Correspondence
Transfusion Medicine
N Engl J Med 1999; 341:124-127July 8, 1999
- Article
To the Editor:
The article on transfusion medicine by Goodnough and associates (Feb. 11 and Feb. 18 issues)1 raises two important issues: the physiologic significance of the peripheral hematocrit measurement and the hemostatic defect caused by acute hemodilution.
The hematocrit is a measure of the concentration of red cells in the blood; it is not a measure of the red-cell volume, plasma volume, or total blood volume and thus cannot be used alone to determine whether a patient has hypovolemia, normovolemia, or hypervolemia (Figure 1Figure 1
Hematocrit, Red-Cell Volume, and Plasma Volume in Patients with Normovolemia and Those with Hypovolemia.).2-4 The hematocrit is correlated with the bleeding time, blood viscosity, and nonsurgical blood loss.5 In the review by Goodnough and associates, the mathematical model that describes the relation between the hematocrit and blood volume is not consistent with studies showing that the hematocrit is not related to the red-cell volume, plasma volume, or total blood volume.2-4 By ignoring these observations, the authors simplify the discussion of the transfusion trigger, but in so doing, they sidestep the fact that a given hematocrit does not provide an accurate estimate of the red-cell volume. The measurement of the red-cell volume itself is the only rational basis for any corrective action to restore the red-cell volume to a more physiologic level. The authors also do not note that acute hemodilution causes a hemostatic defect because of a reversible platelet dysfunction.5,6 This is potentially important in patients who may have bleeding during or after major surgery.
6 ReferencesC. Robert Valeri, M.D.
Linda E. Pivacek, M.P.H.
Boston University School of Medicine, Boston, MA 02118James P. Crowley, M.D.
Rhode Island Hospital, Providence, RI 029021
Goodnough LT ,Brecher ME ,Kanter MH ,AuBuchon JP . Transfusion medicine. N Engl J Med 1999;340:438-47, 525
Full Text | Web of Science | Medline2
Valeri CR ,Cooper AG ,Pivacek LE . Limitations of measuring blood volume with iodinated I125 serum albumin. Arch Intern Med 1973;132:534-538
CrossRef | Web of Science | Medline3
Valeri CR, Altschule MD. Hypovolemic anemia of trauma: the missing blood syndrome. Boca Raton, Fla.: CRC Press, 1981.
4
Cordts PR ,LaMorte WW ,Fisher JB , et al. Poor predictive value of hematocrit and hemodynamic parameters for erythrocyte deficits after extensive elective vascular operations. Surg Gynecol Obstet 1992;175:243-248
Web of Science | Medline5
Valeri CR ,Crowley JP ,Loscalzo J . The red cell transfusion trigger: has a sin of commission now become a sin of omission? Transfusion 1998;38:602-610
CrossRef | Web of Science | Medline6
Valeri CR ,Cassidy G ,Lieberthal W ,Crowley J ,Khuri S ,Loscalzo J . Anemia-induced reversible platelet dysfunction. Blood 1998;92:Suppl1:139b-139b abstract.
Web of Science
To the Editor:
Goodnough and colleagues do not address transfusion-associated graft-versus-host disease and post-transfusion purpura, which are rare but life-threatening immunologic complications of transfusion, as major risks.
Transfusion-associated graft-versus-host disease is characterized by fever, rash, diarrhea, liver dysfunction, and marrow aplasia, and the course is usually fatal. It is initiated by viable immunocompetent donor T lymphocytes in erythrocyte concentrates. In immunocompromised recipients, these lymphocytes can resist host-versus-graft disease, engraft, and proliferate in response to host alloantigens, leading to graft-versus-host disease one to two weeks after transfusion. Patients at the highest risk include neonates, patients with congenital immunodeficiency, patients undergoing chemotherapy for Hodgkin's disease or chemotherapy with fludarabine, and patients who have undergone autologous or allogeneic bone marrow or stem-cell transplantation. Transfusion-associated graft-versus-host disease can occur in immunocompetent hosts, if the recipient shares one HLA haplotype with an HLA-homozygous donor (known as one-way HLA compatibility). Such cases have occurred after transfusion with blood from random donors, especially in genetically homogeneous populations, or after transfusion with blood donated by relatives. Transfusion-associated graft-versus-host disease in patients in high-risk categories can be prevented by prophylactic irradiation of blood or blood products with 2500 cGy.1
Post-transfusion purpura is characterized by severe thrombocytopenia (usually a platelet count of less than 10×109 per liter) of sudden onset and typically occurs 5 to 10 days after erythrocyte transfusion. High titers of platelet-specific alloantibodies are invariably found in the patient's serum, and HPA-1a is the most frequently implicated platelet alloantigen. Why autologous platelets are also destroyed remains unknown. The typical patient with post-transfusion purpura is a woman over the age of 50 years who has a history of pregnancy. Cutaneous, mucosal, and postoperative wound bleeding occurs frequently, and the disorder is fatal in about 5 to 10 percent of patients. Most patients have a favorable response to treatment with high-dose intravenous immune globulin, and in critical situations, platelets that are negative for the platelet antigen involved can be administered, or plasmapheresis can be performed.2
2 ReferencesPeter Vandenberghe, M.D., Ph.D.
Kathelijne Peerlinck, M.D., Ph.D.
University Hospital Leuven, B-3000 Leuven, Belgium1
BCSH Blood Transfusion Task Force
CrossRef | Web of Science | Medline2
Mueller-Eckhardt C . Post-transfusion purpura. Br J Haematol 1986;64:419-424
CrossRef | Web of Science | Medline
To the Editor:
The article by Goodnough et al. provides an excellent snapshot of major trends in transfusion medicine and important risks of blood products. However, even though infectious complications due to viral transmission have virtually disappeared, other preventable risks persist. The authors do not discuss circulatory overload, a frequently overlooked but important cause of transfusion-associated morbidity.
In a study of 382 Medicare patients undergoing total hip or total knee replacement, 1 percent of the patients had circulatory overload after surgery.1 This complication accounted for extended hospital stays, intensive interventions, and increased costs. A study from the Mayo Clinic found that circulatory overload occurred in 1 of every 708 patients receiving red-cell transfusions, making it one of the most important complications of transfusion therapy.2 In the Mayo Clinic study, 20 percent of cases of circulatory overload were associated with single-unit transfusions, contradicting the common belief that pulmonary edema is solely the consequence of massive transfusion.
Goodnough and colleagues suggest that utilization review has failed to influence the use of red-cell transfusions. Although I agree that retrospective reviews have been shown to be of limited value, the authors should have noted the marked success that some groups have had in modifying decisions about the use of transfusion when a face-to-face educational intervention is used. Soumerai and colleagues found a substantial (40 percent) improvement in decisions about transfusions of red cells in a randomized, controlled multicenter study.3 Surgeons enrolled in the study performed transfusions at lower hematocrits after the educational intervention than they had before the intervention.
3 ReferencesMark A. Popovsky, M.D.
American Red Cross Blood Services, New England Region, Dedham, MA 020261
Popovsky MA ,Audet AM ,Andrzejewski C . Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematology 1996;12:87-89
Medline2
Popovsky MA ,Taswell HF . Circulatory overload: an underdiagnosed consequence of transfusion. Transfusion 1985;25:469-469 abstract.
Web of Science3
Soumerai SB ,Salem-Schatz S ,Avorn J ,Casteris CS ,Ross-Degnan D ,Popovsky MA . A controlled trial of educational outreach to improve blood transfusion practice. JAMA 1993;270:961-966
CrossRef | Web of Science | Medline
To the Editor:
We wish to note some recent developments in the use of red-cell substitutes, which Goodnough et al. mention in their review of transfusion medicine and blood conservation. We served as coinvestigators in a multicenter, phase 3 clinical trial comparing a red-cell substitute (derived from expired human red cells) with allogeneic blood from random donors to determine whether the red-cell substitute could reduce or eliminate the need for perioperative transfusion in patients undergoing uncomplicated aortic repair, hip surgery, or bilateral knee replacement. The manufacturer notified us in March 1998 that a simultaneous multicenter, phase 3 clinical trial comparing the manufacturer's red-cell substitute with isotonic crystalloid in patients with severe, traumatic, hemorrhagic shock had been voluntarily suspended after an interim data review demonstrated an increased mortality rate among the patients receiving the investigational product. The perioperative study, as well as an identical European trauma study, was placed on hold shortly thereafter. Last fall, the company decided to suspend the research supporting this product in order to focus on developing second-generation, genetically engineered hemoglobin products.
This manufacturer's unfavorable experience suggests that the complex physiologic effects of artificial hemoglobin solutions in humans (e.g., potentially deleterious vasoconstriction from nitric oxide scavenging1) may limit the clinical usefulness of products currently being developed. We think it is unlikely that an approved red-cell substitute will be marketed for clinical use in the United States for quite some time.
1 ReferencesJeffrey S. Kelly, M.D.
Richard C. Prielipp, M.D.
Wake Forest University School of Medicine, Winston-Salem, NC 27157-1009Author/Editor Response
The authors reply:
To the Editor: Valeri et al. accurately point out that the hematocrit poorly reflects diminished red-cell mass (anemia), especially in dynamic conditions such as hemorrhage. Our mathematical model of hemodilution assumes the presence of normovolemia.
We addressed the limitations of using hematocrit levels as clinical indicators for transfusion in our discussion of utilization review and have covered this topic elsewhere.1 The risks entailed by the rigid use of hematocrit levels are also inherent in calls for prospective trials of transfusion2 to define the appropriate “transfusion trigger”; such calls ignore this issue as well as the fact that patients and their anemias are heterogeneous. We therefore concluded, “It is unlikely that any level of hemoglobin can be used as a universal threshold for transfusion.” Moderate hemodilution has no more effect on platelet function than natural hemodilution with surgical blood loss, since nadir hematocrit levels in the two cases are the same.
Post-transfusion purpura and transfusion-associated graft-versus-host disease are rare complications confined to populations at risk.3 We reviewed the complications that are most relevant to the general readership of the Journal.
Dr. Popovsky notes the complication of volume overload, citing his retrospective review of 382 Medicare patients who underwent orthopedic surgery, 4 of whom had volume overload.4 The age of these patients was 84 years (range, 75 to 101), the transfusion trigger was a hematocrit of 26 percent (range, 22.1 to 28.5 percent), and the perioperative fluid balance was 2480 ml. One could argue that this complication is more likely to be a problem of appropriate management of volume expansion in the setting of surgical anemia and is therefore a complication of crystalloid therapy and anemia.
We agree that educational efforts lead to improvement in transfusion patterns, but the literature fails to indicate that these efforts are successful over the long term. Blood costs may provide the “carrot” for improvements in transfusion practices that the “stick” of retrospective utilization review has failed to accomplish.5
One of the most vexing problems with regard to blood substitutes is that enhanced delivery of oxygen through these carriers to prearteriolar capillaries paradoxically results in elevated vascular resistance and the shunting of blood away from capillary beds,6 which is associated with the absence of a correlation between the pressor effect of red-cell substitutes and survival. Three hemoglobin solutions remain in phase 2–3 clinical trials in the United States, and one bovine-derived product has been approved for use in dogs. Blood substitutes that optimize the properties of oncotic pressure, viscosity, and oxygen binding may accomplish the goal of maintaining blood volume with low vascular resistance.6 The potential uses of blood substitutes in military and trauma settings make the endeavor promising.
6 ReferencesLawrence T. Goodnough, M.D.
Washington University School of Medicine, St. Louis, MO 63110-1093Mark E. Brecher, M.D.
University of North Carolina, Chapel Hill, NC 27514Michael H. Kanter, M.D.
Southern California Permanente Medical Group, Woodland Hills, CA 91365James P. AuBuchon, M.D.
Dartmouth–Hitchcock Medical Center, Lebanon, NH 037561
Goodnough LT ,Despotis GJ ,Hogue CW Jr ,Ferguson TB Jr . On the need for improved transfusion indicators in cardiac surgery. Ann Thorac Surg 1995;60:473-480
CrossRef | Web of Science | Medline2
Carson JL ,Duff A ,Berlin JA , et al. Perioperative blood transfusion and postoperative mortality. JAMA 1998;279:199-205
CrossRef | Web of Science | Medline3
Shivdasani RA ,Haluska FG ,Dock NL ,Dover JS ,Kineke EJ ,Anderson KC . Graft-versus-host disease associated with transfusion of blood from unrelated HLA-homozygous donors. N Engl J Med 1993;328:766-770
Full Text | Web of Science | Medline4
Popovsky MA ,Audet AM ,Andrzejewski C . Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematology 1996;12:87-89
Medline5
Goodnough LT . The transfusion medicine specialist and utilization review. Transfus Sci 1998;19:65-67
CrossRef | Medline6
Winslow RM ,Gonzales A ,Gonzales ML , et al. Vascular resistance and the efficacy of red cell substitutes in a rat hemorrhage model. J Appl Physiol 1998;85:993-1003
Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
C. Robert Valeri, Richard C. Dennis, Gina Ragno, Hollace MacGregor, James O. Menzoian, Shukri F. Khuri. (2006) Limitations of the hematocrit level to assess the need for red blood cell transfusion in hypovolemic anemic patients. Transfusion 46:3, 365-371
CrossRef2
C. Robert Valeri, Hollace MacGregor, Albert Giorgio, Rithy Srey, Gina Ragno. (2003) Comparison of radioisotope methods and a nonradioisotope method to measure the RBC volume and RBC survival in the baboon. Transfusion 43:10, 1366-1373
CrossRef3
C. Robert Valeri. (2002) Status Report on the Quality of Liquid and Frozen Red Blood Cells. Vox Sanguinis 83, 193-196
CrossRef
