Transcript UNFRACTIONATED HEPARIN

Ramon C. Mora M.D.
 Year
Graduated : 1985
 School : FEU-NRMF Institute of Medicine
 Residency : Veterans Memorial Medical
Center (1987-1990)
 Fellowship : National Kidney & Transplant
Institute (1990-1992)
 Affiliations: VMMC, FEU-NRMF MC,
UDMC, NKTI
UFH
UFH
UFH
CITRATE
LMWH
UFH
DTI
UFH
CITRATE
CITRATE
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)
Target Clotting Times During
Dialysis
Test
Reagent
Routine heparin
Tight heparin
Desired range
Desired range
Baseline
Value
During
dialysis
At the end
of dialysis
+40% (85105)
WBPTT
Actin FS
60-85 sec
+80%
(120-140)
ACT
Siliceous
earth
120-150
sec
+80%
(200-250)
LWCT
None
4-8 min
20-30
+40%
(170-190)
9-16
During
dialysis
At the end
of dialysis
+40% (85105)
+40% (85105)
+40%
(170-190)
+40%
(170-190)
9-16
9-16
Daugirdas, Handbook Dial, 3rd ed, p. 185
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
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 40-45 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
CRRT Nomogram for Heparin
aPTT(seconds)
Bolus dose
Rate change
Repeat aPTT
<40
1000 U
+200 U/hr
In 6 hours
40.1-45.0
Nothing
+100 U/hr
In 4 hours
45.1-55.0
Nothing
No change
In 6 hours
55.1-65.0
Nothing
Stop ½ hour and 100 U/hr
In 4 hours
>65.0
Nothing
Stop 1 hour and 200 U/hr
In 4 hours
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
Regional Heparin
CRRT circuit showing infusion sites for heparin and protamine and collecting
sites for patient and circuit aPTT samples
Heparin
Patient aPTT
Arterial Line
Protamine
Circuit aPTT
Venous Line
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
Regional Heparin
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: 566-571
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
Low Molecular Weight Heparin
Enoxaparin
Dalteparin
Tinzaparin
1 mg/kg/dose
(mean 0.7)
39 u/kg/dose
Polkinghorne; AJKD, 2002
2000-2500 IU
anti-Xa
Hemostasis, 1996
Polkinghorne; AJKD, 2002
Low Molecular Weight Heparin
Tinzaparin
Plasma anti-Xa
activity
0.5 IU/ml (1 hour
after dialysis
Hemostasis, 1996
Dalteparin
anti-Xa activity
0.4-0.5 U/ml at 4
hrs
SD, 2006
0.2-0.25 U/ml at 4
hrs
AJKD, 2002
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
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
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
Regional Citrate
Regional Citrate

Citrate 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
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
0.25-0.35
No change
In 4 hours
0.36-0.40
+10 ml/hr
In 1 hour
0.41-0.45
+20 ml/hr
In 1 hour
>0.45
+30 ml/hr
In 1 hour
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
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
0.75-0.85
+30 ml/hr (1.65 mmol/hr)
In 2 hours
0.86-0.90
+20 ml/hr (1.1 mmol/hr)
In 4 hours
0.91-0.99
+10 ml/hr (0.5 mmol/hr)
In 6 hours
1.0-1.35
No change
In 6 hours
>1.35
-20 ml/hr (1.1 mmol/hr)
In 4 hours
Calcium chloride solution is made by mixing 80 ml of 10% calcium chloride in
1000 ml of normal saline for a concentration of 0.056 mmol/L. Systemic
calcium homeostasis is maintained by infusion for a targeted systemic ionized
calcium of 1.00-1.35 mmol/L. The infusion is initiated at 40 ml/hr (2.2
mmol/hr).
Seminars in Dialysis – Vol. 19, No. 4 (July – August) 2006
Regional Citrate
 Potential




Complications
Hypernatremia
Metabolic alkalosis
Hypocalcemia
Hypercalcemia
Continuous renal
replacement therapies:
anticoagulation in the
critically ill at high risk of
bleeding
Morabito et al, J Nephrol 2003
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
Continuous renal replacement
therapies…
Regional Coagulation
Baseline aPTT 36.7 + 6.4 sec
Patient aPTT 41.5 + 12.6 sec
Circuit aPTT 77.7 + 43.3 sec
Morabito et al, J Nephrol 2003
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 38.3 + 30.5 h
Regional heparin 35.6 + 25 h
Morabito et al, J Nephrol 2003
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
CANBERRA HOSPITAL NURSING
SERVICE

ANTICOAGULATION FREE DIALYSIS
1.
2.
3.
4.
5.
6.
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.
EUROPEAN BEST PRACTICE
GUIDELINES
EUROPEAN BEST PRACTICE
GUIDELINES
EUROPEAN BEST PRACTICE
GUIDELINES
EUROPEAN BEST PRACTICE
GUIDELINES
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, heparininduced platelet aggregation assay, solid phase immunoassays
Treatment: avoidance
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 0.1-0.2 mg/kg/hr
0.5 ug/kg/min (hepatic impairment)
Target aPTT values 1.5-3.0 times baseline
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
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
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
Danaparoid
 Mixture
of dermatan sulfate and heparan
sulfate.
 Has anti-factor Xa activity
 Disadvantages:




Need to determine anti-Xa activity
Long half-life (25+ 100 h) in renal failure
Absence of reversing agent
High cost
THANKS PO