The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review

Gögenur et al. Critical Care (2017) 21:14 DOI 10.1186/s13054-016-1578-9 RESEARCH Open Access The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review Mikail Gögenur*, Jakob Burcharth and Ismail Gögenur Abstract Background: Cell-free DNA has been proposed as a means of predicting complications among severely injured patients. The purpose of this systematic review was to assess whether cell-free DNA was useful as a prognostic biomarker for outcomes in trauma patients in the intensive care unit. Methods: We searched Pubmed, Embase, Scopus and the Cochrane Central Register for Controlled Trials and reference lists of relevant articles for studies that assessed the prognostic value of cell-free DNA detection in trauma patients in the intensive care unit. Outcomes of interest included survival, posttraumatic complications and severity of trauma. Due to considerable heterogeneity between the included studies, a checklist was formed to assess quality of cell-free DNA measurement. Results: A total of 14 observational studies, including 904 patients, were eligible for analysis. Ten studies were designed as prospective cohort studies; three studies included selected patients from a cohort while one study was of a retrospective design. We found a significant correlation between higher values of cell-free DNA and higher mortality. This significant correlation was evident as early as on intensive care unit admission. Likewise, cell-free DNA predicted the severity of trauma and posttraumatic complications in a majority of patients. Conclusion: The amount of cell-free DNA can function as a prognostic tool for mortality and to a lesser extent severity of trauma and posttraumatic complications. Standardizing cell-free DNA measurement is paramount to ensure further research in cell-free DNA as a prognostic tool. Keywords: cfDNA, mtDNA, nDNA, Trauma, Intensive care unit Background In recent years cell-free DNA (cfDNA) has become increasingly used as a clinical and noninvasive biomarker in the fields of cancer [1–3], pre-natal diagnostics [4], organ transplantation [5], and in several emergency conditions [6–8]. cfDNA, defined as extracellular DNA circulating freely in the blood, can be further subcategorized to circulating mitochondrial DNA (mtDNA) and circulating nuclear DNA (nDNA). Within cancer research, cfDNA has been proposed to have the ability to act as a noninvasive biopsy of the tumor (i.e., liquid-biopsy) [9] and * Correspondence: Center for Surgical Science, Department of Gastrointestinal Surgery, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark as a prognostic marker for clinical outcomes such as disease burden [3], progression-free survival [10], and overall survival [11]. In patients admitted to an intensive care unit (ICU) as a result of trauma, cfDNA has received increasing attention under the hypothesis that cfDNA originates from cell death [12, 13] and could correlate with the severity of trauma with prognostic and predictive abilities. Preliminary reports have confirmed that the amount of cfDNA correlates inversely to mortality [14], trauma severity [15], and post-traumatic complications [16]. Due to the short half-life of cfDNA [17], it is suitable as a marker of the patient’s condition in the immediate emergency phase. mtDNA has also been increasingly investigated in © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gögenur et al. Critical Care (2017) 21:14 trauma patients in recent years and it has been argued that mtDNA could be considered a damageassociated molecular pattern (DAMP). It is well established that circulating DAMPs lead to an increase in the innate immune response [18], possible leading to a systematic inflammatory response syndrome (SIRS) [19]. The use of cfDNA as a predictive marker of clinical outcome have not been systematically analyzed. The aim of this study was to review the literature on cfDNA as a predictive marker of clinical outcomes as measured in trauma patients in ICUs. Methods This systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [20]. Eligibility criteria The inclusion criteria for studies in this review were cohort human studies that investigated levels of cfDNA in plasma or serum in trauma patients aged ≥18 years in the ICU. Trauma was defined as all grades of trauma ranging from minor to severe trauma, including isolated traumatic brain injury (TBI) that resulted in ICU admission. Studies exclusively evaluating circulating RNA as well as studies conducted outside the ICUs were excluded. A thorough assessment of the quality of DNA sampling and processing was conducted for all included studies using previous definitions [21] (see Additional file 1). We included studies that analyzed DNA by specific sequencing (beta-globin, GAPDH, NADH dehydrogenase) or fluorescent methods. We only included published studies and only studies published in the English language. Study search A computerized comprehensive search strategy was conducted using four databases (PubMed, EMBASE, SCOPUS, and the Cochrane Central Register for Controlled Trials) from January 1974 to January 2016. The search was performed on 20 January 2016. The following literature search was used in PubMed: “(circulating cell free dna) OR cfdna) OR circulating nucleic acids) OR cell free mitochondrial DNA) OR nDNA) AND (injury) OR trauma) OR stress) OR surgery) OR intensive care unit) OR perioperative) OR postoperative) OR intraoperative) OR preoperative)”. The literature search was adapted from the PubMed literature search to EMBASE, SCOPUS, and the Cochrane Central Register for Controlled Trials. We supplemented the structured literature search with searching of the reference lists from the included articles in order to find additional eligible studies. Page 2 of 10 Study selection The Cochrane systematic review tool Covidence.org was used in the screening process. Two reviewers (MG and JB) independently screened titles and abstracts until the full-text articles were found. Two authors (MG and JB) independently assessed the full-text articles. Whenever different opinions emerged a third author (IG) was included in the discussion until consensus was reached. Data collection and data items All included articles were assessed for the following informati (...truncated)