54). Met-abolic acidosis may develop when impaired citrate metab-olism prevents bicarbonate generation or, alternatively,from an insufficient buffer supply. The latter may be re-lated to the suboptimal setting of RCA CRRT parametersand/or an inadequate combination of CRRT fluids result-ing in an imbalance between the amount of buffers (citrate/bicarbonate) delivered to the patients and the amount re-moved with the effluent fluid (Table 2). Conversely, meta-bolic alkalosis may develop when buffer overload is caused

by inappropriate setting of RCA parameters and/or inade-quate matching of RCA CRRT solutions (Table 2) (10,22). Inpatients receiving significant amounts of citrate-containingblood products, the exogenous citrate load may increase therisk of buffer overload and metabolic alkalosis and must betaken into account in the RCA protocol (10).The development of well designed RCA protocols, char-

acterized by a balanced combination of citrate and CRRTsolutions, facilitates the modulation of the buffer supplyaccording to clinical needs, minimizing the risk of acid-baseimbalances. For example, the combination of a highly con-centrated trisodium citrate solution (136 mmol/L) with acustomized low-bicarbonate dialysate (20 mmol/L) hasbeen successfully used for CVVHD (46). Acid-base andelectrolyte control was excellent in the majority of patients,and any occurrence of metabolic imbalances was rapidlycorrected by modifying either the dialysate or the bloodflow rate (46). An appropriate matching of citrate and CRRTsolutions is also required with the use of isotonic solutions.In a comparison between two different low-concentrationcitrate solutions in RCA CVVHDF, the use of a citrate con-centration of 23 mmol/L was frequently associated withmetabolic alkalosis, whereas a lower citrate concentration(18 mmol/L) provided more appropriate acid-base balance

Table 3. Monitoring of regional citrate anticoagulation for continuous RRT

Parameter Monitoring Intervals Aim

Circuit ionized calcium(postfilter)

Within 1 h from the start of thetreatment and then at leastevery 6–8 h

To evaluate the maintenance ofcircuit ionized calcium withinthe intended target and modifycitrate dose accordingly

Systemic ionized calcium Baseline (before starting RRT) To check baseline levels and setinitial calcium infusion rate


To evaluate the maintenance ofsystemic ionized calciumwithin the physiologic rangeand modulate calcium infusionrate accordingly

Systemic total calcium At least every 12–24 h(simultaneous to systemicionized calcium)

To calculate calcium ratio (total-to-ionized systemic calcium) asan indirect index of citrateaccumulation ($2.5)

Acid-base parameters (pH andbicarbonate)a

Baseline (before starting RRT) To exclude acid-base imbalances(metabolic acidosis or alkalosis)and modify RCA and RRTparameters setting if needed


Magnesium At least every 24 h To modulate the amount ofmagnesium supplementation ifneeded

Serum sodium Once daily To exclude hypernatremia orhyponatremia (rarely observedwith a correct matching of RCAsolutions)

Citratemia (if available) Not routinely used for clinicalpurposes

To confirm hypercitratemia in thepresence of indirect signs ofcitrate accumulation

Serum lactate Baseline (before starting RRT) To identify patients at higher riskfor citrate accumulation andmonitor lactate levels duringRCA

At least every 6–12 h or accordingto clinical needs

aSample drawn from an arterial line.


(62). In both cases, the target CRRT dose was 35 ml/kg perhour, and a lower than usual dialysate bicarbonate concen-tration (25 mmol/L) was adopted to optimize the buffersupply to the patient (62). Aside from fluid composition,citrate and dialysis dose may significantly affect acid-basestatus. Indeed, by adopting a lower target blood citrateconcentration (2.5–3 mmol/L) along with a CRRT doseof 30 ml/kg per hour, the above-mentioned 18-mmol/Lcitrate solution was successfully combined with a phosphate-containing dialysate/replacement fluid with a standard bi-carbonate concentration (30 mmol/L). This combinationafforded adequate acid-base control without the occurrenceof metabolic alkalosis. At the same time, it minimizedCRRT-related phosphate depletion (66,67). The use of alower-concentration isotonic citrate solution (12 or 13mmol/L) alone (predilution CVVH) (19,64) or combinedwith postdilution conventional replacement fluid (predilu-tion and postdilution CVVH) (14) may be associated with asuboptimal buffer supply, which is not easily balancedthrough the optimization of RCA settings and frequentlyrequires additional bicarbonate supplementation directly tothe patient.Abnormalities of parathyroid hormone (PTH) release

during RCA have been reported (93,94) and seem to bemainly related to calcium balance during RRT. In particu-lar, negative calcium balance during RCA CRRT seems tostimulate PTH release (93,95). Although the significance ofPTH secretion in this setting is still unclear, concerns aboutthe potential harmful effects on bone metabolism havebeen expressed (10). Indeed, recruitment of body calciumstores as compensation for negative calcium balance couldlead to severe bone reabsorption during prolonged RCACRRT, which was reported after discontinuation of calciumsupplementation in patients with immobilization-relatedhypercalcemia, possibly masked by calcium chelation duringRCA (96). Although additional investigations are required toestablish the most appropriate calcium substitution strate-gies, adequate calcium replacement aimed at avoiding epi-sodes of hypocalcemia should help prevent bone loss duringprolonged RCA (10,93). Strict maintenance of systemic ion-ized calcium within physiologic values has been shown toprevent a short-term increase in PTH levels in acutely illpatients on maintenance hemodialysis undergoing RCA(93). In addition to the potential effects of RCA on PTHlevels, other factors (i.e., immobilization, vitamin D defi-ciency, and cytokine effects) may negatively affect boneturnover rates in critically ill patients (10,93).

RCA Protocols Simplification: Future PerspectivesDespite positive reports about the safety and efficacy of

RCA, use of this alternative method of anticoagulation isstill relatively limited. The Beginning and Ending Support-ive Therapy for the Kidney study, an international surveyof RRT in critically ill patients involving 54 ICUs, reportedthe use of RCA in only about 10% of CRRT treatments (97).More recently, in the multicenter randomized VeteransAffairs/National Institutes of Health Acute Renal FailureTrial Network study, RCA was used in only 20% ofCVVHDF treatments (12). It is likely that many reasonslimit the widespread use of RCA: complexity of publishedprotocols, concerns about the risk of metabolic complications,

and lack of commercially available CRRT-specific citratesolutions and/or custom-designed dialysis equipment(98). However, the growing availability of dedicated com-mercial solutions (Figure 4), along with the introduction oftechnologically advanced CRRT equipment with inte-grated infusion systems and RCA-dedicated software,could help to simplify RCA delivery, improving the safetyof RCA and facilitating a more expanded use of citrate(46,99). In this regard, the use of mathematical modelsand the application of target-oriented algorithms specifi-cally developed for different RRT modalities (87,95,100–102) could provide an estimation of calcium balance duringRCA, allowing modulation of calcium infusion rates onthe basis of variations in treatment- and patient-relatedparameters (i.e., blood flow rate, citrate dose, hematocrit,albumin, and serum calcium). The latest generation ofCRRT equipment partially fulfills the characteristics re-quired for near-automated RCA by keeping the citratedose stable even when blood flow changes and adjustingcalcium replacement according to the estimated RCACRRT calcium balance (46,99). In particular, the initial cal-cium infusion rate as well as subsequent adjustmentscould be calculated according to RCA CRRT operationalparameters, taking into account the estimated calciumlosses with the effluent and the calcium supply possiblyderiving from the optional use of calcium-containingCRRT solutions.Finally, additional refinements of the composition of

RCA CRRT solutions could help minimize the need forsupplementation of calcium, magnesium, potassium, andphosphate, with the aim of simplifying RRT management.For example, the adoption of RCA protocols in whichpredilution citrate is combined with a calcium-containingdialysate and/or replacement fluid may reduce the calciuminfusion requirements and minimize the risks of errorsrelated to the handling of calcium-free solutions(14,51,66,67,103). These protocols seem to be able to pro-vide prolonged filter survival without any increase in ve-nous drip chamber clotting rates or the need to increasethe initial citrate dose (14,66,67). However, in any protocol,variations in operational parameters and calcium concen-tration in the CRRT solutions could significantly affect theneed for citrate dose adjustments.

Costs of RCAConcerns related to cost issues could represent another

potential drawback for a wider use of RCA. Currently,comparative data on the cost-effectiveness ratio of differ-ent anticoagulation methods for RRT in AKI are lacking(21). RCA could be more costly than heparin-based anti-coagulation because of the higher cost of citrate solutions(especially commercial solutions developed specificallyfor CRRT) and the need for more intensive monitoringof metabolic parameters (85). However, it is likely thatsavings related to both the lower incidence of bleedingcomplications and the lower frequency of circuit replace-ment could shift the balance toward RCA (104). Finally, inthe cost-benefit evaluation of RCA, indirect costs shouldbe taken into account, such as platelet and red cell trans-fusions, as well as the need for antithrombin-III supple-mentation (14).


ConclusionsIn conclusion, several studies on RCA use have docu-

mented prolonged filter survival associated with lowerbleeding risk and transfusion needs in critically ill patientswith AKI on RRT. On the basis of these results, the 2012KDIGO Clinical Practice Guidelines for Acute KidneyInjury recommended RCA as the preferred anticoagulation

modality in patients without contraindications for citrate(20). Recently, the Canadian Society of Nephrology com-mentary on these KDIGO guidelines endorsed this state-ment, suggesting the possibility of cautiously extendingRCA use in patients with relative contraindications for cit-rate (21). In this regard, the adoption of well designedRCA protocols, characterized by reduced citrate load and

Figure 4. | Composition of commercially available citrate and CRRT solutions for RCA. To design the appropriate RCA protocol (CVVHD,CVVH, CVVHDF), each citrate solution should be combined with the correctly matched dialysate and/or replacement fluid. Availability andtrade name of each solution may vary according to different countries. The list of commercially available citrate and CRRT solutions derivesfrom the more recently reported RCA protocols and could be partial. N/A, not applicable or not available.


careful monitoring, could permit safe delivery of RCA inpatients with severely impaired liver function and/orshock with tissue hypoperfusion (47,53,56–58). Moreover,although the incidence of metabolic and/or electrolyte dis-orders with RCA is low, operational parameters and com-binations of different CRRT solutions with either isotonicor hypertonic citrate formulations may significantly affectelectrolyte and buffer balance during RCA.Finally, the introduction of simplified protocols and the

development of RRT equipment with RCA-dedicated soft-ware couldminimize the risk of errors in RCA handling, thusimproving the safety of citrate use and facilitating a moreexpanded use of this highly effective anticoagulation mo-dality for RRT.

DisclosuresNone.

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Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI