A multicentre study investigating vital sign changes occurring in complicated and uncomplicated transfusions.

BACKGROUND AND OBJECTIVES: Many hospitals require transfusions to be discontinued when vital signs stray from predetermined ranges, regardless of clinical symptoms. Variations in vital signs may be unrelated to transfusion, however, and needlessly stopping a transfusion may delay medical care while increasing donor exposures and healthcare costs. We hypothesized that a detailed study of vital sign changes associated with transfusion of blood product by component, including those associated with potential reactions (complicated) and those deemed to be uncomplicated, would establish a useful framework of reference for treating clinicians and transfusion services alike. MATERIALS AND METHODS: A retrospective electronic record review of transfusion service and transfusion recipient data was completed on 3852 inpatient transfusion episodes over a 6-month period at four academic tertiary care hospitals across the United States. Vital signs pre- and post-transfusion were recorded by trained clinical research nurses. Serious reactions were adjudicated by a panel of transfusion medicine experts. RESULTS: In both uncomplicated transfusions (n = 3765) and those including an adverse reaction (n = 87), vital sign fluctuations were generally modest. Compared to uncomplicated transfusions, transfusions complicated by febrile reactions were associated with higher pretransfusion temperature and higher pretransfusion pulse rates. Episodes of transfusion circulatory overload were associated with higher pretransfusion respiration rates compared to uncomplicated transfusions. CONCLUSION: Most transfusions are associated with only modest changes in vital signs. Pretransfusion vital signs may be an important yet previously understudied predictor of vital sign changes during transfusion. The optimal role of vital sign assessment during blood transfusion deserves further study.

Clinical and laboratory correlates of platelet alloimmunization and refractoriness in the PLADO trial.

BACKGROUND AND OBJECTIVES: Platelet alloimmunization and refractoriness to platelet transfusion are complications of platelet transfusion therapy. The platelet dose (PLADO) trial, as the largest prospective randomized trial of prophylactic platelet therapy to date, afforded an opportunity to analyse these two issues. MATERIALS AND METHODS: PLADO patient records were examined for evidence of platelet alloimmunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h posttransfusion corrected platelet count increments (CCI) of <5000. Multivariate logistic regression, restricted to platelet-transfused subjects who received exclusively either in-process leucoreduction apheresis or whole blood-derived (WBD) leucocyte-reduced platelets, compared the frequency of these outcomes by platelet unit and patient characteristics. RESULTS: Forty of 816 evaluable platelet-transfused patients (5%) became alloimmunized during the trial. Prior pregnancy, chemotherapy only compared to progenitor cell transplant, and low platelet dose - all were associated with significantly higher rates of alloimmunization. Among 35 alloimmunized patients evaluated for refractoriness, 8 (23%) had two consecutive CCI < 5000/µl. Regardless of alloimmunization status, CCIs < 5000/µl were observed following 17% of platelet transfusions. Among 734 patients receiving at least two platelet transfusions, two consecutive CCIs of ≤5000 occurred in 102 (14%). CONCLUSIONS: The incidence of new platelet alloimmunization was low in the PLADO study, but follow-up was at most 30 days. Alloimmunization was present in only 8 of 102 (8%) of observed cases of refractoriness, suggesting that other causes of poor posttransfusion increments are frequent.

Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft.

In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.

A dose escalation study for salvage chemotherapy in patients with refractory lymphoma prior to high-dose myeloablative therapy with stem cell transplantation.

Chemosensitive response prior to transplantation has been shown to be most significant for survival post transplant. To estimate toxicity of a dose-intensive regimen that was to improve chemosensitive response rate, 15 patients with primary refractory lymphoma were enrolled in dose escalation of pre-transplant salvage chemotherapy. The first cycle had a fixed dose of ifosfamide 6 g/m2 and mitoxantrone 12 mg/m2, with arabinosyl cytosine (Ara-C) 2 g/m2, and methylprednisolone 2.0 g. Each cycle of the second and third had cisplatin 90 mg/m2, Ara-C 6 g/m2, methylprednisolone 2.0 g, and escalated doses of ifosfamide from 7.5 g/m2 to 15 g/m2 and mitoxantrone from 16 to 28 mg/m2. Blood stem cells were collected before the second cycle and > or = 3 x 10(6) CD34 cells/kg were infused 2 days after the second and third cycles, respectively. The maximum tolerated doses of ifosfamide and mitoxantrone were 11.25 g/m2 and 16 mg/m2, respectively. Acute renal failure and bacterial infection occurred as non-hematologic dose limiting toxicities. Eleven patients completed therapy. Five patients achieved complete remission and five had partial remission. Nine patients received autologous and four received allogeneic transplants. Currently, six are alive without evidence of disease, with a 3-year survival of 40%. Although preliminary, the regimen suggests acceptable toxicity and significant activity that warrants further study.

Prophylactic T cell infusion after T cell-depleted bone marrow transplantation in patients with refractory lymphoma.

Fifty-two patients with refractory lymphoma were prospectively treated with prophylactic T lymphocyte infusion after T cell-depleted allogeneic bone marrow transplantation, to induce graft-versus-lymphoma effect. Thirty-three patients had related donors; 19 had unrelated donors. After transplantation with marrow that had 0.8 +/- 0.4 x 10(5)CD3(+) cells/kg, T cells up to 1.75 x 10(6) CD3(+) cells/kg were given over 3 months provided > or = grade II acute graft-versus-host disease (GVHD) was not seen. The cumulative incidence of grades II-IV acute GVHD was 69%. Twenty of 32 evaluable patients (63%) developed chronic GVHD. Ten patients (19%) died of GVHD. The Kaplan-Meier 5-year overall survival of all patients was 34%. On multivariate analyses, chronic GVHD was significant for relapse (hazard ratio of 1.7, P < 0.05), and for overall survival (hazard ratio 1.4, P < 0.001). Chemosensitivity was significant for relapse only on univariate analysis. Patients who developed chronic GVHD had 4 years median survival, compared with 9 months in patients without chronic GVHD, P < 0.001. The study shows that patients with chronic GVHD have superior survivals, most probably related to a graft-versus-lymphoma effect, which could be modulated by prophylactic T cell infusion.

Managing the anemia of prematurity: red blood cell transfusions versus recombinant erythropoietin.

Transfusion-dependent anemia remains a problem for preterm infants, particularly those with a birth weight less than 1.0 kg. Several studies have documented the efficacy and safety of transfusing red blood cells stored up to 42 days as a means to diminish donor exposures. Recombinant erythropoietin therapy has not been widely adopted because it does not consistently reduce the need for red blood cell transfusions in very low-birth weight preterm infants.

Etiology of differences in hematocrit between males and females: sequence-based polymorphisms in erythropoietin and its receptor.

INTRODUCTION: Males have a higher hematocrit (Hct) than females. The cause of this gender-based difference is unclear. We sought to determine whether polymorphisms of the erythropoietin (EPO) gene or of its receptor (EPOR) explain this situation. METHODS: We designed primers for the EPO and EPOR genes. Previously undescribed polymorphisms were found based on band migration on polyacrylamide gel, and when then sequenced. The distribution of these polymorphisms was studied in a population of 819 non-iron-deficient, healthy blood donors. To test the gender differences, analysis was done based on groups defined by Hct levels. The chi-square statistic was used to compare the frequency differences between groups, with P < .05 considered statistically significant. RESULTS: We found previously reported polymorphisms in both the EPO and EPOR genes. Sequence analysis showed that the EPO polymorphism was due to a difference in the repeat copy number of the tetranucleotide cytosine adenine cytosine thymine (CACT) at position 2153. A previously undescribed 12th allele was found for the EPOR polymorphic site. Statistical analysis showed that the EPOR alleles, EPORA1 and EPORA10, were present at a significantly higher frequency in females than in males (P = .027 and P = .041, respectively), and EPOR5 was found less frequently in females than in males (P = .048). The allelic frequency of the EPO polymorphism was not significantly different by gender or Hct groups. DISCUSSION: These results suggest that the variation of Hct level by gender may have a genetic basis. The sequence-based polymorphism for EPOR may be partly responsible for this gender-based variation in Hct level. These findings offer new clues to understanding Hct variation in the general population and to elucidating mechanisms of controlling Hct levels.

Meta-analysis of controlled clinical trials studying the efficacy of rHuEPO in reducing blood transfusions in the anemia of prematurity.

BACKGROUND: Recombinant human EPO (rHuEPO) has not gained broad acceptance in the treatment of the anemia of prematurity, because its efficacy in diminishing RBC transfusions is questionable. Meta-analysis was used to investigate the extent and reasons for variation in the results of published clinical trials. STUDY DESIGN AND METHODS: Prospective controlled trials published from 1990 through 1999 were retrieved; 21 met the criteria for meta-analysis. Calculated across these studies were the summary OR of RBC transfusion in treated neonates as compared with controls and the summary mean difference between controls and treated neonates in the volume of RBCs transfused and the number of RBC transfusions per infant. Twelve study descriptors were examined as possible reasons for the variation in results. RESULTS: Results of 21 eligible studies varied widely (p<0.001 for the Q test statistic), and this variation persisted in most analyses when studies were stratified by individual study descriptors. When the difference in volume of RBCs transfused was the outcome measure, variation was modest across the four studies with highly desired characteristics (i.e., high blindness and design quality scores, "conservative" transfusion criteria, and the majority of neonates weighing <1 kg at birth), and treatment with rHuEPO reduced RBC transfusions by an average of 11.0 mL per kg (p<0.001). CONCLUSION: Benefit from rHuEPO is detected across high-quality studies using conservative RBC transfusion criteria. However, there is extreme variation overall in the findings of available trials, and-until this variation is accounted for-it is premature to recommend rHuEPO as standard treatment for the anemia of prematurity.

Cataracts in neutrophil donors stimulated with adrenal corticosteroids.

BACKGROUND: A relatively young man (43 years old) was found to have a cataract after receiving prednisone before each of 35 neutrophil (PMN) donations over several years. Because corticosteroids are known to induce posterior subcapsular cataracts (PSCs), additional repeat PMN donors were examined ophthalmologically. STUDY DESIGN AND METHODS: A controlled, blinded study was performed in 11 PMN donors who received prednisone with or without G-CSF before 17 to 46 leukapheresis donations over an average of 8.5 years. Control subjects were nine plateletpheresis donors of comparable age and donation experience, but they had never donated PMNs. A complete eye examination was performed by an ophthalmologist who was unaware of the donor's status (PMN vs. platelet). RESULTS: Mild PSCs were found in 36 percent (4/11) of PMN donors versus 0 of 9 platelet donors (p = 0.068). Five of the 22 PMN donor eyes involved versus 0 of the 18 platelet donor eyes involved exhibited PSCs (p = 0.040). Cortical and nuclear cataracts were found similarly in both groups of donors (82% PMN vs. 56% platelet donors; p = 0.217); this indicated that lifestyle factors, independent of corticosteroids, that might predispose to cataract formation probably were comparable. CONCLUSION: Corticosteroids given before PMN donations by leukapheresis might increase the risk of PSCs. Because of widespread renewed interest in PMN transfusions, this potential risk factor--if confirmed by studies of additional PMN donors--is of great international importance. Other centers are urged to perform ophthalmologic examinations on repeat PMN donors to clarify this issue.

Phlebotomy overdraw in the neonatal intensive care nursery.

OBJECTIVE: Because blood loss attributable to laboratory testing is the primary cause of anemia among preterm infants during the first weeks of life, we quantified blood lost attributable to phlebotomy overdraw, ie, excess that might be avoided. We hypothesized that phlebotomy overdraw in excess of that requested by the hospital laboratory was a common occurrence, that clinical factors associated with excessive phlebotomy loss would be identified, and that some of these factors are potentially correctable. DESIGN, OUTCOME MEASURES, AND ANALYSIS: Blood samples drawn for clinical purposes from neonates cared for in our 2 neonatal special care units were weighed, and selected clinical data were recorded. The latter included the test performed; the blood collection container used; the infant's location (ie, neonatal intensive care unit [NICU] and intermediate intensive care unit); the infant's weight at sampling; and the phlebotomist's level of experience, work shift, and clinical role. Data were analyzed by univariate and multivariate procedures. Phlebotomists included laboratory technicians stationed in the neonatal satellite laboratory, phlebotomists assigned to the hospital's central laboratory, and neonatal staff nurses. Phlebotomists were considered experienced if they had worked in the nursery setting for >1 year. Blood was sampled from a venous or arterial catheter or by capillary stick from a finger or heel. Blood collection containers were classified as tubes with marked fill-lines imprinted on the outside wall, tubes without fill-lines, and syringes. Infants were classified by weight into 3 groups: <1 kg, 1 to 2 kg, and >2 kg. The volume of blood removed was calculated by subtracting the weight of the empty collection container from that of the container filled with blood and dividing by the specific gravity of blood, ie, 1.050 g/mL. The volume of blood withdrawn for individual laboratory tests was expressed as a percentage of the volume requested by the hospital laboratory. RESULTS: The mean (+/- standard error of the mean) volume of blood drawn for the 578 tests drawn exceeded that requested by the hospital laboratory by 19.0% +/- 1.8% per test. The clinical factors identified as being significantly associated with greater phlebotomy overdraw in the multiple regression model included: 1) collection in blood containers without fill-lines; 2) lighter weight infants; and 3) critically ill infants being cared for in the NICU. Because the overall R(2) of the multiple regression for these 3 clinical factors was only.24, the random factor of individual phlebotomist was added to the model. This model showed that there was a significant variation in blood overdraw among individual phlebotomists, and as a result, the overall R(2) increased to.52. An additional subset analysis involving 2 of the 3 groups of blood drawers (ie, hospital and neonatal laboratory phlebotomists) examining the effect of work shift, demonstrated that there was significantly greater overdraw for blood samples obtained during the evening shift, compared with the day shift when drawn using unmarked tubes for the group of heavier infants cared for in the NICU. CONCLUSION: Significant volumes of blood loss are attributable to overdraw for laboratory testing. This occurrence likely exacerbates the anemia of prematurity and may increase the need for transfusions in some infants. Attempts should be made to correct the factors involved. Common sense suggests that blood samples drawn in tubes with fill-lines marked on the outside would more closely approximate the volumes requested than those without. Conversely, the use of unmarked tubes could lead to phlebotomy overdraw because phlebotomists may overcompensate to avoid having to redraw the sample because of an insufficient volume for analysis. We were surprised to observe that the lightest and most critically ill infants experienced the greatest blood overdraw. (ABSTRACT TRUNCATED)

Randomized trial assessing the feasibility and safety of biologic parents as RBC donors for their preterm infants.

BACKGROUND: Most very low birth weight (<1.0 kg) infants receive RBC transfusions. Several reports have demonstrated that RBCs stored up to 42 days can be transfused safely in small volumes to preterm infants to decrease donor exposure without consequent hyperkalemia, acidosis, or other adverse effects. Although biologic parents are likely candidates as donors of blood for their neonates, it has been suggested that their blood may be serologically incompatible with that of their infants. STUDY DESIGN AND METHODS: A two-arm randomized study was conducted to compare the feasibility and immediate safety of two single-donor programs for providing small-volume RBC transfusions to preterm infants: in one arm, infants received RBCs collected from unrelated donors and stored up to 42 days, and in the other arm, RBCs were collected from one of the biologic parents and stored identically. All infants received compatible RBCs that were WBC reduced before storage, stored in AS-3, and gamma-radiated. All transfusions were given uniformly as 15 mL per kg of RBCs transfused over 5 hours, during which time the infants were closely observed for clinical reactions. In addition, laboratory studies were performed shortly before and after each transfusion. RESULTS: A total of 40 preterm infants received 120 RBC transfusions. Biologic parents experienced several donor eligibility problems. However, once enrolled as donors, they were able to supply all RBCs needed by their infants. Significant differences in rates of clinical transfusion reactions and laboratory abnormalities were rare and had no apparent clinical importance, regardless of whether RBCs were donated by biologic parents or unrelated donors. CONCLUSION: A single-donor system, in which AS-3 RBCs were collected either from unrelated blood donors or from biologic parents and then stored up to 42 days, was able to supply small-volume RBC transfusions needed by individual preterm infants without immediate, adverse effects. Because the risk of infectious disease transmission is likely reduced by limiting donor exposure, it is logical to conclude that single-donor programs should increase transfusion safety and that biologic parents should be considered as blood donors for their infants.

Feasibility and safety of AS-3 red blood cells for neonatal transfusions.

OBJECTIVES: Most extremely low birth weight (<1 kg) infants receive red blood cell (RBC) transfusions. RBCs stored up to 42 days can be transfused safely in small volumes to preterm infants; however, because the formulation of RBC anticoagulant/preservative solutions differs, clinical studies are required to document the safety of each solution before widespread use. Our goal was to study the feasibility and safety of AS-3 anticoagulant/preservative solution to preterm infants. STUDY DESIGN: Two clinical studies were conducted in sequence: (1) a randomized trial to compare RBC transfusions given as stored (< or =42 days) AS-3 RBCs (11 infants) versus fresh (< or = 7 days) citrate, phosphate, dextrose, and adenine RBCs (10 infants) and (2) a subsequent evaluation of the safety of stored AS-3 RBCs in 33 additional preterm infants given 120 AS-3 RBC transfusions. RESULTS: Results of both the randomized study and the subsequent evaluation documented that AS-3 RBCs stored < or =42 days and transfused in small volumes (15 mL/kg) were safe for RBC transfusions of preterm infants. Donor exposure was significantly reduced, clinical transfusion reactions were rare, and post-transfusion blood hematocrit, pH, and plasma Na, K, Ca, lactate, and glucose measurements were similar when AS-3 and citrate, phosphate, dextrose, and adenine RBC transfusions were compared. CONCLUSIONS: AS-3 RBCs can be used safely for small-volume RBC transfusions for preterm infants.