bims-heshmo 2021-05-16 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–05–16
nine papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Prehospital shock index and systolic blood pressure are highly specific for pediatric massive transfusion.
Addition of Drag-Reducing Polymers to Colloid Resuscitation Fluid Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.
Embolization versus Surgery for Stabilized Patients with Solid Organ Injury.
Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial.
Predicting Acute Respiratory Distress Syndrome in Severe Blunt Trauma: The Utility of Interleukin-18.
Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis.
TLR4 Transactivates CD8+ T Lymphocytes upon Acute Sterile Tissue Injury.
Defining major trauma: a Delphi study.
Anticoagulation Is Associated with Increased Mortality in Splenic Injuries.

J Trauma Acute Care Surg. 2021 May 10.

Prehospital shock index and systolic blood pressure are highly specific for pediatric massive transfusion.

Caroline S Zhu, Maxwell Braverman, Sabrina Goddard, Ashley C McGinity, Douglas Pokorny, Tracy Cotner-Pouncy, Brian J Eastridge, Sondra Epley, Leslie J Greebon, Rachelle B Jonas, Lillian Liao, Susannah E Nicholson, Randall Schaefer, Ronald M Stewart, Christopher J Winckler, Donald H Jenkins.

BACKGROUND: While massive transfusion protocols (MTP) are associated with decreased mortality in adult trauma patients, there is limited research on the impact of MTP on pediatric trauma patients. The purpose of this study was to compare pediatric trauma patients requiring massive transfusion to all other pediatric trauma patients to identify triggers for MTP activation in injured children.
METHODS: Using our level I trauma center's registry, we retrospectively identified all pediatric trauma patients from January 2015 to January 2018. Massive transfusion (MT) was defined as infusion of 40 mL/kg of blood products in the first 24 hours of admission. Patients missing prehospital vital sign data were excluded from the study. We retrospectively collected data including: demographics, blood utilization, variable outcome data, prehospital vital signs, prehospital transport times, and injury severity scores (ISS). Statistical significance was determined using Mann-Whitney U test and chi-square test. P values less than 0.05 were considered significant.
RESULTS: Thirty-nine of the 2,035 pediatric patients (1.9%) met criteria for MT. All-cause mortality in MT patients was 49% (19/39) versus 0.01% (20/1996) in Non-MT patients. The two groups significantly differed in ISS, prehospital vital signs, and outcome data.Both systolic blood pressure (SBP) <100 mmHg and shock index (SI) >1.4 were found to be highly specific for massive transfusion with specificities of 86% and 92%, respectively. The combination of SBP<100 mmHg and SI>1.4 had a specificity of 94%. The positive and negative predictive values of SBP<100 mmHg and SI >1.4 in predicting massive transfusion were 18% and 98%, respectively. Based on positive likelihood ratios, patients with both SBP<100 mmHg and SI>1.4 were 7.2 times more likely to require massive transfusion than patients who did not meet both of these vital sign criteria.
CONCLUSIONS: Pediatric trauma patients requiring early blood transfusion present with lower blood pressures and higher heart rates, as well as higher shock indexes and lower pulse pressures. We found that shock index and systolic blood pressure are highly specific tools with promising likelihood ratios that could be used to identify patients requiring early transfusion.
LEVELS OF EVIDENCE AND STUDY TYPE: Therapeutic/Care Management, Level V.

DOI: https://doi.org/10.1097/TA.0000000000003275
Adv Exp Med Biol. 2021 ;1269 283-288

Addition of Drag-Reducing Polymers to Colloid Resuscitation Fluid Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.

Denis E Bragin, Olga A Bragina, Lucy Berliba, Marina V Kameneva, Edwin M Nemoto.

  Hemorrhagic shock (HS) is a severe complication of traumatic brain injury (TBI) that doubles mortality due to severely compromised microvascular cerebral blood flow (mvCBF) and oxygen delivery reduction, as a result of hypotension. Volume expansion with resuscitation fluids (RF) for HS does not improve microvascular CBF (mvCBF); moreover, it aggravates brain edema. We showed that the addition of drag-reducing polymers (DRP) to crystalloid RF (lactated Ringer's) significantly improves mvCBF, oxygen supply, and neuronal survival in rats suffering TBI+HS. Here, we compared the effects of colloid RF (Hetastarch) with DRP (HES-DRP) and without (HES). Fluid percussion TBI (1.5 ATA, 50 ms) was induced in rats and followed by controlled HS to a mean arterial pressure (MAP) of 40 mmHg. HES or HES-DRP was infused to restore MAP to 60 mmHg for 1 h (prehospital period), followed by blood reinfusion to a MAP of 70 mmHg (hospital period). In vivo two-photon microscopy was used to monitor cerebral microvascular blood flow, tissue hypoxia (NADH), and neuronal necrosis (i.v. propidium iodide) for 5 h after TBI+HS, followed by postmortem DiI vascular painting. Temperature, MAP, blood gases, and electrolytes were monitored. Statistical analyses were done using GraphPad Prism by Student's t-test or Kolmogorov-Smirnov test, where appropriate. TBI+HS compromised mvCBF and tissue oxygen supply due to capillary microthrombosis. HES-DRP improved mvCBF and tissue oxygenation (p < 0.05) better than HES. The number of dead neurons in the HES-DRP was significantly less than in the HES group: 76.1 ± 8.9 vs. 178.5 ± 10.3 per 0.075 mm3 (P < 0.05). Postmortem visualization of painted vessels revealed vast microthrombosis in both hemispheres that were 33 ± 2% less in HES-DRP vs. HES (p < 0.05). Thus, resuscitation after TBI+HS using HES-DRP effectively restores mvCBF and reduces hypoxia, microthrombosis, and neuronal necrosis compared to HES. HES-DRP is more neuroprotective than lactated Ringer's with DRP and requires an infusion of a smaller volume, which reduces the development of hypervolemia-induced brain edema.

Keywords:  Drag-reducing polymer (DRP); Hemorrhagic shock (HS); Hetastarch; Resuscitation fluid (RF); Traumatic brain injury (TBI)

DOI:  https://doi.org/10.1007/978-3-030-48238-1_45
J Vasc Interv Radiol. 2021 May 11. pii: S1051-0443(21)01085-X. [Epub ahead of print]

Embolization versus Surgery for Stabilized Patients with Solid Organ Injury.

Makoto Aoki, Toshikazu Abe, Shuichi Hagiwara, Daizoh Saitoh, Kiyohiro Oshima.

   PURPOSE: Embolization is generally limited to stable patients with solid organ injury. The effectiveness of embolization versus laparotomy for unstable patients who responded to initial resuscitation with solid organ injury remains unknown. The aim of this study was to compare embolization with laparotomy for the management of unstable patients who responded to initial resuscitation with isolated solid organ injury.
MATERIALS AND METHODS: Data from a Japanese nationwide trauma registry were analyzed. Hemodynamically unstable (sBP <90 mmHg and blood transfusion within the first 24 h) patients with solid organ injury (liver and/or spleen) after initial computed tomography assessment performed were included. A total of 224 patients were included (median age: 53.0 years, interquartile-range (IQR): 32.0-69.0 years; 73.3% male; liver = 131 (58%) and spleen = 98 (44%); median organ injury scale: 3, IQR: 3-4; median injury severity score: 19, IQR: 16-25). Patients who underwent embolization were compared with those who underwent laparotomy. The primary outcome was in-hospital survival. The data were evaluated using a propensity score matching analysis.
RESULTS: Laparotomy and embolization were performed in 133 (59.1%) and 91 (40.4%) patients, respectively. Of those, 111 (84%) and 84 (92%) patients achieved in-hospital survival after laparotomy and embolization, respectively. There was no significant difference in in-hospital survival (P=0.053). The propensity score matching model did not reveal a significant difference in in-hospital survival (P=0.276).
CONCLUSIONS: There was no significant difference between embolization and laparotomy in terms of in-hospital survival among unstable patients who responded to initial resuscitation with isolated solid organ injury.

Keywords:  angiography; liver; propensity score; shock; spleen; traumatic

DOI:  https://doi.org/10.1016/j.jvir.2021.02.028
Adv Ther. 2021 May 10.

Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial.

Anil Gulati, Dinesh Jain, Nilesh Radheshyam Agrawal, Prashant Rahate, Rajat Choudhuri, Soumen Das, Deba Prasad Dhibar, Madhav Prabhu, Sameer Haveri, Rohit Agarwal, Manish S Lavhale.

   INTRODUCTION: Centhaquine (Lyfaquin®) showed significant efficacy as a resuscitative agent in animal models of haemorrhagic shock. Its safety and tolerability were confirmed in healthy human volunteers. In this study, our primary objective was to determine the safety, and the secondary objective was to assess the efficacy of centhaquine in patients with hypovolemic shock.
METHODS: A prospective, multicentre, randomized phase II study was conducted in male and female patients aged 18-70 years with hypovolemic shock having systolic BP ≤ 90 mmHg. Patients were randomized in a 1:1 ratio to either the control or centhaquine group. The control group received 100 ml of normal saline infusion over 1 h, while the centhaquine group received 0.01 mg/kg of centhaquine in 100 ml normal saline infusion over 1 h. Every patient received standard of care (SOC) and was followed for 28 days.
RESULTS: Fifty patients were included, and 45 completed the trial: 22 in the control group and 23 in the centhaquine group. The demographics of patients in both groups were comparable. No adverse event related to centhaquine was recorded in the 28-day observation period. The baseline, Injury Scoring System score, haemoglobin, and haematocrit were similar in both groups. However, 91% of the patients in the centhaquine group needed major surgery, whereas only 68% in the control group (p = 0.0526). Twenty-eight-day all-cause mortality was 0/23 in the centhaquine group and 2/22 in the control group. The percent time in ICU and ventilator support was less in the centhaquine group than in the control group. The total amount of vasopressors needed in the first 48 h of resuscitation was lower in the centhaquine group than in the control group (3.12 ± 2.18 vs. 9.39 ± 4.28 mg). An increase in systolic and diastolic BP from baseline through 48 h was more marked in the centhaquine group than in the control group. Compared with the control group, blood lactate level was lower by 1.75 ± 1.07 mmol/l in the centhaquine group on day 3 of resuscitation. Improvements in base deficit, multiple organ dysfunction syndrome (MODS) score and adult respiratory distress syndrome (ARDS) were greater in the centhaquine group than in the control group.
CONCLUSION: When added to SOC, centhaquine is a well-tolerated and effective resuscitative agent. It improves the clinical outcome of patients with hypovolemic shock.
TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT04056065.

Keywords:  Centhaquine; Haemorrhage; Hypovolemia; Resuscitative agent; Shock

DOI:  https://doi.org/10.1007/s12325-021-01760-4
Surg Infect (Larchmt). 2021 May 13.

Predicting Acute Respiratory Distress Syndrome in Severe Blunt Trauma: The Utility of Interleukin-18.

Genna Beattie, Caitlin M Cohan, Gregory P Victorino.

  Background: In trauma, direct pulmonary injury and innate immune response activation primes the lungs for acute respiratory distress syndrome (ARDS). The inflammasome-dependent release of interleukin-18 (IL-18) was recently identified as a key mediator in ARDS pathogenesis, leading us to hypothesize that plasma IL-18 is a diagnostic predictor of ARDS in severe blunt trauma. Patients and Methods: Secondary analysis of the Inflammation and Host Response to Injury database was performed on plasma cytokines collected within 12 hours of severe blunt trauma. Trauma-related cytokines, including IL-18, were compared between patients with and without ARDS and were evaluated for association with ARDS using regression analysis. Threshold cytokine concentrations predictive of ARDS were determined using receiver-operating curve (ROC) analysis. Results: Cytokine analysis of patients without ARDS patients (n = 61) compared with patients with ARDS (n = 19) demonstrated elevated plasma IL-18 concentration in ARDS and IL-18 remained correlated with ARDS on logistic regression after confounder adjustment (p = 0.008). Additionally, ROC analysis revealed IL-18 as a strong ARDS predictor (area under the curve [AUC] = 0.83), with a threshold IL-18 value of 170 pg/mL (Youden index, 0.3). Unlike in patients without ARDS, elevated IL-18 persisted in patients with ARDS during the acute injury phase (p ≤ 0.02). Other trauma-related cytokines did not correlate with ARDS. Conclusions: In severe blunt trauma, IL-18 is a robust predictor of ARDS and remains elevated throughout the acute injury phase. These findings support the use of IL-18 as a key ARDS biomarker, promoting early identification of trauma patients at greater risk of developing ARDS. Timely recognition of ARDS and implementation of advantageous supportive care practices may reduce trauma-related ARDS morbidity and costs.

Keywords:  Host Response to Injury Database; acute respiratory distress syndrome; blunt trauma; cytokines; interleukin-18; lung injury

DOI:  https://doi.org/10.1089/sur.2021.084
Crit Care Med. 2021 May 07.

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis.

Charlie J Nederpelt, Leon Naar, Pieta Krijnen, Saskia le Cessie, Haytham M A Kaafarani, Menno V Huisman, George C Velmahos, Inger B Schipper.

OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies.
DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library.
STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage.
DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event.
DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents.
CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.

DOI: https://doi.org/10.1097/CCM.0000000000005059
Immunohorizons. 2021 May 12. 5(5): 298-306

TLR4 Transactivates CD8+ T Lymphocytes upon Acute Sterile Tissue Injury.

Lisa Wienhöfer, Max Marker, Anne-Charlotte Antoni, Kathrin Sutter, André Sander, Marcel Dudda, Stefanie B Flohé.

Acute major tissue injury induces immune dysregulation that is characterized by the development of systemic sterile inflammation and an increased risk for opportunistic infections. Although the contribution of the innate immune system has been examined in detail, research on the impact of acute sterile tissue damage on the T cell compartment remains limited. In the current study, we used a clinically relevant mouse model for traumatic skeletal muscle injury to investigate the impact of sterile tissue damage on diverse subpopulations of CD4+ Th and CD8+ cytotoxic T cells in systemic and local lymphoid organs. For the first time, to our knowledge, we provide evidence that injury selectively induced the expression of the activation marker CD69 on naive and central/virtual memory CD8+ T cells in the lymph nodes but not in the spleen of male mice. CD4+ Th cells remained unaffected in both organs. The activation of CD8+ T cells was dependent on signaling through TLR4. Within a few hours, injury triggered the expression of IL-12 in the lymph nodes in a TLR4-dependent manner. Blocking of IL-12 prevented the activation of naive and central memory CD8+ T cells after injury. Thus, early after traumatic tissue damage, TLR4 transactivates naive and central/virtual memory CD8+ T cells through innate cytokines in local lymph nodes, where they might modulate forthcoming local immune responses.

DOI: https://doi.org/10.4049/immunohorizons.2100001
Scand J Trauma Resusc Emerg Med. 2021 May 10. 29(1): 63

Defining major trauma: a Delphi study.

Lee Thompson, Michael Hill, Fiona Lecky, Gary Shaw.

   INTRODUCTION: Retrospective trauma scores are often used to categorise trauma, however, they have little utility in the prehospital or hyper-acute setting and do not define major trauma to non-specialists. This study employed a Delphi process in order to gauge degrees of consensus/disagreement amongst expert panel members to define major trauma.
METHOD: A two round modified Delphi technique was used to explore subject-expert consensus and identify variables to define major trauma through systematically collating questionnaire responses. After initial descriptive analysis of variables, Kruskal-Wallis tests were used to determine statistically significant differences (p < 0.05) in response to the Delphi statements between professional groups. A hierarchical cluster analysis was undertaken to identify patterns of similarity/difference of response. A grounded theory approach to qualitative analysis of data allowed for potentially multiple iterations of the Delphi process to be influenced by identified themes.
RESULTS: Of 55 expert panel members invited to participate, round 1 had 43 participants (Doctor n = 20, Paramedic n = 20, Nurse n = 5, other n = 2). No consistent patterns of opinion emerged with regards to professional group. Cluster analysis identified three patterns of similar responses and coded as trauma minimisers, the middle ground and the risk averse. Round 2 had 35 respondents with minimum change in opinion between rounds. Consensus of > 70% was achieved on many variables which included the identification of life/limb threatening injuries, deranged physiology, need for intensive care interventions and that extremes of age need special consideration. It was also acknowledged that retrospective injury severity scoring has a role to play but is not the only method of defining major trauma. Various factors had a majority of agreement/disagreement but did not meet the pre-set criteria of 70% agreement. These included the topics of burns, spinal immobilisation and whether a major trauma centre is the only place where major trauma can be managed.
CONCLUSION: Based upon the output of this Delphi study, major trauma may be defined as: "Significant injury or injuries that have potential to be life-threatening or life-changing sustained from either high energy mechanisms or low energy mechanisms in those rendered vulnerable by extremes of age".

Keywords:  Delphi; Major trauma; Prehospital

DOI:  https://doi.org/10.1186/s13049-021-00870-w
J Surg Res. 2021 May 08. pii: S0022-4804(21)00230-4. [Epub ahead of print]266 1-5

Anticoagulation Is Associated with Increased Mortality in Splenic Injuries.

Bishwajit Bhattacharya, Robert D Becher, Kevin M Schuster, Kimberly A Davis, Adrian A Maung.

   INTRODUCTION: Anticoagulation (AC) is associated with worse outcomes after trauma in some but not all studies. To further investigate the effect of AC on outcomes in patients with splenic injury, we analyzed the Trauma Quality Programs Participant Use File (PUF) METHODS: The 2017 PUF was used to identify adult (18+ y) with all mechanisms and grades of splenic injury. Demographics, comorbidities, hospital course and outcomes were compared between AC and non-AC patients.
RESULTS: A total of 18,749 patients were included, 622 were on AC. The AC patients were older but had comparable gender composition to non-AC patients. Injury Severity Score (18.2 versus 22.5) and rates of serious (AIS ≥ 3) injury were all lower in the AC group (P = 0.001). AC patients received fewer units of RBC (5.7 versus 8.0 units, P < 0.001) and FFP (3.9 versus 5.4 units, P < 0.001) in the first 24 h but underwent angiography at similar rates (23.6 versus 24.5%, P = 0.8). Among those who underwent angiography, patients were more likely to undergo embolization if they were on AC (89.7 versus 73.9%, P = 0.04). Rates of splenic surgery were comparable (19.3 versus 21.5%, P = 0.2) between AC versus non-AC patients. Median LOS was longer in AC patients (6.3 versus 5.6 d, P = 0.002). AC patients had a higher mortality (13.3 versus 7.0%, P = 0.001). In a multivariable binary logistic regression, AC was an independent risk factor for mortality with OR 1.4 (95% CI: 1.1-1.9) CONCLUSIONS: Anticoagulation is associated with increased mortality in patients with splenic injury.

Keywords:  Adult; Anticoagulation; Injury; Outcomes; Spleen; Trauma

DOI:  https://doi.org/10.1016/j.jss.2021.04.002