Metabolismo del citrato nei pazienti critici Filippo MARIANO Dipartimento di Area Medica, SCDO di Nefrologia e Dialisi Ospedale CTO, Torino

Regional citrate anticoagulation: the history

Morita Y, Johnson RW, Dorn RE, Hall DS. Regional anticoagulation during hemodialysis using citrate. Am J Med Sci 1961; 242: 32-43.

First in hemodialysis

Citrate Dialysate 1000 ml/h

(Na 117, K 4, Mg 1.5 Cl 122, glucose 2.5%, O alkali, calcium free)

Ultrafiltrate

Calcium (1 mEq/10ml, 40 ml/h)

Return to patient

Substitution fluid Na Cl 0.9%

4% sodium citrate (170ml/h)

Hemofilter

…then in CRRT Mehta RL, McDonald BR, Aguilar MM, Ward DM. Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990; 38:976–81.

Spent dialysate (loss of calcium and citrate)

Calcium infusion

Citrate

Dialysate Ca++ free

Citrate 2-4 mmol/L iCa++ <0.3 mmol/L

Citrate and iCa++ are lost in the dialysate ......

Tab. 2: Citrate levels (mmol/L) in blood circuit and ultrafiltrate, ---------------------------------------------------------------------------------- TIME 30 min 1 hour 5 hours 7 hours 10 hours --------------------------------------------------------------------------------- BLOOD CIRCUIT 4.06±0.23 4.56±0.21 4.04±0.30 3.09±0.38 3.92±0.33 ULTRAFILTRATE nd nd 3.84±0.21 nd 3.74±0.28 ---------------------------------------------------------------------------------------- nd = no data

Mariano et al, Blood Purif 22: 313, 2004

Citrate anticoagulation in HDF (or HF/HD)

Dept of Medicine Area, Nephrology and Dialysis Unit, CTO Hospital, Turin, Italy

Citrate incidence in patients undergoing RRT throughout period 1999-2009

Time

% o

f al

l tre

atm

ents

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 20090

20

40

60

80

100 Citrate

Krebs‘ cycle Amino-acid synthesis

Gluconeogenesis

Fatty acid synthesis

Na3-Citrate + 3H2CO3 -- > Citric acid + 3 NaHCO3

CO2 + H2O (consuming 3 H+)

Citrate as an intermediate metabolite

CITRATE MW 192 daltons

Metabolism of citrate

Figure 1. Comparison of cirrhotic (filled circles) and noncirrhotic (open circles) critically ill patients with respect to concentrations of citrate (A) and standard bicarbonate (C), after 2-hr infusion of sodium citrate (35 mmol/hr) and calcium chloride (0.17 mmol/Kg/hour)

Liver play a main role in citrate metabolism

Kramer et al. Crit Care Med 31:2450-5, 2003

Buffer overload

Na3-Citrate

Complexation

Metabolic complications of RCA

Metabolic acidosis • Increased Anion Gap • Decreased iCa++ • Ca-Ratio >2.5 (totCa++ / iCa++)

Metabolic alkalosis

Decreased metabolization

Hypernatremia

Hypocalcemia, Hypomagnesemia

Morgera et al. Nephron Clin Pract 97:c131-c136, 2004

Development of metabolic alkalosis

Application of a RCA protocol on commercial monitor with a specific software. Large observational study (n 161 pts, 25% septic) with evaluation of - efficacy (survival of circuit) - safety (metabolic alteration and acid-base derangements)

Metabolic tolerance of citrate in ICUs patients

Morgera S, Schneider M, Slowinski T, et al. A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid-base status. Crit Care Med 2009; 37(6):2018–2024

Morgera S et al. Crit Care Med 2009; 37(6):2018–2024

Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37(2):545–552

………..the most cases of hypernatriemia and metabolic alkalosis were observed with nadroparin and not with citrate…..

Table 1: Demographic and biochemical of severe burn patients underwent HDF (period january 2000-december 2007). Biochemical data of groups with citrate (n 31 patients) or with heparin (n 39 patients) were recorded at start of HDF -------------------------------------------------------------------------------------------------------------------------------------------------------------- with citrate with heparin pa -------------------------------------------------------------------------------------------------------------------------------------------------------------- Patients (n) 31 39 ---- Sex ratio (male/female) 22/9 27/12 ---- Mean age (years) 60.4±3.7 (14-90) 55.9±3.3 (17-87) ns 0.367 TBSA Burned (%) 42.0±4.1 (5-90) 48.3±3.5 (15-95) ns 0.244 Mortality in ICU (%, dead/alive)b 70.9%, 22/9 71.8%, 28/11 ns 0.847 at start of RRT Septic shock (%,n) 77.4%, 24 74.3%, 29 ns 0.984 Mechanical ventilation (%, n) 96.8%, 30 100%, 39 ns 0.915 Delay of RRT occurrence (days) 22.2±3.2 (2-75) 21.6±3.0 (1-84) ns 0.892 Biochemical data •  MAP (mmHg) 85.3±2.6 82.7±2.2 ns 0.463 •  Norepinephrine (ug/Kg/min) 0.40±0.059 0.28±0.044 ns 0.089 •  Dopamine (ug/Kg/min) 5.06±0.59 4.87±0.31 ns 0.766 •  SOFA score 11.97±0.43 11.49±0.36 ns 0.379 •  Creatinine (mg/dl) 2.68±0.23 2.44±0.16 ns 0.383 •  Urea (mg/dl) 160.5±10.6 153.6±12.9 ns 0.684 •  PO2/FIO2 ratio 2.30±0.14 2.06±0.13 ns 0.215 •  Bilirubin (mg/dl) 2.99±0.45 3.18±0.36 ns 0.738 •  WBC (1/mm3) 18,137±2,124 12,133±895 p <0.005 •  Htc (%) 26.8±0.61 27.9±0.54 ns 0.185 •  Platelets (1/mm3) 152,690±21,400 190,322±19,567 ns 0.208 •  Quick (%) 63.6±2.98 61.4±2.38 ns 0.557 •  PTT (sec) 36.6±1.5 38.9±1.3 ns 0.211 •  Fibrinogen (mg/dl) 458.5±57.6 567.00±38.9 ns 0.109 • ----------------------------------------------------------------------------------------------------------------------------------------------------------- Data are expressed as mean ± SE (range min-max) aStudent t-test or proportion test when appropriated between groups with citrate and with heparin, p value bIntention-to-treat analysis.

Mariano F, Tedeschi L, Morselli M, Stella M, Triolo G. Normal citratemia and metabolic tolerance of citrate anticoagulation for hemodiafiltration in severe septic shock burn patients. Intensive Care Med, 2010, 36:1735-43

70 severe burn septic shock patients. 31 treated with citrate and 39 with heparin

Systemic blood Na+

Time (days)

Na+ (m

mol

/L)

0 1 2 3 4 5 6 7 8 9 10120

130

140

150

160

Systemic blood lactate

Time (days)

Lact

ate

(mm

ol/L

)

0 1 2 3 4 5 6 7 8 9 10

-2

0

2

4

6

8

10

12Systemic blood bilirubin

Time (days)B

iliru

bin

(mg/

mL)

0 1 2 3 4 5 6 7 8 9 10

-2

0

2

4

6

8

10

Norepinephrin requirement

Time (days)

Norepinephrin

(ug/

Kg/

hour

)

0 1 2 3 4 5 6 7 8 9 10

0.0

0.3

0.6

0.9

1.2

Total Ca++/iCa++ ratio

Time (days)

Tota

l Ca++

/iCa++

ratio

0 1 2 3 4 5 6 7 8 9 101.0

1.5

2,0

2.5

3.0

Systemic blood bicarbonates

Time (days)

Bic

arbo

nate

s (m

mol

/L)

0 1 2 3 4 5 6 7 8 9 10

12

18

24

30

36

42

*

Systemic blood pH

Time (days)

pH (u

nits

)

0 1 2 3 4 5 6 7 8 9 107.0

7.2

7.4

7.6

7.8

Systemic blood iCa++

Time (days)

Ca++

(mm

ol/L

)

0 1 2 3 4 5 6 7 8 9 100.6

0.8

1.0

1.2

1.4

1.6

Systemic blood K+

Time (days)

K+

(mm

ol/L

)

0 1 2 3 4 5 6 7 8 9 100

1

2

3

4

5

6

7

Metabolic tolerance in septic shock patients with liver dysfunction

31 severe burn septic shock patients treated with citrate as anticogulant Over 10 days of CVVHDF no significant alterations in pH, bicarbonates, Na+, K+, Ca++ or ratio total Ca++/iCa++ were observed.

However, if clinical experience in ICU patients has shown that citrate is well tolerated and metabolic alterations are rare b) availability of citrate level in patients at risk of citrate accumulation is a key point for a safety treatment

0 20 40 60 80

100 120 140

Na+ Cl -

HCO3-

mm

ol/l

Physiologic

Na+ Cl -

Accumulation of citrate possible

HCO3-

Metabolic acidosis

Citrate-

Anion gap: Na+-(Cl-+HCO3-)=8–12 mmol/L

Heparinised blood from healthy volunteers supplemented with citrate by serial dilution.

Measured blood citrate (mmol/L)

Cal

cula

ted

bloo

d ci

trat

e (m

mol

/L)

Regression confid 95%0 1 2 3 4 5 6

0

1

2

3

4

5

6

r = 0.997 p < 0.001y = 0.000665 + 1.020300x

.. citrate does not penetrate red blood cells, and it has only an extracellular distribution.

.. taking into account the hematocrit value (only distribution in plasma)

F Mariano et al, Nephrol Dial Tranplant 2011, in press

CLINICAL STUDY IN PATIENTS -  12 critically-ill patients with septic shock in RCA for CVVHDF -  30 sessions, total 37 days of CVVHDF for a cumulative time of 824 hours -  median duration of sessions 20.0 hours (interquartiles 11-43)

Time (hours)

Sys

tem

ic p

lasm

a ci

trat

e (m

mol

/L)

0 12 24 36 48 60 720,0

0,2

0,4

0,6

0,8

1,0

0

2

4

6

8

10

.. systemic citratemia

F Mariano et al, Nephrol Dial Tranplant 2011, in press

CLINICAL STUDY IN PATIENTS -  12 critically-ill patients with septic shock in RCA for CVVHDF -  30 sessions, total 37 days of CVVHDF for a cumulative time of 824 hours -  median duration of sessions 20.0 hours (interquartiles 11-43)

Time (hours)

Citr

ate

conc

entra

tions

(mm

ol/L

)

0 12 24 36 48 60 72

1

2

3

4

5

6

7

8

0

2

4

6

8

10

Prefilter plasma citrate Venous plasma citrate Ultrafiltrate citrate

… circuit citrate in blood and effluent

reduced of 50%

F Mariano et al, Nephrol Dial Tranplant 2011, in press

.. citrate losses in effluent … calcium losses in effluent

Ultrafiltrate (ml/hour)

Loss

of c

itrat

e (m

mol

/hou

r)

Regression confid 95%

0 1000 2000 3000 4000 5000 60000

6

12

18

24

30

36

r = 0.804 p < 0.01y = -0.623+ 0.0039x

Ultrafiltrate (ml/hour)

Loss

of C

a++

(mm

ol/h

our)

Regression confid 95%

0 1000 2000 3000 4000 5000 60000

1

2

3

4

5

6

7

8

9

r = 0.780 p < 0.01y = 1.45 + 0.009x

Citrate and calcium losses correlate with effluent volume ..

"   In patients potentially at risk of metabolic complications (septic shock patients, liver failure) regional citrate anticoagulation demonstrated a good metabolic tolerance.

"   Metabolic tolerance of citrate was most likely due to a low blood flow, a marked loss of citrate in effluent volume and subsequent low total citrate patient load.

"   In septic shock patients with liver dysfunction, the routine determination of citrate may be a useful tool in guiding the clinical application of citrate anticoagulation in RRT.

"   Concerning the costs of direct automated citrate determinations instead of total/ionized calcium ratio for monitoring citrate dialysis, they increased from 2.96 to 3.51 euro. These costs are irrelevant and do not take into account the costs saved due to potential extended use of citrate anticoagulation.

Conclusions