Inventory management.

A critical aspect of blood transfusion is the timely provision of high quality blood products. This task remains a significant challenge for many blood services and blood systems reflecting the difficulty of balancing the recruitment of sufficient donors, the optimal utilization of the donor's gift, the increasing safety related restrictions on blood donation, a growing menu of specialized blood products and an ever-growing imperative to increase the efficiency of blood product provision from a cost perspective. As our industry now faces questions about our standard practices including whether or not the age of blood has a negative impact on recipients, it is timely to take a look at our collective inventory management practices. This International Forum represents an effort to get a snap shot of inventory management practices around the world, and to understand the range of different products provided for patients. In addition to sharing current inventory management practices, this Forum is intended to foster an exchange of ideas around where we see our field moving with respect to various issues including specialty products, new technologies, and reducing recipient risk from blood transfusion products.

Diabetic nephropathy in hypertransfused patients with beta-thalassemia. The role of oxidative stress.

OBJECTIVE: Pathogenesis of diabetes-related microvascular complications involving oxidative damage by free radicals has been demonstrated. Free radical generation has been shown to derive largely from iron. Our objectives, therefore, were to determine if there is an increased incidence and/or an accelerated course of nephropathy in patients with diabetes, secondary to transfusional hemochromatosis, and to examine whether free radical activity contributes to the development of this complication. RESEARCH DESIGN AND METHODS: We evaluated nine patients with homozygous beta-thalassemia, complicated by clinically overt diabetes, for diabetic nephropathy over a 7-year period. Lipid peroxidation was quantified by measuring the presence of 20 saturated and unsaturated aldehydes, and results were compared with five normotensive type 1 diabetic patients without iron overload. RESULTS: Nephropathy developed in five of nine patients (55%) after a mean duration of overt diabetes of 3.6 +/- 2.0 years. Three patients showed evidence of progressive microalbuminuria over a 7-year period (24.7-46.2, 52.2-430.1, and 17.7-54.3 micrograms/min, respectively). Two patients with borderline microalbuminuria (19.9 and 14.5 micrograms/min, respectively) demonstrated stable albumin excretion rates over the follow-up period. Total aldehyde concentration was significantly higher in beta-thalassemia diabetic patients, compared with nonthalassemic diabetic control subjects (8,106 +/- 1,280 vs. 4,594 +/- 247 nmol/l; P < 0.0001). The three patients with progressive microalbuminuria demonstrated significantly higher total aldehyde concentration, compared with the other beta-thalassemia diabetic patients with stable albumin excretion (9,428 +/- 337 vs. 7,445 +/- 1,003 nmol/l; P < 0.01). Serum vitamin E concentrations were significantly lower in beta-thalassemia patients with diabetes, compared with diabetic patients without iron overload (12.1 +/- 6.0 vs. 25.9 +/- 11.4 mumol/l; P = 0.02). Serum vitamin C concentrations did not differ between the two groups. Multiple regression analysis demonstrated total aldehyde concentration to be the most significant predictor for the development of microalbuminuria (P = 0.01), followed by the duration of diabetes (P = 0.02) and glycemic control (P = 0.02). CONCLUSIONS: Early development and an accelerated course of diabetic nephropathy in iron-loaded patients with beta-thalassemia are observed. These findings may be attributed to high oxidative stress in these patients, which is secondary to iron-derived free radicals and to the patients' diminished antioxidant reserves.

Myelodysplastic syndrome with prolonged reticulocyte survival mimicking hemolytic disease.

A patient with myelodysplastic syndrome (refractory anemia) with marked and persistent reticulocytosis is presented. A referring diagnosis of hemolytic disease had been made. However, the 51Cr red cell survival was normal (T1/2 24 days). Reticulocyte morphology, red cell creatine content, and in vitro reticulocyte survival studies have suggested that the reticulocytosis arose as a consequence of delayed maturation of the reticulocytes. Two patients with myelodysplastic syndrome and delayed reticulocyte maturation have previously been described; in both patients, however, red cell survival was also shortened. Anemia with reticulocytosis, mimicking hemolytic disease, may be an unusual presentation of myelodysplastic syndrome.

Deletion of the long arm of chromosome 5 in essential thrombocythemia.

A 51-year-old woman with no history of prior chemotherapy or radiation therapy was diagnosed with essential thrombocythemia (ET) according to the diagnostic criteria established by the Polycythemia Vera Study Group (PVSG). Cytogenetic analysis of bone marrow metaphases revealed both normal female karyotype and a single clonal abnormality, 46,XX,del(5)(q22q35). While chromosomal abnormalities have been reported in ET, their incidence is very low, and no specific abnormality has been found. Many of the reported cases of ET with chromosomal aberrations, including 5q-, do not meet the diagnostic criteria proposed by the PVSG, and may represent one of the other myeloproliferative disorders or a myelodysplastic syndrome. Furthermore, it is important to distinguish the 5q- syndrome, which may present with thrombocytosis and megakaryocytic hyperplasia, from ET. Our patient appears to be the first example of untreated ET clearly meeting the PVSG criteria in which 5q- was the only clonal abnormality seen at diagnosis.

N-methyl-D-aspartate receptors mediate responses of rat dorsal horn neurones to hindlimb ischemia.

We have investigated the role of NMDA receptors in the rat dorsal horn in mediating neuronal responses to noxious hindlimb ischemia, induced by acute occlusion of the femoral artery, as well as in the hyperalgesia evident when noxious mechanical stimuli were applied to the ischemic limb. Two specific NMDA antagonists, D-2-amino-5-phosphonovalerate (APV) and ketamine hydrochloride were applied intrathecally directly on to the spinal cord, in enflurane-anaesthetised rats. Both APV (1 microM and 100 microM) and ketamine (1 mM and 100 mM) inhibited the increase of dorsal horn neuronal firing rate induced by ischemia, but did not alter the neuronal response to noxious pinching or innocuous brushing of the receptive field. Both agents, however, abolished the hyperalgesia to noxious pinching induced by ischemia. Our results support the hypothesis that the excitatory amino acids are involved in the transmission of nociceptive information in the spinal dorsal horn, and also favour a central mechanism for hyperalgesia at the spinal level, possibly also mediated by the NMDA receptor.

Intrathecal N-methyl-D-aspartate induces hyperexcitability in rat dorsal horn convergent neurones.

We have investigated the effects of intrathecal (i.t.) N-methyl-D-aspartate (NMDA) and an NMDA antagonist D-2-amino-5-phosphonovalerate (APV) on spontaneous and evoked activity in rat dorsal horn convergent neurones. Extracellular recordings were made from 54 convergent neurones located in both the superficial and deep dorsal horn. NMDA induced a dose-dependent increase in the spontaneous firing rate of convergent neurones, with 1 microM and 1 mM NMDA producing firing rates significantly greater than i.t. saline. In addition, NMDA induced hyperexcitability to subsequent noxious mechanical stimuli at 1 microM and 1 mM, and to innocuous stimuli at 1 mM. The NMDA-induced spontaneous hyperexcitability was reversed by pretreatment with 1 microM APV i.t. Diffuse noxious inhibitory controls (DNIC) applied to areas of the body remote from the receptive field also inhibited the NMDA-induced effects. There was no difference between the responses of superficial and deep dorsal horn neurones, suggesting a uniform excitatory action of NMDA on convergent neurones. Our results support a role for the NMDA receptor in mediating a central component of hyperalgesia, at the level of the spinal cord dorsal horn.

Changes in intravenous immunoglobulin prescribing patterns during a period of severe product shortages, 1995-2000.

BACKGROUND AND OBJECTIVES: Canadian consumption of intravenous immunoglobulin (IVIG) has increased dramatically since it was first marketed in the early 1980s, and Canada is now the world's largest per capita consumer. During the late 1990s, worldwide product shortages of IVIG occurred. This study was designed to identify the disease conditions for which IVIG was being prescribed in academic hospitals during this period, and to explore the effects that IVIG shortages had on prescribing patterns. MATERIALS AND METHODS: Blood bank and pharmacy records of IVIG distribution were collected retrospectively from four Toronto teaching hospitals for the period 1995-2000. These records were then cross-referenced with patient medical records to determine the indication for IVIG administration. RESULTS: A total of 100,208 g of IVIG was prescribed to 429 patients over a 6-year period. Most of the IVIG consumption was in patients with haematological (22%) or neurological (20%) conditions, in recipients of bone marrow transplants (19%) and in patients with infectious disease-related conditions (including congenital and acquired hypogammoglobulinaemia, 18%). Dermatological conditions (7%) were the most rapidly growing indication for IVIG usage during the 6-year period of review, increasing from 0% of annual IVIG usage in 1995 to 16% in 2000. Over 80% of the diseases treated were supported by published recommendations. After 1997 there was an abrupt decline in the annual number of patients treated, primarily owing to a decline in single-use recipients. Annual consumption of IVIG, however, remained stable. CONCLUSIONS: IVIG shortages were followed by a decrease in the number of single-use recipients, who probably represented empirical use of IVIG; this had little effect on the total amount of IVIG distributed annually. Stricter adherence to currently available published recommendations may not be the optimal means of controlling IVIG use within an academic hospital setting. Rather, emphasis may be better placed on improving the evidence base upon which these recommendations are made, for example by conducting controlled prospective clinical trials.

Acute Myocardial Infarction in Sickle Cell Disease: Case Report and Review of the Literature.

Although vascular occlusion is a hallmark of sickle cell disease, documented myocardial infarction is an uncommon event in these patients. We report a case of an acute lateral myocardial infarction in a 25 year old male homozygous for HbS, who had previously had a relatively benign course of his sickle cell disease. Management of the case included an exchange transfusion and a 6 month period of chronic simple transfusions (2 units packed red cells every 3-4 weeks). We review here the available literature on cardiovascular manifestations of sickle cell disease.

Irreversible loss of donor blood leucocyte activation may explain a paucity of transfusion-associated graft-versus-host disease from stored blood.

Transfusion-associated graft-versus-host disease (TA-GVHD) is usually a fatal outcome of blood transfusion therapy, caused by viable leucocytes contained in the donor blood. Most cases of TA-GVHD occur when less than 4-d-old blood is transfused. We therefore examined the molecular changes that occur during storage that may account for the paucity of TA-GVHD following infusion of older blood. Leucocyte number and viability were essentially unchanged from freshly obtained blood, but the expression of cell-surface lymphocyte activation antigens (CD3, CD4, CD28, CD2, CD45) decreased rapidly within the first 24 h and continued to fall to less than 20% of original levels by d 9 of storage at 4 degrees C. The decrease in CD antigen expression directly correlated with a decreasing ability to induce activation of the T-lymphocyte cellular signal transduction pathway. As a result, cells became less responsive in a mixed lymphocyte culture (MLC) by d 3, with abrogation of the MLC responsiveness by d 5. Donor leucocytes stored for 4 d or less at 4 degrees C were able to partially re-express CD antigens and reconstitute their signalling pathway when placed at 37 degrees C. whereas those stored for more than 4 d were not. These irreversible changes result from a permanent downregulation of donor cell protein synthesis. These findings provide a mechanism to explain the paucity of TA-GVHD following transfusion of blood that is more than 4 d-old. Further study may show that aged blood provides additional assurances for the prevention of TA-GVHD; however, use of aged blood should not replace current protocols using irradiation.

Desferrioxamine ototoxicity in an adult transfusion-dependent population.

OBJECTIVE: The purpose of this study was to identify the incidence of hearing loss in a population of 75 adult (19-68 years old) transfusion-dependent patients with thalassemia major, sickle cell disease, Diamond-Blackfan anemia, and various other hematologic disorders treated with regular transfusion schedules. Ninety-three percent (70/75) of patients had a history of long-term subcutaneous or intravenous desferrioxamine therapy. METHODS: The patients underwent routine otolaryngologic history and physical examination, along with standard pure-tone audiometry at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz, with hearing loss defined as 25 dB or greater at one or more frequencies. RESULTS: Hearing loss was present in 57% (43/75) of patients. More importantly, hearing loss attributable to desferrioxamine ototoxicity was present in 29% (22/75) of patients. Sixteen patients treated previously with desferrioxamine were switched to the experimental oral chelating agent, L1. Eight of these 16 patients had hearing loss attributable to desferrioxamine, with 5 of these patients worsening with the experimental oral chelating agent L1. Seventy-nine percent (59/75) of patients were thalassemic. Fifty-four percent (33/59) of these thalassemic patients had hearing loss. However, 35% (21/59) of the thalassemic patients had hearing loss attributable to desferrioxamine ototoxicity. All thalassemic patients with desferrioxamine ototoxicity had high-frequency sensorineural hearing loss, with 33% (7/21) having a notch at 6 kHz. In addition, 5% (1/21) had notching at 3 khz. Few of the hearing losses were disabling. CONCLUSIONS: Management of these patients requires proper dosing of desferrioxamine and transfusion therapy, along with regular monitoring of body iron burden and hemoglobin. In addition, regular otolaryngologic and audiometric follow-up with special care to include the frequencies of 3 and 6 kHz may help recognize and prevent permanent ototoxicity.

A multivariable model for predicting the need for blood transfusion in patients undergoing first-time elective coronary bypass graft surgery.

BACKGROUND: The incidence of blood transfusion in coronary artery bypass graft (CABG) surgery remains high. Preoperative identification of those at high risk for requiring blood will allow for the cost-effective use of some blood conservation modalities. Multivariable analysis techniques were used in this study to develop a prediction rule for such a purpose. STUDY DESIGN AND METHODS: Data were prospectively collected for all patients undergoing elective first-time CABG surgery from January 1997 to September 1998 at a tertiary-care teaching hospital (n = 1007). The prediction rule was developed on the first two-thirds of the sample by using logistic regression methods to examine the relationship of patient demographics, comorbidities, and preoperative Hb with perioperative blood transfusion. The remaining one-third of the sample was used to validate the rule. RESULTS: The transfusion rate was 29.4 percent. The prediction rule included preoperative Hb (g/dL, OR 0.928, p<0.0001), weight (kg, OR 0.938, p<0.0001), age (years, OR 1.037, p<0.01), and sex (male/female, OR 0.493, p<0.01); receiver operating characteristic = 0.86. When externally validated, the rule had a sensitivity of 82.1 percent and a specificity of 63.6 percent (at a selected probability cutoff). CONCLUSION: A simple and valid prediction rule is developed for predicting the risk of blood transfusion in patients undergoing first-time elective CABG surgery.

The impact of inhibitors on the cost of clotting factor replacement therapy in Haemophilia A in Canada.

A retrospective case controlled study was performed to determine the comparative costs of clotting factor concentrate therapy for haemophilia A patients with and without inhibitors. We examined treatment records for a 3.5-year period for nine patients with factor VIII inhibitors and nine noninhibitor control patients matched for age and severity of disease. Inhibitor patients used FEIBA, porcine factor VIII, recombinant factor VIIa, and recombinant factor VIII over the study period. Controls used recombinant factor VIII and small amounts of monoclonal antibody purified plasma-derived factor VIII and DDAVP. The total and mean cost for treating the nine inhibitor patients was 2.25-fold greater than the cost for treating the controls. However, in six of the nine pairs the replacement product costs were actually less for the control patient than for the inhibitor patient, and the median cost of concentrates was comparable in the two groups (CDN$150 686 and $133 342 for inhibitor and control patients, respectively). This discrepancy was largely accounted for by a single inhibitor patient who required frequent hospitalizations for severe bleeding episodes. This individual, who did not receive an immune tolerance protocol, accounted for 62% of the total costs for the entire inhibitor group. In summary, over the study period the cost of haemostatic therapy for most inhibitor patients did not exceed that of control patients. However, due to the high per-unit cost of the products used to treat inhibitor patients, the effect of individual outliers greatly magnifies the overall costs of treating patients with this complication.

Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature.

A patient being treated for sickle cell disease with hydroxyurea (1 g/d) conceived, and drug treatment was discontinued at nine weeks gestational age. The pregnancy and delivery were complicated by vaso-occlusive crises. A healthy male infant was born at 39 weeks with no evidence of congenital malformations. A literature review, including this case, suggests that the risk of hydroxyurea exposure during in pregnancy may have been overestimated. Further studies are required to determine its safety in pregnancy.

Microinjection of lidocaine into human thalamus: a useful tool in stereotactic surgery.

A new method was developed to aid in the localization of the optimal site for a permanent lesion in movement disorder patients undergoing stereotactic thalamotomy. The method involved making small injections of a local anesthetic into the thalamus, which was also useful in assessing any possible side effects that could potentially arise from the lesion. Initial results indicate that 0.5 to 2-microliters injections of 2% lidocaine at appropriate sites in the thalamic ventrocaudal or ventrointermedius nucleus can produce a temporary marked suppression of tremor. In most cases the lidocaine induced effects mimicked those produced by high frequency electrical stimulation delivered to the same site. However, lidocaine had no effect at some sites where stimulation arrested tremor. This technique promises to be useful not only in the treatment of motor disorder patients but also in other cases where functional localization prior to lesioning is desirable.

DNA diagnosis of Hb S and Hb Caribbean (alpha 2 beta 2 91 Leu-->Arg) in a Jamaican family.

We describe a Canadian infant of Jamaican descent who presented with mild anemia. Hb electrophoresis revealed Hb S and an unknown Hb variant that migrated slightly faster than Hb S on cellulose acetate. Molecular studies of the family indicated that the proband is a compound heterozygote for Hb S and Hb Caribbean. Hb Caribbean has previously been characterized as a mildly unstable hemoglobin with low oxygen affinity, due to a Leu-->Arg substitution at amino acid residue 91. The present study establishes the molecular basis for Hb Caribbean (beta 91, CTG-->CGG) and confirms that Hb S/Hb Caribbean syndrome is not associated with serious clinical manifestations.

Allogeneic red blood cell transfusion is an independent risk factor for the development of postoperative bacterial infection.

BACKGROUND AND OBJECTIVES: Allogeneic red blood cell transfusions may exert immunomodulatory effects in recipients including an increased rate of postoperative bacterial infection. It is controversial whether allogeneic transfusion is an independent predictor for the development of postoperative bacterial infection. METHODS: We analysed a prospectively collected database of 1,349 patients undergoing colorectal surgery in 11 centres across Canada. The primary outcome was the development of either a postoperative wound infection or intra-abdominal sepsis in transfused and nontransfused patients. The effect of allogeneic transfusion on postoperative infection was evaluated with adjustment for all the confounding factors in a multiple regression analysis. RESULTS: The 282 patients who received a total of 832 allogeneic units had a significantly higher frequency of wound infections and intra-abdominal sepsis than the patients who were not transfused (25. 9 vs. 14.2%, p = 0.001). A significant dose-response relationship between transfusion and infection rate was demonstrated. Multiple regression analysis identified allogeneic transfusion as a statistically significant independent predictor for postoperative bacterial infection (OR 1.18, 95% CI 1.05-1.33, p = 0.007). Other independent predictors were anastomotic leak, repeat operation, patient age and preoperative haemoglobin level. The mortality rate was also significantly higher in the transfused group. CONCLUSION: These data support the hypothesis that allogeneic red cell transfusion is an independent risk factor for the development of postoperative bacterial infection in patients undergoing colorectal surgery. This association provides further reason to minimise exposure to allogeneic transfusions in the perioperative setting.

Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies.

BACKGROUND: Enhanced production of fetal hemoglobin lessens the severity of beta-thalassemia and sickle cell disease. Intravenous infusion of arginine butyrate can increase the number of reticulocytes containing fetal hemoglobin in patients with these disorders, and it has induced a substantial increase in hemoglobin in one patient with thalassemia. We therefore tested the efficacy of this agent in patients with beta-hemoglobinopathies. METHODS: We treated 10 patients with severe beta-thalassemia or sickle cell disease with arginine butyrate at an initial dose of 500 mg per kilogram of body weight per day (final dose, 2000 mg per kilogram per day), 6 days per week, for a mean (+/- SD) of 10 +/- 1.2 weeks (range, 9 to 13). A hematologic response was defined as an increase in the hemoglobin concentration of at least 2 g per deciliter in patients with thalassemia and as a twofold increase in the fetal hemoglobin concentration in patients with sickle cell disease. RESULTS: Increase in gamma-globin messenger RNA and in reticulocytes containing fetal hemoglobin but not in hemoglobin were observed in the patients with thalassemia. A small, unsustained increase in fetal hemoglobin was observed in two patients with sickle cell disease. Drug toxicity was minimal at standard doses. One patient had a grand mal seizure after inadvertently receiving 2000 mg of arginine butyrate per kilogram over a period of six hours. CONCLUSIONS: Ten weeks of intravenous arginine butyrate did not produce a hematologic response in 10 patients with either severe beta-thalassemia or sickle cell disease.

Prospective audit of cytomegalovirus-negative blood product utilization in haematology/oncology patients.

The transfusion management of immunocompromised patients often requires special blood product use such as cytomegalovirus (CMV)-negative cellular products, which are more costly than standard blood products and occasionally in short supply. We audited the use of CMV-negative products in haematology/oncology patients to determine the appropriateness of their use. A concurrent-prospective audit was conducted of all orders for CMV-negative packed red blood cell (PRBC) and platelet products in 201 haematology/ oncology patients. Once CMV serostatus was determined, orders for inappropriate CMV-negative units were cancelled, and filled as CMV untested units. During the 21-month period of this audit, the rates of inappropriate transfusions decreased for PRBC from 73.2% to 14.3% (chi2 = 68.4, P<0.001) and for platelets from 68.1% to 10.6% (chi2 = 65.6, P<0.001). The median time to cancellation of inappropriate CMV-negative orders was 11 days. This audit resulted in estimated cost savings of $16500 over the 21-month duration. Inappropriate requests for scarce and expensive blood products are substantially reduced by concurrent-prospective auditing of transfusion practice, in a manner that is both simple and cost effective.