1. 1
Sitrat Antikoagülasyonun Kısıtlılıkları
Dr Emre Karakoç
Çukurova Üniversitesi
Dahiliye Yoğun Bakım Bilim Dalı
2. Sitrat
Tipler:
2
• Tri sodium citrate - contains 3 Na+ ions
• Citric acid - contains 3 H+ ions
Karaciğer, iskelet kası ve böbrekte
bikarbonata metabolize edilir:
• 1mmol sitrat: 3mmol bikarbonat
• Karaciğer yetmezliğinde kontrendike
O
O-O
O-Na+
H H
O-Na+
Tri sodium citrate
OH
H
H
C
C
C
C
C
C
Na+ O
O-H+
O-H+
O-O-O
H H
O-H+
OH
H
H
C
C
C
C
C
C
O
O
Citric acid
3. Etki Mekanizması:
Regional antikoagülasyon için (ekstrakorporel setler
için)
Kalsiyumu bağlayarak koagülasyonda kullanılmasını
önler pıhtı oluşumunu inhibe eder
3
• Filte iyonize Ca seviyesi için hedef = 0.25 and 0.35 mmol/l
• Hasta serum iyonize Ca için hedef seviyeler = 1.1-1.3 mmol/l
Sitrat santral venle karışınca Ca ile birleşerek
karaciğer, iskelt kası ve böbrekte yıkılmaya gider.
4. Plasma Kalsiyum seviyeleri
Total kalsiyum
~ 2.2 - 2.6 mmol/L
4
iyonize kalsiyum (~%50)
~ 1.1 - 1.3 mmol/L
Proteine bağlı kalsiyum (~%40)
(albumin)
~ 0.95 - 1.2 mmol/L
Komplex yapmış kalsiyum (~%10)
(tuzlar, kalsiyum fosfat)
~ 0.05 mmol/L
6. Sitrat kullanımı endikasyonları
Artmış kanama riski:
6
• Yakın zamanda cerrahi, travma
• Aktif mukozal kanama
• Kafaiçi lezyon
• Üremik perikardit
• Ciddi diabetik retinopati
• Maliğn hipertansiyon
• Ciddi koagülopati
Heparin ilişkili trombositopeni
Hiperkalsemi
Guidelines for regional anticoagulation with citrate in continuous hemofiltration,
H.M. Oudemans-van Straaten, in cooperation with the Nephrology and
Intensive Care Committee of the NVIC
7. Kontraindikasyonlar:
Ciddi karaciğer yetmezliği ve kas perfüzyonunda
azalma
7
• CVVH kullanılıyorsa alkaloz için daha sık takip.
Ağır siroz
Sitrat intoleransı (progressive metabolik asidoz)
15. 15
Moniterizasyon:
Başlamadan önce: AKG, biyokimya (+Mg), karaciğer
fonksiyon testleri, CBC, Total Ca, serum iCa
1 saat sonra: AKG, biyokimya panel, serum iCa,
postfilter iCa
Her 6 saatte: AKG, kimyasal panel, serum iCa,
postfilter iCa
Daha eğitimli personel ve daha fazla iş gücü
There are two types of Citrate solutions used in CRRT: Tri- sodium citrate which is made up of citrate with 3 of NA; and citric acid which is made up of citrate with 3 of H+ ions.
Citrate is metabolized by the liver, skeleton, muscles, and kidneys into bicarbonate. 1mmol of citrate is converted to 3mmol of bicarbonate.
Regional Trisodium Citrate Anticoagulation and Calcium Chloride Calculations
1. 4% Trisodium Citrate Solution Calculations
a) Stock solution 46.7% (0.467 g/ml) Trisodium Citrate (Tricitrasol 30 mL vials).
b) Withdraw 90 mL (90 mL x 0.467 g/mL = 42 g) of stock 46.7% trisodium citrate solution and inject it into 1000 mL bag of D5W.
42 g/1090 mL x 100% = 3.9% (w/v) trisodium citrate solution.
c) There is no need to withdraw the 90 mL from the 1000 mL D5W bag before injecting the 90 mL of trisodium citrate because:
The percentage error when calculating out the actual difference in mg/ml from 3.9% to 4% is not significant.
The infusion rate is titrated to circuit ionized calcium levels between 0.25 and 0.35 mmol/L.
0.75% Calcium Chloride Solution Calculation
Stock solution 10% (0.1 g/mL) calcium chloride (10 mL amps).
Withdraw 80 mL (80 mL x 0.1 g/mL = 8 g) of stock calcium chloride and inject it into 1000 mL of normal saline.
8 g/1080 mL x 100% = 0.74% (w/v) of calcium chloride solution.
d.) There is no need to withdraw the 80 mL from the normal saline bag because:
1) The percentage error when calculating the actual difference in mg/mL from 0.74% to 0.75% is not significant.
2) The infusion rate is titrated to systemic ionized calcium levels between 0.90 and 1.20 mmol/L.
Sliding Scale for Trisodium Citrate infusion in CRRT
Circuit ionized calcium (mmol/L)
Change in trisodium citrate infusion rate
> 0.50
Increase rate by 30 mL/hr
0.40 – 0.50
Increase rate by 20 mL/hr
0.36 – 0.39
Increase rate by 10 mL/hr
0.25 – 0.35
No change
0.25
Decrease rate by 10 mL/hr
Monitoring:
ACT & post-filter ionized calcium levels
Advantages:
anticoagulation restricted to extracorporeal circuit
decreased risk of bleeding
does not induce thrombocytopenia
longevity of filter life may be increased
Disadvantages:
labour intensive
requires close monitoring of calcium, pH, electrolytes and clotting times
trisodium citrate is metabolized to bicarbonate which translates to into an increased risk of metabolic alkalosis
Trisodium citrate to NaHCO3 Metabolism
high sodium load in citrate solution - risk of hypernatremia
citrate toxicity (if it is not metabolized)
Citrate Toxicity
Citrate toxicity is due to large amounts of citrate being infused more rapidly than they can be cleared by either dialysis or metabolic pathways. The excess citrate binds with calcium, thus causing hypocalcemia. Toxicity is evidenced by progressive ionized hypocalcemia (<0.95) with increasing total serum calcium levels. Clinical manifestations of citrate toxicity include prolonged Q-T interval, tetany, seizures, hypotension, and cardiac dysrhythmias. Another indirect indicator of citrate toxicity is an increasing anion gap.
There is an increased risk of citrate toxicity in liver failure patients. Hence, citrate should be avoided or used with caution with these patients.
Citrate toxicity is evidenced by progressive ionized hypocalcemia (<0.95) with increasing total serum calcium levels. Clinical manifestations of citrate toxicity include prolonged Q-T interval, tetany, seizures, hypotension, and cardiac dysrhythmias
Citrate, administered pre-filter, prevents coagulation by chelating ionized calcium and inducing deep hypocalcemia in the filter. Part of the calcium-citrate complex is lost in the ultrafiltrate and the other part enters the systemic circulation, where it is diluted in the venous blood. In the systemic circulation, ionized calcium (ion Ca) rises again due to dilution of the extracorporal blood, the intravenous administration of calcium and the liberation of calcium from the calcium-citrate complex when citrate is metabolized. As a result, a systemic effect on coagulation does not occur.
Citrate is infused directly into the access line of the circuit. In order to maintain circulating blood calcium levels, calcium must be replaced post-circuit via the return line or a separate venous access line. Trisodium citrate is the most common solution used and is infused on the arterial side of the circuit while 0.75% calcium may be infused to maintain acceptable serum ionized calcium levels. The solutions are titrated so as to maintain circuit ionized calcium levels between 0.25 and 0.35 mmol/L, and systemic ionized calcium levels between 0.9 and 1.20 mmol/L. Below is an example of a regional trisodium citrate anticoagulation and calcium chloride titration algorithm
Citrate is converted to citric acid --" HCO3 and is metabolized (Krebs cycle) in the liver, skeletal muscle, and renal cortex, or metabolized to glucose.
Tri-sodium-citrate acts as buffer by conversion to citric acid generating NaHCO3
Citric acid has a plasma life of 5 min and metabolized to CO2 and H2O by liver, kidney, and muscle
To prevent clotting of the extracorporal circuit during CRRT, anticoagulation is required for a long period of time. Unfractionated or low molecular weight heparin are generally used., however, Many critically ill patients cannot tolerate prolonged systemic anticoagulation because of:
Bleeding risks due to:
recent surgery or trauma
o haemorrhagic diathesis
o mucous ulceraties
o intracranial laesions
o uremic pericarditis
o severe diabetic retinopathy
o malignant hypertension
o uncontrolable coagulopathy
• Heparin-induced thrombocytopenia and thrombosis (HITT). It should be noted that patients with HITT need some form of systemic anticoagulation since HITT is associated with a pro-coagulant state [12].
• Hypercalcemia. Since plasma calcium falls if calcium is not infused separately, citrate hemo(dia)filtration is the renal replacement therapy of choice in a patient with hypercalcemia.
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Metabolic alkalosis can lead also to hypocalcaemia: Alkalosis increases the binding from calcium to albumin and decreases in this way the ionized calcium fraction in blood.
Symptomatic hypocalcaemia appears more often in respiratoric alkalosis (think about hyperventilation and the consequences because of decreased calcium level → tetany
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Think about hyperventilation & tetany
(talk about how it occurs, such as decreased return of calcium to the patient )
Alkalosis, low magnesium levels, bloodtransfusion (citrate!), some medicaments, renal failure and pancreatitis can also lead to hypocalcemia.
Dysarthry: disorder of speaking
Dysphagy: disorder of swallowing
Ataxy: disorder of coordination (movements)
A fasciculation (or "muscle twitch") is a small, local, involuntary muscle contraction (twitching) visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibres.