Title: The ORiF (Operative Rib Fixation) Procedure mEchanisms of Rib fixAtion (OPERA) STUDY
Funder: Medical Research Council

Abstract: Background_x000D_ Broken ribs are a serious injury affecting both young and older people. They are usually caused by a serious accident, like a car crash. They cause pain and difficulties in breathing. Both pain and loss of oxygen (hypoxia) cause a response in the body resulting in an excess of inflammation. When patients can’t breathe deeply or cough they are more likely to get a chest infection. Our bodies normally release chemicals into our blood to fight infection or heal injuries. When the levels of these chemicals are too high it can cause organ failure or death. This is called “systemic inflammatory response syndrome” (SIRS) and is common in severely injured patients. Some patients also lose a large amount of muscle and these patients seem more likely to die. However, people with broken ribs can get surgery and we are doing a study to show that they are less likely to die. Is that because they get less of the inflammatory chemical imbalance?_x000D_ _x000D_ A research study (called ORiF) is studying the potential benefit of performing surgery for broken ribs. As part of a new project called OPERA Study, we want to collect blood and stool samples from 212 injured patients from the ORiF study. We will use these samples to measure the levels of chemical imbalances after broken ribs and see if the effect of reducing pain and hypoxia from surgery reduces inflammation as well._x000D_ _x000D_ Research aims_x000D_ We want to understand what molecules are altered when surgery is done to fix a person’s broken ribs so they don’t become seriously unwell or die. We will identify who develops a chemical imbalance after broken ribs, and who does better after surgery._x000D_ _x000D_ We want to answer 4 questions that will help us treat future patients:_x000D_ 1) Does surgery reduce the inflammatory chemical imbalances?_x000D_ 2) Do some people benefit from surgery more than others?_x000D_ 3) Where should we focus future research to develop new related treatments to increase the benefit of surgery?_x000D_ 4) How well do biological and patient characteristics predict recovery after surgery?_x000D_ _x000D_ Study design_x000D_ This embedded study will use biological data, and data from the ORiF trial. We will measure substances produced by blood cells during healing and muscle loss. We will take blood samples to measure chemical markers. We will look at scans performed during the care of these patients to assess their muscles and also measure the types of bacteria present within the gut and a substance produced by harmful bacteria to measure leakiness to know if bacteria are moving from the gut. We will compare these between operated and unoperated people with rib fractures. _x000D_ Statistical modelling will also show us which of the things we have measured are important, and how they may affect patients’ recovery. This will allow us to better understand where we can target new treatments to go with surgery._x000D_ _x000D_ Patient and public involvement_x000D_ We designed the study with the help of 15 patients who had surgery after a serious injury or broken_x000D_ ribs. They all thought the design was acceptable to patients and that the research question was important. They were keen that doctors looked at the patient as a whole. They felt the study may allow future patients to have access to more personalised information, which they don’t currently receive._x000D_ _x000D_ Dissemination_x000D_ The study results will be published in medical journals, presented at scientific conferences and shared with the public via press releases and articles.

Lay abstract: Research question_x000D_ Do the anticipated inflammatory pathway effects account for mechanisms of action of rib fixation in patients with multiple traumatic rib fractures. Specifically do they influence recovery and clinical outcomes, and do patient characteristics modulate these processes, enabling more stratified and improved clinical care? _x000D_ _x000D_ Background_x000D_ The NIHR HTA programme funded "The Operative Rib Fixation” (ORiF) Study" provides the opportunity to assess mechanisms of action affecting recovery following severe traumatic rib fracture injury and surgical treatment. Appropriate surgery is known to improve outcomes, but can also worsen prognosis. Several interacting underlying mechanisms contribute to the variation in recovery and efficacy of surgery in the setting of a severely injured patient and need evaluating._x000D_ _x000D_ Aims and objectives_x000D_ Aim To inform patient care by assessing whether the patient pro-inflammatory responsiveness to injury and patient characteristics, impact upon the proposed inflammatory pathway mechanisms of action of rib fixation for severely injured patients with traumatic rib fractures._x000D_ _x000D_ Objectives _x000D_ 1. To assess if the efficacy of rib fixation surgery is through modulation of patient pro-inflammatory responses by reducing pain mediated catecholamine responses, and by reducing hypoxia through improved ventilation thereby resulting in a lower risk of atelectasis. These effects will be measured by: _x000D_ a. Assessing if the patient’s inflammatory response is altered by rib fixation;_x000D_ b. Quantifying the effect of rib fixation on the patient’s gut bacterial microbiome and on secondary sepsis and systemic inflammatory response syndrome (SIRS); _x000D_ c. Establishing if higher diaphragmatic and costovertebral muscle strength contributes to improved ventilation, and increased sarcopenic decline or lower baseline muscle strength results in higher breathlessness, hypoxemia/hypoxia and inflammation._x000D_ 2. To assess treatment pathway mechanisms by assessing if the proposed patient stratification and treatment pathway modifiers affect the efficacy of rib fixation;_x000D_ 3. To identify biological targets, responsible for the mechanisms of action of rib fixation surgery, for potential ancillary treatment to optimise the efficacy of rib fixation surgery._x000D_ 4. To explore the prognostic value of the findings by undertaking prediction modelling of recovery using both treatment pathway and biological factors to quantify how predictive the hypothesised mechanisms involved in the efficacy of rib fixation are. _x000D_ _x000D_ Methods: The ORiF Procedure mEchanisms of Rib fixAtion (OPERA) will utilise data from 2 sources: 1) The ORiF trial cohort (n=532 including body composition); 2) Additional blood and faecal samples in a subset of ORiF participants (n=212) to collect mechanism biomarkers (inflammatory and gut microbiome). The main outcome is complication free recovery. Statistical analyses for the different objectives include mixed modelling, mediation analysis, and prognostic modelling.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.4 SURGERY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INJURIES AND ACCIDENTS;MUSCULOSKELETAL