ADDENDA Dec. 10, 2005

11. A Quality Manager of a Blood and Tissues Bank in Cantabria Santander, Spain reports that they perform stem cell collections for their University Hospital (about 175 procedures a year) and use a prophylactic protocol for the prevention of citrate adverse effects for both in autologous and allogeneic stem cell donors. The use only ACD-A as anticoagulant and have found no differences in the incidence of adverse effects. He adds that their aim is to process at least 4-5 blood volumes per procedure with automated equipment. In their experience they find it is better to use a robust prophylactic protocol, because overt symptoms are harder to treat. What they reporting doing is:

• The donor must have had breakfast, including milk products.
• They administer 2 tablets of calcium orally (dissolved in water) prior to beginning the procedure.
• A solution of calcium gluconate (60ml in 250 ml saline) is infused over the duration of the entire procedure via the "return" lumen of the apheresis disposable.

Exceptions to using this protocol are:

• The donor does not tolerate oral calcium: in such cases the dose of intravenous calcium gluconate is adjusted by the physician.
• The catheter is not working well, not allowing infusion of calcium. In such cases they administer 2 additional tablets of calcium orally at mid-procedure and then another 2 tablets towards the end of the procedure. They replace magnesium only if the donor has low magnesium levels, which they find to be the usual case when donors have been treated with ethoposide. In that case, they measure magnesium levels before the apheresis procedure. A difficult issue comes up with autologous myeloma patients who are forbidden to receive calcium !!!

ADDENDA Dec. 13, 2005

12. A transfusion medicine physician in Michigan reports that in her experience over the years working at three different hospitals, no two of these hospitals employs the exact same practice for calcium replacement during apheresis procedures. At her current hospital, the SOP for peripheral blood stem cell collections includes the use of a calcium gluconate drip, with a sliding scale based on donor weight, adjusted upward as necessary according to the stem cell donor's clinical condition. They seldom administer magnesium. In her experience, she believes that calcium (intravenous) replacement during apheresis is superior over oral replacement. For stem cell donors with low-normal K and Mg levels, they have provided sports drinks during the procedure. She reports (anecdotally) that the use of sports drinks appeared to help two young donors that were symptomatic despite essentially normal electrolytes.

ADDENDA Dec. 14, 2005

13. According to Drs. Charles Bolan and Susan Leitman of the Department of Transfusion Medicine, Clinical Center, NIH (attribution used with permission), the control of citrate toxicity during peripheral blood stem cell (PBSC) collection is a critical factor in donor safety and also exerts a significant impact on cell yields. They caution that an adequate concentration of citrate must be present to protect the PBSC product from clumping, and this fact combined with the large volumes processed result in prolonged administration of citrate during PBSC procedures. In their experience, a substantial portion of donors will have uncomfortable to severe degrees of citrate toxicity if prophylactic calcium is not given. They advise that centers performing PBSC procedures establish policies for prevention of citrate toxicity, rather than waiting to initiate treatment when citrate-related symptoms to occur. Published studies document the ineffectiveness of oral calcium carbonate tablets and strongly support the use of intravenous calcium prophylaxis in this setting. Based on the studies described below, their center at NIH uses intravenous calcium chloride infusions during all PBSC procedures in which greater than one to two blood volumes are processed (greater than 5-10 liters). Calcium is infused as a 2 mg calcium ion per mL of 0.5N saline solution into a port connected to the apheresis return line, using an electronic infusion pump equipped with a "guardrail" system to prevent inadvertent overdose of calcium. The calcium solution is administered at a rate proportional to the whole blood flow rate and is modified according to donor symptoms, without use of laboratory testing. Drs. Bolan and Leitman generously offer that an SOP may be obtained from their apheresis nurse team leader by e-mail at dgladden@mail.nih.gov.

They further add the rationale for use of calcium prophylaxis and cite relevant studies which are included in the following list:

Citrate toxicity during PBSC collections is not uncommon or unusual when using citrate anticoagulant infusions at administration rates that are similar to those employed in plateletpheresis procedures. Even healthy normal donors may experience serious symptoms. Blood citrate levels generally do not reach steady state during the 90 to 120 minute time of a standard plateletpheresis procedure, during which ionized calcium levels drop by 20 to 40% below baseline. These effects may be even greater during the larger volumes processed during PBSC procedures (Comprehensive analysis of citrate effects during plateletpheresis in normal donors. Transfusion 41:1165-71, 2001)

Female donors are at higher risk of symptoms because of smaller body mass, lower blood albumin levels, and lower reservoirs of mobilizable calcium; oral calcium carbonate (TUMS) tablets exert a minimal effect on blood ionized calcium levels and have no clinically significant effect on symptoms in both male and female donors undergoing plateletpheresis. (Randomized placebo-controlled study of oral calcium carbonate administration in plateletpheresis. Transfusion 43:1403-1411, 2003).

The unopposed administration of citrate during PBSC procedures (ie, without iv calcium prophylaxis) results in profound depletion of ionized calcium and also causes hypokalemia and significant donor symptoms; infusion of intravenous calcium stabilizes the decreases in ionized calcium and potassium, results in a more stable metabolic state, and is associated with a >90% reduction in symptoms: calcium chloride is more effective than equimolar amounts of calcium gluconate, and is used in all PBSC procedures in our center. (Controlled study of citrate effects and response to IV calcium administration during allogeneic peripheral blood progenitor cell donation. Transfusion 42:935-46, 2002).

Intravenous magnesium does not improve donor symptoms during PBSC collections conducted with prophylactic intravenous calcium (Randomized placebo-controlled study of intravenous magnesium supplementation in large volume leukapheresis. Transfusion 45:934-44, 2005).

In community practice, the use of unopposed citrate anticoagulant during PBSC collection should be discouraged, and either prophylactic intravenous calcium or use of heparin with reduced-dose citrate (depending on tolerance for increased bleeding risk and the experience of the center) should be used in all PBSC collections. Calcium may be infused without laboratory monitoring, with the dose based on the processing rate and adjusted according to donor symptoms (Guidelines for Management of Anticoagulant Toxicity in Large Volume Leukapheresis. National Marrow Donor Program).

With appropriate control of anticoagulant toxicity, faster processing of larger-volume PBSC procedures can be safely performed, allowing efficient collection of an adequate CD34 dose in a single day. This practice significantly reduces the time required for central venous access in donors who require placement of a central venous access catheter. The standard PBSC processing volume in our center is 25 liters, which generally requires less than 6 hours of procedure time (Prospective evaluation of cell kinetics, yields, and experiences of allogeneic peripheral blood stem cell donors during a single large volume apheresis versus two smaller consecutive day collections. Brit J Haematol 120:801-7, 2003).

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Ira A. Shulman, MD
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