Characteristics and clinical outcomes of patients with combined burns and trauma in Japan: Analysis of a nationwide trauma registry database.

INTRODUCTION: Patients with combined burns and trauma are often seen in the United States. The combination of trauma with burns increases mortality. In contrast, the characteristics and outcomes of these cases remain unknown in Japan. This study investigated the characteristics and outcomes of trauma associated with burns in Japan. METHODS: This multicenter retrospective cohort study was conducted by utilizing data from the Japan Trauma Data Bank for the period between 2004 and 2017. We evaluated the characteristics of burn patients (n = 5783) divided into two groups: burns only (n = 5537) and combined burns and trauma (n = 246). Clinical characteristics, including patient background, severity of trauma, injury mechanism, total body surface area affected, injury location, treatments, and clinical outcomes, were examined. RESULTS: Most patients in both the groups were injured by flames. The number proportion of patients with 40-89% of the total body surface area affected was 1069/5537 (19.3%) in the burn-only group and 23/246 (9.3%) in the combined burn and trauma group. The in-hospital mortality was 1006/5537 (18.2%) in the burn-only group and 17/246 (6.9%) in the combined burn and trauma group. CONCLUSIONS: We demonstrated the characteristics of Japanese patients with burns only compared with those with combined burns and trauma. Flames were the main cause of burns, and in-hospital mortality was lower in the combined burn and trauma group associated with a smaller burn area.

Therapeutic interventions and the length of hospital stay for pediatric patients with COVID-19: a multicenter cohort study.

The evidence for pediatric patients with COVID-19 was very limited, which was attributed to the small number of the cases as well as the rare incidence of severe pneumonia in this population. This retrospective cohort study aimed to identify the characteristics of pediatric patients with COVID-19 in the early period of the pandemic by analyzing Diagnosis Procedure Combination (DPC) data in Japan. This retrospective cohort analysis of Japanese multicenter research on COVID-19 using DPC data compared the outcomes and costs of treatment for pediatric patients with COVID-19. Of 4700 patients with COVID-19, 186 pediatric patients were included in this study. Among the included pediatric patients, 17 received therapeutic drugs specifically for COVID-19, while the remaining 169 pediatric patients received only symptomatic therapy. There were no significant differences in the length of hospital stay (9 vs. 8 days, p = 0.96), and medical cost (97,585 vs. 73,291 JPY) for the intervention and control groups, respectively by multiple regression analysis. This is the first epidemiological study to use DPC data to summarize the pathophysiology of pediatric patients in the early period of COVID-19 pandemic. There was no significant difference in length of hospital stay or medical cost by intervention.

Use of preoperative contrast-enhanced computed tomography in damage control strategy for blunt liver injury: A case report.

For patients with unstable abdominal trauma unresponsive to initial transfusion, the damage control strategy includes prompt hemostasis by open surgery and packing. Recently, a hybrid treatment that combines packing and transcatheter arterial embolization as a damage control strategy was reported to be effective; however, the indications and techniques are yet to be established. A 25-year-old male patient who was in shock due to severe liver injury after a traffic accident was brought to our emergency room by emergency services. After initial resuscitation, including resuscitative endovascular balloon occlusion of the aorta and blood transfusion, preoperative contrast-enhanced computed tomography indicated grade IV liver injury with active bleeding from the right hepatic artery. Damage control strategy with packing and subsequent transcatheter arterial embolization was determined to be useful. During treatment, bile leakage was observed. An endoscopic nasobiliary drainage tube was inserted, and the patient was treated conservatively. He was discharged on day 83 of hospitalization. Although using preoperative contrast-enhanced computed tomography before damage control surgery remains controversial, it can provide useful information to determine damage control strategy, including morphological evaluation of the injured area and the presence of active bleeding.

Use of two parallel oxygenators during veno-venous extracorporeal membrane oxygenation in a patient with severe obesity and COVID-19 pneumonia.

Background: Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is one effective treatment for COVID-19 pneumonia, but controversy regarding VV-ECMO management in obese patients still exists. In this report, we described a case in which two oxygenators were used in parallel in a severely obese patient (Body mass index: 60 kg/m2, body surface area: 2.8 m2).Case: The case was of a 27-year-old man diagnosed with COVID-19 pneumonia and admitted to our hospital. VV-ECMO was required on the fifth day after admission due to gradually worsening respiratory conditions and partial pressure of arterial oxygen (PaO2)/FiO2 ratio of 77. Immediately after the initiation of VV-ECMO, post-oxygenator in circuit, PaO2 was low at 134 mmHg. Even though the VV-ECMO circuit was replaced on the same day, the PaO2 still was low at 261 mmHg. Thus, we decided to use two oxygenators in parallel, after which the PaO2 stabilized at 400-500 mmHg.Conclusions: In this case, VV-ECMO oxygenation could be stabilized by utilizing two oxygenators in parallel. Using two membrane oxygenators may be a treatment option in severely obese patients with respiratory failure.

Complement Activation in Patients With Heat-Related Illnesses: Soluble CD59 Is a Novel Biomarker Indicating Severity of Heat-Related Illnesses.

OBJECTIVES: Although multiple organ dysfunction syndrome (MODS) is the main cause of death in patients with heat-related illnesses, its underlying pathophysiological mechanism remains elusive. Complement activation is considered one of the main causes of MODS in patients with sepsis and trauma. Considering the pathophysiological similarity of heat related-illnesses with sepsis and trauma, the complement system might be activated in patients with heat-related illnesses as well. Our aim was to investigate whether excessive complement activation occurs in patients with heat-related illnesses. DESIGN: Prospective observational study. SETTING: Emergency department in the university hospital. PATIENTS: Thirty-two patients with heat-related illnesses and 15 age-matched healthy controls were enrolled in this study. INTERVENTIONS: Blood samples were collected from the study subjects for the measurement of complement factors. MEASUREMENTS AND MAIN RESULTS: Complement component 3a (C3a), complement component 5a (C5a), C5b-9, complement factor B (Ba), Factor H, and soluble CD59 in plasma were measured. The levels of C3a, C5a, C5b-9, and Ba significantly increased in patients with heat-related illnesses on day 0 compared with those in the healthy controls. Soluble CD59 was significantly high in patients with heat-related illnesses on day 0 and showed a correlation with the severity of the condition (Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and staging scores), Japanese Association for Acute Medicine disseminated intravascular coagulation scores, and the coagulation system (prothrombin time and fibrin degradation products). CONCLUSIONS: The complement system was activated in patients with heat-related illnesses, suggesting that it is one of the causes of MODS. Soluble CD59 may be a potent biomarker for the severity of heat-related illnesses.

Causal relation of tricuspid regurgitation for heart failure outcomes: a mediation analysis of echocardiographic predictors.

Aims: Although significant tricuspid regurgitation (TR) is critically associated with heart failure (HF) prognosis, the predictors for large TR impact on HF outcomes remain unknown. This study aimed to identify echocardiographic predictors for a causal relation of TR to HF outcomes. Methods and results: In a retrospective, acute HF cohort of 462 patients, multivariate logistic regression analysis was performed to determine subgroups with strong association of greater-than-moderate TR with HF readmission or cardiovascular death in a year. We then conducted causal mediation analysis according to persistent atrial fibrillation (Af) or mitral regurgitation (MR) to identify the echocardiographic predictors. The association of TR with HF outcomes was prominent in subgroups of females, with Af, the enlarged indexed tricuspid annular diameter (TADi) or right atrial area, or within certain ranges of the left ventricular ejection fraction, indexed right ventricular end-systolic area, or fractional area change (FAC). Causal mediation analysis found that the TR impact was significant in patients with Af. Furthermore, combination of TADi ≥2.1 cm/m2 and FAC ≥30%, which accounted for half of TR patients, predicted a much larger TR impact irrespective of Af and MR. Its prediction ability was superior to that of the modified Model for End-stage Liver Disease score. Conclusion: The causal impact and burden of TR on HF outcomes was significant in patients with Af, and combining TADi ≥2.1 cm/m2 with FAC ≥30% could provide superior echocardiographic prediction of larger TR impact in HF patients.

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse.

T cells form an immune synapse (IS) with antigen-presenting cells (APCs) to detect antigens that match their TCR. Mitochondria, pannexin-1 (panx1) channels, and P2X4 receptors congregate at the IS where mitochondria produce the ATP that panx1 channels release in order to stimulate P2X4 receptors. P2X4 receptor stimulation causes cellular Ca2+ influx that up-regulates mitochondrial metabolism and localized ATP production at the IS. Here we show that P2Y11 receptors are essential players that sustain these T cell activation mechanisms. We found that P2Y11 receptors retract from the IS toward the back of cells where their stimulation by extracellular ATP induces cAMP/PKA signaling that redirects mitochondrial trafficking to the IS. P2Y11 receptors thus reinforce IS signaling by promoting the aggregation of mitochondria with panx1 ATP release channels and P2X4 receptors at the IS. This dual purinergic signaling mechanism involving P2X4 and P2Y11 receptors focuses mitochondrial metabolism to the IS where localized ATP production sustains synaptic activity in order to allow successful completion of T cell activation responses. Our findings have practical implications because rodents lack P2Y11 receptors, raising concerns as to the validity of rodent models to study treatment of infections and inflammatory conditions.

Combinations of cardiac and non-cardiac predictors for prognoses in patients with acute heart failure.

AIMS: In contemporary heart failure (HF) practice, prognostic value for combinations of cardiac and non-cardiac predictors remains poorly understood. We analysed the combinatorial predictors of outcomes in acute HF patients. METHODS AND RESULTS: This longitudinal cohort study included consecutive patients admitted for acute decompensated HF between April 2015 and March 2018 in an urban hospital. The main outcomes are HF readmission within 6 months after discharge or all-cause death. A total of 451 patients with 662 admissions were enrolled and the data including frailty and echocardiographic parameters were analysed by multivariate and matched cohort analyses. The mean age of the patients was 76.8 years. We constructed a multi-frailty index (MFI) ranging from 0 to 3 points as a composite of non-cardiac comorbidities and biopsychosocial frailty. In matched cohort of patients with ejection fraction ≧50% (HFpEF), MFI ≧1, pulmonary hypertension (PH; peak flow velocity of tricuspid regurgitation ≧2.9 m/s by echocardiography), and pancytopenia at discharge were strong predictors of HF readmission [odds ratios (ORs), 4.33, 2.5, and 2.86; P = 0.02, 0.05, and 0.02, respectively], and MFI ≧2 was the only predictor for all-cause death. For ejection fraction <40%, age, BNP ≧800 pg/mL, increase in estimated glomerular filtration rate during hospitalization, and lymphocytopenia plus anaemia predicted HF readmission (ORs, 1.77, 2.72, 0.73, and 2.89; P = 0.001, 0.05, 0.04, and 0.03, respectively). In contrast, diabetes mellitus was the only specific predictor found in patients over 80 years old. CONCLUSION: These data identified multi-frailty and PH or mild pancytopenia as synergistic predictors of HF readmission in HFpEF patients.

Early outcome prediction for out-of-hospital cardiac arrest with initial shockable rhythm using machine learning models.

AIM: Early outcome prediction for out-of-hospital cardiac arrest with initial shockable rhythm is useful in selecting the choice of resuscitative treatment by clinicians. This study aimed to develop and validate a machine learning-based outcome prediction model for out-of-hospital cardiac arrest with initial shockable rhythm, which can be used on patient's arrival at the hospital. METHODS: Data were obtained from a nationwide out-of-hospital cardiac arrest registry in Japan. Of 43,350 out-of-hospital cardiac arrest patients with initial shockable rhythm registered between 2013 and 2017, patients aged <18 years and those with cardiac arrest caused by external factors were excluded. Subjects were classified into training (n = 23,668, 2013-2016 data) and test (n = 6381, data from 2017) sets for validation. Only 19 prehospital variables were used for the outcome prediction. The primary outcome was death at 1 month or survival with poor neurological function (cerebral performance category 3-5; "poor" outcome). Several machine learning models, including those based on logistic regression, support vector machine, random forest, and multilayer perceptron classifiers were compared. RESULTS: In validation analyses, all machine learning models performed satisfactorily with area under the receiver operating characteristic curve values of 0.882 [95% confidence interval [CI]: 0.869-0.894] for logistic regression, 0.866 [95% CI: 0.853-0.879] for support vector machine, 0.877 [95% CI: 0.865-0.890] for random forest, and 0.888 [95% CI: 0.876-0.900] for multilayer perceptron classifiers. CONCLUSIONS: A favourable machine learning-based prognostic model available to use on patient arrival at the hospital was developed for out-of-hospital cardiac arrest with initial shockable rhythm.

Characteristics, injuries, and clinical outcomes of geriatric trauma patients in Japan: an analysis of the nationwide trauma registry database.

Geriatric trauma is a major socio-economic problem, especially among the aging Japanese society. Geriatric people are more vulnerable to trauma than younger people; thus, their outcomes are often severe. This study evaluates the characteristics of geriatric trauma divided by age in the Japanese population. We evaluated trauma characteristics in patients (n = 131,088) aged ≥ 65 years by segregating them into 2 age-based cohorts: age 65-79 years (65-79 age group; n = 70,707) and age ≥ 80 years (≥ 80 age group; n = 60,381). Clinical characteristics such as patient background, injury mechanism, injury site and severity, treatment, and outcome were examined. Injuries among men were more frequent in the 65-79 age group (58.6%) than in the ≥ 80 age group (36.3%). Falls were the leading cause of trauma among the 65-79 age group (56.7%) and the ≥ 80 age group (78.9%). In-hospital mortality was 7.7% in the 65-79 age group and 6.6% in the ≥ 80 age group. High fall in the ≥ 80 age group showed 30.5% mortality. The overall in-hospital mortality was 11.8% (the 65-79 age group, 12.3%; the ≥ 80 age group, 11.2%). Most hospitalized patients were transferred to another hospital (the 65-79 age group, 52.5%; the ≥ 80 age group, 66.2%). We demonstrated the epidemiological characteristics of Japanese geriatric trauma patients. The overall in-hospital mortality was 11.8%, and fall injury in the ≥ 80 age group required caution of trauma care.

Late i.v. steroid treatment for severe COVID-19-induced acute respiratory distress syndrome: a case report.

BACKGROUND: The efficacy of steroid treatment for coronavirus disease (COVID-19) is unknown. CASE PRESENTATION: A 67-year-old man was transported to our hospital due to impaired consciousness and respiratory failure. After admission, tracheal aspirate of the patient was harvested, and it tested positive for severe acute respiratory syndrome coronavirus 2 nucleic acid. He required veno-venous extracorporeal membrane oxygenation to sustain his oxygenation. However, his respiratory failure did not improve for 20 days. On day 20 of admission, we started to use i.v. steroid therapy. On day 23, lung opacity on the chest X-ray cleared and the patient's oxygen saturation improved significantly. We successfully removed extracorporeal membrane oxygenation on day 27. CONCLUSION: Our case report encourages more future trials to evaluate the therapeutic use of i.v. steroid in severe COVID-19-induced acute respiratory distress syndrome.

The purinergic receptor P2Y11 choreographs the polarization, mitochondrial metabolism, and migration of T lymphocytes.

T cells must migrate to encounter antigen-presenting cells and perform their roles in host defense. Here, we found that autocrine stimulation of the purinergic receptor P2Y11 regulates the migration of human CD4 T cells. P2Y11 receptors redistributed from the front to the back of polarized cells where they triggered intracellular cAMP/PKA signals that attenuated mitochondrial metabolism at the back. The absence of P2Y11 receptors at the front of cells resulted in hotspots of mitochondrial metabolism and localized ATP production that stimulated P2X4 receptors, Ca2+ influx, and pseudopod protrusion at the front. This regulatory function of P2Y11 receptors depended on their subcellular redistribution and autocrine stimulation by cellular ATP release and was perturbed by indiscriminate global stimulation. We conclude that excessive extracellular ATP-such as in response to inflammation, sepsis, and cancer-disrupts this autocrine feedback mechanism, which results in defective T cell migration, impaired T cell function, and loss of host immune defense.

Evaluation of appropriate indications for the use of sivelestat sodium in acute respiratory distress syndrome: a retrospective cohort study.

AIM: Sivelestat sodium, a selective neutrophil elastase inhibitor, is the only commercially available, specific therapy for acute respiratory distress syndrome (ARDS); however, its clinical efficacy is controversial. We aimed to evaluate appropriate indications for its use in ARDS. METHODS: We studied 66 patients with ARDS who were treated with sivelestat sodium. They were divided into survivors (n = 37) or non-survivors (n = 29) at 60 days, and clinical characteristics were analyzed. RESULTS: Patients' backgrounds evaluated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the sequential organ failure assessment (SOFA) score were significantly different between both groups (survivors versus non-survivors: APACHE II score, 14.7 ± 6.7 versus 20.5 ± 4.7, P < 0.01; SOFA, 7.25 ± 2.5 versus 9.82 ± 3.5, P < 0.01). There were no significant differences in other patients' characteristics. On receiver operator characteristic analysis of APACHE II scores before the use of sivelestat sodium, the estimated cut-off value for survival was calculated to be 18.5.On receiver operator characteristic analysis of the PaO2/FIO2 ratio, the area under the curve was the highest 3 days after the treatment, with the optimal cut-off point at 198. CONCLUSION: An APACHE II score ≤18, and a PaO2/FIO2 ratio >198 at 3 days after the use of sivelestat sodium predicted a good outcome.

Adenosine 5'-Monophosphate Protects from Hypoxia by Lowering Mitochondrial Metabolism and Oxygen Demand.

Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly vulnerable because hypoxia rapidly damages neurons due to their heavy reliance on oxidative phosphorylation. Therapeutic hypothermia can reduce ischemia-induced brain damage, but cooling procedures are slow and technically difficult to perform in critical care settings. It has been previously reported that injection of naturally occurring adenosine 5'-monophosphate (AMP) can rapidly induce hypothermia in mice. We studied the underlying mechanisms and found that AMP transiently reduces the heart rate, respiratory rate, body temperature, and the consciousness of adult male and female C57BL/6J mice. Adding AMP to mouse or human neuronal cell cultures dose-dependently reduced the membrane potential (ΔΨm) and Ca signaling of mitochondria in these cells. AMP treatment increased intracellular AMP levels and activated AMP-activated protein kinase, which resulted in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and of mitochondrial and cytosolic Ca signaling in resting and stimulated neurons. Pretreatment with an intraperitoneal injection of AMP almost doubled the survival time of mice under hypoxic (6% O2) or anoxic (<1% O2) conditions when compared to untreated mice. These findings suggest that AMP induces a hypometabolic state that slows mitochondrial respiration, reduces oxygen demand, and delays the processes that damage mitochondria in the brain and other organs following hypoxia and reperfusion. Further examination of these mechanisms may lead to new treatments that preserve organ function in critical care patients.

Frontline Science: Escherichia coli use LPS as decoy to impair neutrophil chemotaxis and defeat antimicrobial host defense.

Bacterial infections and sepsis are leading causes of morbidity and mortality in critically ill patients. Currently, there are no effective treatments available to improve clinical outcome in sepsis. Here, we elucidated a mechanism by which Escherichia coli (E. coli) bacteria impair neutrophil (PMN) chemotaxis and we studied whether this mechanism can be therapeutically targeted to improve chemotaxis and antimicrobial host defense. PMNs detect bacteria with formyl peptide receptors (FPR). FPR stimulation triggers mitochondrial ATP production and release. Autocrine stimulation of purinergic receptors exerts excitatory and inhibitory downstream signals that induce cell polarization and cell shape changes needed for chemotaxis. Here we show that the bacterial cell wall product LPS dose-dependently impairs PMN chemotaxis. Exposure of human PMNs to LPS triggered excessive mitochondrial ATP production and disorganized intracellular trafficking of mitochondria, resulting in global ATP release that disrupted purinergic signaling, cell polarization, and chemotaxis. In mice infected i.p. with E. coli, LPS treatment increased the spread of bacteria at the infection site and throughout the systemic circulation. Removal of excessive systemic ATP with apyrase improved chemotaxis of LPS-treated human PMNs in vitro and enhanced the clearance of E. coli in infected and LPS-treated mice. We conclude that systemic ATP accumulation in response to LPS is a potential therapeutic target to restore PMN chemotaxis and to boost the antimicrobial host immune defense in sepsis.

Lipopolysaccharide suppresses T cells by generating extracellular ATP that impairs their mitochondrial function via P2Y11 receptors.

T cell suppression contributes to immune dysfunction in sepsis. However, the underlying mechanisms are not well-defined. Here, we show that exposure of human peripheral blood mononuclear cells to bacterial lipopolysaccharide (LPS) can rapidly and dose-dependently suppress interleukin-2 (IL-2) production and T cell proliferation. We also report that these effects depend on monocytes. LPS did not prevent the interaction of monocytes with T cells, nor did it induce programmed cell death protein 1 (PD-1) signaling that causes T cell suppression. Instead, we found that LPS stimulation of monocytes led to the accumulation of extracellular ATP that impaired mitochondrial function, cell migration, IL-2 production, and T cell proliferation. Mechanistically, LPS-induced ATP accumulation exerted these suppressive effects on T cells by activating the purinergic receptor P2Y11 on the cell surface of T cells. T cell functions could be partially restored by enzymatic removal of extracellular ATP or pharmacological blocking of P2Y11 receptors. Plasma samples obtained from sepsis patients had similar suppressive effects on T cells from healthy subjects. Our findings suggest that LPS and ATP accumulation in the circulation of sepsis patients suppresses T cells by promoting inappropriate P2Y11 receptor stimulation that impairs T cell metabolism and functions. We conclude that inhibition of LPS-induced ATP release, removal of excessive extracellular ATP, or P2Y11 receptor antagonists may be potential therapeutic strategies to prevent T cell suppression and restore host immune function in sepsis.