ramon c. mora m.d. year graduated : 1985 year graduated : 1985 school : feu-nrmf institute of...

Ramon C. Mora M.D.Ramon C. Mora M.D.

Year Graduated : 1985Year Graduated : 1985 School : FEU-NRMF Institute of MedicineSchool : FEU-NRMF Institute of Medicine Residency : Veterans Memorial Medical Residency : Veterans Memorial Medical

Center (1987-1990)Center (1987-1990) Fellowship : National Kidney & Transplant Fellowship : National Kidney & Transplant

Institute (1990-1992) Institute (1990-1992) Affiliations: VMMC, FEU-NRMF MC, Affiliations: VMMC, FEU-NRMF MC,

UDMC, NKTIUDMC, NKTI

UFH

DTI

UFH

UFH

CITRATE

CITRATE

CITRATE

UFH

LMWH

UFH

Unfractionated HeparinUnfractionated Heparin

I.D.I.D. 2000 ‘u’ 2000 ‘u’ (Daugirdas)(Daugirdas) 25 – 30 u/kg 25 – 30 u/kg (Sonawane; SD)’06(Sonawane; SD)’06

M.D.M.D. 1200 u/h 1200 u/h (Daugirdas)(Daugirdas) 1500 – 2000 u/hr 1500 – 2000 u/hr (Sonawane; (Sonawane; SD)’06SD)’06

Routine Heparin

Tight Heparin

I.D.I.D. 750 ‘u’ 750 ‘u’ (Daugirdas)(Daugirdas)

M.D.M.D. 600 ‘u’/h 600 ‘u’/h (Daugirdas)(Daugirdas)

Target Clotting Times During Target Clotting Times During DialysisDialysis

TestTest ReagentReagentBaseline Baseline ValueValue

Routine heparinRoutine heparin Tight heparinTight heparin

Desired rangeDesired range Desired rangeDesired range

During During dialysisdialysis

At the end At the end of dialysisof dialysis

During During dialysisdialysis

At the end At the end of dialysisof dialysis

WBPTTWBPTT Actin FSActin FS 60-85 sec60-85 sec +80% +80% (120-140)(120-140)

+40% (85-+40% (85-105)105)

+40% (85-+40% (85-105)105)

+40% (85-+40% (85-105)105)

ACTACT Siliceous Siliceous earthearth

120-150 120-150 secsec

+80% +80% (200-250)(200-250)

+40% +40% (170-190)(170-190)

+40% +40% (170-190)(170-190)

+40% +40% (170-190)(170-190)

LWCTLWCT NoneNone 4-8 min4-8 min 20-3020-30 9-169-169-169-16 9-169-16

Daugirdas, Handbook Dial, 3rd ed, p. 185

CRRTCRRT

I.D.I.D. 2000 ‘u’ 2000 ‘u’ (Daugirdas)(Daugirdas) 25 ‘u’/kg 25 ‘u’/kg (Amanzadeh; (Amanzadeh; SD)’06SD)’06

M.D.M.D. 500 ‘u’/h 500 ‘u’/h (Daugirdas)(Daugirdas) 5 ‘u’/kg 5 ‘u’/kg (Amanzadeh; (Amanzadeh; SD)’06SD)’06


Unfractionated Heparin

Heparin protocol for continuous Heparin protocol for continuous therapiestherapies

Initial therapyInitial therapy:: Heparin in priming and rinsing solution. At start of Heparin in priming and rinsing solution. At start of procedure, give 2,000-5,000 IU heparin in arterial line. Start 500-1,000 procedure, give 2,000-5,000 IU heparin in arterial line. Start 500-1,000 IU/h constant infusion.IU/h constant infusion.

MonitoringMonitoring:: PTT measured at the arterial and venous blood lines every PTT measured at the arterial and venous blood lines every 6 h.6 h.

Maintain arterial PTT 40-45 secMaintain arterial PTT 40-45 sec

Maintain venous PTT >65 secMaintain venous PTT >65 sec

If arterial PTT >45 sec, decrease heparin by 100 IU/hrIf arterial PTT >45 sec, decrease heparin by 100 IU/hr

If venous PTT <65 sec, increase heparin by 100 IU/hr, but only if If venous PTT <65 sec, increase heparin by 100 IU/hr, but only if arterial PTT <45 secarterial PTT <45 sec

If arterial PTT <40 sec, increase heparin by 200 IU/hrIf arterial PTT <40 sec, increase heparin by 200 IU/hr


CRRT Nomogram for HeparinCRRT Nomogram for HeparinaPTT(seconds)aPTT(seconds) Bolus doseBolus dose Rate changeRate change Repeat aPTTRepeat aPTT

<40<40 1000 U1000 U +200 U/hr+200 U/hr In 6 hoursIn 6 hours

40.1-45.040.1-45.0 NothingNothing +100 U/hr+100 U/hr In 4 hoursIn 4 hours

45.1-55.045.1-55.0 NothingNothing No changeNo change In 6 hoursIn 6 hours

55.1-65.055.1-65.0 NothingNothing Stop ½ hour and -Stop ½ hour and -100 U/hr100 U/hr

In 4 hoursIn 4 hours

>65.0>65.0 NothingNothing Stop 1 hour and -Stop 1 hour and -200 U/hr200 U/hr

In 4 hoursIn 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 HeparinRegional HeparinCRRT circuit showing infusion sites for heparin and protamine and collecting sites for patient and circuit aPTT samples

ProtamineHeparin

Venous LineArterial Line

Patient aPTT Circuit aPTT

Regional HeparinRegional Heparin

Heparin Infusion Heparin Infusion (500 IU/ml)(500 IU/ml)

IU/hrIU/hr 0.15 IU/min x 0.15 IU/min x blood flow blood flow (ml/min) x 60 (ml/min) x 60 (Morabito)(Morabito)

9 x blood flow 9 x blood flow (ml/min) (ml/min) (Amanzadeh)(Amanzadeh)

Protamine InfusionProtamine Infusion 5 mg/ml5 mg/ml 1 mg Protamine: 1 mg Protamine: 100 ‘u’ heparin100 ‘u’ heparin

Regional HeparinRegional HeparinAdjustments of Heparin and Protamine Infusion Rate According to aPTT Values

aPTT ValuesaPTT Values Adjustments (Adjustments (++20%)20%)

Patient aPTT <45 and circuit aPTT 55-90Patient aPTT <45 and circuit aPTT 55-90 No modificationsNo modifications

Patient aPTT <45 and circuit aPTT <55Patient aPTT <45 and circuit aPTT <55 ++ Heparin and protamine Heparin and protamine

Patient aPTT >45 and circuit aPTT 55-90Patient aPTT >45 and circuit aPTT 55-90 ++ Protamine Protamine

Patient aPTT >45 and circuit aPTT >90Patient aPTT >45 and circuit aPTT >90 -- Heparin Heparin

Patient aPTT <45 and circuit aPTT >90Patient aPTT <45 and circuit aPTT >90 - - Heparin and protamineHeparin and protamine

J Nephrol 2003; 16: 566-571

Regional HeparinRegional Heparin

Potential problemsPotential problems Complexity (balancing infusion rates)Complexity (balancing infusion rates) Rebound anticoagulation/ dissociation of Rebound anticoagulation/ dissociation of

heparin-protamine complexheparin-protamine complex Side effects of protamine – flushing, Side effects of protamine – flushing,

bradycardia, hypotension, dyspnea, bradycardia, hypotension, dyspnea, anaphylactic reaction among DM patientsanaphylactic reaction among DM patients

Low Molecular Weight HeparinLow Molecular Weight Heparin

EnoxaparinEnoxaparin 1 mg/kg/dose 1 mg/kg/dose (mean 0.7)(mean 0.7)

Polkinghorne; AJKD, 2002Polkinghorne; AJKD, 2002

Dalteparin Dalteparin 39 u/kg/dose39 u/kg/dose Polkinghorne; AJKD, 2002Polkinghorne; AJKD, 2002

TinzaparinTinzaparin 2000-2500 IU 2000-2500 IU anti-Xaanti-Xa

Hemostasis, 1996Hemostasis, 1996

Low Molecular Weight HeparinLow Molecular Weight HeparinTinzaparinTinzaparin Plasma anti-Xa Plasma anti-Xa

activityactivity0.5 IU/ml (1 hour 0.5 IU/ml (1 hour after dialysisafter dialysis

Hemostasis, 1996Hemostasis, 1996

DalteparinDalteparin anti-Xa activityanti-Xa activity 0.4-0.5 U/ml at 4 0.4-0.5 U/ml at 4 hrshrs

SD, 2006SD, 2006

0.2-0.25 U/ml at 4 0.2-0.25 U/ml at 4 hrshrs

AJKD, 2002AJKD, 2002

ConclusionConclusion This meta-analysis identified no difference in bleeding This meta-analysis identified no difference in bleeding

events or thrombosis of extracorporeal circuit when events or thrombosis of extracorporeal circuit when LMWH was compared with UFH.LMWH was compared with UFH.

There was great deal of heterogeneity among studies, a There was great deal of heterogeneity among studies, a variety of LMWH dosing regimens were used, and variety of LMWH dosing regimens were used, and comparison between different preparations was not comparison between different preparations was not possible.possible.

Inferences from these trials assessing anti-coagulation Inferences from these trials assessing anti-coagulation for patients who undergo hemodialysis will continue to be for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are weak until larger, more rigorous randomized trials are conducted.conducted.

Lim, et al J Am Soc Nephrol 2004

Hemodialysis anticoagulation and Hemodialysis anticoagulation and adequacyadequacy

No clear differences in hemodialysis adequacy No clear differences in hemodialysis adequacy results have been demonstrated using UFH and results have been demonstrated using UFH and LMWH. (Level II, limited data)LMWH. (Level II, limited data)

No differences in dialysis adequacy results are No differences in dialysis adequacy results are achieved using different LMWH. (Level II, limited achieved using different LMWH. (Level II, limited data)data)

There is no clear difference in the risk of There is no clear difference in the risk of thrombosis or hemorrhage with LMWH thrombosis or hemorrhage with LMWH compared with UFH, although the results of compared with UFH, although the results of individual studies have been quite variable. individual studies have been quite variable. (Level I)(Level I)

The CARI Guidelines – Caring for Australians with Renal Impairment, July 2005

ConclusionConclusion

Standard oral regimen with an INR Standard oral regimen with an INR between 2 and 3 is insufficient to prevent between 2 and 3 is insufficient to prevent clotting during hemodialysis.clotting during hemodialysis.

Additional low-dose anticoagulation with a Additional low-dose anticoagulation with a LMWH or heparin is necessary to facilitate LMWH or heparin is necessary to facilitate treatment.treatment.

Ziai, et al, KI 2005

Regional CitrateRegional Citrate

Regional CitrateRegional Citrate Citrate SolutionCitrate Solution

D5W 1L + 40 gm trisodium citrate (40 mg/ml)D5W 1L + 40 gm trisodium citrate (40 mg/ml) Initial infusionInitial infusion

• 180 ml/hr180 ml/hr• 90 ml/hr (liver failure/cirrhosis)90 ml/hr (liver failure/cirrhosis)

Goal: post filter ionized calcium between 0.25 – 0.35 Goal: post filter ionized calcium between 0.25 – 0.35 mmol/Lmmol/L

Calcium Chloride SolutionCalcium Chloride Solution 80 ml of 10% CaCl in 1000 ml of NS (0.056 mmol/L) 80 ml of 10% CaCl in 1000 ml of NS (0.056 mmol/L)

via central venous catheter to maintain systemic via central venous catheter to maintain systemic ionized calcium of 1.0 – 1.35 mmol/Lionized calcium of 1.0 – 1.35 mmol/L

Initial infusion: 40 ml/hr (2.2 mmol/hr)Initial infusion: 40 ml/hr (2.2 mmol/hr)


CRRT Nomogram for CitrateCRRT Nomogram for Citrate

Postfilter ionized CaPostfilter ionized Ca++ (mmol/L)(mmol/L) Rate ChangeRate Change

Repeat postfilter Repeat postfilter ionized Caionized Ca++ (mmol/L) (mmol/L)

<0.25<0.25 -20 ml/hr-20 ml/hr In 1 hourIn 1 hour

0.25-0.350.25-0.35 No changeNo change In 4 hoursIn 4 hours

0.36-0.400.36-0.40 +10 ml/hr+10 ml/hr In 1 hourIn 1 hour

0.41-0.450.41-0.45 +20 ml/hr+20 ml/hr In 1 hourIn 1 hour

>0.45>0.45 +30 ml/hr+30 ml/hr In 1 hourIn 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.


CRRT Nomogram for Calcium CRRT Nomogram for Calcium ChlorideChloride

Systemic ionized CaSystemic ionized Ca++ (mmol/L)(mmol/L) Rate ChangeRate Change

Repeat systemic Repeat systemic ionized Caionized Ca++ (mmol/L) (mmol/L)

<0.75<0.75 +40 ml/hr (2.2 mmol/hr)+40 ml/hr (2.2 mmol/hr) In 2 hoursIn 2 hours

0.75-0.850.75-0.85 +30 ml/hr (1.65 mmol/hr)+30 ml/hr (1.65 mmol/hr) In 2 hoursIn 2 hours



1.0-1.351.0-1.35 No changeNo change In 6 hoursIn 6 hours

>1.35>1.35 -20 ml/hr (1.1 mmol/hr)-20 ml/hr (1.1 mmol/hr) In 4 hoursIn 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).


Regional CitrateRegional Citrate

Potential ComplicationsPotential Complications HypernatremiaHypernatremia Metabolic alkalosisMetabolic alkalosis HypocalcemiaHypocalcemia HypercalcemiaHypercalcemia

Continuous renal Continuous renal replacement therapies: replacement therapies: anticoagulation in the anticoagulation in the

critically ill at high risk of critically ill at high risk of bleedingbleeding

Morabito et al, J Nephrol 2003Morabito et al, J Nephrol 2003

Continuous renal replacement Continuous renal replacement therapies…therapies…

MethodsMethods 59 patients underwent CRRT for ARF following 59 patients underwent CRRT for ARF following

cardiac surgerycardiac surgery Non-anticoag CRRT: Non-anticoag CRRT: spontaneous bleeding, aPTT spontaneous bleeding, aPTT

>45 seconds, thrombocytopenia, recent surgery (<48 h)>45 seconds, thrombocytopenia, recent surgery (<48 h)

ResultsResults 22 (37.3%) non-anticoagulation22 (37.3%) non-anticoagulation 12 patients continued (38.3 h filter life)12 patients continued (38.3 h filter life) 10 patients switched to regional heparin (38 h filter 10 patients switched to regional heparin (38 h filter

life)life)

Morabito et al, J Nephrol 2003


Regional Coagulation

Baseline aPTTBaseline aPTT 36.7 36.7 ++ 6.4 sec 6.4 sec

Patient aPTTPatient aPTT 41.5 41.5 ++ 12.6 sec 12.6 sec

Circuit aPTT Circuit aPTT 77.7 77.7 ++ 43.3 sec 43.3 sec



Non-anticoagulationNon-anticoagulation Regional HeparinRegional Heparin

24 h24 h 55.5%55.5% 76.2%76.2%

48 h48 h 30.1%30.1% 39.6%39.6%

72 h72 h 16.6%16.6% 19.8%19.8%

Probabilities of circuit remaining free from clotting


Filter life

Non-anticoagulationNon-anticoagulation 38.3 38.3 ++ 30.5 h 30.5 h

Regional heparinRegional heparin 35.6 35.6 ++ 25 h 25 h


ConclusionConclusion Non-anticoagulaiton CRRT allowed an Non-anticoagulaiton CRRT allowed an

adequate filter life in most patients with a high adequate filter life in most patients with a high risk of bleeding for risk of bleeding for prolonged aPTTprolonged aPTT and/or and/or thrombocytopeniathrombocytopenia. Despite concerns . Despite concerns regarding the need for careful monitoring, regarding the need for careful monitoring, regional anticoagulation with heparin and regional anticoagulation with heparin and protamine can be considered as a safe and protamine can be considered as a safe and valid alternative when non-anticoagulation is valid alternative when non-anticoagulation is unsuitable because of early filter failure.unsuitable because of early filter failure.


CANBERRA HOSPITAL NURSING CANBERRA HOSPITAL NURSING SERVICESERVICE

ANTICOAGULATION FREE DIALYSISANTICOAGULATION FREE DIALYSIS1.1. Rapid blood flow rate desirable to reduce clotting Rapid blood flow rate desirable to reduce clotting

(>300 ml/min). Where disequilibrium is an issue, (>300 ml/min). Where disequilibrium is an issue, use a smaller filter and co-current dialysate flow.use a smaller filter and co-current dialysate flow.

2.2. Routine flushes using NaCl 0.9%. Make sure NS Routine flushes using NaCl 0.9%. Make sure NS flushes are added to UF volume.flushes are added to UF volume.

3.3. Change whole circuit after 1.5 to 2 hours of Change whole circuit after 1.5 to 2 hours of hemodialysis.hemodialysis.

4.4. Avoid giving blood transfusion and high UFR.Avoid giving blood transfusion and high UFR.5.5. Decrease dialysis length time where possible but Decrease dialysis length time where possible but

ensure patient does extra time for the next dialysis.ensure patient does extra time for the next dialysis.6.6. Watch out for signs and symptoms of clotting in the Watch out for signs and symptoms of clotting in the

circuit.circuit.

EUROPEAN BEST PRACTICE GUIDELINES

EUROPEAN BEST PRACTICE EUROPEAN BEST PRACTICE GUIDELINESGUIDELINES

EUROPEAN BEST PRACTICE GUIDELINES

Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia

Type IType I Transient reduction of platelet count occurring after 5 days.Transient reduction of platelet count occurring after 5 days.

Type IIType II Antibody mediated complex of heparin and platelet factor 4Antibody mediated complex of heparin and platelet factor 4 >20,000 platelet count, severe bleeding is rare>20,000 platelet count, severe bleeding is rare Prevalence 1-3%Prevalence 1-3% Main clinical complication: arterial thrombosisMain clinical complication: arterial thrombosis Specific tests for type II HIT: Serotonin release assay, heparin-Specific tests for type II HIT: Serotonin release assay, heparin-

induced platelet aggregation assay, solid phase immunoassaysinduced platelet aggregation assay, solid phase immunoassays Treatment: avoidanceTreatment: avoidance

Direct Thrombin InhibitorsDirect Thrombin Inhibitors Bivaluridin, Lepirudin, ArgatrobanBivaluridin, Lepirudin, Argatroban

DOSE: 3 dose regimens for ArgatrobanDOSE: 3 dose regimens for Argatroban 250 ug/kg bolus, with an additional 250 ug/kg if the ACT at 2 250 ug/kg bolus, with an additional 250 ug/kg if the ACT at 2

hours was less than 140% of baselinehours was less than 140% of baseline 250 ug/kg bolus followed by 2 ug/kg/min continuous infusion250 ug/kg bolus followed by 2 ug/kg/min continuous infusion Steady state infusion of 2 ug/kg/min initiated 4 hours prior to Steady state infusion of 2 ug/kg/min initiated 4 hours prior to

sessionsession Other recommended dosesOther recommended doses

15-25 mg/hr or 0.1-0.2 mg/kg/hr15-25 mg/hr or 0.1-0.2 mg/kg/hr 0.5 ug/kg/min (hepatic impairment)0.5 ug/kg/min (hepatic impairment) Target aPTT values 1.5-3.0 times baselineTarget aPTT values 1.5-3.0 times baseline

ProstacyclinProstacyclin Inhibits interaction between platelets and Inhibits interaction between platelets and

artificial membranesartificial membranes Dose: 0.4 – 0.5 ng/kg/minDose: 0.4 – 0.5 ng/kg/min Intensive Care Medicine, 2002Intensive Care Medicine, 2002

Safety and efficacy of EpoprostenolSafety and efficacy of Epoprostenol• 7.8% (4/51): major bleeding7.8% (4/51): major bleeding• 15.5%: hypotension requiring vassopressors15.5%: hypotension requiring vassopressors• Median life of filter = 15.0 hrsMedian life of filter = 15.0 hrs

Blood Purification, 2005Blood Purification, 2005 Citrate anticoagulation has longer filter survival during Citrate anticoagulation has longer filter survival during

continuous hemofiltration compared to the continuous hemofiltration compared to the combination of PGI2 and heparincombination of PGI2 and heparin

ProstacyclinProstacyclin

Adverse EffectsAdverse Effects Increased intracranial pressureIncreased intracranial pressure Decreased systemic and pulmonary vascular Decreased systemic and pulmonary vascular

resistance and MAPresistance and MAP Increased pulmonary ventilation/perfusion Increased pulmonary ventilation/perfusion

mismatch resulting in decreased tissue mismatch resulting in decreased tissue oxygen delivery and uptake worsening oxygen delivery and uptake worsening acidosis and lactate productionacidosis and lactate production

High costHigh cost

NafamostatNafamostat

Synthetic serine protease inhibitor, mainly Synthetic serine protease inhibitor, mainly used in Japanused in Japan

Safer than anticoagulation with regional or Safer than anticoagulation with regional or low dose heparinlow dose heparin

Adsorbed by negatively charged Adsorbed by negatively charged membranes, cannot be used with PANmembranes, cannot be used with PAN

DanaparoidDanaparoid

Mixture of dermatan sulfate and heparan Mixture of dermatan sulfate and heparan sulfate.sulfate.

Has anti-factor Xa activity Has anti-factor Xa activity Disadvantages:Disadvantages:

Need to determine anti-Xa activityNeed to determine anti-Xa activity Long half-life (25Long half-life (25++ 100 h) in renal failure 100 h) in renal failure Absence of reversing agentAbsence of reversing agent High costHigh cost

THANKS POTHANKS PO

ramon c. mora m.d. year graduated : 1985 year graduated : 1985 school : feu-nrmf institute of...

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