The primary aim of this study is to evaluate the effect of repetitive low dose rhEPO administered within 21 days in severely thermally injured patients. There are several reasons to believe that repetitive low dose rhEPO will improve wound healing in this patient population without severe adverse events or other grave complications. rhEPO is a well-known drug and has been used for nearly 30 years in daily clinical practice to treat anemia
. Thus the risk/benefit ratio for patients is relatively concrete to estimate, and will be discussed later. In addition the erythropoietic response to EPO is markedly decreased in thermally injured patients
During the last two decades of the 20th century, scientific interest has turned towards treating burned patients with EPO, especially those patients who refuse blood transfusions and blood products due to religious reasons
[35, 36]. Several single-case reports have been published and two trials have been performed on thermally injured patients in intensive burn care units in an attempt to improve erythropoiesis. Both trials failed to show that doses between 300 and 500 IU rhEPO per kilogram of body weight daily for 7 days could significantly reduce the amount of required red blood cell transfusions. No statistically significant differences in hemoglobin, hematocrit, reticulocyte count, ferritin, serum iron, total iron binding capacity or transfusion requirements were found in either study. The effects on wound healing were not within the scope of the studies and therefore not monitored. In patients with burns involving 25% to 35% of total body surface, the reticulocyte counts were statistically significantly higher. In one trial it became evident that iron supplementation needs to be performed in patients receiving 500 IU EPO/kg body weight daily for 7 days to avoid iron depletion. In the other trial, three patients in the rhEPO group suffered venous thrombosis, compared with one patient in the placebo group. No further adverse side effects, possibly related to EPO, were encountered in either trial.
In 2005, an in vitro study showed that the serum of burned mice had elevated EPO levels, and bone marrow cell cultures treated with this serum reacted with increased proliferation rates
The fact that no increase in hemoglobin, hematocrit, reticulocyte or erythrocyte count was found in either study is an especially interesting aspect regarding the treatment of burned patients; besides the well-known fact of decreased EPO efficacy regarding erytropoiesis in inflammation and in trauma situations of the organism, no explanation for this phenomenon has been given so far.
Known complications of EPO treatment are thromboembolic events. A large multi-center trial investigating the safety of EPO administration to poly-traumatized patients demonstrated EPO is safe and beneficial for these patients and that thromboembolic events were reduced to ranges seen in poly-traumatized patients not receiving EPO when combined with an appropriate anti-thrombotic therapy
. As the thromboembolic risk of thermally injured patients is comparable to that of poly-traumatized patients, we conclude that EPO administration in thermally injured patients is safe when combined with an adequate anti-thrombotic prophylaxis as it is done in our trial.
There are two further well-known adverse events related to EPO. The first is the increase in blood pressure in already hypertonic patients
 with the consequence that therapy resistant arterial hypertension is an exclusion criterion of the trial. The second is the unclear situation of EPO in patients with malignant tumors. In several trials it was shown that the mortality rate of EPO-treated groups is higher than for untreated controls
. Therefore, a known malignancy is also an exclusion criterion of the trial.
Age, nutritional status, affected total body surface, gender, concomitant illnesses, inhalation injury or other concomitant trauma, as well as wound infections, have a large influence on the patient’s prognosis, survival rate and wound healing. Therefore we considered all of these factors carefully and discussed their relevance for our primary and secondary endpoints. As we are unable to foresee which patient group will profit most, we consider an exclusion of one of this groups as unethical.
Dermal thermal traumas are commonly seen in two age groups of adults. The first group comprises young adults aged between 18 and 28 and the second group comprises elderly persons aged over 65 years. As we are not able to foresee which of these groups would benefit most from pro-regenerative treatment, we decided to include patients aged 18 to 75 in our study
The nutrition of burns patients is also a very extensively discussed topic, but so far no official guidelines exist and scientific evidence is not satisfactory. Thus we accepted the regulations of the burns centers and their in-house nutrition regimes. The authors expect that this will influence the results and they will consider this very carefully during the evaluation. This is one of the reasons why we have an adjustment for the centers (hospital).
The severity of the injury (affected total body surface and burn degree) has a significant influence on the prognosis of the patient, especially in combination with age and gender. Here again we are unable to foresee which patient group will profit most.
Concomitant illnesses are important factors especially if they interact with EPO. Thus, as stated above, we exclude patients with illnesses such as hypertension, malignant diseases, etc.
Interesting first reports concerning the prevention of burn progression by systemic administration of EPO in a rat model have been given as congress reports. These promising results need further investigation
We hypothesize, therefore, that EPO can protect the epidermis, dermis and its vital structures – especially the capillaries and blood vessels – from further damage, for example, further burn progression. This very often increases the depth of the thermal injury and, therefore, accelerates the problem. EPO has to be administered in a time frame during which its anti-apoptotic action can prevent the increase of the penumbra.
Overall, we expect EPO treatment in thermally injured patients to be safe and beneficial when combined with an adequate anti-thrombotic prophylaxis, as has already been seen for decades in patients with anemia due to renal failure.
In conclusion, we expect that because of the tissue and cell-protective effects (anti-apoptotic, anti-inflammatory, stem cell recruiting and pro-angiogenic) of EPO, its biomimetic effects will be useful in the treatment of acute thermal dermal injuries.