Discussion
RhEPO is widely recognized to be effective in perioperative autologous
blood donation during TKA (6-11). 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 need for
transfusion, no final consensus has been reached with respect to the
optimal dosing schedule, which has yet to be investigated.
Previous studies have focused on the standard high-dose protocol
(300-600 IU/kg) of rhEPO starting 2-4 weeks before surgery in TJA
patients (10, 17). However, the long-term preoperative dosing schedule
required patients to return to the hospital every week for injections,
which was not only inconvenient to the patients but also increased the
preoperative waiting time and medical costs. In contrast, some
investigators reported that more frequent perioperative application of a
small dose of rhEPO might be more effective. It was reported that high
weekly doses of rhEPO might be considerable wasteful due to limited EPO
receptors on progenitor cells in the bone marrow, which are easily
saturated. When the receptors are saturated, no amount of rhEPO works
until the receptors are free to bind again, but by then, the serum level
of rhEPO has dropped. Therefore, frequent application of a small dose of
rhEPO could maintain a more constant low but more effective serum rhEPO
level (11). Similarly, another study found that repeated multiple doses
of rhEPO were more effective than a single dose in stimulating the
reticulocyte response, even when the total amount of rhEPO was the same
(12). However, even if applied in repeated small doses, there is still
no consensus on many dosing schedules.
In this study, we summarized and compared the main three types of
perioperative rhEPO dosing schedules and found no significant difference
in Hb levels among the three groups until the day after TKA, when
the Hb level in group A was
markedly higher than that in groups B and C (the Hb level in group B was
also significantly higher than that in group C). There was no need for
transfusion in any group. Although the three groups had comparable
intraoperative blood loss, the total blood loss in group A was still the
lowest among the groups (P<0.05), while the total blood loss
in group C was the highest (P<0.05). No treatment-related
adverse events, such as DVT, PE or anaphylactic reaction, occurred
throughout the trial, suggesting that the three dosing schedules of
rhEPO were well tolerated, and no significant differences in other
complication rates were observed among the three groups. Therefore,
recommend initiating the dosing schedule of rhEPO starting from
preoperative day 5.
rhEPO reduces the rate of Hb
decline shortly after application in the postoperative period (9), with
Hb reaching a recovery peak approximately 8-10 days later (18). We found
that patients in group A had markedly higher Hb levels than those in
groups B and C on the day after surgery, with higher Hb levels in group
B than in group C, indicating that the dosing schedule of rhEPO from
preoperative day 5 was better than that from day 3 and the day of
surgery in reducing the rate of Hb decline in the early postoperative
period. When the Hb level reached the lowest concentration on
postoperative day 3, the day of which transfusions mostly occurred (19),
patients in group A also had significantly higher Hb levels than those
in groups B and C, which suggested that the drop in Hb level in group A
was the mildest. The application of rhEPO in group A started 5 days
before surgery, which meant that it was 8 days until postoperative day 3
when the erythropoiesis estimated by rhEPO reached the peak, which was
comparable with prior studies (7). However, it was reported that
patients who suffered a large blood loss in a short time would have a
strong endogenous erythropoietin feedback (20). Another study also
investigated that a linear–logarithmic relationship was found between
the change in Hb level and endogenous erythropoietin feedback, which
meant that the more the Hb dropped, the stronger the endogenous
erythropoietin feedback, even if the effect is small when compared with
the extraerythropoietin (21). Similarly, in this study, on postoperative
day 3, the quick decline in Hb level in group C might be accompanied by
a sharp increase in endogenous erythropoietin feedback, which could
therefore stimulate erythropoiesis quickly, while the decline in Hb
level in group B was not so fast that the exogenous rhEPO in group B
still needed more time to stimulate erythropoiesis and promote the Hb
level after surgery. This may be why the Hb levels between groups B and
C became comparable on postoperative day 3.
Many studies have demonstrated that regardless of which kind of rhEPO
dosing schedule is used, intraoperative blood loss is not influenced (7,
8), which is consistent with our study. In terms of total blood loss, we
calculated the blood loss with the preoperative haematocrit (HCT) and
the HCT tested on postoperative day 3 (19). The trend of HCT was
consistent with the Hb level, so it was not surprising to find that
total blood loss was significantly less in group A than in groups B and
C, which suggested that the application of rhEPO 5 days before surgery
could achieve the least total blood loss. However, the blood loss was
net instead of actual because when losing blood, the body was still
producing blood under the effect of haemopoiesis. Therefore, blood loss
was calculated to compare the blood saving effect of different dosing
schedules of rhEPO. With respect to transfusion requirements, prior
studies all reported the application of rhEPO. In our study, no patients
needed transfusion, which might be mostly due to the effective blood
management in our centre, including the perioperative use of tranexamic
acid (22), the intraoperative controlled hypotension and the application
of rhEPO, leading to little blood loss and an extremely low transfusion
rate.
Reticulocytes are generally released from the marrow 18 to 36 hours
before their final maturation into erythrocytes, and they are regarded
as a real-time assessment of erythropoiesis (20). It was reported that
the blood reticulocyte count peaked 72 hours to day 5 after application
of rhEPO (18). In this study, on preoperative day 1, the reticulocyte
counts in groups A and B were markedly larger than those in group C,
which was consistent with prior studies. We found that on postoperative
day 1, the reticulocyte count in group C did not increase as much as
those in groups A and B in group C, which may be because of the
relatively late application of rhEPO from the day of surgery. However,
on postoperative day 3, the reticulocyte count in group C caught up with
the other two groups. After postoperative day 14, no significant
difference was observed in the reticulocyte count among the three
groups, which suggested that the marrow haematopoietic phase mobilized
by exogenous rhEPO was over.
According to the instructions, rhEPO had the potential effect of
increasing platelet count and blood viscosity, leading to
hypercoagulability, thus increasing the risk of DVT and PE (23, 24). It
was also reported that patients who underwent TJA were at high risk for
developing DVT and PE, which relatively limited the clinical
administration of rhEPO (23, 24). However, in this study, no episodes of
DVT or PE occurred in any patient, which was attributed to not only the
well-tolerated dosing schedules of the three groups but also the good
perioperative thromboembolism prophylaxis in our centre.
However, there are also several limitations in our study. First, the
sample size was calculated according to the decline in Hb level, which
might not be sufficient to identify a significant difference in other
indexes. In addition, we did not record the platelet count or any
quantitative data related to coagulation function, such as D-dimer or
fibrinogen/fibrinogen degradation products (FDPs), so it might be
inaccurate to judge whether different dosing schedules had any influence
on patients’ risk of DVT or PE. Finally, it was reported by prior
studies that the application of rhEPO perioperatively could
significantly increase medical costs (25). However, in this study, we
did not collect health economics indexes.