European Definitions, Current Use and Use of EMA Platelet-Rich Plasma (PRP) in Sports Medicine
Analysis of European regulations allows us to draw the following conclusions regarding the use of blood products for topical use, although they come from the same directive:
• There is a general European principle on which blood components can be used after checking the national authorities responsible for transfusion activities.
• In Italy the policy does not allow exceptions and blood components (considered as blood products) for topical use are always the responsibility of the Blood Transfusion Service, regardless of the amount, type and protocol handling of clinical use.
• In other European countries, in some cases blood components are considered blood products or in other cases a medicine. However, depending on the amount, processing and clinical protocol, they may be used in a less restrictive manner under physician control in some cases. Unlike in Italy, physicians will submit the protocol to the regulatory authorities of each country, under the physician's control and responsibility, to seek advice on how to use certain blood components and to determine whether authorization is required or whether treatment can be considered an action to be taken freely under the law.
• This lack of homogeneity in the European legal environment for the management of product from whole blood processing is likely to lead the Community legislature to intervene in the near future to equalize the “rules of engagement” for this particular class of biomaterial. PRP technologies are offered to European clinicians because of the CE marking, but European countries treat the use of these devices differently. For example, while in Italy the manipulation of blood is always the responsibility of the Blood Transfusion Service, and in other countries, some protocol-based procedures used by the doctor can only be delegated to individual physicians through an authorization (which may vary depending on usage, amount of blood, preparation system, etc.). Outpatient use is possible under the direct responsibility of the physician. There is a general rule in the European country setting, but the "legal" way of use in each country is protocol dependent and so regulation becomes heterogeneous and often complex, sometimes requiring special authorization or the need of other clinicians. Like transfusion services, the surgeon must be involved in the process steps. These requirements make it difficult for clinicians in some countries to use PRP in their surgical and clinical practice. It will be beneficial for a device to work in the same way in terms of processing features/standards for all countries that accept the CE mark, simplifying and preferring the use of PRP. There is a huge difference between using a blood product like a therapeutic platelet infusion to treat thrombocytopenia and using PRP for bone grafting procedures or using PRP to treat something like osteoarthritis or tendonitis. Therefore, as reflected in the recent EMA/CAT June 2014 reflection paper, it is desirable that this historical moment's "drug-centric" European regulatory trend for biological products should lead to a homogeneous regulatory framework to simplify and support the use of PRP.
Study design and endpoints
All data were collected and analyzed prospectively for this regular and haphazard patient group. Readmissions, sternal wound infections, and costs were independently evaluated and verified by the hospital infection committee and the finance office. All patients with sternotomy cases were included in this evaluation.
Definitions
A diagnosis of deep wound infection was made in all patients with one or more of the following findings:
1) Positive mediastinal tissue culture or fluid
2) Clinical finding of mediastinitis during sternal operation
3) Chest pain, sternal imbalance, purulent discharge from the mediastinum with positive blood culture
Standard sternal wound closure
The entire sternotomy operation area was opened with a sternal saw blade. Postoperatively, the sternum was closed with 8 cut stainless wires. The wounds were closed with a stratified absorbable suture. The wounds were covered externally with sterile strips, gauze and paper tape. All surgeons at our institute actively participated in this study and were included in the wound closure procedure.
Preparation and application of platelet rich plasma (PRP)In the treatment application, 52 ml of blood was drawn from the central vein and mixed with 8 ml of citrate (anticoagulant). 60 ml of anticoagulant blood was processed with Magellan Autologous Platelet separation system. This PRP system is FDA approved and is only used to prepare PRP, and the price of 1 kit is $385. Platelet separation took 15 minutes without supervision. From this application, approximately 6 ml of rich PRP was prepared to be applied to the soft tissue and sternum during sternal wound closure. Analysis of growth factors in plasma content is shown in Table 2. Prepared PRP was mixed with 1 ml of calcium chloride and thrombin in 6 ml of plasma and applied to deep chest wounds and soft tissues during wound closure. PRP application time took 30 seconds in total.
Platelet Analysis
Platelet counts and growth factors were analyzed before and after centrifugation. PDGF platelet-derived growth factor, TGF transforming growth factor, VEGF vascular endothelial growth factor, FGF fibroblast growth factor, EGF endothelial growth factor.
Cost analysis
The costs of disposable consumables were also included in the cost of PRP. These are real PRP costs, not hospital expenses. These costs were also confirmed by the hospital room service director, the vendor, and the hospital finance department. Likewise, hospitalization and retreatment costs were approved by the same department. No separate cost was reflected for the 30-second PRP application. Likewise, the 30 seconds needed to draw blood from the intravenous line were not taken into account, only preoperative chemistry was included in the laboratory procedures.
Statistical Analysis
All patients undergoing open cardiovascular surgery between January 2005 and January 2013 were enrolled in this study. For the PRP applied group, patient treatment costs and treatment results were analyzed using Fisher's test. In addition, the clinical and cost benefits of the patients who were treated were calculated. Mean ± SD Basal (60 mL) PRP (mL) PDGF AB (ng/mL) 8.4 ± 2.1 96.1 ± 22.5 PDGF AA (ng/mL) 2.1 ± 0.4 25.4 ± 3.9 PDGF BB (ng/mL) 5.9 ± 1.2 61.3 ± 11.6 TGF B1 (ng/mL) 46.4 ± 4.4 278.2 ± 38.4 VEGF (ng/mL) 76.3 ± 19.5 801 ± 266.1 bFGF (ng/mL) 15.6 ± 2.9 55.1 ± 9.6 EGF (ng/mL) 13.4 ± 2.1 187 ± 29.4 Ethics, volunteerism and permissions: all clinical studies with human content are carried out taking into account the ethical standards published by the national research committee and the 1964 Helsinki declaration and later publications.
Results
Two thousand consecutive patients completed this study. Of these, 1000 patients were those who received PRP application (PRP group), and the other 1000 patients were those who did not see PRP (Control Group). There were significant differences between the two groups in some respects, for example, age and body area were lower in the control group, heart transplant, emergency cases and blood transfusion use were higher in the PRP group. Compared with the control group, the use of PRP reduced deep wound infections from 2% to 0.6%, superficial wound infections from 8% to 2%, and hospital readmission and retreatment from 4% to 0.8%. Analysis of the time to infection after surgery showed that; Infections in the PRP group occurred within the first 2 months, while in the control group, the infection rate extended up to 4 months later (Fig. 1). Similarly, significant decreases were observed in treatment costs, while the costs in the Control Group for deep and superficial wound infections were 1,256,960 dollars, while it was 593,791 dollars in the PRP group (Table 3). Despite this reduction in sternal wound healing costs, the number of patients who needed the desired benefit was 71 people (confidence interval 41.8-244.5) with a 95% rate, and the money spent for 1 sternal deep wound infection was $27,000. However, the number of patients expected to heal superficial wounds was 95% (confidence interval 12.7-24.3) and the cost for 1 superficial infection was $6417. In total, the number of patients with expected recovery was 14 with a confidence interval of 10.5-18.9, with a 95% rate, and 5203 dollars were spent for 1 infection.
Table 3 Results
Evaluation
In most cardiovascular surgery, median sternotomy is the shortest way to reach the heart. However, deep central wound infection (DSWI) is a vital complication. Minimizing the formation of deep wound infection after the operation is of great importance for patients, caregivers, hospitals and payers. With the developments in surgical debridement, continuous antibiotic irrigation, modern wound closure methods have reduced the deep wound infection mortality rate for the last 30 years, but there has been no serious change in sternal wound complications since the 1980s. As a result, it is inevitable that the main goal is to prevent deep wound infections. There are various treatment approaches in this direction; such as closing the sternum more tightly, using more sutures. However, their contribution is limited. There are also several risk models used to predict the incidence of sternal wounds, but these estimates cannot prevent infections. The autologous PRP method to prevent deep wound infections has proven itself with very clear clinical data. The effect of growth factors in PRP on the rapid healing of the wound after median sternotomy is known. During inflammatory tissue healing, activated platelet cells secrete beneficial growth factors such as transforming BF, vascular endothelial BF, and endothelial BF (Table 2). These growth factors trigger cell proliferation, cell migration, cell differentiation and matrix synthesis. The same growth factors also positively affect chondrocyte metabolism, chondrogeny and bone strength [8]. This combination of growth factors in PRP activates and accelerates the healing mechanism in the wound. PRP is used extensively in many areas such as plastic, maxillofacial and orthopedic surgery to accelerate tissue healing [8, 18]. In addition, staphylococcus aureus, bacteria that cause deep wound infections, are inhibited by PRP administration [19]. Some studies have also shown that PRP applied to wounds in cardiac surgery produces different and mixed results [20–23]. Although these studies were properly designed and performed, they were insufficient to assess post-use effects due to the small number of patient enrollments. Previous studies have reported that different growth factor ratios were obtained with different preparation methods of PRP [24]. At the same time, positive results of antibiotic administration in addition to PRP have been revealed, but it has not been clinically proven how much and to what extent PRP increases the effect [25]. Just like the PRP Kit used in this application, the use of a disposable, closed and sterile PRP Kit is important both in terms of platelet concentration to be obtained and in terms of giving the same result, and it eliminates the risk of air contamination. This is the first major clinical study to include all patients entering a median sternotomy case and independent of emergencies, heart transplant cases, ventricular device implantation cases, dialysis, steroid use, emphysema, and reoperation cases. Despite the reports by the Society of Thoracic Surgeons that the rate of deep wound infections was reduced to 0.3%, this is not the case in sternotomy cases. Most of the patients in this report are intended for patients undergoing bypass surgery or isolated valve surgeries. Also, many clinical studies, unlike ours, do not consider the 6-month postoperative period. However, many infections begin to occur 30 days after surgery, which reveals the inadequacy of such studies. In addition, the number of sutures used in wound closure has no effect on wound healing. In addition, no complications were encountered in any patient in whom PRP was used. This study also showed that all infections in the PRP group occurred only within the first 2 months, while infection was observed in the control group even after 4 months. Although it was not observed during the study, it was understood from this study that PRP plays an active role in the early diagnosis and rapid elimination of the infection case. The economic analysis of PRP in sternal wounds is very interesting, because if you prevent even one deep wound infection with PRP, it will save you from a great economic loss, because the cost for one deep wound infection is much more expensive than 1 PRP application. Calculation of the number of patients (NNT) requiring PRP and the benefit to be obtained are effective only in deep wounds and their combinations. Because the cost of superficial wound treatment is lower than the cost of PRP application. If NNT was 17 instead of 3.5 for superficial wound infections, PRP application would be cheaper. This study had some limitations as the patients were not randomly selected from multiple centers. However, due to the high number of patients in the study, it is clear that cardiovascular surgery gives clear and verifiable results in terms of both cost and treatability. Complications related to wound infection were also evaluated by different healthcare professionals, such as nurses, physical therapists, plastic surgeons, and cardiologists, who had no previous experience with PRP. This has eliminated the prejudice that may arise from the evaluation of the same disease by the same people all the time. Patients were not considered as part of this study and all patients undergoing cardiovascular surgery were included in the study. However, a study group of 2,000 patients, including surgeons and their attendants, was included in the complete evaluation, allowing patients undergoing cardiac surgery to be evaluated in real hospital conditions without any extra precautions. Cost analysis was likewise performed and verified by independent hospital and financial analysts unrelated to this study. Medicaid and Medicare services center do not reimburse the treatment costs of deep wound infections that exceed the limits.
Result
In conclusion, this study showed that regular use of PRP reduced the incidence of deep and superficial infections by 7.41%, taking into account the overall cost benefits. For the 2000 patients included in this study, PRP application at the time of wound closure during the surgical operation was reported to be both safe and reducing the risk of post-surgical infection. PRP is a reliable, simple and easy-to-prepare therapy that provides both clinical and financial benefits for the patient undergoing open heart surgery. PRP applied at the time of wound closure after open heart surgery has created added value both in accelerating the treatment and in reducing the costs.
Release permission
The necessary permissions for the publication of this study were obtained from the relevant institution. Declaration
Thanks
Utah Eğitim ve Arşt., who contributed to this study and contributed to financial and cost analysis. Special thanks to Kathy Adamson, hospital director, Shirley Noon, director of the Society of Thoracic Surgeons for database support, and our nurses, anesthesiologists and perfusionists for their care of our cardiovascular patients and their contribution to cost validation, Dr. Many thanks to Richard Nelson.
Funding
The costs of this study were covered by the State of Ohio- 3rd Frontier Fund. Open Access This article is published with Creative Commons Attribution permission.
International Bachelor(http://creativecommons.org/licenses/by/4.0/) In case this work is published, this license link must also be present.