Autologous platelet-rich plasma for treating surgical wounds

  • Protocol
  • Intervention

Authors

  • Maria José Martinez-Zapata,

    Corresponding author
    1. CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Iberoamerican Cochrane Centre. Universitat Autònoma de Barcelona. Institute of Biomedical Research Sant Pau (IIB Sant Pau), Barcelona, Barcelona, Catalonia, Spain
    • Maria José Martinez-Zapata, Iberoamerican Cochrane Centre. Universitat Autònoma de Barcelona. Institute of Biomedical Research Sant Pau (IIB Sant Pau), Barcelona, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Sant Antoni M. Claret 171, Casa de Convalescència, Barcelona, Catalonia, 08041, Spain. mmartinezz@santpau.cat.

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  • Arturo J Martí-Carvajal,

    1. Facultad de Ciencias de la Salud Eugenio Espejo, Centro Cochrane Ecuador, Quito, Ecuador
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  • Ivan Solà,

    1. CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Iberoamerican Cochrane Centre, Institute of Biomedical Research (IIB Sant Pau), Barcelona, Catalunya, Spain
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  • Sergi Bellmunt-Montoya,

    1. Hospital de la Santa Creu i Sant Pau, IBB Sant Pau, Angiology, Vascular and Endovascular Surgery, Barcelona, Spain
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  • Joan Cid,

    1. Hospital Universitari Joan XXIII, Hematology, Tarragona, Spain
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  • Gerard Urrútia

    1. CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Iberoamerican Cochrane Centre - IIB Sant Pau, Barcelona, Spain
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the efficacy and safety of autologous PRP compared to placebo, standard treatment, and  alternative treatments such as plasma poor in platelets, laser (common in plastic surgery) or biomaterials (e.g. acellular xenogeneic dermal matrix or Keratinocyte suspension; Appendix 1), for surgical wounds.

Background

Description of the condition

A wound is an interruption of the integrity and continuity of the structures that comprise a tissue or organ, and may affect only the epidermis or go through deeper structures such as the dermis, subcutaneous tissue, fascia and even muscle and bone (Enoch 2008). These injuries usually result from external causes and surgical wounds are among the most common (Appendix 1). One study has estimated that 234 million major surgical procedures are undertaken every year worldwide (Weiser 2008).

Most surgical wounds are closed by primary intention (wound edges brought together and closed at time of surgery), but they can close by secondary intention (wound left open after surgery and allowed to heal with scar tissue replacing the tissue defect) or tertiary intention (wound left open after surgery, but later wound edges brought together and wound closed, also called delayed primary closure) (Sussman 2007).

The usual process of wound healing, including the healing of surgical wounds, takes place in four phases that subtly overlap: haemostasis (Appendix 1), inflammation, cell multiplication or proliferation, and remodeling of the new tissue to preserve the initial structure (Nguyen 2009). Damage to the blood vessels causes blood loss at the wound bed. Platelets aggregate along the cells of the injured vascular wall (endothelial cells) and release substances to form a clot rich in fibrin that fosters early wound closing (Appendix 1). Platelets that store various growth factor proteins, such as  platelet-derived growth factor (PDGF), epidermal growth factor, vascular endothelial growth factor, and transforming growth factor beta (TGF), are called alpha granules. These growth factors are needed to promote the inflammatory and proliferative phases of wound healing. PDGF initiates the movement to the wound of inflammatory cells such as neutrophils and macrophages that act phagocytically to engulf bacteria and damaged tissue. PDF and TGF also stimulate other reparative cells such as fibroblasts and endothelial cells. Once debris has been removed, fibroblasts and endothelial cells start the proliferative phase. During the remodeling phase, excess matrix materials are removed, collagen fibres are cross-linked, and the wound contracts. Since platelets contain 100 times greater concentrations of many of the proteins liberated during the healing process than other tissues, they can be considered to be the  true activators of wound healing.  

Several factors can delay wound healing. Some are unchangeable, such as age and chronic systemic (whole body) conditions such as diabetes, ischaemia (lack of oxygen), infection or tissue necrosis (tissue death) (Menke 2007). In elective surgery, the risk of infection is mainly conditioned by the local environment of the site of incision. Depending on the incision site and the risk of infection, surgical wounds are classified as clean (class I), clean-contaminated (class II), contaminated (class III), dirty-infected (class IV), or unclassified (Berard 1964; Garner 1986; Simmons 1982) (see Table 1). Clean surgical procedures have lower infection rates than those classified as dirty, where infection rates can be above 30% (McLaws 2000). The Centers for Disease Control and Prevention (CDC) classified surgical site infection (SSI) as superficial incisional (skin and subcutaneous tissue), deep incisional (muscle and fascia) and organ/space (Horan 1992). The Coello 2005 study showed that the incidence of SSI in 140 English hospitals was 4.2%, and that superficial incisional SSI accounted for more than half of all SSIs. The cost attributable to SSI ranged from GBP 959 to GBP 6103 per patient (Coello 2005). Other studies have estimated an attributable mortality to SSI that ranges from 0.64% (Martone 1998), to 0.9% (Astagneau 2001). It is, therefore, clear that measures are needed to shorten healing time and facilitate the healing of the surgical wound.

Table 1. Classification of surgical wounds

Clean wound

  • Uninfected operative wounds

  • Non-traumatic

  • No inflammation is encountered

  • Respiratory, alimentary, genital or uninfected urinary tracts are not entered

  • Primarily closed

Clean-contaminated wound

  • Respiratory, alimentary, genital or urinary tract is entered under controlled conditions

  • Without unusual contamination

  • No evidence of infection

  • Non-traumatic wound with minor break in technique

Contaminated wound

  • Fresh traumatic wound from clean source

  • Operative wound with a major break in technique

  • Gross spillage from the gastrointestinal tract

  • Entrance into the genito-urinary or biliary tracts

  • When infected urine or bile is present

  • Incision encountering acute non-purulent inflammation

Dirty wound

  • Traumatic wound from dirty source

  • Traumatic wound with delayed treatment

  • Faecal contamination

  • Foreign body

  • Retained devitalized tissue

  • Operative wound with acute bacterial inflammation or perforated viscus

  • Operative wound where clean tissue is transected to gain access to a collection of pus

Description of the intervention

Although there is a physiological platelet response to tissue injury, several techniques have been proposed to increase  the number of platelets reaching the wound site in order to accelerate the healing process. One of these techniques is the use of autologous platelet-rich plasma (PRP) (Appendix 1). Autologous PRP is a product that contains a high concentration of platelets and is derived from the patient´s own fresh whole blood. The quantity of blood needed depends upon  the area of the wound, and can range from 55 mL to 450 mL of whole blood in order to obtain between 5 mL and 50 mL of PRP (Khalafi 2008; Powell 2001). It has been postulated that the optimal concentration of PRP platelet count is 1 million/µL (Marx 2004). Preparation of PRP takes about 15 to 20 minutes and is usually done during surgery (Khalafi 2008).

There is no consensus about the use of a specific procedure to obtain a high concentrate of platelets or PRP. However, the procedure used to obtain platelets from the blood affects their volume and concentrates (O'Neill 2001). High concentrates of platelets are obtained with the use of apheresis devices that remove platelets from the blood (O'Neill 2001; Zimmermann 2008). The most common technique involves the use of a centrifuge to separate a concentrate of platelets from a blood sample obtained from the patient. The centrifuge speed and the number of times the blood is centrifuged can influence the final concentrate of platelets (O'Neill 2001). Several centrifuge device systems are available on the market, such as Plateltex®, PRGF®, Curasan®, PCCS®, Harvest®, Vivostat®, Regen® and Fibrinet®; there is little difference between them in relation to the platelet concentrate obtained (Leitner 2006; Mazzuco 2008; Schaaf 2008).

Once the platelet concentrate is obtained, its biologically-active content needs to be released. There are two methods for this: the first is to add thrombin or calcium, which activates platelet-release of the growth factors, to form platelet releasate (Appendix 1). The second approach is to induce physical lysis (breakdown) of the platelets, producing lysate (Appendix 1) by freezing (Weed 2004), or other methods, such as ultrasound (non-audible sound waves), that disrupt cell membranes and release cellular contents (Stacey 2000). The final product is applied locally to the wound as a gel or a solution.

The ease with which the autologous PRP can be obtained and its potential efficacy may make it cheaper than other options such as the recombinant human platelet-derived growth factors. One study showed PRP gel was cost-effective compared with other therapies for non-healing diabetic foot ulcers. The average five-year direct wound care costs per patient were USD 15,159 for patients treated with PRP gel compared to USD 40,073 for standard care, and USD 47,252 for those receiving recombinant human platelet-derived growth factor BB (Dougherty 2008). We did not find any studies about the cost of PRP in treating surgical  wounds.

How the intervention might work

PRP is used to stimulate the regeneration of damaged tissue and accelerate the process of healing. It contains fibrin (Appendix 1) and high concentrations of growth factors that promote and accelerate both healing (Marlovits 2004), and tissue regeneration (Knighton 1988; Munirah 2007; Robinson 1993).

PRP could be useful in surgical wounds that are at risk of delayed healing and are difficult to cure adequately. PRP could accelerate the healing, shorten the hospital stay and reduce health costs. Shortening healing is important in complex interventions such as coronary bypass, where the surgery is traumatic (Khalafi 2008), or in wounds that heal by secondary intention, such as pilonidal abscesses (Spiridakis 2009). In other surgeries, such as plastic surgery, PRP could improve integrity of the tissue and minimize scarring (Powell 2001). For this reason, PRP is an emerging treatment in tissue engineering and cellular therapy (Bertoldi 2009). Autologous PRP has the added advantage that it poses a low, or null, risk of transmissible diseases or immune reactions.

Why it is important to do this review

The use of autologous PRP is increasing in surgical interventions. It is, therefore, important to examine the research evidence behind this technology thoroughly to determine risks and benefits. Many  clinical trials are currently assessing PRP treatment. Most are conducted in the field of traumatology - in bone, muscle and tendon injuries - but others are also underway in other surgical pathologies such as pilonidal abscesses.

Two Cochrane systematic reviews (one assessing PRP in orthopaedic surgery for long bone healing (Griffin 2012), and one evaluating maxillofacial surgery for augmentation procedures of the maxillary sinus (Esposito 2010)), and a recently published meta-analysis assessing  PRP for orthopaedic indications (Sheth 2012), revealed uncertainty about the efficacy of PRP. This uncertainty calls the increasing use of PRP into question. In another (non-Cochrane) systematic review that assessed PRP in patients with chronic and acute cutaneous wounds in a small number of primary studies, the percentage of wound infection and pain scores decreased in PRP-treated acute wounds, but the result was not statistically significant (Carter 2011). Carter 2011 focused only in studies that assessed PRP produced by a process of platelet activation (with thrombin or calcium), but it excluded studies that used other methods to obtain PRP like physical lyses of the platelets. Our inclusion criteria differ of the Carter 2011 because we will include studies that assess autologous PRP produced by any techniques in patient with surgical wounds. We will exclude studies in orthopaedic or maxillary surgery to avoid overlap with existing Cochrane systematic reviews.

Objectives

To determine the efficacy and safety of autologous PRP compared to placebo, standard treatment, and  alternative treatments such as plasma poor in platelets, laser (common in plastic surgery) or biomaterials (e.g. acellular xenogeneic dermal matrix or Keratinocyte suspension; Appendix 1), for surgical wounds.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) that assess efficacy and safety of autologous PRP compared to placebo, standard  treatment, or alternative treatments for surgical wounds.

Types of participants

We plan to consider trials that include people of any age with surgical wounds, defined as an incision in the skin produced by a surgeon to cure a determined pathology. Specifically, we will include people with surgical wounds resulting from general surgical procedures, gynaecological surgery, neurosurgery, urological, endocrine or plastic surgery, and cardiovascular surgery. We will include all wound classes (clean (class I), clean-contaminated (class II), contaminated (class III), dirty-infected (class IV), and unclassified) (Berard 1964; Garner 1986; Simmons 1982) (see Table 1).

We will exclude people undergoing surgical procedures that affect bones (e.g. odontology, maxillofacial, orthopaedic surgery) to avoid overlap with two Cochrane systematic reviews, one assessing PRP for long bone healing, and the other assessing PRP in maxillofacial pathology.

Types of interventions

To be included in the review, eligible studies will have to compare autologous PRP with placebo, standard care, or alternative topical therapies such as plasma poor in platelets, laser (common in plastic surgery) or biomaterials (e.g. acellular xenogeneic dermal matrix). If PRP is given in combination with another treatment, the study will be only be included if this other treatment is implemented in all groups. 

Autologous PRP can be obtained by any technique or method that liberates growth factors from platelets. Autologous PRP can be applied locally as a gel, or as a solution, and for any length of time.

Types of outcome measures

Primary outcomes
  • Time to complete wound healing.

  • Adverse events related to interventions, such as an allergic reaction, measured at one week in wounds that cure by primary intention and at 30 days in wounds that cure by secondary and tertiary intention.

Secondary outcomes
  • Complete surgical wound closure at seven days in wounds that cure by primary intention and at 30 days in wounds that cure by secondary and tertiary intention.

  • Complications of the wound at any time during follow-up, e.g. infection or wound dehiscence.

  • Any recurrence during follow-up, e.g. fistulas.   

  • Pain at 24 hours and one week after surgery, measured by a validated scale such as the visual analogue scale (VAS).

  • Quality of life at seven days in wounds that cure by primary intention and at 30 days in wounds that cure by secondary and tertiary intention, as measured by a validated scale such as SF36 or SF12.

  • Cost of interventions at one year postsurgery.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases to identify reports of relevant randomised clinical trials: 

  • The Cochrane Wounds Group Specialised Register.

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue).

  • Ovid MEDLINE (1946 to present).

  • Ovid EMBASE (1974 to present).

  • EBSCO CINAHL (1982 to present).

  • LILACS (1982 to present).

We will use the following provisional search strategy in the Cochrane Central Register of Controlled Trials (CENTRAL):

#1 MeSH descriptor Platelet-Derived Growth Factor explode all trees
#2 ((platelet-derived NEXT growth NEXT factor*) or PDGF):ti,ab,kw
#3 MeSH descriptor Platelet-Rich Plasma explode all trees
#4 ((platelet NEXT rich NEXT plasma) or (platelet-rich NEXT plasma) or PRP or (platelet NEXT gel*)):ti,ab,kw
#5 MeSH descriptor Blood Platelets explode all trees
#6 MeSH descriptor Platelet Activation explode all trees
#7 (platelet* NEXT activat*):ti,ab,kw
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 MeSH descriptor Surgical Wound Infection explode all trees
#10 MeSH descriptor Surgical Wound Dehiscence explode all trees
#11 (surg* NEAR/5 infect*):ti,ab,kw
#12 (surg* NEAR/5 wound*):ti,ab,kw
#13 (surg* NEAR/5 site*):ti,ab,kw
#14 (surg* NEAR/5 incision*):ti,ab,kw
#15 (surg* NEAR/5 dehisc*):ti,ab,kw
#16 (wound* NEAR/5 dehisc*):ti,ab,kw
#17 (wound NEXT complication*):ti,ab,kw
#18 (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17)
#19 (#8 AND #18)

We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2012). We will not restrict studies with respect to language, date of publication or study setting.

We will search the following clinical trials registries:

Searching other resources

We will check the reference lists of all the trials identified by the above methods. We will contact study authors for additional information when necessary.

Data collection and analysis

We will summarise data using standard Cochrane Collaboration methodologies (Higgins 2011a).

Selection of studies

Each reference identified by the search will be independently assessed by two review authors. One review author (Mª José Martínez Zapata (MMZ)) will assess all the references. Three other review authors (Arturo Martí Carvajal (AMC), Joan Cid (JC), or Sergi Bellmunt (SB)) will each assess a third of the references. Any discrepancies will be resolved by discussion among all members of the review team.

Data extraction and management

Two review authors (MMZ and either AMC, JC, or SB) will independently extract details of studies and record this using a data extraction sheet. If data are missing from reports, or if clarification is needed, attempts will be made to contact the trial authors to obtain missing information. Data from studies published in duplicate will be included only once. Data extraction will be undertaken independently by two review authors. Any discrepancies will be resolved by discussion.

The following data will be extracted from the studies following the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

  • study identification

  • inclusion criteria

  • exclusion criteria

  • study design

  • total duration of study

  • risk of bias: explanations concerning the generation of the randomisation sequence, and concealment of randomisation, participants, outcome assessors, and researchers

  • participant loss to follow-up

  • total number of participants and number allocated to each intervention group

  • sex

  • age (mean or range)

  • setting

  • diagnostic criteria

  • country

  • type of surgery

  • description of experimental intervention: technique used to produce PRP, dose or volume of PRP administered, concentration of platelets in PRP

  • description of control intervention

  • description of co-intervention(s)

  • outcomes of interest: for dichotomous data number of participants with the outcome of interest and number total of participants in each group; means and standard deviations (SDs) for continuous data; estimate of effect with confidence interval, P value

  • type of analysis: intention-to-treat or per protocol

  • other: funding source

Assessment of risk of bias in included studies

Two review authors (MMZ and either AMC, Ivan Solà (IS), or Gerard Urrutia (GU)), will independently assess the risk of bias of the eligible trials.

We will base our assessment on the risk of bias guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). We will examine: the adequacy of the method used to generate the allocation sequence, the method of allocation concealment, the level of blinding (clinician, participant, or outcome assessor), incomplete outcome data, and selective reporting. We will also evaluate whether an intention-to-treat analysis was performed on the data reported in the published trial.

Each domain will be classified as being at high, unclear, or low risk of bias. We will describe the reason for each judgment from details provided in the trial reports or from data sought and provided by the original trial authors. A trial will be considered to be at overall low risk of bias when judged to be at low risk for allocation concealment, generation of the randomisation sequence, blinding of clinicians, participants, and outcome assessors, and incomplete outcome data (as a minimum requirement). If one or more risk of bias criteria are at high risk of bias, the trial will be considered to be at overall high risk of bias. If one or more of the criteria are unclear, the trial will be considered to be 'unclear' with respect to risk of bias (Higgins 2011c).

Measures of treatment effect

For binary outcome measures (proportion of wounds completely healed, adverse events), we will calculate the risk ratio (RR). For continuous outcomes (pain and quality of life), we will record mean difference and standard deviation (SD) for each group. If different measures (for example, different scales for quality of life) are used, we will calculate a pooled estimate of treatment effect using standard mean differences (SMD). Time to wound healing will be analysed as survival (time to event) data, using generic inverse variance to calculate the hazard ratio (HR). We will calculate 95% confidence intervals (95% CI) for all measures.

For cross-over studies, we will only collect and analyse the data from the first period of treatment.

Unit of analysis issues

The unit of analysis will be the participant randomised in the included trials. A single measurement for each outcome from each participant will be collected and analysed.

Studies that presented results of multiple ulcers on a participant will be included in the analysis calculating the effective sample size as per the guidance in the Cochrane Handbook (Higgins 2011d). We will considered an intracluster correlation coefficient of 0.05 based on published data (Scriven 1998; Vas 2008). Studies where the participant is his or her own control will be included if the assignment to treatment has been randomized.

Dealing with missing data

We will contact trial authors to obtain additional information if required.

Assessment of heterogeneity

We will assess statistical heterogeneity using the Chi² test (we will consider a P value significance level of less than 0.1 to indicate heterogeneity). We will consider the I² statistic which examines the percentage of total variation across studies due to heterogeneity rather than to chance. Values of I² over 50% may represent substantial heterogeneity (Higgins 2011e). We will investigate possible causes by exploring the impact of participants' characteristics and the methodological quality of the studies.

Assessment of reporting biases

We will also attempt to assess whether the review is subject to publication bias by using a funnel plot to illustrate variability between trials graphically. If asymmetry is detected, causes other than publication bias will be explored (selective outcome reporting, poor methodological quality in smaller studies, true heterogeneity) (Sterne 2011).

Data synthesis

If the eligible trials are sufficiently comparable, in the absence of clinical heterogeneity, we will perform a meta-analysis using a fixed-effects model. Where there is likely clinical heterogeneity, we will apply a random-effects model. If there are doubts about the similarity of participant characteristics, or the methods used to measure the outcomes, we will consider carefully whether it is appropriate to pool data.

We will include trials with any number of comparative groups. However, we will only pool data that assess the same comparison. For cross-over trials, we will include data from the first period, that is, before the cross-over. We plan to present data about 'time to complete healing' using (log) hazard ratios (HR) and 95% CI. Only trials that report HR or data that we can use for the meta-analysis will be included in the analysis  of 'time to complete healing' .

We will consider other effect measures such as risk ratio (RR) for dichotomous variables and mean differences (MD) for continuous variables. If the trials provide only standard  errors and not standard deviations, we will calculate the standard deviations following the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (sections 7.7.3.2 and 7.7.3.3; Higgins 2011c). If the continuous variables in the studies are measured by different scales, we will calculate the SMD. We will also calculate the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH).

We will use the statistical package RevMan provided by The Cochrane Collaboration (Revman 2011).

Trial sequential analysis

Trial sequential analysis (TSA) is a group sequential analysis used in single trials that may be applied to meta-analysis (Wetterslev 2008). TSA is a tool for quantifying the statistical reliability of data in a cumulative meta-analysis adjusting P values for repetitive testing on accumulating data.TSA could be conducted on the binary and continuous outcomes (Thorlund 2009; Wetterslev 2008).

Meta-analysis may result in type I errors due to sparse data, or due to repeated significance testing when updating meta-analysis with new trials (Higgins 2011f; Wetterslev 2008).

In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries are applied to decide whether a trial could be terminated early because a sufficiently small P value, that is the cumulative Z-curve, crosses the monitoring boundaries (Lan 1983). In TSA, the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to clarify whether additional trials are needed. Sequential monitoring boundaries can also be applied to meta-analysis, called trial sequential monitoring boundaries (Wetterslev 2008).The idea in TSA is that if the cumulative Z-curve crosses the boundary, a sufficient level of evidence is reached and no further trials may be needed. If the Z-curve does not cross the boundary then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries the required information size is needed and is calculated as the least number of participants needed in a well-powered single trial (Wetterslev 2008).

We will apply TSA since it prevents an increase in the risk of type I error (less than 5%) due to potential multiple updating in a cumulative meta-analysis, and it will provide important information to estimate the level of evidence of the experimental intervention. Additionally, TSA will provide the required sample size for a future clinical trial. Based on our meta-analysis results, we will calculate the information size required to demonstrate or reject an a priori anticipated PRP effect of 10% relative risk reduction (RRR) with an alpha of 5% and a beta of 20% (CTV 2011; Thorlund 2011).

We will perform a TSA based on the results obtained from 'complete surgical wound closure' and 'complications of the wound'.

Summary of findings

We will use the principles of the GRADE system to assess the quality of the body of evidence associated with the main outcomes and we will construct a 'Summary of findings' (SoF) table using the GRADE profiler software (GRADEpro 2008). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the quality of a body of evidence considers within study risk of bias, the directness of the evidence, heterogeneity in the data, precision of effect estimates, and risk of publication bias (Shünemann 2011)

Two review authors (MMZ, and either AMC, or SB) will independently assess the quality of the eligible trials. We will assess the following outcomes:

  • Time to wound healing.

  • Complete surgical wound closure.

  • Complications of the wound.

  • Safety of interventions.

Subgroup analysis and investigation of heterogeneity

We will conduct a subgroup analyses of the following points because we anticipate these will be sources of clinical heterogeneity:

  • the type of wound (I, II, III, IV or uncertain classification) (Table 1; Berard 1964);

  • variations in treatment regimens to obtain plasma rich in platelets and platelet growth factors, e.g. platelet lysate versus platelet releasate (Appendix 1);

  • the intention of wound closure (primary, secondary or tertiary);

  • the type of surgery (elective versus non-elective);

  • the age of participants (less than 18 years old versus 18 years or older) if there are trials which randomise participants according to age or if there are trials conducted in adult populations; compared with participants less than 18 years old.

Sensitivity analysis

If sufficient trials are identified, we plan to conduct a sensitivity analysis of the principal outcomes, excluding RCTs with overall high risk of bias (that is high risk of bias in at least two domains).

Acknowledgements

The authors would like to acknowledge the contribution of the peer referees (Dirk Ubbink, Ruth Foxlee, Fiona Paton, Gill Worthy, John McCall, Daniel Casey, Madhu Periasamy, and Dayanithee Chetty) for their comments on the protocol, Elizabeth Royle, copy editor and Sally Bell-Syer for her assistance in the process of the protocol development.

Appendices

Appendix 1. Glossary

Apheresis is a procedure in which blood is drawn from a donor and separated into its components; some of these components - such as plasma or platelets -  are retained and the remainder are returned by transfusion to the donor.
Biomaterial is a natural or synthetic substance used in medicine and introduced into the body  to support or replace a natural function.
Fibrin is a fibrous non-globular protein involved in the clotting of blood.
Haemostasis is a process that causes bleeding to stop.
Lysate refers to the breaking down of a cell.
Platelet lysate refers to the breaking down of the platelet membrane by physical methods such as freezing or sonication.
Platelet releasate refers to activation of the platelet by chemical methods using  thrombin or calcium to liberate the contents.
Synonyms of autologous platelet-rich plasma (PRP): Autologous platelet gel, autologous plasma-rich growth factors (PRGFs), autologous platelet concentrate.
Surgical wounds are breaks in any body tissue due to an external action by the surgeon.

Contributions of authors

MMZ wrote the first draft of protocol with the support of AMC, SB and JC.
All authors contributed to improve the draft, respond to the peer referee feedback and approved the final version of the protocol.

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content.
Kurinchy Gurusamy, Editor: approved the final protocol prior to submission.
Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol.
Ruth Foxlee: designed the search strategy and edited the search methods section.

Declarations of interest

In 2004, Arturo Martí-Carvajal was employed by Eli Lilly to run a four-hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review.
In 2007, Arturo Martí-Carvajal was employed by Merck to run a four-hour workshop on 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review.
Gerard Urrutia has received honoraria for educational activites (workshops) from several laboratories.

The other authors have no conflicts of interest.

Sources of support

Internal sources

  • Iberoamerican Cochrane Center (Barcelona). CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.

External sources

  • NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

Ancillary