Rejuvesol - Clinical Pharmacology
A gradual depletion of red blood cell adenosine triphosphate (ATP) and 2,3 diphosphoglycerate (2,3-DPG) occurs with storage of RBC at 1-6 °C.1 The level of 2,3-DPG in RBC stored for greater than 14 days is less than 10% of normal1,2,12,17,18. Rejuvenation of RBC with Rejuvesol® Solution increases the levels of ATP and 2,3-DPG.1-5,8,13,17-22,24, 25
An in vitro loss of red blood cells occurs with the preservation and processing of RBC. Thus, the effectiveness of a transfusion is influenced by both the total number of red blood cells transfused and the number of those cells which remain in circulation. Therefore, the "dose" of a transfusion is defined as the percentage of pre-transfusion recovered red blood cells multiplied by the 24 hour post-transfusion survival value.
Rejuvenation is accomplished by incubating the contents of one 50 mL vial of Rejuvesol® Solution with one unit of RBC (prepared from up to 550 mL of whole blood) for sixty (60) minutes at 37 °C. Citra recommends that the entire 50 mL of Rejuvesol® Solution be added to a "smaller than normal" RBC as long as the prerejuvenation net packed cell weight is greater than 110 grams.1,9
Indication and usage
Rejuvesol® Solution is intended only to be used as an in vitro processing solution for the rejuvenation of a unit of RBC. RBC may be rejuvenated after storage in CPD (non-leukocyte reduced), CPDA-1, (non-leukocyte reduced), CPD/ADSOL® (CPD/AS-1 leukocyte reduced), or CP2D/Nutricel® (CP2D/AS-3, leukocyte reduced). The final concentration of ATP and 2,3-DPG achieved after rejuvenation will vary depending on the number of days of liquid storage at 1-6 °C prior to rejuvenation. NOTE: For simplicity, RBC stored in CPD (non-leukocyte reduced), CPDA-1 (non-leukocyte reduced), CPD/ADSOL® (CPD/AS-1 leukocyte reduced), CP2D/Nutricel® (CP2D/AS-3, leukocyte reduced) are referred to hereafter as CPD, CPDA-1, CPD/AS-1, and CP2D/AS-3, respectively. Citra Labs, LLC, recommends that rejuvenation of RBC be performed after 14 days or longer of liquid storage. RBC (CPD, CPDA-1, CPD/AS-1, and CP2D/AS-3) rejuvenated before 6 days of storage may achieve 2,3-DPG levels in excess of 2 times normal and ATP levels in excess of 1.5 times normal5,6 (See Warning and Contraindications).
Rejuvenation of CPD or CPDA-1 RBC for Immediate use or for Cryopreservation
RBC which have been collected and stored in CPD or CPDA-1 anticoagulant may be rejuvenated up to three days after the expiration date of the RBC, as long as storage at 1-6 °C is not interrupted.3,4 After rejuvenation, RBC (CPD and CPDA-1) must be either washed and stored at 1-6 °C for up to 24 hours prior to transfusion or glycerolized and frozen at –80 °C (below –65 °C). Red Blood Cells Frozen Rejuvenated which were collected and stored in CPD or CPDA-1 may be stored frozen up to 10 years.10
When RBC are rejuvenated after maximum liquid storage, i.e., CPD RBC at 24 days or CPDA-1 RBC at 38 days, the concentrations of 2,3-DPG and ATP increase typically to above normal.1,3-5,6
CAUTION: RBC collected in CPD or CPDA-1 cannot be leukocyte reduced prior to rejuvenation.
Rejuvenation of CPD/AS-1 RBC or CP2D/AS-3
Rejuvesol® Solution has not been approved for the rejuvenation of RBC stored in any additive systems other than AS-1 or AS-3. RBC stored in CPD/AS-1 or CP2D/AS-3 at 1-6 °C may be rejuvenated up to, but not exceeding, 42 days of storage as long as storage at 1-6 °C is not interrupted. Rejuvenated CPD/AS-1 RBC must be either washed and stored at 1-6 °C for up to 24 hours prior to transfusion or glycerolized and frozen at –80 °C (below –65 °C). Red Blood Cells Frozen Rejuvenated which were collected and stored in CPD/AS-1 may be stored for up to 3 years. Rejuvenated CP2D/AS-3 RBC must be washed and stored at 1-6 °C for up to 24 hours prior to transfusion. Unlike rejuvenated CPD, CPDA-1, CPD/AS-1 RBC, and CP2D/AS-3, rejuvenated RBC collected and stored in any other anticoagulant/additive solution combination have not been approved to be immediately washed and transfused or for cryopreservation.Rejuvenation of CPD/AS-1 RBC for Cryopreservation
When CPD/AS-1 RBC are rejuvenated at 42 days of liquid storage, frozen, deglycerolized, and stored for 24 hours, the concentration of 2,3-DPG and ATP increases to above normal. In a limited study, the average 24 hour post-transfusion survival value of these cells was statistically higher than the reported12 survival value of CPD/AS-1 red blood cell concentrates which are stored for 42 days prior to transfusion. The "dose" may be equivalent for a CPD/AS-1 RBC whether the unit is stored for 42 days prior to transfusion or stored for 42 days, rejuvenated, frozen, deglycerolized, and stored for 24 hours prior to transfusion. Unlike rejuvenated CPD/AS-1 RBC, rejuvenated RBC (CP2D/AS-3) has not been approved for cryopreservation.Rejuvenation of CPD/AS-1 RBC or CP2D/AS-3 for Immediate Use
When CPD/AS-1 RBC are rejuvenated at 42 days of liquid storage, washed, and stored for 24 hours, the concentration of ATP increases to day 0 values. For 2,3-DPG rejuvenation of RBCs stored in CPD/AS-1 for 42 days, the range of 2,3 DPG relative to day 0 value was 46%-172% with a mean of 98% ± 29%. For 66% of the RBC units (44/67, 33/33 in Site A and 11/34 in Site B) the concentration of 2,3-DPG reached at least 80% of the day 0 value.
When CP2D/AS-3 RBC are rejuvenated at 42 days of liquid storage, washed, and stored for 24 hours, the concentration of ATP increases to day 0 values. For 2,3-DPG rejuvenation of RBCs stored in CPD/AS-1 for 42 days, the range of 2,3 DPG relative to day 0 value was 48%-150% with a mean of 96% ± 23%. For 76% of the RBC units (52/68, 30/35 in Site A and 22/33 in Site B) the concentration of 2,3-DPG reached at least 80% of the day 0 value.
How is Rejuvesol Supplied
PN 7012: 50 mL vial; 12 vials per case
- Valeri CR, CG Zaroulis, Rejuvenation and Freezing of Outdated Stored Human Red Blood Cells; NEJMED 1972;287:1307-1313.
- Valeri CR. Unpublished Data.
- Valeri CR, AD Gray, GP Cassidy, et al.; The 24-hour posttransfusion survival, oxygen transport function, and residual hemolysis of human outdated-rejuvenated red cell concentrates after washing and storage at 4 °C for 24 to 72 hours. Transfusion 1984; 24:323-6.
- Valeri CR, CG Zaroulis, JJ Vecchione, et al.; Therapeutic effectiveness and safety of outdated human red blood cells rejuvenated to restore oxygen transport function to normal, frozen for 3 to 4 years at –80 °C, washed, and stored at 4 °C for 24 hours prior to rapid infusion. Transfusion 1980; 20:159-70.
- Valeri, CR, DA Valeri, JJ Vecchione, and CP Emerson; Biochemical modification and freeze preservation of red blood cells, Critical Care Med. 7 (9):439-477, 1979.
- Valeri CR; Status report on rejuvenation and freezing of red blood cells. Plasma Therapy 2 (3): 155-170, 1981.
- Boston University School of Medicine/Naval Blood Research Laboratory, Boston, MA Standard Operating ProcedureRed Blood Cells Collected in the CPDA-1 800 mL Primary PVC Plastic Collection Bag System and Stored for 3 to 35 Days (Indated-Rejuvenated) or for 36 to 38 Days (Outdated-Rejuvenated), Biochemically Modified with PIPA Solution Prior to Glycerolization in the Primary 800 mL Bag with the Special Adaptor Port Using 40% W/V Glycerol and Storage at –80 °C, Washed in the Haemonetics Blood Processor 115, and Stored at 4 °C for 24 Hours Prior to Transfusion (Revised 5/91).
- Whitely, PH, et al; Improved recovery of ATP and 2,3-DPG with agitation during incubation at 37 °C in Rejuvesol® Solution treated CPD/AS-1 RBC. Transfusion 53 (supp), SP81, 2013.
- Valeri CR; Simplification of the Methods for Adding and Removing Glycerol During Freeze-Preservation of Human Red Blood Cells with the High or Low Glycerol Methods: Biochemical Modification Prior to Freezing . Transfusion 15(3): 195-218, 1975.
- AABB Standards for Blood Banks and Transfusion Services, 27th Edition.
- American Association of Blood Banks Technical Manual, pages 946-953, 17th Edition, 2011.
- Valeri CR, LE Pivacek, M Palter, RC Dennis, N Yeston, CP Emerson, and MD Altschule; A clinical experience with ADSOL® preserved erythrocytes. Surgery, Gynecology, and Obstetrics 166:33-46, 1988.
- Szymanski IO, Teno RA, Lockwood WB, Hudgens, R, and Johnson, GS; Effect of rejuvenation and frozen storage on 42-day-old AS-1 RBCs. Transfusion 41: 550-555, 2001.
- Gelderman MP and Vostal JG; Rejuvenation Improves Roller Pump-Induces Stress resistance of Fresh and Stored Red Blood Cells. Transfusion 51:1096-1104, 2011.
- Meyer EK, et al; Rejuvenation Capacity of Red Blood Cells in Additive Solutions Over Long-Term Storage. Transfusion, 51(7):1574-1579, 2011.
- Koshkaryev A, et al; Rejuvenation Treatment of Stored Red Blood Cells Reverses Storage-Induced Adhesion to Vascular Endothelial Cells. Transfusion, 49:2136-2143, 2009.
- Dennis RC, et al; Transfusion of 2,3-DPG-Enriched Red Blood Cells to Improve Cardiac Function. Ann. Thor. Surg., 26:16-17, 1978.
- Valeri CR, et al; Improved Oxygen Delivery to the Myocardium During Hypothermia by Perfusion with 2,3-DPG Enriched Red Blood Cells. Ann. Thorac. Surg., 30(6): 527-535, 1980.
- Valeri CR, et al; Human Red Blood Cells with Normal or Improved Oxygen Transport Function Prepared and Frozen in the Primary Polyvinyl Chloride Plastic Blood Collection Container. Transfusion and Immunohaematology, 22:467-486, 1979.
- Ragno G and Valeri, CR, Salvaging of Liquid-Preserved O-Positive and O-Negative Red Blood Cells by Rejuvenation and Freezing. Transfus. Apher. Sci., 35(2): 137-143, 2006.
- Valeri CR, et al; Automation of the Glycerolization of Red Blood Cells with the High-Separation Bowl in the Haemonetics ACP 215 Instrument. Transfusion 45: 1621-1627, 2005
- Lockwood WB, et al; Effects of Rejuvenation and Frozen Storage on 42-Day-Old AS-3 RBCs. Transfusion 43(11): 1527-153, 2003.
- Loeb, WF, V.M.D, Ph.D; A Literature Review to Investigate the Feasibility of Modifying the Current Protocol for Use and Developing New Applications. unpublished communication, 19 Oct 2000.
- Valeri CR, et al; The Survival, Function, and Hemolysis of Human RBCs Stored at 4 °C in Additive Solution (AS-1, AS-3, and AS-5) for 42 Days and then Biochemically Modified, Frozen, Thawed, Washed, and Stored at 4 °C in Sodium Chloride and Glucose for 24 Hours. Transfusion 40: 1341-1345, 2000.
- Whitely, PH, et al; Improved ATP and 2,3-DPG recovery using the Sahara III dry-air blood warmer in CPD/AS-1 RBC treated with Rejuvesol® Solution. Transfusion 54 (supp), SP69, 2014.
- Whitely PH, et al; Restoration of morphology following rejuvenation of stored red blood cells (RBC), Transfusion 55 (supp 3), 74A-75A, 2015.
- Gray AD, et al; Extended Storage (>24 Hours) of Rejuvenated and Washed RBC, Transfusion 55 (supp 3), 68A-69A, 2015.
Rejuvesol® Solution is a registered trademark of Citra Labs, LLC, a Biomet Biologics Company
ADSOL® is a registered trademark of Fenwal, Inc.
Nutricel® is a registered trademark of Haemonetics, Corp
Manufactured for: Citra Labs, LLC
55 Messina Drive, Braintree, MA 02184 • USA
1-800-299-3411 • Fax 781-848-6781
Manufactured by: Grand River Aseptic Manufacturing, Inc.
140 Front Ave SW, Suite 3 Grand Rapids, MI 49504 USA
Printed in USA
PRINCIPAL DISPLAY PANEL - 50 mL Vial Label
red blood cell processing solution
15°C - 25°C
Not for direct
administration to patients.
To be used only for
of red blood cells.
PN 7012 50 mL
Manufactured for: Citra Labs, LLC.
55 Messina Drive • Braintree, MA 02184 • USA
1-800-299-3411 • Fax 781-848-6781
Manufactured by: Grand River Aseptic Manufacturing, Inc.
140 Front Ave. SW, Suite 3 • Grand Rapids, MI 49504 • USA