Ann Thorac Surg 1999;68:1652-1656
© 1999 The Society of Thoracic Surgeons
Original Articles
Autologous blood donation with recombinant human erythropoietin in anemic patients
Hiroshi Kiyama, MDa,
Nagahisa Ohshima, MDa,
Takao Imazeki, MDa,
Takashi Yamada, MDa
a Division of Cardiovascular Surgery, Sekishinkai Sayama Hospital, Saitama, Japan
Address reprint requests to Dr Kiyama, Department of Cardiovascular and Thoracic Surgery, Dokkyo University Koshigaya Hospital, 2-1-50 Minamikoshigaya, Koshigaya, Saitama 343, Japan
e-mail: yukayuka{at}tv.sony.co.jp
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Abstract
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Background. Various blood management strategies can be used to reduce the need for allogeneic blood in cardiac surgery. In anemic patients, however, avoidance of allogeneic blood transfusion is difficult to achieve. This study was performed to assess the safety and effectiveness of preoperative blood collection using recombinant human erythropoietin (rHuEPO) for reducing the exposure to allogeneic blood in anemic patients.
Methods. Thirty-two anemic patients undergoing cardiac surgery at our hospital between January 1994 and October 1997 were divided into two groups according to preoperative strategies: 3-week treatment with rHuEPO and blood donation (group 1, n = 16) or iron supplementation alone (group 2, n = 16).
Results. There were no statistically significant differences between the two groups in patients’ characteristics and surgical data. The number of reticulocytes was increased at just before surgery in group 1, whereas group 2 showed no significant increase. The estimated hemoglobin increases in group 1 were higher at 7 days and just before surgery. The mean number of required allogeneic blood for patients during surgery was 0.59 ± 1.12 U in group 1 and 5.01 ± 2.63 U in group 2. In 75% of group 1 patients, allogeneic blood transfusion was successfully avoided, whereas all patients in group 2 received allogeneic blood.
Conclusions. This study suggests that the combination of rHuEPO administration and autologous blood donation can reduce the need for allogeneic blood in anemic patients.
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Introduction
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Reducing exposure to allogeneic blood is an important means of lowering the associated risks to patients, such as the transmission of infectious diseases, allergic reactions, or immunosuppression. Because of these risks, clinicians and surgeons are strongly motivated to minimize or avoid allogeneic transfusion. In the field of open heart surgery, the incidence of allogeneic blood transfusion can be reduced by strategies such as preoperative autologous blood donation with recombinant human erythropoietin (rHuEPO) [1–3], intraoperative and postoperative blood salvage techniques [4], and pharmacologic therapy with agents such as aprotinin [5]. We previously demonstrated that reducing exposure to allogeneic blood can be achieved by a combination of blood management techniques [6]. However, anemia can preclude the collection of sufficient blood from the patient to cover his or her transfusion needs. Hemoglobin level is a major determinant in the use of allogeneic blood [7–9], and patients with baseline hemoglobin levels below 11.0 g/dL have been excluded from donation and administration of rHuEPO in most reported series, because the safety and effectiveness of blood donaton in anemic patients with heart disease has been unknown [10]. The present study was undertaken to determine whether preoperative collection of blood for autologous use with rHuEPO can reduce the exposure to allogeneic blood in anemic patients.
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Material and methods
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The subjects were 32 patients with baseline hemoglobin levels below 11.0 g/dL who underwent elective open heart surgery at our hospital between January 1994 and October 1997. There were 19 (59.4%) men and 13 (40.6%) women, with a mean age of 68.9 ± 8.4 years (range 50 to 84 years). The causes of anemia were iron deficiency including recent bleeding, chronic renal failure, and other causes that could not be clarified. Patients with unstable angina, active blood loss, infectious disease, and neoplasia were excluded from the study. Although the lower margin of the baseline hemoglobin was not limited, anemic patients who required blood transfusion before entry were excluded. Advanced age and chronic renal failure did not preclude participation. Informed consent was obtained from each patient enrolled. All patients in the study were randomly assigned to 3-week treatment with rHuEPO and blood donation (group 1) or iron supplementation alone (group 2). The patients in group 1 received subcutaneous administration of rHuEPO at a dose of 500 U/kg once a week at least 3 weeks before the scheduled surgery date. Initial rHuEPO administrations were started at 23.3 ± 1.8 days (range 21 to 26 days) before the scheduled surgery date. In addition, all outpatients in both groups received oral administration of iron sulfate at a dose of 100 mg daily, and all inpatients with serum ferritin levels below 100 ng/dL received intravenous administration of chondroitin sulfate-iron at a dose of 40 mg daily just before surgery. Autologous blood was scheduled to be collected from the patients in group 1 once a week for 3 weeks. All patients received 500 mL of Ringer’s lactate solution at the time of autologous blood donation. The volume of blood taken was determined by measured hemoglobin concentration before each donation. Four hundred grams of whole blood was collected if the hemoglobin level was more than 11.0 g/dL, and 200 g was collected if it was less than 11.0 g/dL. Patients were excluded from donation if the hemoglobin level was less than 10.5 g/dL. All patients were closely questioned regarding changes in cardiac symptoms, and the following parameters were recorded in all patients at baseline and at each predonation and postdonation: blood pressure, pulse rate, complete blood cell count, and the 12-lead electrocardiography.
Patients in both groups were treated according to the same standard anesthetic and cardiopulmonary bypass (CPB) techniques. The extracorporeal circuits were primed with 1,200 mL of Ringer’s lactate solution with 5,000 IU heparin. Before CPB, 250 IU/kg heparin was administrated intravenously through a central venous cannula, with additional dosing as necessary to maintain the activated clotting time greater than 400 seconds. In addition to continuous infusion of 106 KIU aprotinin, another 106 KIU aprotinin was added to the priming solution of the CPB circuit. CPB was performed with core cooling to 32°C and nonpulsatile flow of 2.4 L/min/m2. After aortic cross-clamping, an initial dose of blood cardioplegic solution (24°C) was delivered via the aortic root to arrest the heart. Cardioplegia (24°C) via the coronary sinus was repeated every 20 minutes or whenever electrical activity resumed. Just before removal of the aortic clamp, 700 mL of warm blood cardioplegia was delivered via the coronary sinus. Heparin was neutralized after the end of CPB with protamine sulfate (1 mg/100 IU heparin). The estimated hemoglobin increase in the patients was calculated as
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To eliminate as many variables as possible, all patients were operated on by the same surgeon at the same hospital during the study. Administration of allogeneic blood during extracorporeal circulation was allowed when the hemoglobin level was less than 6.0 g/dL. After extracorporeal circulation, allogeneic blood transfusion was avoided if the hemoglobin level was more than 7.5 g/dL or if the patient was in a hemodynamically stable condition. One patient in group 2 required exploration for postoperative bleeding, but there were no operative deaths or important adverse complications such as cerebral infarction or perioperative myocardial infarction.
Statistical methods
Statistical analysis of the data was performed using factorial analysis of variance with a commercially available software package (Statview 4.5; Abacus Concepts, Berkeley, CA) on a Macintosh personal computer. All data are expressed as mean ± standard deviation. Statistical significance was calculated using Student’s t test for unpaired observations and the 
2 test. Significance was assumed when the calculated p value was 0.05 or less.
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Results
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The clinical characteristics of the 32 patients in the two groups are shown in Table 1. (Table 2) There were no statistically significant differences between the two groups in patient characteristics or surgical data, including age, gender, weight, height, body surface area, cause of anemia, reticulocyte count, procedures, aortic cross-clamp time, extracorporeal bypass time, blood loss during surgery, or total blood loss into the chest drain. No serious adverse events after phlebotomy were observed in patients donating autologous blood, although 1 patient in group 1 had a palpitation right after blood donation. The iron administration periods were not significantly different between the two groups (26.2 ± 7.4 days versus 28.5 ± 5.4 days). The hemoglobin levels for patients in both groups are shown in Figure 1. The baseline hemoglobin levels were not significantly different between the two groups (10.5 ± 0.4 versus 10.2 ± 0.2 g/dL). The lowest initial hemoglobin levels in group 1 and group 2 were 9.6 and 9.4 g/dL, respectively. The hemoglobin levels in group 1 increased significantly 10.5 ± 0.4 g/dL from before first donation to 11.3 ± 0.5 g/dL 7 days before surgery. Patients in group 1 had significantly higher hemoglobin levels than patients in group 2 at 7 days before surgery. The patients in group 2 continued to have low hemoglobin levels despite the administration of iron sulfate. However, there were no significant differences in the hemoglobin levels between the two groups during and after surgery. The number of reticulocytes began to increase in group 1 significantly, although group 2 did not show a significant increase (Fig 2). The estimated hemoglobin increases for patients are shown in Figure 3. The estimated hemoglobin increases in group 1 were significantly higher than in group 2 at 7 days before surgery (1.7 ± 0.7 versus 0.5 ± 0.5 g/dL) and just before operation (2.1 ± 0.9 versus 0.5 ± 0.4 g/dL). In group 1, the mean collected blood volumes per patient at 14 days, 7 days, and just before surgery were 156.2 ± 159.0, 251.9 ± 136.0, and 304.4 ± 161.4 mL, respectively. Total collected blood volume before surgery was 721.3 ± 302.1 mL (range 0 to 1,200 mL). In 75% of group 1 patients, allogeneic blood transfusion was successfully avoided, whereas all patients in group 2 received allogeneic blood transfusion. The mean number of required allogeneic blood for each patient during surgery was 0.59 ± 1.12 U in group 1 and 5.01 ± 2.63 U in group 2. In the group of patients who received rHuEPO and collected blood (group 1), a significantly lower percentage of patients needed allogeneic transfusions, and a lower mean number of units of allogeneic blood per patient was transfused than in group 2. The mean number of required allogeneic blood for each patient after surgery was similar in both groups (0.49 ± 1.32 U in group 1 and 0.98 ± 1.01 U in group 2).
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Fig 1. Preoperative hemoglobin levels in group 1 increased significantly from before first donation to 7 days before surgery. The mean hemoglobin level at 7 days before surgery was significantly higher in group 1. ap < 0.05 in comparison between both groups. bp < 0.05 versus 21 days before surgery.
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Fig 2. The number of reticulocytes began to increase in group 1 significantly, although group 2 did not show a significant increase. The reticulocyte count at just before surgery was significantly higher in group 1. ap < 0.001 in comparison between both groups. bp < 0.01 versus 21 days before operation.
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Fig 3. Estimated hemoglobin increase (EHI) in group 1 was significantly higher than in group 2 at 7 days before operation and just before operation. ap < 0.001 in comparison between both groups.
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Comment
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rHuEPO has proven effective in treating anemia in patients with chronic renal failure [11]. In the presence of adequate iron stores, rHuEPO improves the quality of life in these patients and maintains the level of hemoglobin so that the need for allogeneic transfusion is decreased or eliminated. Recently, much interest has arisen regarding the use of rHuEPO perioperatively. Previous studies have demonstrated that autologous blood donation and administration of rHuEPO reduce the need for transfusion by increasing preoperative hemoglobin and enhancing postoperative erythropoietic recovery [1, 2]. In Japan, predonation of autologous blood with rHuEPO therapy was approved, so it was usually performed in elective cardiac and orthopedic procedures to correct perioperative anemia. However, complete avoidance of allogeneic blood transfusion in patients undergoing elective surgery is hard to achieve. Despite reducing exposure to allogeneic blood in cardiac surgery, most patients with anemia still require allogeneic blood.
In orthopedic surgery, treatment with rHuEPO has proven effective in correcting anemia, allowing preoperative donation blood for autologous use, and thus reducing exposure to allogeneic blood among anemic patients [12, 13]. In cardiac surgery, Konishi and associates report that, when time permits, it is possible to correct a low hemoglobin concentration and reduce the need for allogeneic blood [14].
To our knowledge, predonation of blood for cardiac patients with baseline hemoglobin levels below 11.0 g/dL within a limited period has not been reported. Decreasing the oxygen-carrying capacity of blood in cardiac patients has always been considered dangerous. Therefore, blood donation for anemic patients has been recognized as an absolute contraindication before cardiac surgery [4]. Most authors consider cardiac patients eligible for predonation if their hemoglobin level is 11.0 g/dL or greater [10], but this figure remains arbitrary. There has been no theoretical evidence that drawing blood in cardiac patients with hemoglobin levels over 11.0 g/dL is safer than in patients with hemoglobin below 11.0 g/dL. In this study, we attempted to harvest blood from cardiac patients with baseline hemoglobin levels below 11.0 g/dL. No serious reactions during and after blood withdrawal were apparent in any of the cardiac patients with anemia, and the frequency of side effects was comparable in our study and previous reports in nonanemic patients [2, 10]. Therefore, the collection of the blood in cardiac patients with hemoglobin levels above 10.5 to below 11.0 g/dL proved safe and was well tolerated.
In the group receiving iron supplementation alone (group 2), mean increases in hemoglobin levels and in reticulocyte counts were not observed to be significant during the prestudy-to-presurgery period. Iron deficiency anemia usually can be corrected by administration of iron supplementation. The patients in group 2 were maintained on the administration of iron sulfate for several weeks, with no apparent improvement in the anemia, presumably due to decreased hemopoietic function and suppressed serum erythropoietin response associated with aging and chronic renal dysfunction. Treatment with rHuEPO has proven effective in correcting preoperative anemia [15]; it has also been shown to be effective in increasing the volume of autologous blood. In this study, the group receiving iron supplementation alone received more allogeneic blood units. In the anemic patients, the administration of rHuEPO in combination with autologous blood donation led to a significant reduction in the allogeneic blood requirement, and to mean increases in hemoglobin levels and in reticulocyte counts.
Relatively small blood losses, such as 1 or 2 U blood donation, stimulate endogenous erythropoietin production [3]. Thus, preoperative autologous blood donation has been widely endorsed to increase the red blood cell mass and reduce the allogeneic blood requirement. However, treatment with perioperative rHuEPO alone, without concomitant preoperative blood donation, has been recently found to reduce the need for allogeneic blood [3, 16]. Sowade and associates reported that intravenous rHuEPO treatment is an adequate therapy for increasing mean hemoglobin levels and reducing the allogeneic blood requirement in patients undergoing elective open heart surgery and in whom autologous blood donation is contraindicated [16]. The baseline values for hemoglobin in our trial were apparently lower than those employed by Sowade and associates. We presume that aggressive preoperative blood donation in anemic patients is a necessary factor for reducing the transfusion requirement and increasing the red blood cell mass within a limited period, although there is no theoretical evidence. This conclusion may be backed up by objective data obtained from comparison of rHuEPO therapy with blood donation and rHuEPO therapy alone in anemic patients.
Although maintaining optimal hemoglobin levels before cardiac surgery is important to achieve sufficient oxygen delivery, increased blood viscosity, such as a high hemoglobin level, may increase the risk of myocardial infarction in ischemic heart disease. No data exist regarding the best hemoglobin value before cardiac surgery, and there has been no theoretical evidence that the safety margin to anemia is a hemoglobin level of 11.0 g/dL. The number of patients included in this study may be too small to make a valid conclusion regarding the efficacy and safety of our program in anemic patients. However, our results strongly suggest that the combination of rHuEPO administration and preoperative blood donation is safe and effective in significantly reducing perioperative blood requirements in patients with baseline hemoglobin levels below 11.0 g/dL. Studies of more patients are needed to confirm the optimal dose, routes, and frequency of rHuEPO administration and the low hemoglobin limit for cardiac patients with anemia. Furthermore, a safe lower limit of hemoglobin will be established by harvesting preoperative autologous blood in anemic patients aggressively.
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References
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Accepted for publication May 12, 1999.
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Abstract
Introduction
