Mitochondrial dysfunction in platelets from severe trauma patients - A prospective case-control study.

INTRODUCTION: Trauma-induced coagulopathy (TIC) refers to an abnormal coagulation process, an imbalance between coagulation and fibrinolysis due to several pathological factors, such as haemorrhage and tissue injury. Platelet activation and subsequent clot formation are associated with mitochondrial activity, suggesting a possible role for mitochondria in TIC. Comprehensive studies of mitochondrial dysfunction in platelets from severe trauma patients have not yet been performed. METHODS: In this prospective case-control study, patients with severe trauma (ISS≥16) had venous blood samples taken at arrival to the Emergency Unit of a Level 1 Trauma Centre. Mitochondrial functional measurements (Oxygraph-2k, Oroboros) were performed to determine oxygen consumption in different respiratory states, the H2O2 production and extramitochondrial Ca2+ movements. In addition, standard laboratory and coagulation tests, viscoelastometry (ClotPro) and aggregometry (Multiplate) were performed. Measurements data were compared with age and sex matched healthy control patients. RESULTS: Severe trauma patients (n = 113) with a median age of 38 years (IQR, 20-51), a median ISS of 28 (IQR, 20-48) met our inclusion criteria. Oxidative phosphorylation in platelet mitochondria from severe trauma patients significantly decreased compared to controls (34.7 ± 8.8 pmol/s/mL vs. 48.0 ± 19.7 pmol/s/mL). The mitochondrial H2O2 production significantly increased and greater endogenous Ca2+ release was found in the polytrauma group. Consistent with these results, clotting time (CT) increased while maximum clot firmness (MCF) decreased with the EX-test and FIB-test in severe trauma samples. Multiplate aggregometry showed significantly decreased ADP-test (38 ± 12 AUC vs. 112 ± 14 AUC) and ASPI test (78 ± 22 AUC vs. 84 ± 28 AUC) also tended to decrease in mitochondria of polytrauma patients as compared with controls. Significant strong correlation has been demonstrated between mitochondrial OxPhos and MCF while it was negatively correlated with ISS (R2=0.448, P˂0.05), INR, CT and lactate level of patients. CONCLUSIONS: The present study revealed that severe trauma is associated with platelet mitochondrial dysfunction resulting in reduced ATP synthesis and impaired extramitochondrial Ca2+ movement. These factors are required for platelet activation, recruitment and clot stability likely thus, platelet mitochondrial dysfunction contributes to the development of TIC.

Anterior cruciate ligament reconstruction in the elderly: 5-Year follow-up study.

BACKGROUND: Older adults remain active for longer and continue sports and activities that require rotation on one leg later in life. The rate of anterior cruciate ligament (ACL) tears is therefore increasing in those over 40 years old, with an associated increase in the rate of surgical reconstruction (ACLR), but there is limited literature on its effectiveness. Our aim was to compare the outcomes of elderly patients who have undergone ACLR with those of a younger group of patients. MATERIALS AND METHODS: Patients who underwent ACLR with bone-patella tendon-bone grafting (BPTB) at a level I trauma center between 2015 and 2017 were included in the study with a 5-year follow-up. Patients were divided into 4 groups: below 40 years, 40-49 years, 50-59 years and over 60 years. The graft function was evaluated by the International Knee Documentation Committee (IKDC) Objective Score, the anteroposterior (AP) displacement was measured by arthrometer (KT-1000; MEDMetric) and the Lysholm scale was used for subjective evaluation. RESULTS: 195 patients were included in the final analysis. The IKDC score showed significantly poorer scores in the 50-59 years and over 60 years group than in the younger groups, however in 83 % and 66 % of cases reached normal or nearly normal grades, respectively. A significant difference was found in the knee AP displacement (measured in mm) between the below 40 years group and 50-59 years as well as over 60 years old groups; however, the number of graft failure (laxity >5 mm) and elongation (>3 mm) did not increased in these senior groups. The patient-reported Lysholm scores in the 40-49 years, 50-59 years and 60 years groups was lower than in the below 40 years group, but the average score was "good". CONCLUSIONS: The long-term results of ACL reconstruction in older athletes are comparable to those of younger patients, both in terms of knee function and patient satisfaction. Furthermore, there is no difference in outcomes for older patients over the age of 40 compared to those in their 50 s or even 60 s. There is still insufficient published evidence to define an upper age limit for ACL reconstruction in older athletes.

Could exhaled methane be used as a possible indicator for hemodynamic changes in trauma induced hemorrhagic shock? Scientific basis supported by a case study.

INTRODUCTION: Identification of severe blood loss and hemorrhagic shock in polytrauma patients poses a key challenge for trauma teams across the world, as there are just a few objective parameters, on which clinicians can rely. We investigated the relationship between exhaled air methane (CH4) concentration and blood loss in a polytrauma patient. Decreased blood flow in the superior mesenteric artery (SMA) is one of the first compensatory responses to blood loss. Gases produced by the anaerobic flora of the intestinal segment supplied by the SMA are the primary source of exhaled CH4, which diffuses through the intestinal microvessels into the circulation and is finally eliminated through the lungs. We hypothesized that diminution of exhaled CH4 indicates blood loss and tested our theory in a severely injured patient. METHODS: Exhaled CH4 concentrations of a severely injured patient were measured using a photoacoustic spectroscope (PAS) attached to the exhalation side of the breathing circuit. The primary objective was to investigate the relationship between exhaled CH4 and conventional indicators of hemorrhage including hemoglobin (Hb) levels, base deficit (BD) values and vital parameters (heart rate and systolic blood pressure) in the early phase of in-hospital care (first 4 h). RESULTS: A severely injured patient was admitted with unstable hemodynamic parameters and incomplete left lower limb amputation, (Injury Severity Score: 38, 74/36 mmHg, 76 bpm). At the time of arrival, considerably lower CH4 levels were detected (22,800 PAU) in the exhaled air. During the first 4 h fluid and massive blood resuscitation, the exhaled CH4 levels were continuously rising in parallel with Htc and Hb values. Corresponding to these changes, BD values displayed a decreasing tendency. DISCUSSION: Our study was conducted to characterize the changes in exhaled air CH4 concentration in response to hemorrhagic shock and to provide data on a viable clinical use of an experimental technique. According to our results, the real-time detection of exhaled air CH4 concentration is an applicable and promising technique for the early detection of bleeding and hemorrhagic shock in severely injured patients. Further research on large sample size and refinement of the PAS technique is required.

Impairment of Mesenteric Perfusion as a Marker of Major Bleeding in Trauma Patients.

The majority of potentially preventable mortality in trauma patients is related to bleeding; therefore, early recognition and effective treatment of hemorrhagic shock impose a cardinal challenge for trauma teams worldwide. The reduction in mesenteric perfusion (MP) is among the first compensatory responses to blood loss; however, there is no adequate tool for splanchnic hemodynamic monitoring in emergency patient care. In this narrative review, (i) methods based on flowmetry, CT imaging, video microscopy (VM), measurement of laboratory markers, spectroscopy, and tissue capnometry were critically analyzed with respect to their accessibility, and applicability, sensitivity, and specificity. (ii) Then, we demonstrated that derangement of MP is a promising diagnostic indicator of blood loss. (iii) Finally, we discussed a new diagnostic method for the evaluation of hemorrhage based on exhaled methane (CH4) measurement. Conclusions: Monitoring the MP is a feasible option for the evaluation of blood loss. There are a wide range of experimentally used methodologies; however, due to their practical limitations, only a fraction of them could be integrated into routine emergency trauma care. According to our comprehensive review, breath analysis, including exhaled CH4 measurement, would provide the possibility for continuous, non-invasive monitoring of blood loss.

Mitochondrial Dysfunction in Trauma-Related Coagulopathy: Is There Causality? Study Protocol for a Prospective Observational Study.

Hemorrhage control often poses a great challenge for clinicians due to trauma-induced coagulopathy (TIC). The pathogenesis of TIC is not completely revealed; however, growing evidence attributes a central role to altered platelet biology. The activation of thrombocytes and subsequent clot formation are highly energetic processes being tied to mitochondrial activity, and the inhibition of the electron transport chain (ETC) impedes on thrombogenesis, suggesting the potential role of mitochondria in TIC. Our present study protocol provides a guide to quantitatively characterize the derangements of mitochondrial functions in TIC. One hundred eleven severely injured (injury severity score ≥16), bleeding trauma patients with an age of 18 or greater will be included in this prospective observational study. Patients receiving oral antiplatelet agents including cyclooxygenase-1 or adenosine diphosphate receptor inhibitors (aspirin, clopidogrel, prasugrel, and ticagrelor) will be excluded from the final analysis. Hemorrhage will be confirmed and assessed with computer tomography. Conventional laboratory markers of hemostasis such as prothrombin time and international normalized ratio will be measured and rotational thromboelastometry (ROTEM) will be performed directly upon patient arrival. Platelets will be isolated from venous blood samples and subjected to high-resolution fluororespirometry (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria) to evaluate the efficacy of mitochondrial respiration. Oxidative phosphorylation (OxPhos), coupling of the ETC, mitochondrial superoxide formation, mitochondrial membrane potential changes, and extramitochondrial Ca2+-movement will be recorded. The association between OxPhos capacity of platelet mitochondria and numerical parameters of ROTEM aggregometry will constitute our primary outcome. The relation between OxPhos capacity and results of viscoelastic assays and conventional markers of hemostasis will serve as secondary outcomes. The association of the OxPhos capacity of platelet mitochondria upon patient arrival to the need for massive blood transfusion and 24-h mortality will constitute our tertiary outcomes. Mitochondrial dysfunction and its importance in TIC are yet to be assessed for the deeper understanding of this common, life-threatening condition. Disclosure of mitochondria-mediated processes in thrombocytes may reveal new therapeutic targets in the management of hemorrhaging trauma patients, thereby leading to a reduction of potentially preventable mortality. The present protocol was registered to ClinicalTrials.gov on 12 August 2021, under the reference number NCT05004844.

Predictive value of tachycardia for mortality in trauma-related haemorrhagic shock: a systematic review and meta-regression.

OBJECTIVES: Heart rate (HR) is one of the physiological variables in the early assessment of trauma-related haemorrhagic shock, according to Advanced Trauma Life Support (ATLS). However, its efficiency as predictor of mortality is contradicted by several studies. Furthermore, the linear association between HR and the severity of shock and blood loss presented by ATLS is doubtful. This systematic review aims to update current knowledge on the role of HR in the initial haemodynamic assessment of patients who had a trauma. DESIGN: This study is a systematic review and meta-regression that follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. DATA SOURCES: EMBASE, MEDLINE, CENTRAL and Web of Science databases were systematically searched through on 1 September 2020. ELIGIBILITY CRITERIA: Papers providing early HR and mortality data on bleeding patients who had a trauma were included. Patient cohorts were considered haemorrhagic if the inclusion criteria of the studies contained transfusion and/or positive focused assessment with sonography for trauma and/or postinjury haemodynamical instability and/or abdominal gunshot injury. Studies on burns, traumatic spinal or brain injuries were excluded. Papers published before January 2010 were not considered. DATA EXTRACTION AND SYNTHESIS: Data extraction and risk of bias were assessed by two independent investigators. The association between HR and mortality of patients who had a trauma was assessed using meta-regression analysis. As subgroup analysis, meta-regression was performed on patients who received blood products. RESULTS: From a total of 2017 papers, 19 studies met our eligibility criteria. Our primary meta-regression did not find a significant relation (p=0.847) between HR and mortality in patients who had a trauma with haemorrhage. Our subgroup analysis included 10 studies, and it could not reveal a linear association between HR and mortality rate. CONCLUSIONS: In accordance with the literature demonstrating the multiphasic response of HR to bleeding, our study presents the lack of linear association between postinjury HR and mortality. Modifying the pattern of HR derangements in the ATLS shock classification may result in a more precise teaching tool for young clinicians.

Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.

There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.

Detection of exhaled methane levels for monitoring trauma-related haemorrhage following blunt trauma: study protocol for a prospective observational study.

INTRODUCTION: Early recognition and effective treatment of internal bleeding impose a cardinal challenge for trauma teams. The reduction of the superior mesenteric artery (SMA) blood flow is among the first compensatory responses to blood loss, thus being a promising candidate as a diagnostic tool for occult haemorrhage. Unfortunately, methods for monitoring the SMA flow have not been elaborated to date. Nevertheless, animal experiments suggest that exhaled methane (CH4) levels correspond to the SMA perfusion. We hypothesise that real-time detection of CH4 concentrations in the exhaled air is an applicable technique for the early recognition of haemorrhage in severely injured patients. We also hypothesise that exhaled CH4 levels reflect the volume of blood loss more accurately than conventional markers of blood loss and shock such as shock index, haemoglobin, base deficit, lactate, end-tidal carbon dioxide and sublingual microcirculatory indices. METHODS AND ANALYSIS: One hundred and eleven severely injured (Injury Severity Score ≥16), intubated, bleeding patients sustaining blunt trauma will be included in this prospective observational study. Blood loss will be detected with CT and estimated with CT-linked radiologic software. Exhaled CH4 concentrations will be monitored by attaching a near-infrared laser technique-based photoacoustic spectroscopy apparatus to the exhalation outlet of the ventilator on patient arrival. The primary outcome is the volume of blood loss. Need for massive transfusion and 24-hour mortality will constitute secondary outcomes. The relation of exhaled CH4 to study outcomes and its performance in predicting blood loss in comparison with conventional shock markers and microcirculatory indices will be tested. ETHICS AND DISSEMINATION: Our protocol (ID: 5400/2021-SZTE) has been registered on ClinicalTrials.gov (NCT04987411) and complies with the Declaration of Helsinki and has been approved by the medical ethics committee at the University of Szeged (Ref.nr.:121/2021-SZTE RKEB). It is in data collection phase, theresults will be shared with the scientific community through publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04987411; ClinicalTrials.gov, registered on 27 July 2021.

Mitochondrial Side Effects of Surgical Prophylactic Antibiotics Ceftriaxone and Rifaximin Lead to Bowel Mucosal Damage.

Despite their clinical effectiveness, a growing body of evidence has shown that many classes of antibiotics lead to mitochondrial dysfunction. Ceftriaxone and Rifaximin are first choice perioperative antibiotics in gastrointestinal surgery targeting fundamental processes of intestinal bacteria; however, may also have negative consequences for the host cells. In this study, we investigated their direct effect on mitochondrial functions in vitro, together with their impact on ileum, colon and liver tissue. Additionally, their impact on the gastrointestinal microbiome was studied in vivo, in a rat model. Rifaximin significantly impaired the oxidative phosphorylation capacity (OxPhos) and leak respiration in the ileal mucosa, in line with increased oxidative tissue damage and histological changes following treatment. Ceftriaxone prophylaxis led to similar changes in the colon mucosa. The composition and diversity of bacterial communities differed extensively in response to antibiotic pre-treatment. However, the relative abundances of the toxin producing species were not increased. We have confirmed the harmful effects of prophylactic doses of Rifaximin and Ceftriaxone on the intestinal mucosa and that these effects were related to the mitochondrial dysfunction. These experiments raise awareness of mitochondrial side effects of these antibiotics that may be of clinical importance when evaluating their adverse effects on bowel mucosa.

Early Return to Play After Anterior Cruciate Ligament Reconstruction: Is It Worth the Risk?

OBJECTIVE: To compare the outcomes of a 6-month-long accelerated rehabilitation with a 12-month-long rehabilitation. There is no consensus on the optimal duration of rehabilitation after anterior cruciate ligament reconstruction (ACLR). Trends in the past decades have shifted towards accelerated programs, often resulting in a return to play (RTP) at 4-6 months, postoperatively. However, longer rehabilitation cycles have recently experienced renaissance due to a greater understanding of graft remodeling. METHODS: Adult athletes who underwent ACLR between 2015 and 2018 by the same surgeon were included and followed-up prospectively for 24 months. Participants were allocated into two groups based on their RTP (6 months vs. 12 months) and compared with graft elongation, reoperation rate, and sports career (quit or continue) outcomes. RESULTS: Fifty-four patients underwent accelerated rehabilitation and 92 completed conventional rehabilitation. The accelerated rehabilitation was significantly associated with graft elongation-the accelerated rehabilitation group (n=9) and the conventional rehabilitation group (n=0), p<0.001-and need for reoperation-the accelerated rehabilitation group (n=5) and the conventional rehabilitation group (n=1), p=0.026. Although the relationship between rehabilitation time and quitting competitive sports did not reach significance at 0.05 level (p=0.063), it was significant when p<0.1, thereby showing a clear trend. CONCLUSION: Accelerated rehabilitation increased graft elongation risk. Knee laxity ≥3 mm measured at 6 months after ACLR should be accompanied by RTP time frame re-evaluation. Arthrometry checkups or routine magnetic resonance imaging shortly after RTP may be considered in cases of accelerated rehabilitation.

Comparison of the Previous and Current Trauma-Related Shock Classifications: A Retrospective Cohort Study from a Level I Trauma Center.

PURPOSE: The aim was to examine the predictive value of the hypovolemic shock classification currently accepted by the Advanced Trauma Life Support (ATLS) program over the previous one, which used only vital signs (VS) for patient allocation. The primary outcome was 30-day mortality; as secondary outcome, heart rate (HR), systolic blood pressure (SBP), Glasgow Coma Scale (GCS) and base deficit (BD) data were compared and investigated in terms of mortality prediction. METHODS: Retrospective analysis at a level I trauma center between 2014 and 2019. Adult patients treated by trauma teams were allocated into severity classes (I-IV) based on the criteria of the current and previous ATLS classifications, respectively. The prognostic values for the classifications were determined with Fisher's exact test and χ2 test for independence, and compared with the 2-proportion Z test. The individual variables were analyzed with receiver-operating characteristic (ROC) analyses. RESULTS: A total of 156 patients met the inclusion criteria. Mortality was effectively predicted by both classifications, and there was no statistically significant difference between the predictive performances. According to ROC analyses, GCS, BD and SBP had significant prognostic values while HR change was ineffective in this regard. CONCLUSIONS: The currently used ATLS shock classification does not appear to be superior to the VS-based previous classification. GCS, BD and SBP are useful parameters to predict the prognosis. Changes in HR do not reflect the clinical course accurately; thus, further studies will be needed to determine the value of this parameter in trauma-associated hypovolemic-hemorrhagic shock conditions.

Should we abandon the patient-specific instrumentation ship in total knee arthroplasty? Not quite yet!

Patient-specific Instrumentation (PSI) is an innovative technique aiding the precise implementation of the preoperative plan during total knee arthroplasty (TKA) by using patient-specific guides and cutting blocks. Despite of the theoretical advantages, studies have reported contradictory results, thus there is no consensus regarding the overall effectiveness of PSI. Through the critical assessment of a meta-analysis published lately, this correspondence aims to highlight the complexity of comparing the efficacy of PSI to standard instrumentation (SI). The accuracy of component alignment, patient-reported outcome measures (PROMs), surgery time, blood loss, transfusion rate, and postoperative complications are commonly used outcomes for investigating the efficacy of PSI-aided TKA. By assessing component alignment, the expertise of the surgeon(s) should be taken into consideration, since PSI may not provide benefits for expert surgeons but might improve accuracy and patient safety during the learning curve of novice surgeons. With respect to PROMs and postoperative complications, PSI may not improve short-term results; however, long-term follow up data is missing. Regarding transfusion rates, favorable trends can be observed, but further studies utilizing recent data are needed for a clear conclusion. When assessing surgery time, we suggest focusing on operating room turnover instead of procedure time.

Periosteal and endosteal microcirculatory injury following excessive osteosynthesis.

INTRODUCTION: We examined the endosteal and periosteal circulations in a patient with fracture non-union who had undergone excessive osteosynthesis applications (two long plates had been placed medially and laterally on the left tibia extending from the proximal 2/7 to the distal 6/7 parts of the bone, while a tibial component of a total knee prosthesis with a long stem had been inserted at the same time). METHODS: Concomitant perfusion changes were determined in the anterolateral and anteromedial periosteal sheath of the non-united bone ends and intramedullary nearest the osteosynthesis materials during their surgical removal on re-operation. The blood flow in the periosteum and endosteum was recorded by a laser-Doppler flowmetric device using a novel approach. Control measurements were made at identical points of the right tibia. RESULTS: Considerably lower blood flow values were measured along the tibial periosteal region of the re-operated limb than on the contralateral side (the average perfusion unit (PU) was 76 vs. 106 PU, respectively). Perfusion values were markedly lower in the endosteal region (average values of approx. 30 PU) in the control tibia and were even more diminished in the re-operated tibial endosteum (average 9 PU). CONCLUSIONS: Our study was conducted to characterize the microcirculatory changes of a long bone in response to intramedullary implantation and to provide quantitative data on the insufficiency of local perfusion in a patient with fracture non-union. Our results highlight the association between local perfusion failure and the unfavorable outcome (i.e. fracture non-union), confirming that the vital aspects of the microcirculation should not be disregarded when aiming for mechanical stability. Microcirculatory measurements constitute a new area of improvement in planning the adequate treatment for fracture non-unions with an unclear aetiology. Further refinement of the laser-Doppler technique could have potential benefits for bone surgery and postoperative trauma care in the future.

Novel coronavirus and trauma surgery: successful infection control from a level I trauma centre.

PURPOSE: In the absence of effective treatment options, the recent SARS-CoV2 pandemic poses a great challenge to the health and social sectors worldwide. Hereby, we would like to share our proposals in the hope that it will prove helpful for our colleagues in this difficult time. METHODS: The present recommendations are based on the opinion of experts as well as the experience of a group of traumatologists directly involved in the organization of traumatology wards. The reassignment of the healthcare personnel, the separation of the potentially infected patients and the different levels of restriction on the trauma care are all key elements of our protocol. RESULTS: Since the first SARS-CoV2-positive case was confirmed in Hungary, our trauma surgeons were able to avoid contamination with the help of the new guidelines, without reducing the quality of trauma care. CONCLUSION: Reasonably adjusted patient care protocols in every medical field are key to contain the spread of infection and to avoid public health crisis. Sharing experience can be an important element of a successful fight against the recent pandemic.