1. Ramon C. Mora M.D. Year Graduated : 1985
School : FEU-NRMF Institute of Medicine
Residency : Veterans Memorial Medical Center ( )
Fellowship : National Kidney & Transplant Institute ( )
Affiliations: VMMC, FEU-NRMF MC, UDMC, NKTI

2. Measures to Optimize
Anticoagulation in HD

3. UFH
UFH
UFH
CITRATE
LMWH
DTI
UFH
UFH
CITRATE
CITRATE

4. Unfractionated Heparin
Routine Heparin
I.D.
2000 ‘u’ (Daugirdas)
25 – 30 u/kg (Sonawane; SD)’06
M.D.
1200 u/h (Daugirdas)
1500 – 2000 u/hr (Sonawane; SD)’06
Tight Heparin
I.D.
750 ‘u’ (Daugirdas)
M.D.
600 ‘u’/h (Daugirdas)

5. Target Clotting Times During Dialysis
Test
Reagent
Baseline Value
Routine heparin
Tight heparin
Desired range
During dialysis
At the end of dialysis
WBPTT
Actin FS
60-85 sec
+80% ( )
+40% (85-105)
ACT
Siliceous earth
sec
+80% ( )
+40% ( )
LWCT
None
4-8 min
20-30
9-16
Daugirdas, Handbook Dial, 3rd ed, p. 185

6. CRRT Unfractionated Heparin I.D. 2000 ‘u’ (Daugirdas)
25 ‘u’/kg (Amanzadeh; SD)’06
M.D.
500 ‘u’/h (Daugirdas)
5 ‘u’/kg (Amanzadeh; SD)’06
Daugirdas, Handbook Dial, 3rd ed, p. 185

7. Heparin protocol for continuous therapies
Initial therapy: Heparin in priming and rinsing solution. At start of procedure, give 2,000-5,000 IU heparin in arterial line. Start 500-1,000 IU/h constant infusion.
Monitoring: PTT measured at the arterial and venous blood lines every 6 h.
Maintain arterial PTT sec
Maintain venous PTT >65 sec
If arterial PTT >45 sec, decrease heparin by 100 IU/hr
If venous PTT <65 sec, increase heparin by 100 IU/hr, but only if arterial PTT <45 sec
If arterial PTT <40 sec, increase heparin by 200 IU/hr
Daugirdas, Handbook Dial, 3rd ed, p. 221

8. CRRT Nomogram for Heparin
aPTT(seconds)
Bolus dose
Rate change
Repeat aPTT
<40
1000 U
+200 U/hr
In 6 hours
Nothing
+100 U/hr
In 4 hours
No change
Stop ½ hour and -100 U/hr
>65.0
Stop 1 hour and -200 U/hr
Heparin solution is made by mixing 1 ml of 10,000 U/ml of heparin in 19 ml of normal saline for a heparin concentration of 500 U/ml. initial bolus is 25 U/kg followed by an infusion of 5 U/kg/hr. The goal of treatment is to maintain systemic prefilter aPTT between 45 and 55 seconds (1.5 times control).
Seminars in Dialysis – Vol. 19, No. 4 (July – August) 2006

9. Regional Heparin
CRRT circuit showing infusion sites for heparin and protamine and collecting sites for patient and circuit aPTT samples
Protamine
Heparin
Patient aPTT
Circuit aPTT
Arterial Line
Venous Line

10. Regional Heparin Heparin Infusion (500 IU/ml) IU/hr
0.15 IU/min x blood flow (ml/min) x 60 (Morabito)
9 x blood flow (ml/min) (Amanzadeh)
Protamine Infusion
5 mg/ml
1 mg Protamine: 100 ‘u’ heparin

11. Regional Heparin + Heparin and protamine + Protamine
Adjustments of Heparin and Protamine Infusion Rate According to aPTT Values
aPTT Values
Adjustments (+20%)
Patient aPTT <45 and circuit aPTT 55-90
No modifications
Patient aPTT <45 and circuit aPTT <55
+ Heparin and protamine
Patient aPTT >45 and circuit aPTT 55-90
+ Protamine
Patient aPTT >45 and circuit aPTT >90
- Heparin
Patient aPTT <45 and circuit aPTT >90
- Heparin and protamine
J Nephrol 2003; 16:

12. Regional Heparin Potential problems
Complexity (balancing infusion rates)
Rebound anticoagulation/ dissociation of heparin-protamine complex
Side effects of protamine – flushing, bradycardia, hypotension, dyspnea, anaphylactic reaction among DM patients

13. Low Molecular Weight Heparin
Enoxaparin
1 mg/kg/dose (mean 0.7)
Polkinghorne; AJKD, 2002
Dalteparin
39 u/kg/dose
Tinzaparin
IU anti-Xa
Hemostasis, 1996

14. Low Molecular Weight Heparin
Tinzaparin
Plasma anti-Xa activity
0.5 IU/ml (1 hour after dialysis
Hemostasis, 1996
Dalteparin
anti-Xa activity
U/ml at 4 hrs
SD, 2006
U/ml at 4 hrs
AJKD, 2002

19. Conclusion
This meta-analysis identified no difference in bleeding events or thrombosis of extracorporeal circuit when LMWH was compared with UFH.
There was great deal of heterogeneity among studies, a variety of LMWH dosing regimens were used, and comparison between different preparations was not possible.
Inferences from these trials assessing anti-coagulation for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are conducted.
Lim, et al J Am Soc Nephrol 2004

20. Hemodialysis anticoagulation and adequacy
No clear differences in hemodialysis adequacy results have been demonstrated using UFH and LMWH. (Level II, limited data)
No differences in dialysis adequacy results are achieved using different LMWH. (Level II, limited data)
There is no clear difference in the risk of thrombosis or hemorrhage with LMWH compared with UFH, although the results of individual studies have been quite variable. (Level I)
The CARI Guidelines – Caring for Australians with Renal Impairment, July 2005

24. Conclusion
Standard oral regimen with an INR between 2 and 3 is insufficient to prevent clotting during hemodialysis.
Additional low-dose anticoagulation with a LMWH or heparin is necessary to facilitate treatment.
Ziai, et al, KI 2005

25. Regional Citrate

26. Regional Citrate Citrate Solution Calcium Chloride Solution
D5W 1L + 40 gm trisodium citrate (40 mg/ml)
Initial infusion
180 ml/hr
90 ml/hr (liver failure/cirrhosis)
Goal: post filter ionized calcium between 0.25 – 0.35 mmol/L
Calcium Chloride Solution
80 ml of 10% CaCl in 1000 ml of NS (0.056 mmol/L) via central venous catheter to maintain systemic ionized calcium of 1.0 – 1.35 mmol/L
Initial infusion: 40 ml/hr (2.2 mmol/hr)
Seminars in Dialysis – Vol. 19, No. 4 (July – August) 2006

27. CRRT Nomogram for Citrate
Postfilter ionized Ca+ (mmol/L)
Rate Change
Repeat postfilter ionized Ca+ (mmol/L)
<0.25
-20 ml/hr
In 1 hour
No change
In 4 hours
+10 ml/hr
+20 ml/hr
>0.45
+30 ml/hr
Citrate solution is made by mixing trisodium citrate 40 g in 1000 ml D5W for a final concentration of 40 mg/ml. The infusion is started at 180 ml/hr. If the patient has suspected liver failure or cirrhosis, the infusion is started at 90 ml/hr. The goal of treatment is to maintain postfilter ionized calcium between 0.25 and 0.35 mmol/L.
Seminars in Dialysis – Vol. 19, No. 4 (July – August) 2006

28. CRRT Nomogram for Calcium Chloride
Systemic ionized Ca+ (mmol/L)
Rate Change
Repeat systemic ionized Ca+ (mmol/L)
<0.75
+40 ml/hr (2.2 mmol/hr)
In 2 hours
+30 ml/hr (1.65 mmol/hr)
+20 ml/hr (1.1 mmol/hr)
In 4 hours
+10 ml/hr (0.5 mmol/hr)
In 6 hours
No change
>1.35
-20 ml/hr (1.1 mmol/hr)
Calcium chloride solution is made by mixing 80 ml of 10% calcium chloride in 1000 ml of normal saline for a concentration of mmol/L. Systemic calcium homeostasis is maintained by infusion for a targeted systemic ionized calcium of mmol/L. The infusion is initiated at 40 ml/hr (2.2 mmol/hr).
Seminars in Dialysis – Vol. 19, No. 4 (July – August) 2006

29. Regional Citrate Potential Complications Hypernatremia
Metabolic alkalosis
Hypocalcemia
Hypercalcemia

35. Morabito et al, J Nephrol 2003
Continuous renal replacement therapies: anticoagulation in the critically ill at high risk of bleeding
Morabito et al, J Nephrol 2003

36. Continuous renal replacement therapies…
Methods
59 patients underwent CRRT for ARF following cardiac surgery
Non-anticoag CRRT: spontaneous bleeding, aPTT >45 seconds, thrombocytopenia, recent surgery (<48 h)
Results
22 (37.3%) non-anticoagulation
12 patients continued (38.3 h filter life)
10 patients switched to regional heparin (38 h filter life)
Morabito et al, J Nephrol 2003

37. Continuous renal replacement therapies…
Regional Coagulation
Baseline aPTT
sec
Patient aPTT
sec
Circuit aPTT
sec
Morabito et al, J Nephrol 2003

38. Continuous renal replacement therapies…
Probabilities of circuit remaining free from clotting
Non-anticoagulation
Regional Heparin
24 h
55.5%
76.2%
48 h
30.1%
39.6%
72 h
16.6%
19.8%
Filter life
Non-anticoagulation h
Regional heparin h
Morabito et al, J Nephrol 2003

39. Continuous renal replacement therapies…
Conclusion
Non-anticoagulaiton CRRT allowed an adequate filter life in most patients with a high risk of bleeding for prolonged aPTT and/or thrombocytopenia. Despite concerns regarding the need for careful monitoring, regional anticoagulation with heparin and protamine can be considered as a safe and valid alternative when non-anticoagulation is unsuitable because of early filter failure.
Morabito et al, J Nephrol 2003

40. CANBERRA HOSPITAL NURSING SERVICE
ANTICOAGULATION FREE DIALYSIS
Rapid blood flow rate desirable to reduce clotting (>300 ml/min). Where disequilibrium is an issue, use a smaller filter and co-current dialysate flow.
Routine flushes using NaCl 0.9%. Make sure NS flushes are added to UF volume.
Change whole circuit after 1.5 to 2 hours of hemodialysis.
Avoid giving blood transfusion and high UFR.
Decrease dialysis length time where possible but ensure patient does extra time for the next dialysis.
Watch out for signs and symptoms of clotting in the circuit.

41. EUROPEAN BEST PRACTICE GUIDELINES

42. EUROPEAN BEST PRACTICE GUIDELINES

43. EUROPEAN BEST PRACTICE GUIDELINES

44. EUROPEAN BEST PRACTICE GUIDELINES

45. Heparin-Induced Thrombocytopenia
Type I
Transient reduction of platelet count occurring after 5 days.
Type II
Antibody mediated complex of heparin and platelet factor 4
>20,000 platelet count, severe bleeding is rare
Prevalence 1-3%
Main clinical complication: arterial thrombosis
Specific tests for type II HIT: Serotonin release assay, heparin-induced platelet aggregation assay, solid phase immunoassays
Treatment: avoidance

46. Direct Thrombin Inhibitors
Bivaluridin, Lepirudin, Argatroban
DOSE: 3 dose regimens for Argatroban
250 ug/kg bolus, with an additional 250 ug/kg if the ACT at 2 hours was less than 140% of baseline
250 ug/kg bolus followed by 2 ug/kg/min continuous infusion
Steady state infusion of 2 ug/kg/min initiated 4 hours prior to session
Other recommended doses
15-25 mg/hr or mg/kg/hr
0.5 ug/kg/min (hepatic impairment)
Target aPTT values times baseline

47. Prostacyclin
Inhibits interaction between platelets and artificial membranes
Dose: 0.4 – 0.5 ng/kg/min
Intensive Care Medicine, 2002
Safety and efficacy of Epoprostenol
7.8% (4/51): major bleeding
15.5%: hypotension requiring vassopressors
Median life of filter = 15.0 hrs
Blood Purification, 2005
Citrate anticoagulation has longer filter survival during continuous hemofiltration compared to the combination of PGI2 and heparin

48. Prostacyclin Adverse Effects Increased intracranial pressure
Decreased systemic and pulmonary vascular resistance and MAP
Increased pulmonary ventilation/perfusion mismatch resulting in decreased tissue oxygen delivery and uptake worsening acidosis and lactate production
High cost

49. Nafamostat Synthetic serine protease inhibitor, mainly used in Japan
Safer than anticoagulation with regional or low dose heparin
Adsorbed by negatively charged membranes, cannot be used with PAN

50. Danaparoid Mixture of dermatan sulfate and heparan sulfate.
Has anti-factor Xa activity
Disadvantages:
Need to determine anti-Xa activity
Long half-life ( h) in renal failure
Absence of reversing agent
High cost

51. THANKS PO