DAMPs and radiation injury.

The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising effective countermeasures against radiation injury. High-dose ionizing radiation exposure triggers acute radiation syndrome (ARS), manifesting as hematopoietic, gastrointestinal, and neurovascular ARS. Hematopoietic ARS typically presents with neutropenia and thrombocytopenia, while gastrointestinal ARS results in intestinal mucosal injury, often culminating in lethal sepsis and gastrointestinal bleeding. This deleterious impact can be attributed to radiation-induced DNA damage and oxidative stress, leading to various forms of cell death, such as apoptosis, necrosis and ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or in the process of dying, either through passive or active pathways. These molecules then interact with pattern recognition receptors, triggering inflammatory responses. Such a cascade of events ultimately results in further tissue and organ damage, contributing to the elevated mortality rate. Notably, infection and sepsis often develop in ARS cases, further increasing the release of DAMPs. Given that lethal sepsis stands as a major contributor to the mortality in ARS, DAMPs hold the potential to function as mediators, exacerbating radiation-induced organ injury and consequently worsening overall survival. This review describes the intricate mechanisms underlying radiation-induced release of DAMPs. Furthermore, it discusses the detrimental effects of DAMPs on the immune system and explores potential DAMP-targeting therapeutic strategies to alleviate radiation-induced injury.

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice.

Introduction: Exposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been demonstrated to critically amplify and dysregulate immune responses. However, the role of TREM-1 in radiation injury remains unknown. Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern, is released from activated or stressed cells during inflammation. We hypothesized that ionizing radiation upregulates TREM-1 expression via eCIRP release to worsen survival. Methods: RAW264.7 cells and peritoneal macrophages collected from C57BL/6 wild-type (WT) mice were exposed to 5- and 10-Gray (Gy) radiation. C57BL/6 WT and CIRP-/- mice underwent 10-Gy total body irradiation (TBI). TREM-1 expression on RAW264.7 cells and peritoneal macrophages in vitro and in vivo were evaluated by flow cytometry. eCIRP levels in cell culture supernatants and in peritoneal lavage isolated from irradiated mice were evaluated by Western blotting. We also evaluated 30-day survival in C57BL/6 WT, CIRP-/- and TREM-1-/- mice after 6.5-Gy TBI. Results: The surface protein and mRNA levels of TREM-1 in RAW264.7 cells were significantly increased at 24 h after 5- and 10-Gy radiation exposure. TREM-1 expression on peritoneal macrophages was significantly increased after radiation exposure in vitro and in vivo. eCIRP levels were significantly increased after radiation exposure in cell culture supernatants of peritoneal macrophages in vitro and in peritoneal lavage in vivo. Moreover, CIRP-/- mice exhibited increased survival after 6.5-Gy TBI compared to WT mice. Interestingly, TREM-1 expression on peritoneal macrophages in CIRP-/- mice was significantly decreased compared to that in WT mice at 24 h after 10-Gy TBI. Furthermore, 30-day survival in TREM-1-/- mice was significantly increased to 64% compared to 20% in WT mice after 6.5-Gy TBI. Conclusion: Our data indicate that ionizing radiation increases TREM-1 expression in macrophages via the release of eCIRP, and TREM-1 contributes to worse survival after total body irradiation. Thus, targeting TREM-1 could have the potential to be developed as a novel medical countermeasure for radiation injury.

Deep sedation predicts pressure injury in patients admitted to intensive care units.

BACKGROUND: Patients in intensive care units (ICU) are frequently prescribed sedatives, which might increase the risk for pressure injury (PI). Although the association between sedation and incidence of PI has been noted, the adequate sedation level to prevent the incidence of PI in patients admitted to ICU is still unclear. AIM: This study aimed to investigate the association between fluctuating sedation levels and the incidence of PI in patients admitted to ICU. STUDY DESIGN: We retrospectively reviewed the medical records of 104 patients admitted to ICU. Data regarding the length of ICU stay (LOS) and comorbid infection were abstracted from medical records. The Richmond Agitation-Sedation Scale (RASS) was scored twice per day, and the standardized RASS (S-RASS, summation of RASS values divided by the number of samples) was used to evaluate changes in sedation levels. RESULTS: Among the 104 included patients, 65 patients (62.5%) were male (median age: 68.0 years), and 13 patients (12.5%) had PI during ICU admission. S-RASS scores were lower in patients with PI than in those without PI (P = .0001) even after adjustment for confounders (OR [95%CI]: 0.14 [0.03-0.58], P = .006). The LOS and infections were higher in patients with PI than in those without PI (P < .0001 and P = .005, respectively). The cut-off value of S-RASS for PI incidence was -3.2 (sensitivity: 88%; specificity: 85%), and a significant predictor of PI incidence (HR [95%CI]: 20.07 [2.53-159.11], P = .005). CONCLUSIONS: Deeper sedation levels based on S-RASS scores, which account for the effects of fluctuating sedation levels, were a strong, highly accurate predictor of PI incidence in patients admitted to ICU. RELEVANCE TO CLINICAL PRACTICE: Assessing fluctuations in the level of sedation using the S-RASS might help to identify sedative-induced PI in patients admitted to ICU.

A novel system that continuously visualizes and analyzes respiratory sounds to promptly evaluate upper airway abnormalities: a pilot study.

Although respiratory sounds are useful indicators for evaluating abnormalities of the upper airway and lungs, the accuracy of their evaluation may be limited. The continuous evaluation and visualization of respiratory sounds has so far been impossible. To resolve these problems, we developed a novel continuous visualization system for assessing respiratory sounds. Our novel system was used to evaluate respiratory abnormalities in two patients. The results were not known until later. The first patient was a 23-year-old man with chronic granulomatous disease and persistent anorexia. During his hospital stay, he exhibited a consciousness disorder, bradypnea, and hypercapnia requiring tracheal intubation. After the administration of muscle relaxant, he suddenly developed acute airway stenosis. Because we could not intubate and ventilate, we performed cricothyroidotomy. Subsequent review of our novel system revealed mild stridor before the onset of acute airway stenosis, which had not been recognized clinically. The second patient was a 74-year-old woman who had been intubated several days earlier for tracheal burn injury, and was extubated after alleviation of her laryngeal edema. After extubation, she gradually developed inspiratory stridor. We re-intubated her after diagnosing post-extubation laryngeal edema. Subsequent review of our novel system revealed serially increased stridor after the extubation, at an earlier time than was recognized by healthcare providers. This unique continuous monitoring and visualization system for respiratory sounds could be an objective tool for improving patient safety regarding airway complications.

Prevalence of rapid response systems in small hospitals: A questionnaire survey.

ABSTRACT: The rapid response system (RRS) was introduced for early stage intervention in patients with deteriorating clinical conditions. Responses to unexpected in-hospital patient emergencies varied among hospitals. This study was conducted to understand the prevalence of RRS in smaller hospitals and to identify the need for improvements in the responses to in-hospital emergencies.A questionnaire survey of 971 acute-care hospitals in western Japan was conducted from May to June 2019 on types of in-hospital emergency response for patients in cardiac arrest (e.g., medical emergency teams [METs]), before obvious deterioration (e.g., rapid response teams [RRTs]), and areas for improvement.We received 149 responses, including those from 56 smaller hospitals (≤200 beds), which provided fewer responses than other hospitals. Response systems for cardiac arrest were used for at least a limited number of hours in 129 hospitals (87%). The absence of RRS was significantly more frequent in smaller hospitals than in larger hospitals (13/56, 23% vs 1/60, 2%; P < .01). METs and RRTs operated in 17 (11%) and 15 (10%) hospitals, respectively, and the operation rate for RRTs was significantly lower in smaller hospitals than in larger hospitals (1/56, 2% vs 12/60, 20%; P < .01). Respondents identified the need for education and more medical staff and supervisors; data collection or involvement of the medical safety management sector was ranked low.The prevalence of RRS or predetermined responses before obvious patient deterioration was ≤10% in small hospitals. Specific education and appointment of supervisors could support RRS in small hospitals.

Hypothermia, Poorly Recognized by clinicians, is associated with Higher Mortality Among Critically Ill Patients with infections: A Retrospective Observational Study.

We investigated the relationship between the presence of hypothermia in infection and mortality in 233 infectious critically ill patients. The adjusted hazard ratio for death at 28 days in the low body temperature group was 3.30 compared with the high body temperature group. The proportion of appropriate antimicrobial therapy significantly decreased with decreasing body temperature. The proportion of medical records that documented body temperature abnormality in the low body temperature group (33%) was significantly lower than that in the high body temperature group (69%). Delayed antimicrobial therapy in patients with hypothermia, which may be due to poor recognition by physicians, could result in mortality.

Decreased intracellular histamine concentration and basophil activation in anaphylaxis.

BACKGROUND: Histamine is a crucial mediator in the development of anaphylaxis. Although histamine is promptly degraded because of its short half-life in plasma, basophils, which release histamine, remain in the blood for days. To explore basophils as a potential marker and their involvement in the pathogenesis of anaphylaxis, we evaluated the intracellular histamine concentration and the degree of basophil activation in anaphylaxis patients. METHODS: We conducted a case-control study enrolling anaphylaxis patients and healthy controls. Basophil activation was evaluated by flow cytometry using up-regulation of CD203c expression. RESULTS: We enrolled 23 patients and measured their blood histamine concentration. Basophil activation was analyzed in seven of 23 patients. The median intracellular histamine concentrations at admission were significantly lower in patients compared with controls (16.4 ng/mL [interquartile range {IQR}, 2.70 to 34.0] vs. 62.3 ng/mL [IQR, 46.0 to 85.1]; p < 0.0001). The median basophil number at admission was also significantly lower in patients compared with controls (2.21 cell/µL [IQR, 0.75 to 12.3] vs. 21.0 cell/µL [IQR, 19.5 to 28.9]; p = 0.027). CD203c expression was not up-regulated in any of the seven patients in vitro, but it was up-regulated in response to anti-IgE stimulation in vitro in two patients at admission and four patients at follow-up. CONCLUSIONS: Anaphylaxis is associated with a decrease in intracellular histamine, and a reduced number and reactivity of peripheral basophils. Impaired basophil function and a decrease in their number and intracellular histamine levels in the circulation may reflect the underlying mechanism, suggesting that basophils may be a marker of anaphylaxis.

Sera from Septic Patients Contain the Inhibiting Activity of the Extracellular ATP-Dependent Inflammasome Pathway.

Immunoparalysis is a common cause of death for critical care patients with sepsis, during which comprehensive suppression of innate and adaptive immunity plays a significant pathophysiological role. Although the underlying mechanisms are unknown, damage-associated molecular patterns (DAMPs) from septic tissues might be involved. Therefore, we surveyed sera from septic patients for factors that suppress the innate immune response to DAMPs, including adenosine triphosphate (ATP), monosodium urate, and high mobility group box-1. Macrophages, derived from THP-1 human acute monocytic leukemia cells, were incubated with each DAMP, in the presence or absence of sera that were collected from critically ill patients. Secreted cytokines were then quantified, and cell lysates were assayed for relevant intracellular signaling mediators. Sera from septic patients who ultimately did not survive significantly suppressed IL-1ß production only in response to extracellular ATP. This effect was most pronounced with sera collected on day 3, and persisted with sera collected on day 7. However, this effect was not observed when THP-1 cells were treated with sera from survivors of sepsis. Septic sera collected at the time of admission (day 1) also diminished intracellular levels of inositol 1,4,5-triphosphate and cytosolic calcium (P < 0.01), both of which are essential for ATP signaling. Finally, activated caspase-1 was significantly diminished in cells exposed to sera collected on day 7 (P < 0.05). In conclusion, the sera of septic patients contain certain factors that persistently suppress the immune response to extracellular ATP, thereby leading to adverse clinical outcomes.

Association between appropriate empiric antimicrobial therapy and mortality from bloodstream infections in the intensive care unit.

BACKGROUND: Empirical antimicrobial treatment for patients presenting with bloodstream infections is considered to affect patients' outcome. METHOD: We conducted a single-center, retrospective study of critically-ill patients hospitalized in the intensive care unit, to examine whether the appropriateness of antimicrobial therapy is associated with mortality from bloodstream infections. The primary study endpoints were the mortality and survival time up to 60 days after the sampling of the blood cultures. RESULTS: We enrolled 62 patients with bloodstream infection, of whom 46 received appropriate and 16 received inappropriate, empirical, antimicrobial therapy. The 60-day mortality of appropriately treated (35%) was significantly lower than that of inappropriately treated (88%) patients (p = .0003), with an adjusted odds ratio of dying = 0.043 (95% confidence interval 0.0047-0.23; p = .0011). Survival time differed significantly between the two groups (p = .0004), with an adjusted hazard ratio = 0.34 (95% confidence interval 0.16-0.70; p = .0043). CONCLUSION: Appropriate antimicrobial therapy administered to critically-ill patients presenting with bloodstream infections was associated with a lower 60-day mortality than inappropriate therapy.

Pediatric cardiorespiratory failure successfully managed with venoarterial-venous extracorporeal membrane oxygenation: a case report.

BACKGROUND: Venoarterial-venous extracorporeal membrane oxygenation (VAV ECMO) configuration is a combined procedure of extracorporeal membrane oxygenation (ECMO). The proportion of cardiac and respiratory support can be controlled by adjusting arterial and venous return. Therefore, VAV ECMO can be applicable as a bridging therapy in the transition from venoarterial (VA) to venovenous (VV) ECMO. CASE PRESENTATION: We present an 11-year-old girl with chemotherapy-induced myocarditis requiring extracorporeal cardiorespiratory support. She showed progressive hypotension, tachycardia, hyperlactemia, and tachypnea under support of catecholamines. Echocardiography showed severe left ventricular hypokinesis with an ejection fraction of 30 %. She was placed on VA ECMO with a drainage catheter from the right femoral vein (19.5 Fr) and a return catheter to the right femoral artery (16.5 Fr). Extracorporeal circulation was initiated at a blood flow of 2.0 L/min (59 mL/kg/min). On day 31, although cardiac function had improved, persistent pulmonary failure made weaning from VA ECMO difficult. We planned transition from VA ECMO to VAV ECMO to ensure gradual tapering of extracorporeal cardiac support while evaluating cardiopulmonary function. An additional return cannula (13.5 Fr) was inserted from the right internal jugular vein, which was connected to the circuit branch from the original returning cannula. We then gradually shifted the blood from the femoral artery to the right internal jugular vein over 24 h. She was successfully switched from VA to VV ECMO via VAV ECMO. CONCLUSIONS: VAV ECMO might be an option in ensuring oxygenation to the coronary circulation and allowing time to adequately evaluate cardiac function during transition from VA to VV ECMO. Further investigations using larger cohorts are necessary to validate the efficacy of VAV ECMO as a bridging therapy in the transition from VA to VV ECMO.

Tracheal intubation of a difficult airway using Airway Scope, Airtraq, and Macintosh laryngoscope: a comparative manikin study of inexperienced personnel.

BACKGROUND: The Airway Scope (AWS) (Pentax-AWS, Hoya Corp., Tokyo, Japan) and the Airtraq (ATQ) (Prodol, Vizcaya, Spain) have similarities in the novel structures of their blades. In this study, we evaluated the ease of use of the AWS and ATQ compared with the Macintosh laryngoscope (ML) by inexperienced personnel in a simulated manikin difficult airway. METHODS: Twenty-four fifth-year medical students with no previous experience in tracheal intubation participated in this study. We used an advanced patient simulator (SimMan(R), Laerdal Medical, Stavanger, Norway) to simulate difficult airway scenarios including cervical spine rigidity, limited mouth opening, and pharyngeal obstruction. The sequences in selecting devices and scenarios were randomized. Success rates for tracheal intubation, and the time required for visualization of the glottis, tracheal intubation, and inflation of the lungs, and the number of optimization maneuvers and dental click sounds were analyzed. The 3 different intubation devices were tested in 4 different scenarios by 24 students. RESULTS: Both the AWS and ATQ had very high success rates of tracheal intubation compared with the ML (AWS 100%*; ATQ 98%*; and ML 89%; *P < 0.05 AWS, ATQ versus ML). The time to intubation with the AWS was significantly shorter than with the ATQ and ML (AWS 11 +/- 6 seconds; ATQ 16 +/- 12 seconds; and ML 16 +/- 11 seconds; *P < 0.05 AWS versus ATQ, ML). The number of optimization maneuvers with the AWS was significantly lower than with the ATQ and ML. There were significantly more audible dental click sounds with the ML than with the AWS and ATQ. CONCLUSION: Both the AWS and ATQ may be suitable devices for difficult intubation by inexperienced personnel in this manikin simulated scenario. Further studies in a clinical setting are necessary to confirm these findings.

Inhibition of secretory phospholipase A2 activity attenuates lipopolysaccharide-induced acute lung injury in a mouse model.

This study evaluated the hypothesis that LY374388, an inhibitor of secretory phospholipase A(2) (sPLA(2)) activity, may exert a protective effect on lipopolysaccharide (LPS)-induced acute lung injury in male C57BL/6J mice. Intratracheal administration of LPS increased histopathological changes in lung tissue, lung wet to dry ratios, and the bronchoalveolar lavage fluid levels of neutrophil numbers, sPLA(2) activity, leukotriene B(4), and thromboxane B(2). However, a simultaneous intraperitoneal treatment with LY374388 significantly attenuated these LPS-induced changes. Thus, inhibition of sPLA(2) activity significantly attenuated the acute lung injury induced by LPS. sPLA(2) played an important role in the pathogenesis of LPS-induced acute lung injury in mice.

Practical use of airway pressure release ventilation for severe ARDS--a preliminary report in comparison with a conventional ventilatory support.

Airway pressure release ventilation (APRV) is a ventilatory mode that allows unsupported spontaneous breathing at any phase of the ventilatory cycle with high mean airway pressures. We hypothesized that use of APRV might produce potential beneficial effects on oxygenation, reducing mortality in patients with severe acute respiratory distress syndrome (ARDS) in comparison with synchronized intermittent mandatory ventilation (SIMV) as a conventional mode of ventilation. We retrospectively reviewed data of 58 patients with severe ARDS (the ratios of partial arterial oxygen tension to fraction of inspired oxygen, PaO2/F(I)O2 ratio <150). The patients' data were divided into two groups: SIMV-group and APRV-group. Patients' backgrounds, oxygenation on day 0, 1, 3, 5 and 7 following initiation of each mode, vasopressor dependence, duration of ventilation, duration of ICU stay, and mortality in ICU were analyzed. PaO2/F(I)O2 ratios were statistically higher in the APRV-group (APRV vs. SIMV on day 1, 3, 5, 7: 201.6 +/- 76 vs.150 +/- 59.1, 256.7 +/- 71.5 vs.182.1 +/- 65.4, 268.8 +/- 73.3 vs. 204.6 +/- 72.8, and 263 +/- 74.5 vs. 204.1 +/- 67.1, respectively, p<0.05). Vasopressors were less used (p=0.018), and mortality in ICU tended to be lower in the APRV group (31%) than in the SIMV group (59%) (p=0.050). Use of APRV in patients with severe ARDS appears to be associated with improvements in oxygenation, and a trend toward lower mortality in ICU. No significant adverse effects were observed. Prospective controlled studies are required to confirm the benefits of this ventilatory mode in comparison with conventional methods for severe ARDS.