There is general agreement of the effective function of rhEPO in reducing transfusion requirements and accelerating the recovery of Hb level after THA (5–10). Despite the common application of rhEPO in total joint arthroplasty during the last decade, with benefits including attenuated Hb drop, decreased blood loss, and reduced transfusion requirement, no final consensus has been reached with respect to the optimal regimen, which is yet to be investigated.
Prior studies mostly focused on the application of rhEPO in TJA patients started from 2–4 weeks before surgery and each dose were large (300–600 IU/kg), and the protocol was generally accepted as the standard regimen (9, 16, 17). However, the long-term of preoperative treatment requested the patients to come back to hospital weekly for injections, which would not only cause inconvenience to the patients but also increase the preoperative waiting interval. Contrary to the studies supporting the long-term and high-dose protocol, some investigators reported that more frequent perioperative application of small-dose rhEPO could be more efficacious. Cody et al (10) suggested that weekly high dose of rhEPO may be wasted for the limited erythropoietin receptors on progenitor cells in marrow which is easy to be saturated. When the receptors are saturated, no amount of rhEPO is effective until the receptors are again free for binding, but by then, the level of serum rhEPO would drop. So, frequent application of small-dose rhEPO could maintain a more constant low but more effective level of serum rhEPO. Similarly, Cheung et al (11) found that repeated application of rhEPO is more effective in stimulating the reticulocyte response than the single dose even if the total amount of rhEPO given to patients are the same. However, even if being applied in frequent small-dose, the rhEPO still has many regimens without a consensus.
In this study, we summarized and compared the main three types of perioperative rhEPO regimens, and found: Hb levels in the three groups didn’t show difference until the postoperative day one, when the Hb level in group A was significantly higher than in group B and C, in the meantime, Hb level in group B was also markedly higher than in group C. In terms of transfusion requirement, no difference in either transfusion rates or amounts was found among all the three regimens even if the intraoperative and total blood loss in group A was markedly less than those in group B and C, but no significant difference was found between group B and C. Few treatment-related adverse events occurred perioperatively, indicating the three regimens of rhEPO in this study were generally well tolerated, and no markedly difference in complication rates were observed among the three groups. So, we finally recommended the regimen of rhEPO started from 5 days preoperatively.
Primary Outcomes
Hb levels
It was reported that rhEPO could exert its effect of attenuating postoperative Hb drop soon after administration (8), and the Hb peaked on approximately 8–10 days subsequently (18). In this study, on postoperative day 1, patients in group A showed significantly higher Hb level than those in group B and C, the Hb level in group B was also markedly higher than group C, which indicated that the application of rhEPO started from 5 days preoperatively was better than 3 days and the day of surgery. On postoperative day 3, when the Hb was the lowest during the postoperative period of THA and the transfusion also happened most likely in this period (19), patients in group A showed significantly higher Hb level than those in group B and C, which also indicated the Hb drop of group A was the least. The application of rhEPO in group A started 5 days before surgery which means that it has been 8 days till 3 days postoperatively when the erythropoiesis estimated by the rhEPO reached the peak, which is coincident with the prior studies. However, it was reported by Goodnough et al (20) that for patients subjected to a relatively large amount of blood loss, the endogenous erythropoietin response would be very substantial. Besides, in one clinical trial conducted by Goodnough et al (21), a linear–logarithmic relationship was demonstrated between change in Hb level and endogenous erythropoietin response, which meant that the more Hb drop, the stronger the endogenous erythropoietin response was, even if the effect is small. In this study, comparing postoperative day 1 and 3, the Hb level between group B and C became comparable. It was the sharp drop of Hb in group C that led to a sharp increase of the endogenous erythropoietin response, which could therefore stimulate erythropoiesis quickly, while the drop of Hb level in group B was not so large that the exogenous rhEPO in group B still needed more time to stimulate erythropoiesis and promote the Hb level after surgery.
Blood loss and transfusion
It was reported that no matter under which kind of rhEPO regimen, the intraoperative blood loss would not be decreased: Kourtzis et al (7) applied rhEPO from preoperative 5 days and recorded the comparable intraoperative blood loss between study and control group. Similarly, Cao et al (6) recorded the intraoperative blood loss between two rhEPO regimens, one started from 3 days preoperatively and the other one from the day of surgery, and they found comparable intraoperative blood loss between the two groups. The trials above all indicated that the intraoperative blood loss is a parameter that has nothing to do with the application of rhEPO, which was also coincident with our study. In terms of total blood loss, we calculated the blood loss with the hematocrit (HCT) tested preoperatively and 3 days postoperatively (19). The trend of HCT was consistent with the Hb level, and the trend of Hb levels in the three groups were presented above, so, it was not surprise to find that total blood loss was significantly less in group A than those in group B and C, which suggested that the application of rhEPO 5 days before surgery could achieve the least total blood loss.
With respect to transfusion requirements, prior studies all reported that application of rhEPO, no matter under which regimen, would decrease the requirement of allogeneic transfusion (5–10, 16, 17). However, in this study, only 2 patients in each group received allogeneic transfusion of 2 units of red blood cells. The very low transfusion requirements might due to the relatively little blood loss of patients in our center. The perioperative use of tranexamic acid (22), the intraoperative controlled hypotension as well as the application of rhEPO combined with ferralia all accounted for the little blood loss and the low transfusion rate.
Secondary Outcomes
Reticulocyte count
Because reticulocytes are normally released from the marrow 18 to 36 hours before their final maturation into erythrocytes, they provide a real-time assessment of the functional state of erythropoiesis (20). Ait-Oudhia et al (18) discovered that blood reticulocyte count peaked on 72hr to day 5 after application of rhEPO. In this study, on the day before surgery, the reticulocyte count in group A and B were markedly larger than in group C, which was consistent with the prior studies. In group C, however, the application of rhEPO started from the day of surgery which was relatively late. So, we found that on postoperative day one the reticulocyte count in group C didn’t increase as much as those in group A and B. However, on postoperative day 3 the reticulocyte count in group C caught up with the other two groups and finally on postoperative day 14 and 21, no markedly difference was observed in reticulocyte count among the three groups, indicating that the marrow hematopoietic phase mobilized by perioperative application of rhEPO was over.
Complications
In theory, rhEPO could cause increased platelet count, enhanced blood viscosity, leading to hypercoagulability, thus increasing the risk of thrombosis (23, 24). Some investigators reported that patients after THA and TKA are naturally at high risk for developing DVT and the application of rhEPO might increase such risk, which limited the application of rhEPO to some extent (23, 24). However, in this study, no case of DVT were found in all the three groups. Only a few cases of asymptomatic IMVT were observed without markedly difference among groups. It was reported that no significant correlation was found between the incidence of postoperative PE and IMVT, and no special treatment to postoperative IMVT was needed (25). Besides, the three regimens of erythropoietin in this study were generally well tolerated, with few treatment-related adverse events such as nausea, pyrexia and headache and no difference were found in rates of different adverse events among three groups. Most patients were satisfied with the treatment they received during the whole hospitalization and follow-up phases.
Limitation and advantage
Although this study was carefully designed, several limitations still exist. First, the sample size was calculated according to the change in Hb level, which would be therefore not sufficient to identify a significant difference in other parameters like the transfusion rates and different complication rates. Second, we did not record the platelet count or the indexes related to coagulation such as D-dimer or Fibrin/Fibrinogen Degradation Products (FDP), so it might be inaccurate to judge that the three different regimens of rhEPO had no difference in the influence on patients’ risk of DVT by simply recorded the rates of DVT or IMVT. The comparable rates of DVT among the three groups might also partly due to the anticoagulant therapy implemented in this study which has been proven to be efficacious and safe in our previous study (12). Finally, it was reported by prior studies that the application of rhEPO perioperatively could significantly increase the medical costs (26). However, in this study, we did not collect data with respect to the costs or conduct the cost-effective analysis.