Traumatic brain injury (TBI) is an insult to the brain structure caused by external force and resulting in a physiological disruption of usual brain function.1,2 Globally, 60% of all TBIs occur as a result of a road traffic accident. In 2016, the World Health Organization reported that road traffic accidents were among the top 10 leading causes of death, resulting in 1.4 million fatalities, 75% of which were male.3 The highest incidence of road traffic accidents is found in Latin America and Sub-Saharan Africa, at 150-170/100,100 people, which is higher than the global rate of 106/100,000.3 Within the United Kingdom, TBIs are the most common cause of death and disabilities for people under the age of 40. Around 1.4 million people present to emergency departments with head injuries each year in the United Kingdom. Of those, 200,000 are admitted to hospital for further treatment and one-fifth have evidence of skull fractures and/or brain damage.2
Following the initial brain injury, further damage can occur, known as the secondary injury. The secondary injury arises due to hypoxia, edema and increased intracranial pressures, which subsequently leads to cellular and neuron death.4 Unlike the primary injury, which cannot respond to medical interventions, secondary injuries can.5 A secondary injury can occur within minutes or up to days after the initial injury and the duration is variable.5
Symptoms experienced by patients vary in accordance with the severity of the injury. In mild TBI, symptoms such as headaches, confusion and fatigue can occur. These are often more pronounced in patients with moderate and severe TBI. In severe TBI, the aforementioned symptoms deteriorate, alongside others such as seizure activity, vomiting and personality changes, which significantly impact the patient's quality of life.6
The mechanisms behind the secondary injury will dictate the patient's ability to survive following a TBI. The process of the secondary injury is multifactorial, resulting in changes at molecular, cellular and pathophysiological levels.1,7 The severity of this secondary injury will affect the level and possibility of functional recovery, and impacts long-term recovery.6
One of the main causes of the secondary injury is a significant increase in production of free radicals, which cause damage known as oxidative stress.8 Mitochondria are responsible for energy production imperative for cellular survival and maintaining normal cell function. During energy production, mitochondria produce free radicals, which are usually scavenged by the available antioxidants in the body. Following injury to the brain, the damage caused to the mitochondrial structure results in increased permeability, energy depletion and negatively impacts energy production.8 Altered cell metabolism and upregulation of inflammatory activity exhausts the antioxidant system. Reactive oxygen species (ROS) levels are elevated post TBI, which alters the usual equilibrium between antioxidant defense and free radicals, resulting in oxidative stress and, ultimately, mitochondrial death.9,10
Antioxidants are thought to combat oxidative stress following TBI by altering the imbalance between antioxidants and free radicals, inhibiting ROS formation, which prevents further mitochondrial damage.6,10 Coenzyme Q10 (CoQ10) is a naturally occurring antioxidant known to protect neuronal cells from oxidative stress; the mechanism for this has been examined in studies using rat models. Mitochondria produce ubiquinol (the reduced form of CoQ10) from the oxidized form of CoQ10 known as ubiquinone. Mitochondrial damage can disrupt ubiquinone production and the ability to produce ubiquinol, which leads to reduced energy production and increased oxidative stress.7 Considerable research has been conducted on the role of CoQ10 in other medical conditions such as heart failure,11 hypertension,11 metabolic syndrome12 and Parkinson's disease.13 A small study trialed intravenous administration of ubiquinone at 450-580 mg/day to patients with congestive heart failure and found improved left ventricular function and an overall clinical improvement.14
At present, studies exploring the role of CoQ10 specifically in patients with TBI are limited. Animal studies of CoQ10 supplementation have shown favorable results.7,15 In vitro, ubiquinol decreases ROS production, reducing mitochondrial dysfunction and improving energy production, eventually inhibiting cell necrosis.16 A systematic review of TBI and antioxidant therapy by Shen et al.6 found six human randomized controlled trials that met the criteria for the use of antioxidants, steroids, vitamins, dietary supplements and cannabinoids in TBI. The synthesized findings suggested that pharmacological antioxidant agents resulted in better recovery, improved cognition and reduced mortality when compared to a placebo.6 No meta-analysis was conducted due to the heterogeneity of the antioxidant therapies, limited patient numbers and range in severity of the TBI. The review highlighted a lack of ROS measures to inform the effectiveness of the antioxidants administered.6
In April 2017, a preliminary search into CoQ10 supplementation in TBI was conducted in PubMed, EBSCO, PROSPERO and JBI Database of Systematic Reviews and Implementation Reports. No systematic reviews were identified specific to CoQ10, and most experimental trials were animal studies and discussion papers exploring the mechanisms around antioxidant use in TBI.
A scoping review is required to map the available evidence (regardless of methodological quality) of CoQ10 use in TBI and to identify gaps in the literature to guide future research.17 Using JBI methodology to conduct a scoping review, the reviewers will use guidelines originally devised by Arksey and O’Malley18 but will follow the updated framework by Peters et al.19 as recommended in the JBI Reviewer's Manual.19 Scoping reviews have become increasingly popular with researchers; a scoping review conducted by Tricco et al.20 found that with increased popularity came variance in reporting and conducting the review.20 For the purpose of this scoping review, reviewers will follow the JBI framework.19
This scoping review will explore the available published and unpublished literature on the role of CoQ10 supplementation in TBI. Mapping the literature will inform the reader about gaps in knowledge and inform future research.17 In addition, the limitations to methodological quality and study populations within the available literature will be identified and discussed.21 The review aims to highlight what is known about CoQ10 supplementation (particularly with focus on reducing oxidative stress) in TBI. In addition, the review aims to inform researchers about dose, frequency, duration of supplementation and route of administration. These are important clinical factors that would benefit future study designs and methodologies when exploring the impact of CoQ10 in TBI.
Does CoQ10 supplementation have a role in reducing oxidative stress in humans after TBI? The sub-question is: Does CoQ10 supplementation have a therapeutic role in reducing oxidative stress in animals after TBI?
The current scoping review will include both human and animal subjects who have experienced TBI of any severity in the acute/laboratory-controlled setting, as this is where the secondary injury presents. Animal studies will be included due to their predominance in available literature; however, the reviewers will report on animal and human studies separately to ensure reader clarity. Non-traumatic acquired brain injuries such as stroke, subarachnoid hemorrhage, ischemia and tumors will be excluded as these are irrelevant to the research question. Other clinical conditions such as Parkinson's disease, cardiac arrest, trauma, fertility issues, obesity and other forms of head injuries will also be excluded.
The scoping review will extract dose, frequency, duration of use and route of administration of CoQ10 as these are important factors to consider in both human and animal subjects. CoQ10 supplementation will be extracted, regardless of dose, frequency, duration of use and route of administration.
Subjects from any healthcare setting (such as rehabilitation centers and acute hospitals) will be included as long as the severity of TBI is recorded and CoQ10 is supplemented. It is expected that most of the papers included will be from the hospital setting as this is often where secondary injury onset occurs and interventions are started. A controlled laboratory setting will also be included when selecting papers with animal subjects.
Types of sources
This scoping review will consider both experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before and after studies, and interrupted time-series studies. In addition, analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies will be considered for inclusion. This review will also consider descriptive observational study designs including case series, individual case reports and descriptive cross-sectional studies for inclusion, if these papers meet the objectives of the review. Animal studies will be included but presented separately to human studies. In addition, systematic reviews that meet the inclusion criteria will also be considered. Text and opinion papers will also be considered for inclusion in this scoping review. It is pertinent when extracting data from these studies that information on route, dose, frequency and duration of CoQ10 is recorded.
Studies published in English will be included; non-English papers will be excluded as no funding is available for an interpreter.19 Where possible, if non-English papers have provided an English abstract, authors will be contacted if the paper meets inclusion criteria. From the preliminary search, most studies were published since 1990. Yet, due to such small numbers of CoQ10 TBI papers, and in accordance with the JBI scoping review guidelines, no date restriction has been set.19
The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews.19 The scoping review allows for sub-questions, where reporting on animal and human subjects is important, to scope the sphere of evidence around CoQ10 use in TBI.19
The search strategy aims to locate both published and unpublished studies. An initial limited search of MEDLINE and CINAHL has been undertaken on the topic, followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe these articles. This informed the development of a search strategy, which will be tailored for each information source.
As there are many differing terms for CoQ10, papers will be included if subjects are supplemented with ubiquinol, ubiqinone, co-enzyme Q 10, coenzyme Q10 or CoQ10.
The chemical formula for CoQ10 will also be included in the search: C59H90O4.
A full search strategy for MEDLINE is detailed in Appendix I. The reference list of all studies selected for review will be screened for additional studies.
Search methods include: electronic sources, searching trial registries and a search of the reference lists of all included papers. The search will be conducted using a three-step search strategy. The initial search will use MEDLINE and Embase, as these are the most appropriate databases, given the scientific focus to the research question. The reviewers accept that limiting database searches can reduce overall sensitivity of the scoping review. A list of key terms used to describe the articles will be produced to inform the secondary search phase using all identified databases.
Electronic searches will include the following bibliographic databases:
- Cochrane Library via Wiley (including the Cochrane Central Register of Controlled Trials: CENTRAL) and the JBI Database of Systematic Reviews and Implementation Reports
- MEDLINE via HDAS (1946 to present)
- Embase via HDAS (1974 to present)
- CINAHL via EBSCOhost (1944 to present)
Additionally, a search of the trial registries will be conducted, including: ClinicalTrials.gov, International Prospective Register of Systematic Reviews (PROSPERO) and US National Institute of Health. The search for unpublished studies will include: ProQuest Dissertations and Theses, Scopus, OpenGrey and Google Scholar/Google.
Following the search, all identified citations will be collated and uploaded into Rayyan (Qatar Computing Research Institute, Doha, Qatar) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that meet or could potentially meet the inclusion criteria will be retrieved in full and their details imported into JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI) (Joanna Briggs Institute, Adelaide, Australia). The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full-text studies that do not meet the inclusion criteria will be excluded, and reasons for exclusion will be provided in an appendix in the final scoping review report. The results of the search will be reported in full in the final report and presented in the form of the PRISMA flow diagram.22 Any disagreements that arise between the reviewers will be resolved through discussion or with help from a third reviewer.
Data will be extracted from papers included in the scoping review by two independent reviewers using the standardized data extraction tool from JBI SUMARI. The data extracted will include specific details about the population, concept, context, study methods and key findings. Within the remit of this scoping review, human/animal centred outcomes are appropriate to collect, survival being the most objective. Biochemical markers (pertaining to oxidative stress) will be collated, for both human and animal subjects. Data will be extracted about the route of CoQ10 supplementation, the frequency and duration of use and the dose administered. A draft charting table is provided (see Appendix II). The draft data extraction tool will be modified and revised as necessary during the process of extracting data from each included study, in line with JBI recommendations and using the Arksey and O’Malley18 framework.23 The charting table will be piloted using three papers, not specific to the research question, to ensure reviewers are familiar with using the table, and for the purpose of making modifications, if necessary. Modifications will be detailed in the full scoping review report. Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.
The extracted data will be presented in diagrammatic or tabular form in a manner that aligns with the objective of this scoping review. The tables and charts will report on numbers of animal and human studies included and discuss the route, dose, duration and frequency of CoQ10 administration. It is important to specify the severity of the TBI, as this will inform the readers about what is known in relation to the research questions and help influence future studies. Any additional data found to be relevant to the research objective will be diagrammatically presented in the report. Based on the PRISMA flow diagram, the process of inclusion and rationale for exclusion will be clearly presented.22 A narrative summary will accompany the tabulated and/or charted results and will describe how the results relate to the review objective and question.
Data extraction will be clearly detailed to justify the inclusion of each source and how it supports the evidence around CoQ10 and TBI. The results will indicate the number of human and animal studies relevant to the scoping review questions and explore the methodologies used, primarily focusing on human subjects and secondarily on animal subjects. It is important to map these findings to demonstrate what work has been done and what methods were used, with the view to informing future work.
The Discussion section will provide a commentary on the results of the review and identify any limitations of the sources included in the review. Although no critical appraisal is required for the scoping review, discussing the limitations within the scoping review process is essential, promoting transparency.23 To conclude, the reviewers will summarize the results and relate this to the research questions and objectives.
The recommendations for research will be specific to the research questions, such as oxidative stress and CoQ10 dose, frequency, route and duration, and future primary research around the role of CoQ10 and TBI. It is difficult to make recommendations to clinical practice from the results of a scoping review as there is no critical appraisal of papers included and there is no grading of the methodology.19
This scoping review will contribute toward the completion of a Masters in Clinical Research for author KA undertaken at The University of Plymouth Centre for Innovations in Health and Social Care: a Joanna Briggs Institute Centre of Excellence.
The authors would like to acknowledge the National Institute for Health Research (NIHR) for providing funding to KA to undertake the Masters in Clinical Research.
Appendix I: Search strategy for MEDLINE
MEDLINE was used to preliminary search CoQ10 and TBI. MEDLINE Thesaurus was used to define the search terms.
Appendix II: Draft data extraction instrument
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