Regional citrate anticoagulation for continuous renal replacement therapy without post-filter monitoring of ionized calcium

*Corresponding author: Tibor Fülöp, M.D., FACP, FASN, Division of Nephrology, University of Mississippi Medical Center, 2500 North State Street, L 504; Jackson, Mississippi 39216-4505. Present address of corresponding author: Department of Medicine Division of Nephrology, Medical University of South Carolina, Charleston, USA, Email: tiborfulop.nephro@gmail.com http://journalrip.com DOI: 10.15171/jrip.2018.xx


Introduction
Providing safe and reliable renal replacement therapy in the intensive care setting remains a challenge.While continuous renal replacement therapy (CRRT) modalities are usually preferred in hemodynamically unstable patients, difficulties pertaining to the complexity of such therapy exist.Many aspects of CRRT delivery remain vigorously debated, including the timing and indications of initiation, dose and duration of therapy and the choice of anticoagulants (1)(2)(3)(4).Preventing clot formation is key for successful delivery of renal replacement support (5).Heparin, the agent historically used for anticoagulation of the extracorporeal circuit, may also induce thrombocytopenia (6) or increase the risk of bleeding in patients already at high risk.Further, the suppression of the platelet count is frequently observed in the intensive care unit (ICU) setting due to a multitude of reasons, including drug effects, excessive uptake and the presence of acute critical illness itself (7)(8)(9).Thus, not surprisingly, the search has been on for some time seeking an alternative option of achieving regional anticoagulation in the extracorporeal circuit.

Materials and Methods
We conducted a literature search on three databases including PubMed, EMBASE, Scopus and Google Scholar.The search was performed using a combination of the following terms; continuous renal replacement therapy, hemofiltration, regional citrate anticoagulation, thrombocytopenia and intensive care unit.Further, the authors' clinically experience was considered, when writing this protocol paper.

Regional citrate anticoagulation
Regional citrate anticoagulation (RCA) is an attractive candidate to achieve this goal (10)(11)(12)(13).However, RCA may potentially add substantially to the complexity of an already complicated technology, impeding acceptance and utilizing excessive resources (11,14).Delivering care in a uniform, safe and standardized setting with minimized need for laboratory testing appears to be the cornerstone of the implementation of RCA in the ICU setting.Simplifying the delivery of CRRT and offering uniform protocol may enhance acceptance by nursing staff and hospital administrators alike.In this paper, we would like to offer a description of a safe and effective standardized protocol with a potential to minimize errors.

General concepts of regional citrate anticoagulation
For an adult weighing 70 kg, the total amount of dissolved calcium in the extracellular space is approximately 1000 mg at any given time.Under normal circumstances, total calcium concentration is approximately 2.5 mM/L (or 10 mg/dL), of which about 50% is ionized, 13 % is bound by small anions (lactate, citrate and phosphate) and the rest by negatively charged albumin molecules.This calcium amount is the approximate equivalent of ~4 amps of 10% calcium-chloride (6.8 mM of calcium per each 10 mL) or ~12 amps of 10% calcium gluconate (93 mg of calcium or 2.3 mM per each 10 mL).At physiologic P H and ionic strength, ionized calcium is expected to decrease by 0.1 mM/L with each 0.5-0.6 mM/L (10 mg/ dL) rise of plasma citrate.Assuming an initial ionized calcium concentration of 1.0-1.25 mM/L, ionized calcium is fully expected to be depleted once citrate concentration reaches about 5-6 mM/L (or 100 mg/dL).At this point, similarly to the blood exposed to anticoagulant ethylenediaminetetraacetic acid (EDTA), the coagulation cascade is rendered ineffective and blood clot formation impaired.Citrate exposure is known to confer less filterinduced complement activation, neutrophil degranulation and less endothelial activation than heparin during continuous hemofiltration (15).To deliver a cheap and easily available form of citrate supplementation, the Anticoagulant Citrate Dextrose-A (ACD-A) solution is an obvious choice.It contains an isotonic mixture of citric acid (0.8%), trisodium citrate (2.2%) and dextrose, resulting in a final citrate concentration of 3.0 % (or 112.9 mM/L).The normalization of systemic ionized calcium is achieved by simultaneous infusion of calcium-chloride and the endogenous metabolism of citrate, in the liver converting to bicarbonate in an approximate ratio of 1:3 and, simultaneously, releasing ionized calcium from the chelated form.thus reducing the need for frequent testing and avoiding confusion resulting from markedly "abnormal" results of post-filter ionized calcium values.In 2008, the nephrology faculty of our medical center revised the existing protocols of continuous venovenous hemofiltration (CVVHF) and hemodiafiltration (CVVHDF) regimens to deliver RCA in a uniform manner while minimizing cost, complexity and potential risk for the recipients of the therapy.We specifically desired the practice of abandoning post-filter monitoring of ionized calcium, highly inaccurate procedure during RCA.As we are a training institution regularly working with physicianin-training (nephrology fellows), it was important at that time to minimize handwritten orders to complement existing pre-printed order sets.Samples of our protocols are shown in Figures 1 and 2. These protocols can also easily be converted into electronic instruction formats in the current era.As a rule, we routinely start with a blood flow of 200-250 mL/min for our adult patients.ACD-A solution (available from multiple manufacturers) is infused pre-filter at a rate of ×1.5 of the blood flow rate in mL/L (e.g. for a blood flow rate of 200 mL/min an ACD-A infusion rate of 300 mL/h will be applied).For replacement fluid or dialyzate fluid we are using calcium-free premixed solutions, close to physiologic concentrations (PrismaSate, PrismaSol; Gambro Renal Products Inc., Lakewood, CO), shown in Figures 1 and 2, second parts.The total effluent is calculated to achieve a net clearance of >20-25 mL/kg/h.In pure convective modality (CVVHF), we are routinely splitting the pre-and post-filter rate of the replacement fluid at 50:50 or 70:30 percent.A separate I.V. infusion will deliver calcium with calcium-chloride at an initial rate of 25 g/24 h (500 mL bag containing 25 g of calcium chloride solution with 250 mL of normal saline [manufactured at a compounding pharmacy]).Following the initial 24-48 hours, most patients will need separate infusions of phosphorus (e.g.sodium-phosphate of 30-45 mM/24 h) and magnesium (magnesium chloride of 2-4 gm/24 h).Ionized calcium is not being monitored on the return limb, to minimize expense and avoid potential confusion with regard to very low values (minimizing potential for false alarms and medical errors).For serum ionized calcium, we are targeting normal values (1.25 mM/L) but with a bias to keep it in a high-normal range (1.10-1.30mM/L) for critically ill patients.Target range for phosphorus is between 3.5-4.5 mg/dL and 1.5-2 mg/dL for magnesium.As ACD-A is both a source of bicarbonate

Standard Guidelines for Continuous Renal Replacement Therapy
1. ACD-A citrate is infused though a standard IV pump that should be adjacent to the CRRT machine.It is infused into the dialysis tubing 'Y' access connector (near the arterial access port).
2. The recommended starting rate for ACD-A citrate is 1.5 times the blood flow rate but per hour.That is, if the blood flow rate is at the standard rate of 200 ml/min, the ACD-A rate should be 300 ml/hour.This rate is just a starting point and should be adjusted up if the filter is clotting in less than 24 hours (usually in ~10% increments) or down if citrate retention is becoming apparent (citrate retention or "lock" is manifested by an increase in total calcium with a stable or decrease in ionized calcium).a.It is not necessary to routinely measure total calcium levels; they should be checked when clinically indicated (i.e. if the patient is at high risk for citrate lock, such as in patients with significant liver dysfunction).b.Citrate dose should be based on the frequency of circuit clotting; not on the calcium levels in the venous circuit.
3. The IV calcium drip is infused into the distal port of a central line.Alternative access sites (i.e. the stop-cock attached to the return port of the dialysis access) can be done at the discretion of the Nephrologist (requires a written order).

BOTH THE CITRATE AND CALCIUM DRIPS SHOULD BE DISCONTINUED WHEN THE CRRT MACHINE IS NOT RUNNING.
5. Standard rates for predilution and postdilution hemofiltration solutions are 50% of the total hemofiltration rate for each.

6.
The "CRRT Syringe Pump" will be filled with saline during standard citrate anticoagulation.Heparin or an alternative anticoagulant can be infused here only when approved of by the Nephrologist.
7. Mandatory replacement of the filter sets is at 72 hours or once 780 liters of blood have been processed (whichever comes first).

Heparin Flush Protocol for Priming of the Extracorporeal Circuit
Heparin (10,000 units) will be added to 1L of normal saline and the circuit will be the primed with this fluid.Once the first prime is complete, the entire circuit is primed again using Prismasate or Prismasol (without heparin) thus flushing the excess heparin away.Contraindications to heparin prime/flush: a) Suspected or diagnosed Heparin-Induced Thrombocytopenia.b) Heparin allergy.(16).While it is technically possible to add additional potassium to the pre-mixed solution, we generally avoid such practice.In the anecdotal experience of the authors, filter survival usually reached 48-72 hours under these circumstances for most (~70%) of the patients.

Additional issues of implementation
Large volume hemofiltration or dialysate rates (>2-3 L/h) frequently result in hypothermia in the ICU.The use of blood warmers is therefore routinely needed for the extracorporeal circuits with occasional measures of additional passive warming (heating blanket, additional covering of neck-head area).Thyroid dysfunction should always be on the differential for unexplained hypothermia despite these measures (17).For hemodialysis access we are preferentially using double dialysis catheters placed into the internal jugular vein.Patients also need a triple-lumen catheter placed into a central vein for infusion of calcium, phosphate and magnesium.Only in rare circumstances do we permit the omission of triple-lumen catheter placement and the infusion of calcium via the return limb (attending physician's signature required) for those with critical electrolyte abnormalities and central access difficulties, where even a few hours delay would cause harm.Avoiding post-filter ionized calcium monitoring reduced the expense and potential for misunderstanding, reporting on the extremely low, non-physiologic ionized calcium concentrations.Similar abandonment of routine post-filter monitoring has been reported since by others (18) and the accuracy of measured post-filter ionized calcium has been called into question by others, as well (19,20).We routinely place safety locks on the dialysis catheter-to-extracorporeal connection (e.g., HemaClip Bloodline Connector Clip for Hemodialysis, Fresenius Medical Care North America, Waltham, MA) to prevent accidental disconnection (Figure 3).The back page of the protocol serves also as a quick, hands-on reference guide for physicians to review available solutions for renal

Conclusion
Abandoning post-filter monitoring of ionized calcium during RCA offers improvement over existing approaches, including simplification of management and reducing the burden of complexity, hence decreasing the potential for medical errors.Our paper described sample protocols of RCA-assisted CRRT and briefly reviewed practical points of implementation.We kept the language of this paper deliberately simple, hence it would be easy to read and understand by non-nephrology physicians, nurses and dialysis technicians alike.
and LZ.All authors read and signed the final manuscript.

Conflicts of interest
Dr. Zsom is an employee of Fresenius Medical Care (FMC) Hungary and Dr Fülöp is a former employee of FMC Hungary.However, the views and opinions expressed herewith do not reflect the official opinion of the Fresenius Medical Care Hungary.

Ethical considerations
Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.
Funding/Support None.

Figure 3 .
Figure 3. Blood line connector safety clip in place.


Match input with output.Net Volume Negative _____-_____ mL/hour up to _____ L/24 hours.

Electrolyte Replacement: Infuse IV only while CRRT is running. Discontinue when CRRT is discontinued.
 Ca ++ Chloride: 25 grams in 250 mL NS (total volume: 500 mL) infused at a rate of _______ grams/24 hours.