The relationship of blood transfusion, tumor staging, and cancer recurrence. A multicenter pilot-randomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation. Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Use of red blood cell transfusions in terminally ill cancer patients admitted to a palliative care unit. Tranexamic acid and upper gastrointestinal haemorrhage--a double-blind trial. Large bowel cancer: the effect of perioperative blood transfusion on outcome. Effects of early human recombinant erythropoietin therapy on the transfusion in healthy preterm infants. Aprotinin versus placebo in major orthopedic surgery: a randomized, double-blinded, dose-ranging study. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Effects of red blood cell transfusion on anemia-related symptoms in patients with cancer.
Previous research demonstrated a relationship between transfusions of whole blood, or large numbers of red cell concentrates, and later recurrence of cancers of the colon, rectum, cervix, and prostate. It is possible that the transfusion of whole blood may represent a surrogate marker for advanced or more aggressive clinical disease. The relationship of clinical or histologic tumor stage, blood transfusion status, and disease outcome was studied in detail. Patients receiving no transfusions or small numbers of red cells (less than or equal to 3 units) had uniformly better recurrence and survival experiences than patients receiving similar amounts of blood that included at least 1 unit of whole blood, regardless of the patient's clinical or histologic tumor stage. In multivariate analyses, stage was an independent predictor of outcome, and transfusion status was not a surrogate marker for stage. The effects on recurrence of stage and transfusion appear to be cumulative. These results are consistent with but do not prove the hypothesis that the transfusion of large amounts of stored plasma and cellular debris impairs the host defenses against cancer, regardless of the underlying biologic and clinical aggressiveness of the cancer. Anemia may be an important factor contributing to an increased risk of bleeding, particularly in patients with thrombocytopenia.
                A multicenter, single-blinded pilot randomized controlled trial (RCT) was performed to evaluate the feasibility of conducting a larger RCT to determine the effect of the hemoglobin (Hb) concentration on bleeding risk. Patients with acute leukemia receiving induction chemotherapy or those undergoing stem cell transplantation were assigned to one of two treatment groups: standard transfusion strategy (transfusion of 2 units of red blood cells [RBCs] when their Hb level was less than 80 g/L) or an augmented transfusion strategy (transfusion of 2 units of RBCs when their Hb level was less than 120 g/L).
                Sixty patients were enrolled: 29 in the control group and 31 in the experimental group. The proportions of patients experiencing clinically significant bleeding and the time to first bleed were not significantly different between the control and experimental groups. The experimental group received more RBC transfusions (transfusions/patient-day) than the control group (0.233 vs. 0.151; relative risk, 1.56; 95% confidence interval, 1.16-2.10; p = 0.003). The proportion of patient-days with platelet (PLT) transfusions was not different between the experimental and control groups. The mean number of donor exposures (PLT and RBC transfusions) was not different between experimental and control groups. Bleeding symptoms were systematically documented.
                This pilot study thus indicated that it would be feasible to enroll the required number of patients to enable the performance of a large RCT to investigate the effect of Hb on bleeding risk in thrombocytopenic patients. Large prophylactic doses of aprotinin efficiently reduce blood loss during orthotopic liver transplantation (OLT). Small doses of aprotinin are usually used to treat fibrinolysis. However, no studies have investigated the benefit of prophylactic administration of a smaller dose of aprotinin during liver transplantation. We compared two methods of aprotinin therapy on transfusion outcome in liver transplant patients in a prospective study of 199 patients undergoing OLT who were randomized to large or small prophylactic doses of aprotinin during the transplant procedure. In the large-dose group (n = 94) an initial dose of 2,000,000 kallikrein inactivation units (KIU) was followed by infusion of 500,000 KIU/h until the patient's return to the intensive care unit. In the small-dose group (n = 95), an initial dose of 500,000 KIU was followed by an infusion of 150,000 KIU/h. Outcome measurements included intraoperative transfusion requirements (packed red blood cells, fresh frozen plasma, platelets, intraoperative salvage) and postoperative hematologic values. There were no differences in transfusion requirements in the two groups of patients. Patients treated with low-dose aprotinin had slightly higher postoperative fibrinogen concentrations. Large-dose aprotinin therapy does not appear to offer additional benefit compared to low-dose aprotinin administration. Anemia is often associated with neoplastic disorders. Blood transfusions are used to alleviate the discomfort of anemic cancer patients. Of 246 terminally ill cancer patients admitted to our palliative care unit from October 1991 to December 1993 (128 women and 118 men), 31 patients (12.6%) (17 men and 14 women; age, 69.5 +/- 12 years) received on average 2.8 units of packed red blood cells (PRBCs) (range, 2-7 units/patient) in 35 separate admissions. PRBCs were transfused in the presence of low hemoglobin (Hb) levels ( < or = 8 g/dL) and/or severe fatigue or dyspnea. Pre-transfusion performance status, cognitive function, dyspnea, and fatigue at rest (evaluated by a four-point scale), complete blood count, serum albumin, and C-reactive protein were determined. The day after transfusion, subjective well-being was recorded as "yes/no" improvement in comparison with the pre-transfusion day. Improved subjective well-being after blood transfusion was reported in 51.4%, without significant relationship to pre-transfusion Hb levels or performance status. The influence of blood transfusion on subjective well-being was not related to the severity of dyspnea or fatigue. Twenty-one patients (60%), including seven with subjective improvement, died during the same hospitalization, a median of 49 days after transfusion. Pre-transfusion Hb level did not differ significantly in patients who benefited and did not benefit from transfusion, whereas time before death was significantly (P < 0.001) shorter in patients who did not benefit. In the discharged patients (40%), the median interval between transfusion and discharge was 13 days and the frequency of subjective improvement in well-being was 78.6%. Our data suggest that two main areas should be investigated, namely the relation between low Hb levels and symptoms and signs in terminally ill cancer patients, and the correct timing for effective blood transfusion. A combination of criteria is needed for effective transfusion; they must include not only Hb levels but also type and severity of anemic symptoms and signs. Furthermore, the identification of reliable prognostic indicators for survival would be useful. The efficacy of antifibrinolytic therapy in the management of acute upper gastrointestinal haemorrhage has been investigated in a double-blind clinical trial. Two-hundred patients were studied using tranexamic acid, a potent antifibrinolytic agent. Of these, 103 were in the treatment group and 97 in the control group. Patients were analysed to determine severity of initial blood loss, transfusion requirements, together with the incidence of recurrent bleeding, surgical intervention, and death. Final diagnosis as to the site of bleeding was arrived at using endoscopy, barium studies, and the findings at operation and necropsy. The groups were well matched as regards severity of initial haemorrhage, age, sex, aetiological diagnosis, and precipitating factors. A significant difference was observed in the requirement for surgical intervention to control continuing or recurrent haemorrhage. Twenty-three of 97 in the control group and seven of 103 in the treatment group required surgery. There appeared to be a reduction in the transfusion rate after the first three days of hospitalization in the treatment group. There were no significant differences in mortality or in side-effects between the two groups. Perioperative blood transfusion has been reported to adversely affect survival in cancer patients, but the evidence is inconclusive and may be an epiphenomenon. From the Large Bowel Cancer Project, 961 patients who underwent curative resection and left hospital alive have been reviewed to compare the effect of perioperative blood transfusion on outcome; 591 patients (61%) had been given a blood transfusion while 370 (39%) had not been transfused. Some clinical variables were equally distributed between the two groups; ie age, sex, obstruction, perforation, tumour differentiation. Three other variables known to influence patient prognosis were not equally distributed, ie tumour site, Dukes' stage and tumour mobility. Patients with tumours of the rectum and rectosigmoid, with Dukes' stage C lesions and with some degree of tumour fixation were more likely to have received blood transfusions. Using the logrank method of multivariate analysis to allow for differences in distribution of all those variables known to affect prognosis, there was no survival disadvantage for those patients who had received perioperative blood transfusion. Furthermore, there were no overall differences between the two groups of patients in their risk of developing local tumour recurrence or distant metastases. The distribution of metastases differed: in the 'transfused' group only 37% of distant metastases were found in the liver, while 71% were found in this site in the 'not transfused' group (chi 2 = 18.46, d.f. = 1, P less than 0.001). By contrast, there was a larger proportion of patients with lung metastases in the transfused group (27% vs 11%) (chi 2 = 5.59, d.f. = 1, P less than 0.05). Therefore, these data do not support the concept of an overall deleterious effect of blood transfusion on patient survival, but suggest that blood given in the perioperative period may change the biology of the metastatic process. Early recombinant erythropoietin therapy and iron therapy would decrease the need for red blood cells transfusions and prevents anemia of prematurity.
                Fifty-eight preterm infants in newborn services at Ghaem Medical Center randomly were assigned, among them 18 patients were excluded. A total of 40 preterm infants with gestational age 28-34 weeks, birth weight 1000-1750 g followed the study: 20 infants in treatment group and 20 infants in control group were randomized to treatment (rhu EPO, 500u per kg, per week, 2 times weekly, subcutaneous) and control (no treatment). Therapy was initiated 4 days after birth and continued throughout the 4 weeks. All infants on enteral feeds received supplements: iron 3 mg/kg/d, vitamins and folat. Complete blood cells and reticulocyte counts were measured weekly. Transfusions and phlebotomy data were recorded. Statistical significance was determined by chi-square test, student t test and Mann-Whitney. A P value of < 0.05 was considered statistically significant.
                The reticulocyte counts were higher in treated infants during the study (p: 0.009). Final hematocrits were higher in treated infants (p: 0.02).The volume of packed red blood cells transfusions mililiter per infant significantly reduced (p: 0.05), the average number of transfusion per infant was also lower for treated infant than control [2 (10 % )vs 8 (40%) respectively]. No adverse effects of EPO or supplemental iron occurred.
                The combination of early rhu EPO and iron as administered in the present study stimulated erythropoiesis and decreased red blood cells transfusion in premature infants who were 1000-1750 g at birth. The enrollments of the larger and healthier preterm infants, who are at lower risk for transfusion, are limitation of the present study. We conducted a prospective, multicenter, double-blinded, dose-ranging study to compare the risk/benefit ratio of large- and small-dose aprotinin with placebo after major orthopedic surgery. Fifty-eight patients were randomized into three groups: Large-Dose Aprotinin (4 M kallikrein inactivator unit [KIU] bolus before surgery followed by a continuous infusion of 1 M KIU/h until the end of surgery), Small-Dose Aprotinin (2 M KIU bolus plus 0.5 M KIU/h), and Placebo. Bleeding was measured and calculated. Bilateral ascending venography was systematically performed on the third postoperative day. Measured and calculated blood loss decreased in the Large-Dose Aprotinin group (calculated bleeding, whole blood, hematocrit 30%, median [range], 2,023 mL [633-4,113] as compared with placebo, 3,577 mL [1,670-21,758 mL]). The total number of homologous and autologous units was also significantly decreased in the Large-Dose Aprotinin group (2 U [0-5 U] as compared with placebo, 4 U [0-42 U]). No increase in deep vein thrombosis or pulmonary embolism was observed in the aprotinin groups. Large-dose aprotinin was safe and effective in dramatically reducing the measured and calculated bleeding and the amount of transfused red blood cell units after major orthopedic surgery.
                Large doses of aprotinin decrease blood loss and transfusion amount in major orthopedic surgery. Hydroxyethyl starch (HES) solutions are effective plasma volume expanders. Impairment of coagulation occurs with large HES volumes infused perioperatively. Therefore, a lower substituted novel HES (Voluven; Fresenius Kabi, Bad Homburg, Germany) was developed to minimize hemostatic interactions, and was compared with HAES-steril (Fresenius Kabi) (pentastarch) regarding safety and efficacy. We performed a prospective, randomized, double-blinded study in 100 major orthopedic surgery patients. Because the 95% confidence interval (-330 mL; +284 mL) for the treatment contrast Voluven-HAES-steril was entirely included in the predefined equivalence range (+/- 500 mL), comparable efficacy was established. Voluven interfered significantly less than HAES-steril with coagulation factor VIII levels and partial thromboplastin time postoperatively. Total amounts of red blood cells transfused were comparable between the Voluven and HAES-steril groups, but a significantly reduced need for homologous red blood cells was observed in the Voluven group. We conclude that in large-blood-loss surgery, Voluven has a comparable efficacy with HAES-steril and may reduce coagulation impairment, possibly leading to a smaller number of allogeneic blood transfusions.
                Hydroxyethyl starches are common plasma volume expanders, but may interfere with coagulation at large doses. We tested a novel hydroxyethyl starch specification (Voluven; Fresenius Kabi, Bad Homburg, Germany) which was developed to reduce hemostatic interactions while preserving its efficacy in restoring plasma volume in comparison to HAES-steril (pentastarch; Fresenius Kabi) in major orthopedic surgery. Total knee arthroplasty (TKA) is often carried out using a tourniquet and shed blood is collected in drains. Tranexamic acid decreases the external blood loss. Some blood loss may be concealed, and the overall effect of tranexamic acid on the haemoglobin (Hb) balance is not known.
                Patients with osteoarthrosis had unilateral cemented TKA using spinal anaesthesia. In a double-blind fashion, they received either placebo (n=24) or tranexamic acid 10 mg kg(-1) (n=27) i.v. just before tourniquet release and 3 h later. The decrease in circulating Hb on the fifth day after surgery, after correction for Hb transfused, was used to calculate the loss of Hb in grams. This value was then expressed as ml of blood loss.
                The groups had similar characteristics. The median volume of drainage fluid after placebo was 845 (interquartile range 523-990) ml and after tranexamic acid was 385 (331-586) ml (P<0.001). Placebo patients received 2 (0-2) units and tranexamic acid patients 0 (0-0) units of packed red cells (P<0.001). The estimated blood loss was 1426 (1135-1977) ml and 1045 (792-1292) ml, respectively (P<0.001). The hidden loss of blood (calculated as loss minus drainage volume) was 618 (330-1347) ml and 524 (330-9620) ml, respectively (P=0.41). Two patients in each group developed deep vein thrombosis.
                Tranexamic acid decreased total blood loss by nearly 30%, drainage volume by approximately 50% and drastically reduced transfusion. However, concealed loss was only marginally influenced by tranexamic acid and was at least as large as the drainage volume. The aim of this study was to assess the effects of red blood cell transfusion, and the subsequent increase in hemoglobin values, on anemia-related symptoms in a cohort of patients with cancer with different survival times. A red blood cell transfusion was recommended to a consecutive sample of patients with hemoglobin levels of 8 +/- 0.5 g/dL. The number of units to be ordered was decided according the hemoglobin values with a mean target of increasing the hemoglobin values by approximately 2 g/dL. Hemoglobin values, anemia-related signs and symptoms, including well-being, fatigue, and dyspnea, were recorded at admission (T0), 1 day after the last transfusion (T1), and 15 days afterward (T2) by telephone contact or visit. Well-being, fatigue, and dyspnea were measured on a numerical scale of 0-10. Sixty-one patients were recruited in the period of study. One hundred thirty-three units of red blood cells were transfused (mean 2.18, 95% confidence interval [CI] 0.6). Complete data were available for 40 patients. Hemoglobin values and well-being significantly increased after transfusion (T1), maintaining acceptable values 15 days afterward (T2). Significant changes in fatigue and dyspnea were found immediately after transfusion, although the effect was partially lost 15 days after transfusion. No statistical differences were found between patients with different survival times. Fatigue was significantly lower in patients with longer survival times in comparison with patients with shorter survival times (p = 0.04). Blood transfusion in patients with hemoglobin values of approximately 8 g/dL improved anemia-related symptoms on a short-term basis. This benefit is independent of the stage of disease and survival. However, the effects on dyspnea and fatigue tend to decrease within 15 days, despite the maintenance of hemoglobin values attained after transfusions, suggesting that other factors may play a role.
There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed RCTs of sufficient power are urgently needed.