Is Citrate 4% a Safer Alternative to Heparin in Maintaining Catheter Patency for Children Vulnerable to Systemic Bleeding? Jolyn R. Morgan MSN, RN, CPNP-AC, CDN Amanda N. Snyder MSN, RN, CNL Stuart L. Goldstein, MD Danielle Lazear, PharmD Center for Acute Care Nephrology Hello everyone, my name is Jolyn Morgan and I am a Nurse Practitioner in the Center for Acute Care Nephrology at Cincinnati Children’s Hospital Amanda- Hello, my name is Amanda Snyder and I am a registered nurse in the Center for Acute Care Nephrology at Cincinnati Children’s Hospital Title: Today we are presenting on “Is Citrate 4% a Safer Alternative to Heparin in Maintaining Catheter Patency for Children Vulnerable to Systemic Bleeding?”

Background Goal of Locking Solution Maintaining patency Children with acute/chronic kidney failure requiring RRT initially depend on reliable CVCs Complications Thrombosis Decreased delivered dialysis dose Catheter survival Maintenance Safe anticoagulate locking solution Goal of Locking Solution Maintaining patency Vessel preservation Central venous hemodialysis catheters are the life line for the pediatric population with acute and chronic renal failure that require Renal Replacement Therapy. However, with this comes a multitude of complications including but not limited to: thrombosis, decreased delivered dialysis dose and catheter survival. Maintenance involves instilling a safe locking solution to dwell after each use. This locking solution will dwell in both lumens until the line is accessed and the solution is aspirated. Goal: Ultimately, the goal of the locking solution should be to maintain patency by preventing partial or total thrombus formation. By doing so we can negate any unnecessary catheter exchanges to help preserve vessels for future use. While there are multiple locking solutions to choose from, our institution utilizes heparin 1,000 u/ml which is historically the locking agent of choice.

Locking Solutions Heparin Citrate Mechanism of Action Inactivates thrombin; inhibits fibrin formation Advantages Gold standard Inexpensive Disadvantage Systemic bleeding Thrombus formation HIT Increased biofilm formation Mechanism of Action Binds free ionized calcium Advantages Antithrombotic properties Antibacterial properties Inexpensive Decreased bleeding risk Disadvantage Hypocalcemia It works by inactivating thrombin, thus inhibiting fibrin formation It has a few advantages including being the gold standard and its inexpensive. However, its disadvantages are: systemic bleeding from inadvertent flushing or overspill, thrombus formation, production of heparin induced antibodies, and increased biofilm formation Contrary to heparin, citrate is an attractive alternative. It works by binding free ionized calcium which interrupts the clotting cascade and prevents blood form clotting It has several advantages including; antithrombotic properties, antibacterial properties, inexpensive, and most importantly decreased bleeding risk. A disadvantage of citrate is the risk hypocalcemia

Citrate Alternative Introduced in 1914 Citrate formulations (ACD-A™, ACD-B™, Trisodium) Commercialized vascular lock Trisodium concentrations 4% 30% 46.7%- associated with fatal cardiac arrests Evidence Sodium Citrate 4% has been reported as a safe catheter locking solution for an average size adult Minimal adverse effects Remains unclear in pediatrics Historically speaking, citrate was first used as an anticoagulant in 1914 to prevent coagulation in blood products. Additionally, it has been proven to be both safe and effective as a regional anticoagulant for extracorporeal therapies. There are several different citrate formulations available for use (ACD-A, ACD-B, and Trisodium); however, we are going to focus on the commercialized vascular lock concentrations which include; low concentration 4% citrate, 30% citrate and 46.7% citrate. Of note, the high concentration 46.7% citrate has been associated with fatal cardiac arrests. Literature supports that sodium citrate 4% is a safe locking solution for an average size adult even if the total volume of both lumens is inadvertently flushed into systemic circulation. There are minimal adverse effects and the marginal decrease in ionized calcium levels of 10% is unlikely to cause any adverse physiological effects in adults Although there is adequate support in the adult population, the use of citrate as a safe alternative in the pediatric population is still unclear

Heparin vs Citrate Type of Study Catheter Patency Bleeding Episode Quality Level RCT (2) ↔ C ↓ H ↑ No Comparison 2a-2b Systematic Review (3) C ↓ H ↑ 1a-1b Observational Cohort 4a-4b An extensive review of the literature was completed regarding heparin and 4 % citrate, and 7 articles focused on catheter patency and/ or bleeding events. Go through studies…  

Methods Cincinnati Children’s Hospital Medical Center utilizes caffeine citrate as the treatment of choice for neonates suffering from apnea of prematurity (AOP) Caffeine citrate is a 1.33%, 13.3 mg/ mL (2 mL/kg) citrate solution (0.5% citric acid => 5 mg/ mL, and 0.83% sodium citrate => 8.3 mg/ mL) Standard dose for AOP: 40 mg/ kg (2 mL/ kg) Formulation comparison Total weight based dose for a 5 kg child Caffeine citrate to sodium citrate 4% (40 mg/ mL) Heparin 1,000 u/ mL to a standard heparin bolus dose CVC 1 mL fill volume per lumen Cincinnati Children’s Hospital often times utilizes caffeine citrate as the treatment of choice for neonates suffering from apnea of prematurity. The significance of caffeine citrate is that it is a combination drug comprised of 0.5% citric acid and 0.83% sodium citrate which equates to a 1.33% or 13.3 mg/ml citrate solution. The standard dose administered for AOP is 40 mg/kg or 2 ml/kg A formulation comparison of citrate exposure for each medication was calculated. We compared caffeine citrate (a medication that is commonly used) sodium citrate 4% (what we are proposing to use), and Heparin 1000u/ ml (the locking solution of choice) for a 5 kg child.   Based on the size of the child, the CVC was assumed to have a 1 ml fill volume per lumen

Results Medication Dose Exposure Caffeine citrate (1.33%) 2 mL/ kg 133 mg citrate Sodium citrate (4%) 2 mL 80 mg citrate Heparin 1000 units/ mL 2,000 u (400 u/ kg) Conclusion The amount of sodium citrate 4% a patient would be exposed to is not an excessive dose when compared to caffeine citrate Further research needed to assess the safety and efficacy Based on our formula calculations, you can see that if a patient was treated with caffeine citrate for AOP, with the standard dose of 40 mg/kg or 2ml/kg, they would be exposed to 133 mg of sodium citrate. Looking at sodium citrate 4%, if each lumen of the patient’s catheter was locked with 1 ml of 4% citrate for a total of 2 ml’s, and it was inadvertently administered to the patient, they would be exposed to 80 mg of citrate Lastly, if each lumen of the patient’s catheter was locked with 1,000 u/ml of heparin for a total of 2 ml’s and it was inadvertently administered, the patient would be exposed to 2,000 u of heparin or 400 u/kg. These results are astonishing especially since the standard heparin bolus dose is 10-20 u/kg and for this 5kg patient a standard bolus dose would be 50-100 units of heparin In conclusion, based on our calculations the amount of sodium citrate 4% our patient would be exposed to is not an excessive dose when compared to caffeine citrate (80 mg to 133 mg). Further research is needed to assess the safety and efficacy in the pediatric population surrounding the use of sodium citrate 4% as a locking as a locking solution Standard Heparin Bolus Dose: 10-20 u/ kg (50-100 u)

Future Direction Population We will conduct a prospective randomized controlled study at CCHMC Population Patients with temporary or permanent hemodialysis CVCs Evaluation Catheter patency (BFR, use of TPA, CVC replacement) Side effects (hypocalcemia) We anticipate: 4% citrate will be safe and effective Similar incidence of catheter dysfunction Decreased bleeding episodes compared to heparin-based solutions Outcomes: Improve cost efficiency & adverse outcomes We plan to conduct a prospective randomized controlled study at CCHMC with heparin 1,000 u and sodium citrate 4% The population will include patients with temporary or permanent catheters We will evaluate catheter patency by monitoring whether the ordered blood flow rate is achieved, the administration of TPA, and lastly the need for replacing the catheter. We will also evaluate whether the patients experience any adverse effects to the 4% citrate such as hypocalcemia, by monitoring ionized calcium levels   We anticipate that 4% citrate will be a safe and effective locking solution for catheters, with similar incidence of catheter dysfunction and decreased bleeding episodes when compared to heparin-based solutions Ultimately, if 4% sodium citrate is a safe and effective locking agent for patients with hemodialysis CVCs this practice change may improve cost efficiency and adverse outcomes in the pediatric population.

Acknowledgements Cincinnati Children’s Hospital Medical Center Dr. Francisco Flores, Medical Director, Clinical Services and MARS Program, Division of Nephrology and Hypertension Dr. Gaby Yang, Center for Acute Care Nephrology Fellow We would like to thank Dr. Francisco Flores and Dr. Gaby Yang for their assistance and expertise