bims-heshmo 2021-06-06 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–06–06
nineteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

A Novel Cross-Linked Hemoglobin-Based Oxygen Carrier, YQ23, Extended the Golden Hour for Uncontrolled Hemorrhagic Shock in Rats and Miniature Pigs.
High Interleukin-6 Plasma Concentration upon Admission Is Predictive of Massive Transfusion in Severely Injured Patients.
Extremity trauma exacerbates acute kidney injury following prolonged hemorrhagic hypotension.
A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients.
Getting hit by the bus around the world - a global perspective on goal directed treatment of massive hemorrhage in trauma.
Whole truths but half the blood: Addressing the gap between the evidence and practice of pre-hospital and in-hospital blood product use for trauma resuscitation.
Validation of a Visual-Based Analytics Tool for Outcome Prediction in Polytrauma Patients (WATSON Trauma Pathway Explorer) and Comparison with the Predictive Values of TRISS.
Hydrogen alleviates acute lung injury induced by limb ischaemia/reperfusion in mice.
Design and Development of a Hemorrhagic Trauma Simulator for Lower Limbs: A Pilot Study.
Exogenous Hydrogen Sulfide Plays an Important Role Through Regulating Autophagy in Ischemia/Reperfusion Injury.
Base Deficit ≥ 6 within 24 h of Injury is a risk factor for fracture nonunion in the polytraumatized patient.
Changes in the behaviour of monocyte subsets in acute post-traumatic sepsis patients.
Biomarkers to Guide the Timing of Surgery: Neutrophil and Monocyte L-Selectin Predict Postoperative Sepsis in Orthopaedic Trauma Patients.
Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway.
The Impact of COVID-19 Infection on Outcomes After Injury in a State Trauma System.
Correcting Coagulopathy With Fresh Frozen Plasma in the Surgical Intensive Care Unit: How Much Do We Need to Transfuse?
Fluid Therapy and the Microcirculation in Health and Critical Illness.
Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers.
Target arterial PO2 according to the underlying pathology: a mini-review of the available data in mechanically ventilated patients.

Front Pharmacol. 2021 ;12 652716

A Novel Cross-Linked Hemoglobin-Based Oxygen Carrier, YQ23, Extended the Golden Hour for Uncontrolled Hemorrhagic Shock in Rats and Miniature Pigs.

Lei Kuang, Yu Zhu, Yue Wu, Kunlun Tian, Xiaoyong Peng, Mingying Xue, Xinming Xiang, Billy Lau, Fei Chuen Tzang, Liangming Liu, Tao Li.

  Background: Hypotensive resuscitation is widely applied for trauma and war injury to reduce bleeding during damage-control resuscitation, but the treatment time window is limited in order to avoid hypoxia-associated organ injury. Whether a novel hemoglobin-based oxygen carrier (HBOC), YQ23 in this study, could protect organ function, and extend the Golden Hour for treatment is unclear. Method: Uncontrolled hemorrhagic shock rats and miniature pigs were infused with 0.5, 2, and 5% YQ23 before bleeding was controlled, while Lactate Ringer's solution (LR) and fresh whole blood plus LR (WB + LR) were set as controls. During hypotensive resuscitation the mean blood pressure was maintained at 50-60 mmHg for 60 min. Hemodynamics, oxygen delivery and utilization, blood loss, fluid demand, organ function, animal survival as well as side effects were observed. Besides, in order to observe whether YQ23 could extend the Golden Hour, the hypotensive resuscitation duration was extended to 180 min and animal survival was observed. Results: Compared with LR, infusion of YQ23 in the 60 min pre-hospital hypotensive resuscitation significantly reduced blood loss and the fluid demand in both rats and pigs. Besides, YQ23 could effectively stabilize hemodynamics, and increase tissue oxygen consumption, increase the cardiac output, reduce liver and kidney injury, which helped to reduce the early death and improve animal survival. In addition, the hypotensive resuscitation duration could be extended to 180 min using YQ23. Side effects such as vasoconstriction and renal injury were not observed. The beneficial effects of 5% YQ23 are equivalent to similar volume of WB + LR. Conclusion: HBOC, such as YQ23, played vital roles in damage-control resuscitation for emergency care and benefited the uncontrolled hemorrhagic shock in the pre-hospital treatment by increasing oxygen delivery, reducing organ injury. Besides, HBOC could benefit the injured and trauma patients by extending the Golden Hour.

Keywords:  early treatment; fluid resuscitation; hemoglobin-based oxygen carrier (HBOC); oxygen delivery; uncontrolled hemorrhagic shock

DOI:  https://doi.org/10.3389/fphar.2021.652716
J Clin Med. 2021 May 24. pii: 2268. [Epub ahead of print]10(11):

High Interleukin-6 Plasma Concentration upon Admission Is Predictive of Massive Transfusion in Severely Injured Patients.

Nadja Weichselbaum, Daniel Oberladstätter, Christoph J Schlimp, Johannes Zipperle, Wolfgang Voelckel, Oliver Grottke, Georg Zimmermann, Marcin Osuchowski, Herbert Schöchl.

  Severe bleeding remains a prominent cause of early in-hospital mortality in major trauma patients. Thus, prompt prediction of patients at risk of massive transfusion (MT) is crucial. We investigated the ability of the inflammatory marker interleukin (IL)-6 to forecast MT in severely injured trauma patients. IL-6 plasma levels were measured upon admission. Receiver operating characteristic curves (ROCs) were calculated, and sensitivity and specificity were determined. In this retrospective study, a total of 468 predominantly male (77.8%) patients, with a median injury severity score (ISS) of 25 (17-34), were included. The Youden index for the prediction of MT within 6 and 24 h was 351 pg/mL. Patients were dichotomized into two groups: (i) low-IL-6 < 350 pg/mL and (ii) high-IL-6 ≥ 350 pg/mL. IL-6 ≥ 350 pg/mL was associated with a lower prothrombin time index, a higher activated partial thromboplastin time, and a lower fibrinogen concentration compared with IL-6 < 350 pg/mL (p <0.0001 for all). Thromboelastometric parameters were significantly different between groups (p <0.03 in all). More patients in the high-IL-6 group received MT (p <0.0001). The ROCs revealed an area under the curve of 0.76 vs. 0.82 for the high-IL-6 group for receiving MT in the first 6 and 24 h. IL-6 ≥ 350 pg/mL predicted MT within 6 and 24 h with a sensitivity of 45% and 58%, respectively, and a specificity of 89%. IL-6 ≥ 350 pg/mL appears to be a reasonable early predictor for coagulopathy and MT within the first 6 and 24 h intervals. Large-scale prospective studies are warranted to confirm these findings.

Keywords:  coagulopathy; interleukin-6; massive transfusion; trauma

DOI:  https://doi.org/10.3390/jcm10112268
J Trauma Acute Care Surg. 2021 Jun 04.

Extremity trauma exacerbates acute kidney injury following prolonged hemorrhagic hypotension.

Lusha Xiang, Alfredo S Calderon, Harold G Klemcke, Ian L Hudson, Carmen Hinojosa-Laborde, Kevin K Chung, Kathy L Ryan.

BACKGROUND: The incidence of and mortality due to acute kidney injury (AKI) is high in patients with traumatic shock. However, it is unclear how hemorrhage and trauma synergistically affect renal function, especially when timely volume resuscitation is not available.
METHOD: We hypothesized that trauma impairs renal tolerance to prolonged hemorrhagic hypotension. Sprague Dawley rats were randomized into 6 groups: control, extremity trauma (ET), hemorrhage at 70 mmHg (70-H), hemorrhage at 55 mmHg (55-H), ET + 70 mmHg (70-ETH), and ET + 55 mmHg (55-ETH). Animals were anesthetized and ET was induced via soft tissue injury and closed fibula fracture. Hemorrhage was performed via catheters 5 minutes after ET with target MAP clamped at 70 mmHg or 55 mmHg for up to 3 hours. Blood and urine samples were collected to analyze plasma creatinine (Cr), creatinine clearance (CCr), renal oxygen delivery (DO2), urinary albumin, and kidney injury molecule-1 (KIM-1).
RESULTS: ET alone did not alter renal hemodynamics, DO2, or function. In 70-H, CCr was increased following hemorrhage, while Cr, renal vascular resistance (RVR), KIM-1, and albumin levels remained unchanged. Compared to 70-H, 70-ETH exhibited increases in Cr and RVR with decreases in CCr and DO2. In addition, ET decreased the blood volume loss required to maintain MAP = 70 mmHg by ~50%. 55-H and 55-ETH exhibited a marked and similar decrease in CCr and increases in RVR, Cr, KIM-1, and albumin. However, ET greatly decreased the blood volume loss required to maintain MAP at 55 mmHg and led to 50% mortality.
CONCLUSIONS: These results suggest that ET impairs renal and systemic tolerance to prolonged hemorrhagic hypotension. Thus, traumatic injury should be considered as a critical component of experimental studies investigating outcomes and treatment following hemorrhagic shock.
LEVEL OF EVIDENCE: This is an original article on basic science and does not require a level of evidence.

DOI: https://doi.org/10.1097/TA.0000000000003311
Drugs. 2021 Jun 01.

A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients.

Anil Gulati, Rajat Choudhuri, Ajay Gupta, Saurabh Singh, S K Noushad Ali, Gursaran Kaur Sidhu, Parvez David Haque, Prashant Rahate, Aditya R Bothra, Gyan P Singh, Sanjiv Maheshwari, Deepak Jeswani, Sameer Haveri, Apurva Agarwal, Nilesh Radheshyam Agrawal.

INTRODUCTION: Centhaquine (Lyfaquin®) showed significant safety and efficacy in preclinical and clinical phase I and II studies.
METHODS: A prospective, multicentric, randomized phase III study was conducted in patients with hypovolemic shock, systolic blood pressure (SBP) ≤ 90 mmHg, and blood lactate levels ≥ 2 mmol/L. Patients were randomized in a 2:1 ratio to the centhaquine group (n = 71) or the control (saline) group (n = 34). Every patient received standard of care (SOC) and was followed for 28 days. The study drug (normal saline or centhaquine 0.01 mg/kg) was administered in 100 mL of normal saline infusion over 1 h. The primary objectives were to determine changes (mean through 48 h) in SBP, diastolic blood pressure (DBP), blood lactate levels, and base deficit. The secondary objectives included the amount of fluids, blood products, and vasopressors administered in the first 48 h, duration of hospital stay, time in intensive care units, time on ventilator support, change in acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and the proportion of patients with 28-day all-cause mortality.
RESULTS: The demographics of patients and baseline vitals in both groups were comparable. The cause of hypovolemic shock was trauma in 29.4 and 47.1% of control group and centhaquine group patients, respectively, and gastroenteritis in 44.1 and 29.4%, respectively. Shock index (SI) and quick sequential organ failure assessment at baseline were similar in the two groups. An equal amount of fluids and blood products were administered in both groups during the first 48 h of resuscitation. A lesser amount of vasopressors was needed in the first 48 h of resuscitation in the centhaquine group. An increase in SBP from baseline was consistently higher up to 48 h (12.9% increase in area under the curve from 0 to 48 h [AUC0-48]) in the centhaquine group than in the control group. A significant increase in pulse pressure (48.1% increase in AUC0-48) in the centhaquine group compared with the control group suggests improved stroke volume due to centhaquine. The SI was significantly lower in the centhaquine group from 1 h (p = 0.032) to 4 h (p = 0.049) of resuscitation. Resuscitation with centhaquine resulted in a significantly greater number of patients with improved blood lactate (control 46.9%; centhaquine 69.3%; p = 0.03) and the base deficit (control 43.7%; centhaquine 69.8%; p = 0.01) than in the control group. ARDS and MODS improved with centhaquine, and an 8.8% absolute reduction in 28-day all-cause mortality was observed in the centhaquine group.
CONCLUSION: Centhaquine is an efficacious resuscitative agent for treating hypovolemic shock. The efficacy of centhaquine in distributive shock is being explored.
TRIAL REGISTRATION: Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2019/01/017196; clinicaltrials.gov, NCT04045327.

DOI: https://doi.org/10.1007/s40265-021-01547-5
Curr Opin Anaesthesiol. 2021 Jun 01.

Getting hit by the bus around the world - a global perspective on goal directed treatment of massive hemorrhage in trauma.

Stephan Johannsen, Karim Brohi, Pär I Johansson, Ernest E Moore, Ann-Kristin Reinhold, Herbert Schöchl, Joanna M Shepherd, Ben Slater, Jakob Stensballe, Kai Zacharowski, Patrick Meybohm.

PURPOSE OF REVIEW: Major trauma remains one of the leading causes of death worldwide with traumatic brain injury and uncontrolled traumatic bleeding as the main determinants of fatal outcome. Interestingly, the therapeutic approach to trauma-associated bleeding and coagulopathy shows differences between geographic regions, that are reflected in different guidelines and protocols.
RECENT FINDINGS: This article summarizes main principles in coagulation diagnostics and compares different strategies for treatment of massive hemorrhage after trauma in different regions of the world. How would a bleeding trauma patient be managed if they got hit by the bus in the United States, United Kingdom, Germany, Switzerland, Austria, Denmark, Australia, or in Japan?
SUMMARY: There are multiple coexistent treatment standards for trauma-induced coagulopathy in different countries and different trauma centers. Most of them initially follow a protocol-based approach and subsequently focus on predefined clinical and laboratory targets.

DOI: https://doi.org/10.1097/ACO.0000000000001025
Transfusion. 2021 Jun 04.

Whole truths but half the blood: Addressing the gap between the evidence and practice of pre-hospital and in-hospital blood product use for trauma resuscitation.

Zain G Hashmi, Mohamad Chehab, Avery B Nathens, Bellal Joseph, Eric A Bank, Jan O Jansen, John B Holcomb.

BACKGROUND: In recent years, several studies have demonstrated the efficacy of using pre-hospital blood product and in-hospital whole blood for trauma resuscitation. While some observations suggest an encouraging uptake of this evidence by emergency medical service (EMS) agencies and trauma centers, a nationwide characterization of blood product utilization for bleeding trauma patients remains unknown. The objective of this study is to determine nationwide estimates of pre-hospital blood product and in-hospital whole blood utilization for trauma resuscitation.
STUDY DESIGN AND METHODS: All adult trauma patients reported to the National Emergency Medical Services Information System (NEMSIS) dataset 2019 were included. Proportions of patients who received any pre-hospital blood product were calculated. The American College of Surgeons (ACS) Trauma Quality Programs (TQP) databases 2015-2017 and first quarter of 2020 were used to calculate the proportion of ACS-verified trauma centers that transfused whole blood.
RESULTS: Among a total of 3,058,804 pre-hospital trauma patients, only 313 (0.01%) received any blood transfusion; 208 (0.21%) patients with systolic blood pressure (SBP) ≤90 mmHg and 121 (0.67%) patients with SBP ≤90 mmHg and heart rate ≥120 beats per minute received any blood product. The proportion of ACS-verified trauma centers transfusing whole blood increased from 16.7% (45/269) in 2015 to 24.5% (123/502) in first quarter of 2020.
DISCUSSION: Despite strong evidence and recommendations, pre-hospital utilization of blood products for trauma resuscitation remains low. Additionally, while the overall in-hospital whole blood use also remains low, its use has increased at ACS-verified trauma centers over the past 5 years.

DOI: https://doi.org/10.1111/trf.16515
J Clin Med. 2021 May 14. pii: 2115. [Epub ahead of print]10(10):

Validation of a Visual-Based Analytics Tool for Outcome Prediction in Polytrauma Patients (WATSON Trauma Pathway Explorer) and Comparison with the Predictive Values of TRISS.

Cédric Niggli, Hans-Christoph Pape, Philipp Niggli, Ladislav Mica.

  Introduction: Big data-based artificial intelligence (AI) has become increasingly important in medicine and may be helpful in the future to predict diseases and outcomes. For severely injured patients, a new analytics tool has recently been developed (WATSON Trauma Pathway Explorer) to assess individual risk profiles early after trauma. We performed a validation of this tool and a comparison with the Trauma and Injury Severity Score (TRISS), an established trauma survival estimation score. Methods: Prospective data collection, level I trauma centre, 1 January 2018-31 December 2019.
INCLUSION CRITERIA: Primary admission for trauma, injury severity score (ISS) ≥ 16, age ≥ 16.
PARAMETERS: Age, ISS, temperature, presence of head injury by the Glasgow Coma Scale (GCS).
OUTCOMES: SIRS and sepsis within 21 days and early death within 72 h after hospitalisation.
STATISTICS: Area under the receiver operating characteristic (ROC) curve for predictive quality, calibration plots for graphical goodness of fit, Brier score for overall performance of WATSON and TRISS. Results: Between 2018 and 2019, 107 patients were included (33 female, 74 male; mean age 48.3 ± 19.7; mean temperature 35.9 ± 1.3; median ISS 30, IQR 23-36). The area under the curve (AUC) is 0.77 (95% CI 0.68-0.85) for SIRS and 0.71 (95% CI 0.58-0.83) for sepsis. WATSON and TRISS showed similar AUCs to predict early death (AUC 0.90, 95% CI 0.79-0.99 vs. AUC 0.88, 95% CI 0.77-0.97; p = 0.75). The goodness of fit of WATSON (X2 = 8.19, Hosmer-Lemeshow p = 0.42) was superior to that of TRISS (X2 = 31.93, Hosmer-Lemeshow p < 0.05), as was the overall performance based on Brier score (0.06 vs. 0.11 points). Discussion: The validation supports previous reports in terms of feasibility of the WATSON Trauma Pathway Explorer and emphasises its relevance to predict SIRS, sepsis, and early death when compared with the TRISS method.

Keywords:  SIRS; TRISS; WATSON Trauma Pathway Explorer; artificial intelligence; early death; outcome; polytrauma; sepsis

DOI:  https://doi.org/10.3390/jcm10102115
Life Sci. 2021 May 28. pii: S0024-3205(21)00645-7. [Epub ahead of print]279 119659

Hydrogen alleviates acute lung injury induced by limb ischaemia/reperfusion in mice.

Ling Liu, Chao Yang, Tingting Qiu, Xin Shen, Boyan Liu, Xufeng Qi, Guohua Song.

   AIMS: Limb ischaemia/reperfusion (LIR) occurs in various clinical conditions including critical limb ischaemia, abdominal aortic aneurysm, and traumatic arterial injury. Reperfusion of the acutely ischemic limb can lead to a systemic inflammation response and multiple organ dysfunction syndrome, further resulting in significant morbidity and mortality. Molecular hydrogen exhibits therapeutic activity for the treatment and prevention of many diseases. Our study investigated the possible therapeutic effects of hydrogen and its mechanism of action in a LIR-induced acute lung injury (ALI) model.
MATERIALS AND METHODS: Limb ischaemia/-reperfusion model was established in mice. The hydrogen-saturated saline was administered by intraperitoneal injection. Protein level of nuclear factor erythroid 2-related factor 2 (Nrf2), haem oxygenase-1 (HO1) and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) was evaluated by immunohistochemistry staining and western blotting. Autophagy-related molecules were evaluated by western blotting. Malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by assay kits. Quantification of ceramides in lung was performed by high-performance liquid chromatography-tandem mass spectrometry.
KEY FINDINGS: Molecular hydrogen exhibited a protective effect on the LIR-induced ALI model. Hydrogen decreased malondialdehyde and increased superoxide dismutase activity in lung tissues. Additionally, hydrogen activated Nrf2 signalling in lung tissues. Hydrogen could inhibit the upregulation of autophagy in the present rodent model. Furthermore, ceramide was accumulated in lung tissues because of LIR; however, hydrogen altered the accumulation status.
SIGNIFICANCE: Molecular hydrogen was found to be therapeutically effective in the LIR-induced ALI model; the mechanisms of action included modulation of antioxidation and autophagy.

Keywords:  Autophagy; Limb ischemia-reperfusion; Molecular hydrogen; NRF2

DOI:  https://doi.org/10.1016/j.lfs.2021.119659
Sensors (Basel). 2021 May 31. pii: 3816. [Epub ahead of print]21(11):

Design and Development of a Hemorrhagic Trauma Simulator for Lower Limbs: A Pilot Study.

Blanca Larraga-García, Aurora Pérez-Jiménez, Santiago Ros-Dopico, Javier Rubio-Bolívar, Manuel Quintana-Diaz, Álvaro Gutiérrez.

  One of the main preventable leading causes of death after a trauma injury is the hemorrhagic shock. Therefore, it is extremely important to learn how to control hemorrhages. In this paper, a hemorrhagic trauma simulator for lower limb has been developed and a pilot study has been accomplished to trail the simulator. Four different bleeding scenarios have been tested per participant, gathering information about the manual pressure exerted to control the bleeding. Data, altogether, from 54 hemorrhagic scenarios managed by final year medical students and doctors were gathered. Additionally, a post-simulation questionnaire, related to the usability of the simulator, was completed. All the participants managed to control the simulated bleeding scenarios, but the pressure exerted to control the four different scenarios is different depending if the trainee is a student or a doctor, especially in deep venous hemorrhages. This research has highlighted the different approach to bleeding control treatment between medical students and doctors. Moreover, this pilot study demonstrated the need to deliver a more effective trauma treatment teaching for hemorrhagic lesions and that hemorrhagic trauma simulators can be used to train and evaluate different scenarios.

Keywords:  clinical simulation; hemorrhagic trauma; patient care; training

DOI:  https://doi.org/10.3390/s21113816
Front Mol Biosci. 2021 ;8 681676

Exogenous Hydrogen Sulfide Plays an Important Role Through Regulating Autophagy in Ischemia/Reperfusion Injury.

Shuangyu Lv, Zhu Wang, Jie Wang, Honggang Wang.

  Ischemia/reperfusion (I/R) injury is characterized by limiting blood supply to organs, then restoring blood flow and reoxygenation. It leads to many diseases, including acute kidney injury, myocardial infarction, circulatory arrest, ischemic stroke, trauma, and sickle cell disease. Autophagy is an important and conserved cellular pathway, in which cells transfer the cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. Hydrogen sulfide (H2S), along with carbon monoxide (CO) and nitric oxide (NO), is an important gas signal molecule and regulates various physiological and pathological processes. In recent years, there are many studies on the improvement of I/R injury by H2S through regulating autophagy, but the related mechanisms are not completely clear. Therefore, we summarize the related research in the above aspects to provide theoretical reference for future in-depth research.

Keywords:  apoptosis; autophagy; hydrogen sulfide; ischemia/reperfusion injury; oxidative stress

DOI:  https://doi.org/10.3389/fmolb.2021.681676
Injury. 2021 May 18. pii: S0020-1383(21)00463-0. [Epub ahead of print]

Base Deficit ≥ 6 within 24 h of Injury is a risk factor for fracture nonunion in the polytraumatized patient.

Neil R Sardesai, Greg E Gaski, Zachary J Gunderson, Connor M Cunningham, James Slaven, Ashley D Meagher, Todd O McKinley, Roman M Natoli.

   BACKGROUND: Polytrauma patients are at risk for fracture nonunion, but the reasons are poorly understood. Increased base deficit (BD) is associated with hypovolemic shock. Although shock delays bone healing in animal models, there have been no clinical studies evaluating the impact of BD on nonunion risk.
MATERIALS AND METHODS: Patients age ≥ 16 with injury severity score > 16 that presented to an academic Level One trauma center with an operative femur or tibia fracture were reviewed. Clinical notes and radiographs were assessed to determine fracture healing status. Patient demographics, injury characteristics, BD, and number of packed red blood cell transfusions were recorded. Bivariate and multivariate analyses of multiple risk factors associated with nonunion were conducted to investigate the association of BD with nonunion.
RESULTS: The union group was comprised of 243 fractures; there were 36 fractures in the nonunion group. The following predictors were associated with nonunion: smoking (p = 0.009), alcohol use (p < 0.001), open fracture (p < 0.001), and treatment for deep infection at fracture site (p = 0.016). Additionally, worst BD over 24 h ≥ 6 (p = 0.031) was significant for nonunion development. A multivariate logistic regression analysis revealed worst BD ≥6 over 24 h remained significantly associated with the development of nonunion (odds ratio 3.02, p = 0.011) when adjusting for other risk factors.
CONCLUSIONS: A BD ≥ 6 within 24 h of admission was associated with a significantly increased risk of developing lower extremity fracture nonunion in polytrauma patients, even after adjusting for multiple other risk factors. Acute post-traumatic acidosis may have effects on long-term fracture healing.

Keywords:  Base deficit; Fracture healing; Hemorrhagic shock; Nonunion; Polytrauma; Shock

DOI:  https://doi.org/10.1016/j.injury.2021.05.024
Mol Immunol. 2021 Jun 01. pii: S0161-5890(21)00122-X. [Epub ahead of print]136 65-72

Changes in the behaviour of monocyte subsets in acute post-traumatic sepsis patients.

Dablu Lal Gupta, Ashok Sharma, Kapil Dev Soni, Syed Naqui Kazim, Sanjeev Bhoi, D N Rao.

  Trauma remains a major public health problem worldwide, marked as the fourth leading cause of death among all diseases. Trauma patients who survived at initial stages in the Emergency Department (ED), have significantly higher chances of mortality due to sepsis associated complications in the ICU at the later stage. There is paucity of literature regarding the role of circulating monocytes subsets and development of sepsis complications following trauma haemorrhagic shock (THS). The study was conducted to investigate the circulating level of monocyte subsets (Classical, Inflammatory, and Patrolling) and its functions in patients with acute post-traumatic sepsis. A total 72, THS patients and 30 age matched healthy controls were recruited. Blood samples were collected at different time points on days 1, 7, and 14 to measure the serum levels of cytokines by Cytometric bead assay (CBA), for the immunophenotyping of monocytes subsets, and also for the cell sorting of monocytes subsets for the functional studies. The circulating levels of monocytes subsets were found to be significantly differs among THS patients, who developed sepsis when compared with others who did not. The levels of patrolling monocytes were elevated in THS patients who developed sepsis and showed negative correlation with Sequential organ failure assessment (SOFA) score on days 7 and 14. Classical monocytes responded strongly to bacterial TLR-agonist (LPS) and produced anti-inflammatory cytokines, whereas patrolling monocytes responded with viral TLR agonist TLR-7/8 (R848) and produced inflammatory cytokines in post-traumatic sepsis patients. In conclusion, this study shows disparity in the behaviour of monocytes subsets in patients with acute post-traumatic sepsis.

Keywords:  Cytometric bead assay; Multiple organ failure; Sepsis; Trauma haemorrhagic shock

DOI:  https://doi.org/10.1016/j.molimm.2021.04.005
J Clin Med. 2021 May 20. pii: 2207. [Epub ahead of print]10(10):

Biomarkers to Guide the Timing of Surgery: Neutrophil and Monocyte L-Selectin Predict Postoperative Sepsis in Orthopaedic Trauma Patients.

Gabrielle Daisy Briggs, Karla Lemmert, Natalie Jane Lott, Theo de Malmanche, Zsolt Janos Balogh.

  Deciding whether to delay non-lifesaving orthopaedic trauma surgery to prevent multiple organ failure (MOF) or sepsis is frequently disputed and largely based on expert opinion. We hypothesise that neutrophils and monocytes differentially express activation markers prior to patients developing these complications. Peripheral blood from 20 healthy controls and 162 patients requiring major orthopaedic intervention was collected perioperatively. Neutrophil and monocyte L-selectin, CD64, CD11, CD18, and CXCR1 expression were measured using flow cytometry. The predictive ability for MOF and sepsis was assessed using the Receiver Operating Characteristic (ROC) comparing to C-reactive protein (CRP). Neutrophil and monocyte L-selectin were significantly higher in patients who developed sepsis. Neutrophil L-selectin (AUC 0.692 [95%CI 0.574-0.810]) and monocyte L-selectin (AUC 0.761 [95%CI 0.632-0.891]) were significant predictors of sepsis and were not significantly different to CRP (AUC 0.772 [95%CI 0.650-0.853]). Monocyte L-selectin was predictive of MOF preoperatively and postoperatively (preop AUC 0.790 [95%CI 0.622-0.958]). CD64 and CRP were predictive of MOF at one-day postop (AUC 0.808 [95%CI 0.643-0.974] and AUC 0.809 [95%CI 0.662-0.956], respectively). In the perioperative period, elevated neutrophil and monocyte L-selectin are predictors of postoperative sepsis. Larger validation studies should focus on these biomarkers for deciding the timing of long bone/pelvic fracture fixation.

Keywords:  L-selectin; SIRS; multiple organ failure; sepsis; trauma

DOI:  https://doi.org/10.3390/jcm10102207
Antioxidants (Basel). 2021 May 21. pii: 823. [Epub ahead of print]10(6):

Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway.

Bercis Imge Ucar, Gulberk Ucar, Sarmistha Saha, Brigitta Buttari, Elisabetta Profumo, Luciano Saso.

  Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R injury (IRI) occurs due to the tissue injury following the reestablishment of blood supply to ischemic tissues, leading to enhanced aseptic inflammation and stimulation of oxidative stress via reactive oxygen and nitrogen species (ROS/RNS). Since ROS causes membrane lipids' peroxidation, triggers loss of membrane integrity, denaturation of proteins, DNA damage, and cell death, oxidative stress plays a critical part in I/R pathogenesis. Therefore, ROS regulation could be a promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates the expression of several factors involved in the cellular defense against oxidative stress and inflammation, including heme oxygenase-1 (HO-1). Numerous studies have shown the potential role of the Nrf2/HO-1 pathway in IRI; thus, we will review the molecular aspects of Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling pathway in I/R, and we will also highlight the recent insights into targeting this pathway as a promising therapeutic strategy for preventing IRI.

Keywords:  Nrf2 activators; Nrf2/Keap1/ARE signaling pathway; ischemia-reperfusion injury

DOI:  https://doi.org/10.3390/antiox10060823
J Trauma Acute Care Surg. 2021 Jun 01.

The Impact of COVID-19 Infection on Outcomes After Injury in a State Trauma System.

Elinore J Kaufman, Adrian W Ong, Mark D Cipolle, Gregory Whitehorn, Asanthi Ratnasekera, Stanislaw P Stawicki, Niels D Martin.

BACKGROUND: The COVID-19 pandemic reshaped the healthcare system in 2020. COVID-19 infection has been associated with poor outcomes after orthopedic surgery and elective, general surgery, but the impact of COVID-19 on outcomes after trauma is unknown.
METHODS: We conducted a retrospective cohort study of patients admitted to Pennsylvania trauma centers from March 21-July 31, 2020. The exposure of interest was COVID-19 (COV +) and the primary outcome was inpatient mortality. Secondary outcomes were length of stay and complications. We compared demographic and injury characteristics between positive, negative, and not-tested patients. We used multivariable regression with coarsened exact matching to estimate the impact of COV+ on outcomes.
RESULTS: Of 15,550 included patients, 8,170 (52.5%) were tested for COVID-19 and 219 (2.7%) were positive (COV+). Compared to COVID-19 negative (COV-) patients, COV+ patients were similar in terms of age and sex, but were less often white (53.5% vs. 74.7%, p < 0.0001), and more often uninsured (10.1 vs 5.6%, p = 0.002). Injury severity was similar, but firearm injuries accounted for 11.9% of COV+ patients vs. 5.1% of COV- patients (p < 0.001). Unadjusted mortality for COV+ was double that of COV- patients (9.1% vs 4.7%, p < 0.0001) and length of stay was longer (median of 5 vs. 4 days, p < 0.001). Using coarsened exact matching, COV+ patients had an increased risk of death (OR 6.05, 95% CI 2.29, 15.99), any complication (OR 1.85, 95% CI 1.08, 3.16), and pulmonary complications (OR 5.79, 95% CI 2.02, 16.54) compared to COV- patients.
CONCLUSIONS: Patients with concomitant traumatic injury and COVID-19 infection have elevated risks of morbidity and mortality. Trauma centers must incorporate an understanding of these risks into patient and family counseling and resource allocation during this pandemic.
LEVEL OF EVIDENCE: Level II, Prognostic Study.

DOI: https://doi.org/10.1097/TA.0000000000003310
Am Surg. 2021 May 31. 31348211023412

Correcting Coagulopathy With Fresh Frozen Plasma in the Surgical Intensive Care Unit: How Much Do We Need to Transfuse?

Yassar M Hashim, Navpreet K Dhillon, Nicholas P Rottler, Joshua Ghoulian, Galinos Barmparas, Eric J Ley.

   INTRODUCTION: Thromboelastography (TEG) is an assay that assesses the coagulation status. Patients with prolonged reaction time (R) require fresh frozen plasma (FFP); however, the volume required to correct the R time is unknown. We sought to quantify the volume required to correct the R time and calculate the response ratio in our surgical intensive care unit (SICU) to allow for targeted resuscitation.
METHODS: Surgical intensive care unit patients between Aug 2017 and July 2019 with a prolonged initial R time and at least two TEG tests performed within 24 hours were included. The response ratio was defined as the change in the R time divided by the number of FFP units. High responders (response ratio >5 minutes/unit) were compared to low responders (response ratio ≤5 minutes/unit).
RESULTS: Forty-six patients were included. While the mean response ratio was 5 minutes/unit, there was significant variation among patients. There were 28.0 (60.9%) low responders and 18.0 (39.1%) high responders. Low responders were more likely male (64.0% vs. 33.0%, P = .04), had a higher Acute Physiology and Chronic Health Evaluation (APACHE) IV score (42.0 vs. 27.0, P = .03), and a higher mortality rate (54.0% vs. 22.0%, P = .04).
CONCLUSIONS: On average, one unit of FFP corrects the R time by 5 minutes; however, there was significant variation between high and low responders. Male patients with higher APACHE IV score are expected to be low responders with a higher mortality rate. These findings can guide FFP transfusion and provide additional prognostication.

Keywords:  bleeding; coagulopathy; critical care; fresh frozen plasma; thromboelastography

DOI:  https://doi.org/10.1177/00031348211023412
Front Vet Sci. 2021 ;8 625708

Fluid Therapy and the Microcirculation in Health and Critical Illness.

Edward S Cooper, Deborah C Silverstein.

  Fluid selection and administration during shock is typically guided by consideration of macrovascular abnormalities and resuscitative targets (perfusion parameters, heart rate, blood pressure, cardiac output). However, the microcirculatory unit (comprised of arterioles, true capillaries, and venules) is vital for the effective delivery of oxygen and nutrients to cells and removal of waste products from the tissue beds. Given that the microcirculation is subject to both systemic and local control, there is potential for functional changes and impacts on tissue perfusion that are not reflected by macrocirculatory parameters. This chapter will present an overview of the structure, function and regulation of the microcirculation and endothelial surface layer in health and shock states such as trauma, hemorrhage and sepsis. This will set the stage for consideration of how these microcirculatory characteristics, and the potential disconnect between micro- and macrovascular perfusion, may affect decisions related to acute fluid therapy (fluid type, amount, and rate) and monitoring of resuscitative efforts. Available evidence for the impact of various fluids and resuscitative strategies on the microcirculation will also be reviewed.

Keywords:  glycocalyx; hemorrhage; macrocirculation; microcirculation; sepsis; shock

DOI:  https://doi.org/10.3389/fvets.2021.625708
Eur J Pharm Sci. 2021 Jun 01. pii: S0928-0987(21)00194-9. [Epub ahead of print] 105893

Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers.

Zoe Kane, Roberto Picetti, Alison Wilby, Joseph F Standing, Stanislas Grassin-Delyle, Ian Roberts, Haleema Shakur-Still.

   BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependent on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration.
METHODS: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n=48 participants). The model was verified using separate IV and oral validation datasets (n=26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed.
RESULTS: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67 % and Tmax from 2.6 to 3.2 and 0.4 to 1.0 hours following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing.
CONCLUSIONS: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 minutes and be maintained above this level for approximately 3 hours, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

Keywords:  Pharmacokinetics; intramuscular; intravenous; oral; physiologically based pharmacokinetic modelling; tranexamic acid

DOI:  https://doi.org/10.1016/j.ejps.2021.105893
Ann Intensive Care. 2021 Jun 02. 11(1): 88

Target arterial PO2 according to the underlying pathology: a mini-review of the available data in mechanically ventilated patients.

Julien Demiselle, Enrico Calzia, Clair Hartmann, David Alexander Christian Messerer, Pierre Asfar, Peter Radermacher, Thomas Datzmann.

  There is an ongoing discussion whether hyperoxia, i.e. ventilation with high inspiratory O2 concentrations (FIO2), and the consecutive hyperoxaemia, i.e. supraphysiological arterial O2 tensions (PaO2), have a place during the acute management of circulatory shock. This concept is based on experimental evidence that hyperoxaemia may contribute to the compensation of the imbalance between O2 supply and requirements. However, despite still being common practice, its use is limited due to possible oxygen toxicity resulting from the increased formation of reactive oxygen species (ROS) limits, especially under conditions of ischaemia/reperfusion. Several studies have reported that there is a U-shaped relation between PaO2 and mortality/morbidity in ICU patients. Interestingly, these mostly retrospective studies found that the lowest mortality coincided with PaO2 ~ 150 mmHg during the first 24 h of ICU stay, i.e. supraphysiological PaO2 levels. Most of the recent large-scale retrospective analyses studied general ICU populations, but there are major differences according to the underlying pathology studied as well as whether medical or surgical patients are concerned. Therefore, as far as possible from the data reported, we focus on the need of mechanical ventilation as well as the distinction between the absence or presence of circulatory shock. There seems to be no ideal target PaO2 except for avoiding prolonged exposure (> 24 h) to either hypoxaemia (PaO2 < 55-60 mmHg) or supraphysiological (PaO2 > 100 mmHg). Moreover, the need for mechanical ventilation, absence or presence of circulatory shock and/or the aetiology of tissue dysoxia, i.e. whether it is mainly due to impaired macro- and/or microcirculatory O2 transport and/or disturbed cellular O2 utilization, may determine whether any degree of hyperoxaemia causes deleterious side effects.

Keywords:  Acute subarachnoidal haemorrhage; Cardiopulmonary resuscitation; Hyperox(aem)ia; Intracerebral bleeding; Ischaemic brain injury; Septic shock; Surgical site infection; Traumatic brain injury; Traumatic–haemorrhagic shock

DOI:  https://doi.org/10.1186/s13613-021-00872-y