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

Transcription

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

2 Regional citrate anticoagulation: the history First in hemodialysis Morita Y, Johnson RW, Dorn RE, Hall DS. Regional anticoagulation during hemodialysis using citrate. Am J Med Sci 1961; 242: 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: Citrate 4% sodium citrate (170ml/h) Substitution fluid Na Cl 0.9% Dialysate 1000 ml/h (Na 117, K 4, Mg 1.5 Cl 122, glucose 2.5%, O alkali, calcium free) Hemofilter Ultrafiltrate Calcium (1 meq/10ml, 40 ml/h) Return to patient

3 Citrate anticoagulation in HDF (or HF/HD) Calcium infusion Dialysate Ca++ free Citrate 2-4 mmol/l ica++ <0.3 mmol/l Spent dialysate (loss of calcium and citrate) Citrate 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± ± ± ± ±0.33 ULTRAFILTRATE nd nd 3.84±0.21 nd 3.74± nd = no data Mariano et al, Blood Purif 22: 313, 2004

4 Citrate incidence in patients undergoing RRT throughout period Citrate 80 % of all treatments Time Dept of Medicine Area, Nephrology and Dialysis Unit, CTO Hospital, Turin, Italy

5 Citrate as an intermediate metabolite CITRATE Na 3 -Citrate + 3H 2 CO 3 -- > MW Citric 192 acid daltons + 3 NaHCO 3 Fatty acid synthesis Krebs cycle Amino-acid synthesis CO 2 + H 2 O (consuming 3 H + ) Gluconeogenesis

6 Metabolism of citrate

7 Liver play a main role in citrate metabolism 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) Kramer et al. Crit Care Med 31:2450-5, 2003

8 Metabolic complications of RCA Decreased metabolization Buffer overload Metabolic acidosis Increased Anion Gap Decreased ica ++ Ca-Ratio >2.5 (totca++ / ica++) Metabolic alkalosis Na3-Citrate Complexation Hypernatremia Hypocalcemia, Hypomagnesemia

9 Development of metabolic alkalosis Morgera et al. Nephron Clin Pract 97:c131-c136, 2004

10 Metabolic tolerance of citrate in ICUs patients 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) 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):

11 Morgera S et al. Crit Care Med 2009; 37(6):

12 ..the most cases of hypernatriemia and metabolic alkalosis were observed with nadroparin and not with citrate.. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37(2):

13 70 severe burn septic shock patients. 31 treated with citrate and 39 with heparin 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 p a Patients (n) Sex ratio (male/female) 22/9 27/ Mean age (years) 60.4±3.7 (14-90) 55.9±3.3 (17-87) ns TBSA Burned (%) 42.0±4.1 (5-90) 48.3±3.5 (15-95) ns Mortality in ICU (%, dead/alive) b 70.9%, 22/9 71.8%, 28/11 ns at start of RRT Septic shock (%,n) 77.4%, %, 29 ns Mechanical ventilation (%, n) 96.8%, %, 39 ns Delay of RRT occurrence (days) 22.2±3.2 (2-75) 21.6±3.0 (1-84) ns Biochemical data MAP (mmhg) 85.3± ±2.2 ns Norepinephrine (ug/kg/min) 0.40± ±0.044 ns Dopamine (ug/kg/min) 5.06± ±0.31 ns SOFA score 11.97± ±0.36 ns Creatinine (mg/dl) 2.68± ±0.16 ns Urea (mg/dl) 160.5± ±12.9 ns PO2/FIO2 ratio 2.30± ±0.13 ns Bilirubin (mg/dl) 2.99± ±0.36 ns WBC (1/mm3) 18,137±2,124 12,133±895 p <0.005 Htc (%) 26.8± ±0.54 ns Platelets (1/mm3) 152,690±21, ,322±19,567 ns Quick (%) 63.6± ±2.38 ns PTT (sec) 36.6± ±1.3 ns Fibrinogen (mg/dl) 458.5± ±38.9 ns Data are expressed as mean ± SE (range min-max) a Student t-test or proportion test when appropriated between groups with citrate and with heparin, p value b Intention-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:

14 Metabolic tolerance in septic shock patients with liver dysfunction 7.8 Systemic blood ph 42 Systemic blood bicarbonates 160 Systemic blood Na + ph (units) Bicarbonates (mmol/l) 36 * Na + (mmol/l) Time (days) Time (days) Time (days) Lactate (mmol/l) Systemic blood lactate Bilirubin (mg/ml) Systemic blood bilirubin Ca ++ (mmol/l) Systemic blood ica Time (days) Time (days) Time (days) 3.0 Total Ca++/iCa++ ratio Norepinephrin requirement 7 Systemic blood K + Total Ca ++ /ica ++ ratio 2.5 2, Norepinephrin (ug/kg/hour) K + (mmol/l) Time (days) Time (days) Time (days) 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.

15 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

16 Metabolic acidosis mmol/l HCO - 3 Cl - Na + Physiologic Citrate - HCO - 3 Cl - Na + Accumulation of citrate possible Anion gap: Na + -(Cl - +HCO 3- )=8 12 mmol/l

17 6.. citrate does not penetrate red blood cells, and it has only an extracellular distribution. Calculated blood citrate (mmol/l) r = p < y = x Measured blood citrate (mmol/l).. taking into account the hematocrit value (only distribution in plasma) Regression confid 95% Heparinised blood from healthy volunteers supplemented with citrate by serial dilution.

18 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) Systemic plasma citrate (mmol/l) 1,0 0,8 0,6 0,4 0,2 0, Time (hours).. systemic citratemia F Mariano et al, Nephrol Dial Tranplant 2011, in press

19 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) 8 10 Citrate concentrations (mmol/l) reduced of 50% Prefilter plasma citrate Venous plasma citrate Ultrafiltrate citrate Time (hours) circuit citrate in blood and effluent F Mariano et al, Nephrol Dial Tranplant 2011, in press

20 Citrate and calcium losses correlate with effluent volume Loss of citrate (mmol/hour) r = p < 0.01 y = x Loss of Ca++ (mmol/hour) r = p < 0.01 y = x Ultrafiltrate (ml/hour) Regression confid 95% Ultrafiltrate (ml/hour) Regression confid 95%.. citrate losses in effluent calcium losses in effluent F Mariano et al, Nephrol Dial Tranplant 2011, in press

21 Conclusions " 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.

22

23