Strategies to extend the lifespan of the dialysis circuit

There are several factors which cause the the hemodialysis filter to clog up with clots and debris, and there are several measures which can be taken to prevent this from happening.

Methods of Prolonging the CVVHDF Filter Lifespan
Strategy	Advantages	Disadvantages
Nothing whatsoever (+/- regular saline flushes)	Circuit lifespan may still be acceptable for patients at high risk of bleeding (i.e. those who have "anticoagulated" themselves)	This will not benefit patients with HIT who are actually prothrombotic; another systemic anticoagulant will be required. May not be suitable for patients with a normal or mildly impaired clotting function
High flow rate	Easy and cheap Safe - no added pharmacological complications	Relies on a good vas cath position and a calm compliant patient. The vas cath has to be reasonably widebore, which can increase the risk of vascular complications The higher flow rate may not be tolerated by hemodynamically unstable patients
Pre-dilution	Routine and well-rehearsed modality Reasonably safe in most patient groups Cheap	Reduces small solute clearance; thus: Reduces CVVHDF efficiency
Unfractionated heparin	Routine and well-rehearsed modality Reasonably safe in most patient groups Cheap Anticoagulation is easily reversible Anticoagulation is short-term Does not rely on renal clearance	Unsuitable for HIT patients May cause HIT May be unsuitable for patients at high risk of bleeding
Regional anticoagulation with heparin and protamine	Advantageous for patients at high risk of bleeding in whom filter lifespan is still reduced due to clotting Reversal of anticoagulation at the end of the circuit decreases the risk of bleeding complications	Unsuitable for HIT patients Cumbersome protocols, greatly increased workload The heparin–protamine complex is taken up by the reticuloendothelial system and broken down, but then heparin and protamine are released back into the circulation. Protamine has known disadvantages: Protamine can act as an anticoagulant Protamine causes pulmonary hypertension
Low molecular weight heparin	More convenient (boluses vs. infusion) Identical filter life to unfractionated heparin May be safer in terms of bleeding risk. Lower incidence of HIT No need for monitoring (or, rather, monitoring is too difficult and we give up)	More expensive compared to unfractionated heparin Clearance is renal; there is the potential for accumulation May be unsafe in patients at high risk of bleeding
Warfarin	Cheap The patient may already be warfarinised	No evidence for benefit in preventing catheter thrombosis Difficult to initiate Slow to reverse Metabolism affected by numerous factors
Platelet function inhibitors: NSAIDs, aspirin, etc	Not totally experimental Many patients are already on these drugs	Difficult to monitor No reversal agent - irreversible inhibition Long term effects Many of these drugs rely on renal clearance
Citrate	Reversible Effective Pre-mix solutions have simplified this process; protocols exist to guide the inexperienced	Cumbersome protocol; greatly increased workload Requires frequent monitoring: Sodium Calcium Bicarbonate (or pH) If you are using trisodium citrate, you end up giving a massive amount of sodium Acidosis may result due to excess citrate Alkalosis may result when that citrate is metabolised In hepatic failure, this is contraindicated (as citrate is metabolised mainly by the liver) Special calcium-free hyponatraemic and bufferless dialysate is required If the patient has HITTS, they will still require some sort of systemic anticoagulation Risk of toxicity High anion gap metabolic acidosis Ionised hypocalcemia
Direct thrombin inhibitors: Hirudin / Lepirudin Bivalirudin / Argatroban	Alternative to heparin in HIT Argatroban has a short halflife and is metabolised by the liver There is a predictable near-linear relationship between hirudin levels and APTT	Expensive Hirudin, lepirudin and bivalirudin are renally excreted; halflife will be prolonged Argobatran is metabolised by the liver - halflife will be prolonged in liver failure Argatroban falsely raises PT and INR. All these molecules are too large to be removed by CRRT membranes, and will accumulate. No reversal agent
Heparinoids (Danaparoid)	Alternative to heparin in HIT Probably safe in most cases	Expensive Cross-reactivity with heparin/platelet antibodies (in 5%) Long half life (48 hrs) No reversal agent Higher risk of bleeding than with heparin
Xa inhibitors: Fondaparinux	Alternative to heparin in HIT Probably safe	Renally cleared; may accumulate in high doses Long halflife (15-20hrs) No reversal agent
Serine protease inhibitors: Nafamostat	Very short half-life (8 min) Regional anticoagulation only Probably safe	Suppresses neutrophil activity and may cause agranulocytosis May cause increased bilirubin levels Clearance relies on serum esterases, which may be decreased in chronic liver disease May decrease protein C activity, leading to paradoxically increased circuit clotting May cause anaphylaxis May cause hyperkalemia
Prostacyclin (PGI₂)	Very short half life (90 seconds) Probably safe Decreases platelet consumption in the circuit Can be used together with heparin for a combined effect, as a "heparin-sparing" agent.	Hypotension from vasodilation Ridicuously expensive If the patient has HITTS, they will still require some sort of systemic anticoagulation

References

This article offers a nice overview of anticoagulation in CRRT:

Jamshid Amanzadeh and Robert F. Reilly, Jr. Anticoagulation and Continuous Renal Replacement Therapy Seminars in Dialysis—Vol 19, No 4 (July–August) 2006 pp. 311–316

For a definitive treatment of all of this, you ought to pay homage to the gigantic and all-encompassing "Critical Care Nephrology" by Ronco Bellomo and Kellum (2009).

Finally, the Gambro and Fresenius websites have been an excellent source of information.

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Fiaccadori, Enrico, et al. "Continuous haemofiltration in acute renal failure with prostacyclin as the sole anti-haemostatic agent." Intensive care medicine 28.5 (2002): 586-593.

Han, Sang Jin, et al. "Use of nafamostat mesilate as an anticoagulant during extracorporeal membrane oxygenation." Journal of Korean medical science26.7 (2011): 945-950.

Hu, Z. J., et al. "Time course of activated coagulation time at various sites during continuous haemodiafiltration using nafamostat mesilate." Intensive care medicine 25.5 (1999): 524-527.

Akizawa, T., et al. "Nafamostat mesilate: a regional anticoagulant for hemodialysis in patients at high risk for bleeding." Nephron 64.3 (1993): 376-381.

Wester, J. P., et al. "Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill." Neth J Med 65.3 (2007): 101-108.

Mahieu, Elien, et al. "Anticoagulation With Fondaparinux for Hemodiafiltration in Patients With Heparin‐Induced Thrombocytopenia: Dose‐Finding Study and Safety Evaluation." Artificial organs 37.5 (2013): 482-487.

Morabito, Santo, et al. "Continuous renal replacement therapies: anticoagulation in the critically ill at high risk of bleeding." Journal of nephrology16.4 (2003): 566-571.

Tan, H. K., I. Baldwin, and R. Bellomo. "Continuous veno-venous hemofiltration without anticoagulation in high-risk patients." Intensive care medicine 26.11 (2000): 1652-1657.

Tolwani, Ashita J., and Keith M. Wille. "THE CLINICAL APPLICATION OF CRRT—CURRENT STATUS: Anticoagulation for Continuous Renal Replacement Therapy." Seminars in dialysis. Vol. 22. No. 2. Blackwell Publishing Ltd, 2009.

Davies, H. T., et al. "A randomized comparative crossover study to assess the affect on circuit life of varying pre-dilution volume associated with CVVH and CVVHDF." The International journal of artificial organs 31.3 (2008): 221-227.

Davenport, Andrew. "Pre-dilution or post-dilution fluid replacement for continuous veno-venous hemofiltration: that is the question." Nephron Clinical Practice 94.4 (2004): c83-c84.

Davies, Hugh, and Gavin Leslie. "Maintaining the CRRT circuit: non-anticoagulant alternatives." Australian Critical Care 19.4 (2006): 133-138.

Reeves, John H., et al. "A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration." Critical care medicine 27.10 (1999): 2224-2228.

Jeffrey, R. F., et al. "Anticoagulation with low molecular weight heparin (Fragmin) during continuous hemodialysis in the intensive care unit." Artificial organs 17.8 (1993): 717-720.

Wilkieson, Trevor J., et al. "Low-intensity adjusted-dose warfarin for the prevention of hemodialysis catheter failure: a randomized, controlled trial."Clinical Journal of the American Society of Nephrology 6.5 (2011): 1018-1024.

Teraoka, Satoshi, et al. "Heparin-free hemodialysis with an oral anti-platelet agent." ASAIO journal 38.3 (1992): M560-M563.

De Pont, Anne-Cornelie JM, et al. "Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study."Critical Care 11.5 (2007): R102.

Haase, Michael, et al. "Use of fondaparinux (ARIXTRA®) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II." Nephrology Dialysis Transplantation 20.2 (2005): 444-446.

Ho, Grace, et al. "Use of fondaparinux for circuit patency in hemodialysis patients." American Journal of Kidney Diseases 61.3 (2013): 525-526.

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