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

Measures to Optimize Anticoagulation in HD

UFH UFH UFH CITRATE LMWH DTI UFH 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 Baseline Value Routine heparin Tight heparin Desired range During dialysis At the end of dialysis WBPTT Actin FS 60-85 sec +80% (120-140) +40% (85-105) ACT Siliceous earth 120-150 sec +80% (200-250) +40% (170-190) LWCT None 4-8 min 20-30 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 No change 55.1-65.0 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

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

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 + 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: 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 1 mg/kg/dose (mean 0.7) Polkinghorne; AJKD, 2002 Dalteparin 39 u/kg/dose Tinzaparin 2000-2500 IU anti-Xa Hemostasis, 1996

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 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

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 0.41-0.45 +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

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) 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 >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 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

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

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 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, heparin-induced 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

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