1Department of Anesthesiology, Ospedali Riuniti di Bergamo, Bergamo, Italy. 2Department of Cardiac Surgery Ospedali Riuniti di Bergamo, Bergamo, Italy. 3Blood Transfusion Service, Ospedali Riuniti di Bergamo, Bergamo, Italy*Corresponding author: Blood Transfusion Service, Ospedali Riuniti di Bergamo, Largo Barozzi n.1, I-24100 Bergamo, Italy
Accepted for publication: May 3, 2001
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Abstract |
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Br J Anaesth 2001; 87: 42934
Keywords: blood, erythropoietin; blood, autologous; surgery, cardiac; anaesthesia, paediatric
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Introduction |
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Great efforts have been made in recent years to develop blood-saving techniques so that open heart surgery can be performed without allogenic blood transfusion.3 This goal is more difficult to achieve in children. They often have iron deficiency anaemia, which is made worse by repeated blood sampling. Moreover, their blood is diluted to a greater extent than in adults by extracorporeal circulation. Blood transfusion is therefore more frequent in children during cardiac surgery.4 Storage of autologous blood before surgery would help to reduce exposure to allogenic blood in children.
The use of recombinant human erythropoietin alpha (EPO), the primary growth factor for red blood cells, is safe and effective in the treatment of anaemia associated with chronic renal failure, human immunodeficiency virus infection and cancer.5 Knowledge of the scientific and physiological basis of EPO6 7 has supported its use in patients undergoing elective surgery. As a result, EPO therapy has been approved in the USA, Japan, Europe and Canada for use in patients donating autologous blood before surgery.8
At our institution, the blood conservation programme for children undergoing open heart surgery is based on the use of intraoperative tranexamic acid, intraoperative and postoperative transfusion of shed mediastinal blood and the use of prudent transfusion guidelines.911 More recently, treatment with preoperative subcutaneous EPO to facilitate ABD has been adopted. This study was performed to assess the feasibility and efficacy of such treatment and its effect on allogenic blood transfusion in children undergoing open heart surgery.
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Material and methods |
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Group 1 children received EPO (Eprex, Janssen-Cilag, High Wycombe, UK) 100 U kg1 s.c. three times a week during the 3 weeks preceding the operation and 100 U kg1 i.v. on the day of surgery, to a total dose of 1000 U kg1. Oral iron sulphate supplementation was given (60 mg day1) during the 3 weeks preceding the operation and during the entire hospital stay. Blood for the first and second ABDs was collected 3 and 2 weeks preoperatively respectively, provided that the haematocrit exceeded 33%.
Phlebotomies were performed by the anaesthetist on an outpatient basis. The patients underwent cardiac monitoring (pulse oximetry, blood pressure, ECG) during the procedure. An 18-gauge needle was inserted in the antecubital vein of the arm and connected to the collection bag by a three-way tap to allow infusion of small boluses of saline to prevent needle occlusion. At each phlebotomy, blood (9 ml kg1) was drawn and saline was then infused for volume replacement. The blood was collected in a single 450 ml bag containing 14 ml anticoagulant solution per 100 ml of whole blood (CPDA-1) and stored by the blood transfusion service. The maximum length of storage was 35 days.
As a control for the transfusion requirement, 39 consecutive age-matched patients who had undergone open heart surgery for atrial and/or septal defect at our institution between July 1995 and December 1997 were selected (Group 2). During this 4-yr period, all the children were followed by the same surgical and anaesthetic team and underwent the same blood conservation programme.
For all the children, cardiopulmonary bypass (CPB) was performed using a membrane oxygenator with a prime volume of 700 ml for a body weight of less than 25 kg (Lilliput 2, Dideco D 902, Dideco, Mirandola, Italy) or 900 ml for a body weight more than 26 kg (Midiflo, Dideco D 705). Myocardial protection was performed with a cold, intermittent hyperkalaemic infusion. Tranexamic acid (10 mg kg1) was given before bypass followed by continuous infusion at 2 mg kg1 h1 to prevent fibrinolysis.
Our blood conservation protocol included the use of a cell-saving device (Compact A, Dideco). Depending on the patients haematocrit, the blood remaining in the circuit was returned to the patient as whole blood, directly or after ultrafiltration, or as red blood cell (RBC) concentrate, after washing and concentration in the cell-saving system. Postoperative shed mediastinal reinfusion was performed if 300 ml autologous blood or more was present in the containers at 3 and 6 h.
The decision to give blood was based on each patients clinical condition, with a haematocrit transfusion trigger of 18% during CPB and of 26% in the intensive care unit.
The following laboratory variables were measured: RBC count, haemoglobin concentration, haematocrit, white blood cell count and platelet count. In Group 1, blood samples were drawn before the beginning of EPO therapy; before the second ABD; immediately before surgery; after surgery; and on postoperative days 1 (POD1) and 7 (POD7). In Group 2, these variables were taken from clinical records, but only the preoperative values, the postoperative values and the values on POD1 were always available.
Despite erythropoietin treatment, RBC counts usually decreased during the period of ABD in Group 1. Preoperative autologous RBC production in these patients was therefore estimated from the total volume of RBC collected minus the change in circulating RBC between the first donation and the day of surgery.12 (In the few patients in whom the RBC count increased during this period, the increase was added to the volume of RBC donated.) The volume of autologous RBC collected at each phlebotomy was determined by multiplying the peripheral venous haematocrit by the volume of blood drawn. Circulating RBC volume was determined by multiplying the patients total blood volume by the body haematocrit. Total blood volume was determined by multiplying body weight in kilograms by 75 ml kg1,13 and was assumed not to change during the period of treatment. Body haematocrit was determined by multiplying the peripheral venous haematocrit by 0.91.14
The perioperative RBC loss was estimated from the difference in circulating RBC on the day of surgery and the first postoperative day, plus the RBCs transfused in the same period. A standard unit of allogenic packed RBC was considered to contain 200 ml of RBC15 and the amount of allogenic RBC transfused was therefore determined by multiplying the number of allogenic RBC units transfused by 200.
Statistical analysis
Differences between the two groups were analysed by two-tailed Students t-test for unpaired data. Intragroup analysis was performed by means of two-tailed Students t-test for paired data, when indicated. Proportions were compared with the two-sided Fisher exact test or the 2 test, as indicated. Differences were considered to be significant if the P value was less than 0.05. All values are expressed as mean (standard deviation) unless specified otherwise.
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Results |
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Chest tube drainage was significantly reduced during the first 12 h after surgery in Group 1 compared with Group 2 patients (7.8 (4.8) and 12 (8.7) ml kg1 respectively; P=0.01). In one case in Group 2, chest tube drainage exceeded 100 ml for three consecutive hours and the blood was transfused (Table 3). There were no perioperative deaths and all children were discharged from hospital well. The length of hospital stay was 6.7 (0.8) and 6.4 (0.9) days in Group 1 and Group 2 respectively (P=0.12).
In Group 1, the pretreatment and preoperative haemoglobin concentrations were similar (Table 4). The haemoglobin concentration fell after surgery from 12.4 (1.4) to 10 (1.6) g dl1; it was 10.9 (1.4) g dl1 after discharge from the intensive care unit on POD1 and it remained unchanged during the subsequent 7 days. The preoperative platelet count in Group 1 increased significantly during the treatment period, from 245 x 103 (61 x 103) to 326 x 103 (95 x 103) ml1 preoperatively, decreased after surgery to 188 x 103 (52 x 103) ml1 and returned to the pretreatment value within a week after the operation (Table 4).
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Children in Group 1 received all the ABD collected during the operative or the postoperative period. Three of the 39 children (7.7%) required allogenic blood during surgery: one patient required 1 unit, a second patient required 2 units and the third patient 3 units. Only one of these children needed fresh frozen plasma and none of them needed platelet transfusion.
A total of 33 units of allogenic packed RBC was administered to 24 out of 39 (61.5%) children in Group 2 during the operative or postoperative period. Eighteen of the 24 patients (75%) required 1 unit of packed RBC, four patients required 2 units and two patients required 3 and 4 units respectively. In addition, four of these children needed fresh frozen plasma but no patient needed platelet transfusion. In the control group, allogenic blood transfusion was needed during CPB in 13 out of 39 children (33%).
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Discussion |
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This study assessed the feasibility and safety of preoperative EPO and ABD, its effectiveness in augmenting autologous RBC count and its effect on allogenic blood transfusion in children undergoing open heart surgery. Complications of blood donation, including syncope, has been described in 25% of healthy blood donors.20 Although the consequences of such events could have been more serious in patients with cardiovascular disease, the risk of autologous blood donation is probably overestimated. In a report of autologous donation in patients awaiting heart transplantation, the haemodynamic effects of ABD were not different from those observed in a control population without cardiac disease.21 Available data indicate that ABD is safe and feasible and can be used for children of a wide range of age and weight and in a variety of surgical procedures.2225 Although venous access may be more difficult preoperatively, the benefits of avoiding allogenic blood transfusion are greater in children because of their longer life expectancy, as the possible consequences of blood-borne infections are more serious and long-lasting in younger patients.
In the present study, donations were well tolerated, with only a low incidence of vasovagal reactions (4%). In addition, 96% of the scheduled collections were performed and none cancelled because of refusal by the children or their parents.
The safety of EPO therapy in patients undergoing elective surgery has been demonstrated in more than 1000 patients in placebo-controlled trials.8 Thrombotic events described in patients with chronic renal failure have not been seen with EPO therapy in the surgical setting.26 In our series we did not observe any side-effects of EPO therapy, such as thrombotic events or hypertensive attacks, which is in accordance with the data available in the literature.8 On the other hand, we observed a significant (30%) increase in platelet count from baseline during treatment in children in Group 1 (Table 4). As a result, the preoperative platelet count was significantly higher in children treated with EPO and remained higher after surgery, without the difference reaching significance compared with controls.
The effect of EPO on platelet count remains controversial. In a recent review, Beguin27 suggested that moderate stimulation by EPO causes a moderate elevation of the platelet count, whereas intense EPO stimulation causes some degree of thrombocytopenia, probably as a result of inhibition of platelet production. The two groups of patients reported in this study were not randomized, so our observations should be taken with caution. However, if confirmed in a randomized study, our results could be of some value. In fact, a report on haemostasis in children undergoing open heart surgery found a significant inverse association between platelet count and blood loss.17 In our experience, the perioperative blood loss was not different in the two groups, and the chest drainage after operation in patients treated with EPO was 35% less than in the control group. Though not randomized, the two groups were similar with regard to physical and operative characteristics, were followed by the same surgical and anaesthetic team and underwent the same blood conservation programme. It is tempting to speculate that the higher preoperative platelet count might be considered beneficial rather then a harmful collateral effect of EPO administration, favouring haemostasis in the immediate postoperative period.
It has been suggested that the most effective way to minimize the use of allogenic blood is the combination of preoperative EPO therapy with the procurement of autologous blood by acute normovolemic haemodilution or donation.8 Several studies have addressed the use of EPO to facilitate ABD28 29 and, though it is expensive, general agreement exists on its utility in anaemic autologous donors.30 Few data have been published on the use of EPO, either alone or associated with ABD, in adult cardiac surgery. Nonetheless, EPO seems to be adequate therapy for increasing mean haemoglobin concentrations by approximately 1 g dl1 per week of treatment, and is effective in allowing ABD collection and reducing exposure to allogenic blood.3135 Even fewer data are available on the use of EPO in paediatric cardiac surgery4 36 and, to our knowledge, no data exist on EPO therapy associated with ABD in children.
Our protocol of s.c. administration of EPO at a total dose of 1000 U kg1 during the 3 weeks preceding operation allowed the collection of 6 (1) ml kg1 of autologous RBC without reduction in the haemoglobin concentration and with a net production of new autologous RBC corresponding to nearly 30% of the circulating RBC volume at baseline. This net gain in autologous RBC allowed a reduction in allogenic RBC transfusion compared with controls. The amount of autologous blood collected was generally adequate, because almost 92% of children treated with EPO and ABD received no allogenic blood.
Though effective, this treatment is expensive.37 38 In our experience, the approximate cost of 1000 units of erythropoietin corresponds to about 10 US dollars and that of one ABD unit to about 70 US dollars. For a child weighing 20 kg, the cost of the treatment (20 000 EPO units plus 2 ABD units, manpower and indirect costs excluded) would be almost 340 US dollars. The adoption of weekly regimens with lower doses of EPO will reduce the cost.8 Nonetheless, this treatment should be reserved for carefully considered circumstances in which the cost is offset by well-defined clinical benefits. We think that this regimen is apposite for young patients undergoing open heart surgery, in whom mild preoperative anaemia is frequent, life expectancy is long and a substantial blood requirement is expected, mainly related to haemodilution during CPB.
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References |
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