Autologous blood transfusion in oral and maxillofacial surgery patients with the use of erythropoietin

Journal of Cranio-Maxillofacial Surgery (2001) 29, 118–125 # 2001 European Association for Cranio-Maxillofacial Surgery doi:10.1054/jcms.2001.0200, available online at http://www.idealibrary.com on

Autologous blood transfusion in oral and maxillofacial surgery patients with the use of erythropoietin Maria Christopoulou,1 Harry Derartinian,2 Grammatiki Hatzidimitriou,2 Ioannis Iatrou1 1

Department of Oral and Maxillofacial Surgery (Head: Prof. A. P. Angelopoulos), Evangelismos Hospital, University of Athens, Athens, Greece; 2Department of Blood Donation (Head: Dr G. Hatzidimitriou), Evangelismos Hospital, Athens, Greece

SUMMARY. Background: Autologous blood transfusion presents few infectious or immunologic side effects. The aim of the present study was to determine the impact of autologous blood transfusion with or without recombinant human erythropoietin (rHuEPO) in patients who underwent elective maxillofacial operations. Material: Seventy eight consecutive patients (29 men and 49 women) underwent elective maxillofacial operations during the years 1990-95. Study design and Methods: The patients were randomly assigned to three groups: In group 1, 30 patients preoperatively underwent autologous blood predonation with intravenous injection of erythropoietin 600 IU/kg after each blood predonation and autologous blood transfusion intraoperatively; in group 2, 28 patients underwent the same procedure without erythropoietin and in group 3, 20 patients underwent homologous transfusion serving as control group. All patients received ferrous sulphate daily by mouth, preoperatively until one week postoperatively. Results: Group 1 patients showed higher levels of haematocrit, haemoglobin and red blood cell count pre- and postoperatively than the group 2 patients. It was also shown that the use of rHuEPO contributed to an improvement of the blood parameters of the patients in the group 1 compared with those of the patients in groups 2 and 3. # 2001 European Association for Cranio-Maxillofacial Surgery

kidneys and is responsible for regulating the production of erythrocytes. The recent cloning and expression of the HuEPO gene have provided large amounts of highly purified recombinant rHuEPO, which is indistinguishable from HuEPO (Egrie et al., 1987).

INTRODUCTION In various surgical operations, in spite of improvements in techniques, there is often such a degree of blood loss that replacement is required. Currently the hazards from homologous blood transfusion have been drastically reduced due to careful donor selection and safer screening procedures (Widmann, 1993). However, 1/33 000 homologous blood units lead to a haemolytic reaction of some degree and 1/ 600 000 result in fatal ABO system incompatibility (Linden et al., 1992). Another problem of serious concern is the risk of transmission of diseases such as Hepatitis B Virus (HBV) and Human Immunodeficiency Virus (HIV) (Schreiber et al., 1996). The development of more specific and accurate testing of the homologous blood has greatly reduced the risks of transmission of these diseases. However in every 1/1000 to 1/20 000 units of homologous blood transfused, there is one case of HIV (Menitove, 1990) and for every 10 000 000 units there are 954 cases of hepatitis B (Korelitz et al., 1997). Consequently any homologous blood transfusion should be avoided if there is a safer alternative, such as the autologous blood transfusion. This may be by autologous predonation, autotransfusion, or isovolaemic haemodilution. In this study autologous transfusion was used with and without preoperative administration of recombinant human erythropoietin (rHuEPO) (Adamson, 1996). rHuEPO is a glycoproteinic hormone produced mainly, although not exclusively, in the

MATERIAL AND METHODS In the Oral and Maxillofacial Surgery Department of the University of Athens, Evangelismos Hospital, 78 consecutive patients – 29 men and 49 women – aged between 18 and 45 years, who were undergoing elective maxillofacial operations participated in the study which was approved by the institutional ethical commitee (Table 1). The subjects were randomly assigned to three groups. Group 1 consisted of 30 patients (10 men and 20 women) who preoperatively underwent autologous predonation followed by intravenous injection of rHuEpo at a dose of 600 IU/kg after each donation. Of these 23 (eight male and 15 female) underwent one unit donation, and seven (two male and six female) underwent two units donations. Group 2 consisted of 28 patients (12 men and 16 women), undergoing autologous predonation without rHuEPO. Of these, 24 (14 male and 10 female) underwent one unit donation and four (two male and two female) underwent two unit donations. Group 3 consisted of 20 patients (seven men and 13 women) who received homologous blood, and served as 118

Autologous blood transfusion using erythropoietin 119 Table 1 – Elective maxillofacial operations Operations

Patients (n)

%

(A) Orthognathic surgery Bimaxillary osteotomies Maxillary osteotomies Mandibular osteotomies (B) Reconstruction of bone deficiency (C) Removal of extensive benign tumour or cysts Total

64 18 12 34 7

82.0 23.1 15.4 43.5 9.0

7 78

9.0 100.0

controls. All patients received 150 mg ferrous sulphate daily by mouth pre-operatively until 1 week postoperatively. The pre- and postoperative haematological testing was the same for all three groups. In addition to that, the controls were needed to formulate a maximum surgical blood-ordering schedule for surgery. This is a schedule of commonly performed surgical procedures coupled with the maximum number of units of blood cross-matched before surgery. In our unit bimaxillary operations to correct orthognathic abnormalities required two units of homologous blood on average. This observation led us to carry out predonation of two units of blood preoperatively in the group 1 and 2 patients who were scheduled for bimaxillary osteotomies. The basic criteria for the selection of patients for autologous blood transfusion were: (A) The surgical procedure to be performed had to belong to one of the three following elective surgery groups: (1) orthognathic surgery; (2) reconstruction after trauma or removal of tumours; or (3) removal of benign tumours or malformations. (B) The anticipated need for blood transfusion not to exceed 4 units. (C) The patient should not fall into one of the exclusion categories such as: haemoglobin 511g/dl, haematocrit 534%, anaemia, age 510 or 465, active malignant tumour, coronary disease, recent myocardial infarction, arterial hypertension (systolic 4180 mmHg, diastolic 4100 mmHg), pregnancy, AIDS, diabetes. The preoperative blood donations from patients of groups 1 and 2 were carried out on the basis of a specific protocol which included:

Table 2 – Number and sex of patients in groups 1 and 2 in relation to the number of predonated blood units Patients (n) Men Women Group I Group II 2 predonations 11 1 predonations 47 Total 58

4 18 26

7 29 43

7 23 37

4 24 32

(B) Donation frequency: the time between two donations was one week. The operation was performed at least one week after the last donation. (C) Haematological testing donor-recipient. Before the first donation the haematologic testing included: blood group, rhesus factor genotype, anti-red blood cell antibodies, HBsAg, VDRL, HIV antibody testing, full blood count, serum proteins, ALAT and AS AT transaminases, as well as aminotransferase of alanine (ALT) for detection of hepatitis, iron and serum ferritin, prothrombin-time, urea and electrolytes. A full blood count followed before the second donation, on the first postoperative day, after one week, and after one month.

RESULTS The patients who participated in the study and underwent autologous transfusion with and without use of erythropoietin, showed no significant change in heart rate, pulse or blood pressure. From the 30 patients in group 1, two women and one man reported dizziness, headache and general weakness that subsided in one hour. None had a significant rise in blood pressure. From 11 patients, four male and seven female, who underwent two donations 22 blood units were collected. From 47 patients, 18 male and 29 female, one blood unit each was collected (Table 2). From the total of 69 blood units that were collected 68 were transfused. One unit that was not transfused came from a patient who underwent two donations. All patients received the blood during the operation. No homologous blood transfusion was needed in any of the patients in group 1 and 2. Statistical analysis

(A) Prerequisites for autologous transfusion: 1. Written consent by the donor/patient and in case of a minor of the parent or guardian. 2. Completion of the donor-form. 3. Haemoglobin not less than 11 g/dl or haematocrit not less than 34%. 4. The patient should not have active infection for which treatment was being given.

Statistical analysis of the changes of haematocrit, haemoglobin and red blood cell values of the patients pre- and postoperatively was performed using the two-way analysis of variance (two-way ANOVA). After performing the ANOVA, the post hoc study of the statistical significance was determined by the Scheffe test. The level of statistical significance was chosen to be 5% in all cases (p50.05).

120 Journal of Cranio-Maxillofacial Surgery Table 3 – Changes of mean Ht between patients of groups 1 and 2 Patients Group 1 (n=30) Group 2 (n=28)

mean (SD) mean (SD) p

Before operation

At operation

1st postoperative day

1st postoperative week

1st postoperative month

40 (4) 37 (4) 0.0015

33 (5) 33 (3) NS

37 (5) 35 (4) NS

39 (4) 38 (3) NS

42 (4) 40 (3) NS

NS=not significant. Table 4 – Changes of mean Hb between patients of groups 1 and 2 Patients Group 1 (n=30) Group 2 (n=28)

mean (SD) mean (SD) p

Before operation

At operation

1st postoperative day

1st postoperative week

1st postoperative month

13.1 (1.5) 12.4 (1.3) 0.02

– – –

12.4 (1.6) 11.8 (1.2) NS

13.1 (1.7) 12.6 (1.2) NS

13.9 (1.7) 13.3 (1.2) NS

NS=not significant. Table 5 – Changes of mean RBC between patients of groups 1 and 2 Patients Group 1 (n=30) Group 2 (n=28)

mean (SD) mean (SD) p

Before operation

At operation

1st postoperative day

1st postoperative week

1st postoperative month

4.6 (0.6) 4.3 (0.3) 0.02

– – –

4.4 (0.6) 4.2 (0.4) NS

4.7 (0.6) 4.4 (0.5) NS

4.9 (0.5) 4.8 (0.4) NS

NS=not significant.

Fig. 1 – Changes of mean haematocrit (Ht) between groups 1 and 2.

Preoperatively all patients who were given erythropoietin (group 1) had statistically significantly increased levels of haematocrit (P=0.0003), haemoglobin (p=0.02) and red blood cell counts (p=0.0003) when compared with those who did not (group 2) (Tables 3–5; Figs 1–3). In the male patients given erythropoietin, haematocrit (p=0.00008), haemoglobin (p=0.003) and red blood cell counts (p=0.00005) levels were both preand postoperatively greater than those who were not given erythropoietin (Group 2) (Ht [p=0.035] Hb [p=0.01] and RBC [p=0.02]); these differences being statistically significant (Figs 4–6). In the female patients there was no statistically significant difference between the two groups (1 and 2).

Preoperatively, the Ht (p=0.035) and the RBC (p=0.0002) levels of the patients of group 3, were higher than those of the patients of groups 1 and 2 as a whole. Postoperatively the Ht (p=0.0032) of the patients in group 1 and 2 as a whole was higher than those of the group 3, one month after the operation, while the Hb (p=0.013, p=0.0006) was higher through the whole of the postoperative period (Figs 7–9). All these differences were statistically significant. DISCUSSION Autologous blood transfusion in elective surgical operations is considered to reduce the risks of

Autologous blood transfusion using erythropoietin 121

Fig. 2 – Changes of mean haemoglobin (Hb) between groups 1 and 2.

Fig. 3 – Changes of mean red blood cells counts (RBC) between groups 1 and 2.

Fig. 4 – Changes of mean Ht between groups 1M and 2M.

homologous transfusion such as haemolytic, allergic or feverish reaction in the recipient due to the presence of antigens in the donor’s blood and the transmission of diseases such as hepatitis B, C, G,

syphilis, cytomegalovirus (CMV) disease, malaria and HIV (Carson et al., 1992; Williamson, 1994; Busch et al., 1996; Loiseau et al., 1997; Tada et al., 1997).

122 Journal of Cranio-Maxillofacial Surgery

Fig. 5 – Changes of mean Hb between groups 1M and 2M.

Fig. 6 – Changes of mean RBC between groups 1M and 2M.

Fig. 7 – Changes of mean Ht between groups 1 and 2 as a total and group 3.

The importance of autologous transfusion is not limited to the prevention of these infections, as it also provides a solution to the serious problem of the lack of adequate blood supply from volunteer donors. This problem has become more severe as now the

number of major operations associated with technical advances in surgery has increased. Another advantage of autologous transfusion is that it enables us to perform operations in patients with rare blood groups or subgroups, where there is

Autologous blood transfusion using erythropoietin 123

Fig. 8 – Changes of mean Hb between groups 1 and 2 as a total and group 3.

Fig. 9 – Changes of mean RBC between groups 1 and 2 as a total and group 3.

greater risk that the transfusion of homologous blood may result in the development of antibodies against the donor’s red cell antigens. Autologous transfusion is a relatively safe method, which should be considered by surgeons in elective cases, as there is little risk that the preoperative donation will result in clinically significant lower Hb, Ht, blood volume and blood cell counts. The initial reduction generally corrects itself in patients with normal bone marrow, who are able in the presence of suplementary iron, by mouth, intravenously or subcutaneously to accelerate the production of red blood cells. They are usually restored to previous levels within 8–10 days after the donation, while the plasma volume returns to the predonation levels in 72 h (Widmann, 1993). The only disadvantage of autologous transfusion is the waiting period between donation and operation. It is now possible to minimize this time with the use of erythropoietin, which stimulates the production of red blood cells and enables us to collect blood every 3 days. Thus, in a relatively short time the requisite number of units of blood can be predonated

(Goudnough et al., 1994a; Beris, 1996a; Gombotz, 1996). Erythropoietin has previously been regarded as necessary when the need for blood is more than 3 units (Beris, 1996b; de Pree et al., 1997). The capacity of erythropoietin to stimulate production of red blood cells reduces the need for homologous transfusion in patients with low haematocrits (Price, 1996). It may be given intravenously or subcutaneously, while the patient receives iron simultaneously by mouth, subcutaneously or intravenously in various dosages (Mollmann et al., 1995; Sans et al., 1996). The preoperative use of erythropoietin has also helped to solve a major problem with Jehovah’s witnesses, who may undergo major operations without homologous transfusion (Polley et al., 1994; Sowade et al., 1995; Chikada et al., 1996; Snook et al., 1996). Most of the patients, 49 out of 58, who were given autologous transfusion with and without use of erythropoietin underwent orthognathic surgery, which constitutes a major part of our elective maxillofacial surgical workload (Ash and Mercuri, 1985). Our experience has shown that in bimaxillary

124 Journal of Cranio-Maxillofacial Surgery

osteotomies there is a need of two units of blood, a conclusion with which several authors agree (Breier et al., 1991; Moenning et al., 1995; and Puelacher et al., 1998). The preoperative combination of erythropoietin with autologous blood transfusion been used in orthopaedic surgery but until now not in the field of elective maxillofacial surgery. Our study presents the implementation and the results of this combination, which is in our opinion today the best way to achieve ideal haematological conditions after the donations, and allows the patient postoperatively to readily return to normal values. It is assumed that the combination of erythropoietin and autologous blood transfusion will be more widely used in the future for elective maxillofacial operations. However, it has a higher cost, not only with erythropoietin being an expensive drug but also the process of autologous blood transfusion has increased costs in comparison with homologous transfusion (Goodnough et al., 1994b). However, if we take into account the cost of hospitalization due to the possible complications of homologous transfusion, we would estimate that one unit of autologous blood plus erythropoietin is no more expensive than the extra cost possibly resulting from an homologous unit. The disadvantage of the autologous method in delaying the operation by the need for presurgical donations, has diminished with the use of erythropoietin, which reduces the time to a minimum. Additionally the elimination of homologous transfusion risks is of great importance.

CONCLUSIONS The use of autologous transfusion in patients who undergo elective maxillofacial operations prevented the need for homologous blood transfusion. The use of erythropoietin in combination with autologous transfusions for patients who underwent elective maxillofacial operations resulted in higher haematocrit, haemoglobin, and red blood cell counts pre- and postoperatively than those patients who had received no erythropoietin. In contrast, postoperative haematocrit, haemoglobin and red blood cell counts in patients who had received homologous transfusion were lower than in both groups who had undergone autologous transfusion.

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Assoc. Prof. Dr. I. A. Iatrou 40, Asklipiou Street 114 71 Athens Greece Tel: +30 1 36 35 034 Fax: +30 1 36 28 544 Paper received 27 October 1999 Accepted 24 January 2001