A Disintegrin and Metalloproteinase with Thrombospondin Motifs 4 Regulates Pulmonary Vascular Hyperpermeability through Destruction of Glycocalyx in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) has no specific and effective treatment, and there is an urgent need to understand its pathogenesis. Therefore, based on the hypothesis that molecules whose expression is upregulated in injured pulmonary vascular endothelial cells (VECs) are involved in the pathogenesis of ARDS, we conducted a study to elucidate the molecular mechanisms and identify target factors for treatment. Primary human lung microvascular endothelial cells (HMVEC-Ls) were stimulated with lipopolysaccharide (LPS) or poly (I:C) and analyzed via a microarray to identify target genes for ARDS. We found that a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) was induced in murine lung VECs in an LPS-mediated ARDS model. Elevated ADAMTS4 was also observed by the immunostaining of lung samples from ARDS patients. The suppression of ADAMTS4 by siRNA in VECs ameliorated LPS-stimulated vascular permeability. The impairment of the cell surface expression of syndecan-1, a marker of the glycocalyx that is an extracellular matrix involved in vascular permeability, was dramatically inhibited by ADAMTS4 suppression. In addition, the suppression of ADAMTS4 protected against LPS-induced reductions in syndecan-1 and the adherens junction protein vascular endothelial cadherin. These results suggest that ADAMTS4 regulates VEC permeability in ARDS and may be a predictive marker and therapeutic target for ARDS.

THE CRITICAL ROLE OF THE HISTONE MODIFICATION ENZYME SETDB2 IN THE PATHOGENESIS OF ACUTE RESPIRATORY DISTRESS SYNDROME.

ABSTRACT: Introduction: Acute respiratory distress syndrome (ARDS) is a severe hypoxemic respiratory failure with a high in-hospital mortality. However, the molecular mechanisms underlying ARDS remain unclear. Recent findings have indicated that the onset of severe inflammatory diseases, such as sepsis, is regulated by epigenetic changes. We investigated the role of epigenetic changes in ARDS pathogenesis using mouse models and human samples. Methods: Acute respiratory distress syndrome was induced in a mouse model (C57BL/6 mice, myeloid cell or vascular endothelial cell [VEC]-specific SET domain bifurcated 2 [Setdb2]-deficient mice [Setdb2 ff Lyz2 Cre+ or Setdb2 ff Tie2 Cre+ ], and Cre - littermates) by intratracheal administration of lipopolysaccharide (LPS). Analyses were performed at 6 and 72 h after LPS administration. Sera and lung autopsy specimens from ARDS patients were examined. Results: In the murine ARDS model, we observed high expression of the histone modification enzyme SET domain bifurcated 2 ( Setdb2 ) in the lungs. In situ hybridization examination of the lungs revealed Setdb2 expression in macrophages and VECs. The histological score and albumin level of bronchoalveolar lavage fluid were significantly increased in Setdb2 ff Tie2 Cre+ mice following LPS administration compared with Setdb2 ff Tie2 Cre- mice, whereas there was no significant difference between the control and Setdb2 ff Lyz2 Cre+ mice. Apoptosis of VECs was enhanced in Setdb2 ff Tie2 Cre+ mice. Among the 84 apoptosis-related genes, the expression of TNF receptor superfamily member 10b ( Tnfrsf10b ) was significantly higher in Setdb2 ff Tie2 Cre+ mice than in control mice. Acute respiratory distress syndrome patients' serum showed higher SETDB2 levels than those of healthy volunteers. SETDB2 levels were negatively correlated with the partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen concentration ratio. Conclusion: Acute respiratory distress syndrome elevates Setdb2 , apoptosis of VECs, and vascular permeability. Elevation of histone methyltransferase Setdb2 suggests the possibility to histone change and epigenetic modification. Thus, Setdb2 may be a novel therapeutic target for controlling the pathogenesis of ARDS.

The spleen is the major site for the development and expansion of inhibitor producing-cells in hemophilia A mice upon FVIII infusion developing high-titer inhibitor.

BACKGROUND: Hemophilia A (HA) is a hereditary bleeding disorder caused by defects in endogenous factor (F)VIII. Approximately 30 % of patients with severe HA treated with FVIII develop neutralizing antibodies (inhibitors) against FVIII, which render the therapy ineffective. The managements of HA patients with high-titter inhibitors are especially challenging. Therefore, it is important to understand the mechanism(s) of high-titer inhibitor development and dynamics of FVIII-specific plasma cells (FVIII-PCs). AIMS: To identify the dynamics of FVIII-PCs and the lymphoid organs in which FVIII-PCs are localized during high-titer inhibitor formation. METHODS AND RESULTS: When FVIII-KO mice were intravenously injected with recombinant (r)FVIII in combination with lipopolysaccharide (LPS), a marked enhancement of anti-FVIII antibody induction was observed with increasing FVIII-PCs, especially in the spleen. When splenectomized or congenitally asplenic FVIII-KO mice were treated with LPS + rFVIII, the serum inhibitor levels decreased by approximately 80 %. Furthermore, when splenocytes or bone marrow (BM) cells from inhibitor+ FVIII-KO mice treated with LPS + rFVIII were grafted into immune-deficient mice, anti-FVIII IgG was detected only in the serum of splenocyte-administered mice and FVIII-PCs were detected in the spleen but not in the BM. In addition, when splenocytes from inhibitor+ FVIII-KO mice were grafted into splenectomized immuno-deficient mice, inhibitor levels were significantly reduced in the serum. CONCLUSION: The spleen is the major site responsible for the expansion and retention of FVIII-PCs in the presence of high-titer inhibitors.

Transition of Antibody Titers after SARS-CoV-2 mRNA Vaccination in Japanese Healthcare Workers.

Since February 2021, healthcare workers in Japan have been preferentially vaccinated with a messenger RNA vaccine (BNT162b2; Pfizer/BioNTech) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While many studies have confirmed that this vaccine is highly effective in reducing hospitalization and deaths from coronavirus disease 2019 (COVID-19), antibody titers tend to decline at 3 months after vaccination, leading to a risk of breakthrough infections. Thus, information is needed to support the decision regarding the 3rd vaccination. In this study, we investigated the transition of anti-SARS-CoV-2 spike protein receptor-binding domain (RBD) IgG and neutralizing antibody titers in 37 vaccinated Japanese healthcare workers. Samples were collected 6 times starting before vaccination until 6 months after the second vaccination. The levels of anti-SARS-CoV-2 RBD IgG peaked 1 week after the 2nd vaccination, then declined over time and decreased to < 10% at 6 months after the 2nd vaccination. Additionally, approximately one-third of the healthcare workers were seronegative for the Omicron variant 6 months after the 2nd vaccination. Workers with low anti-SARS-CoV-2 RBD IgG levels also had low neutralizing antibody titers. These data support booster dose administration for healthcare workers, especially those with low anti-SARS-CoV-2 RBD IgG levels.

Sensitivity and specificity analyses of COVID-19 screening protocol for emergency medical services: A STARD-compliant population-based retrospective study.

During the novel coronavirus disease (COVID-19) pandemic, emergency medical services (EMS) has borne a huge burden in transporting emergency patients. However, the protocol's effect on identifying emergency patients who are likely to have COVID-19 is unknown. We aimed to evaluate the diagnostic accuracy of a prehospital COVID-19 screening protocol for EMS. We conducted this population-based retrospective study in Nara Prefecture, Japan. The Nara Prefectural Government implemented a screening protocol for COVID-19 comprising the following symptom criteria (fever, cough, sore throat, headache, malaise, dysgeusia, or anosmia) and epidemiological criteria (contact history with confirmed COVID-19 cases or people with upper respiratory symptoms, or travel to areas with high infection rate). A patient meeting at least one criterion of each class was considered positive. We evaluated all 51,351 patients from the regional EMS database of the Nara Prefecture (emergency Medical Alliance for Total Coordination of Healthcare) who were registered from June 15, 2020 to May 31, 2021 and had results of COVID-19 reverse transcription polymerase chain reaction (RT-PCR) tests. We assessed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this protocol. We also assessed how these outcomes changed by adding vital signs and conducted a 10-fold and 100-fold prevalence simulation. The screening protocol was used for 246/51351 patients (0.5%). Among them, 31 tested positive after EMS transportation. This protocol's sensitivity, specificity, PPV, and NPV were 40.8%, 99.6%, 12.6%, and 99.9%, respectively. With the addition of ≥2 vital signs (body temperature ≥37.5 °C, respiratory rate ≥20 breaths/minute, and oxygen saturation <90%), sensitivity and PPV changed to 61.8% and 1.0%, respectively, while NPV remained 99.9%. With a 10-fold and 100-fold increase in disease, the protocol PPV would be 59.0% and 94.3%, and NPV would be 99.1% and 90.7%, respectively, and with additional vital signs, PPV would be 8.9% and 53.1%, and NPV would be 99.4% and 93.2%, respectively. This COVID-19 screening protocol helped enable EMS transport for patients with COVID-19 with a PPV of 12.6%. Adding other vital sign variables may improve its diagnostic value if the prevalence rate increases.

A case of subcutaneous emphysema/mediastinal emphysema during the use of humidified high-flow nasal cannula.

BACKGROUND: Heated, humidified, high-flow nasal cannula (HHFNC) oxygen therapy allows optimal humidification of inspired gas at high flows and creates a distending pressure similar to nasal continuous positive airway pressure [1]. It has been safely used in adults with moderate hypoxemia with few complications [2, 3]. Hereby, we report serious complications occurred during HHFNC oxygen therapy. CASE PRESENTATION: A 53-year-old female with hemophagocytic lymphohistiocytosis (HLH) was admitted to the intensive care unit because of respiratory failure. After weaning from mechanical ventilation which lasted for 2 weeks, HHFNC therapy at 40 L/min with an FiO2 of 0.5 was started for hypoxemia. Four days later, dyspnea and hypoxemia occurred and chest X-ray and CT scan revealed localized pneumothorax, subcutaneous emphysema, and massive pneumomediastinum. After cessation of HHFNC, respiratory condition improved. CONCLUSION: Subcutaneous emphysema, pneumothorax, and pneumomediastinum should be notified as a serious complication during HHFNC therapy.

A pediatric case developing critical abdominal distension caused by a combination of humidified high-flow nasal cannula oxygen therapy and nasal airway.

BACKGROUND: We describe a pediatric patient who suffered from critical abdominal distention caused by a combination of humidified, high-flow nasal cannula (HHFNC) oxygen therapy and nasal airway. CASE PRESENTATION: A 21-month-old boy with a history of chronic lung disease was admitted to the intensive care unit (ICU). Immediately after admission, his airway was established using a tracheal tube and mechanical ventilation was started. Five days after the commencement of mechanical ventilation, finally, his trachea was extubated. Immediately after extubation, HHFNC therapy at 20 L/min with an FiO2 of 0.35 was applied. However, severe stridor was observed, then a nasal airway was placed in the left nostril. However, he became restless. Critical abdominal distention was observed. A subsequent chest X-ray revealed that the nasal airway was placed too deeply, and the gastrointestinal air was severely accumulated. Immediately, the nasal airway was removed, and HHFNC flow was reduced to 10 L/min. Frequent suctioning and continuous gastric drainage were required, which achieved gradual improvement of respiratory condition. CONCLUSIONS: We need to recognize that HHFNC therapy is one of the positive pressure ventilation system. Therefore, HHFNC therapy might cause the similar adverse events to noninvasive pressure ventilation.

The effects of intensive care environment on postoperative nightmare.

PURPOSE: We retrospectively investigated the incidence of postoperative nightmares and evaluated the impact of postoperative intensive care on the incidence of during subsequent hospital stay. To reduce the effect of selection bias, we compared the incidence of nightmares in propensity-matched pairs with postoperative management in ICUs or in surgical wards. METHODS: This is a retrospective review of an institutional registry containing 21,606 anesthesia cases and was conducted with ethics board approval. Outcomes of surgical patients treated in ICUs and in postsurgical wards (ICU admission vs non ICU admission) were compared first for nightmares using the initial 12,508 patients. To avoid channeling bias, propensity score analysis was used to generate a set of matched cases (ICU admission) and controls (non ICU admission), yielding 642 matched patient pairs. The incidence rate of nightmares was compared as the primary outcome. RESULTS: Before adjusting patients' characteristics, ICU environment exposure increased the incidence of nightmares compared with non-ICU environment during subsequent hospital stay [ICU vs non-ICU: 101/718 (12.3 %) vs 1147/10,542 (9.81 %)]. The odds ratio (95 % CIs) for ICU was 1.29 (1.03-1.61) for nightmares (p = 0.022). After propensity score matching, however, an equal rate of nightmares occurred in the ICU environment exposure compared to the non-ICU environment [ICU vs non-ICU: 81/561 (12.6 %) vs 73/569 (11.4 %)]. The odds ratio and 95 % CIs for ICU were 1.13 (0.80-1.58) for nightmares (p = 0.54). CONCLUSIONS: The incidence of nightmares did not become more evident during subsequent hospital stay after ICU environment exposure.

[Management of a Patient with Aortic Stenosis Undergoing Lung Cancer Surgery].

A 79-year-old man with aortic stenosis (AS) was scheduled for right middle lobectomy under general anesthesia. AS is a significant risk factor for the development of cardiac complications after noncardiac surgery. Anesthetic management adjusting left ventricular preload and coload, and keeping sinus rhythm was successful with no complications. But after moving back to the intensive care unit after surgery, ECG showed paroxysmal complete atrioventricular blocks and we inserted a temporary transvenous pacemaker catheter. We should be very careful with not only the anesthetic but also perioperative management of AS patient.

A case requiring tracheal stenting due to superior vena cava syndrome developing after craniotomy.

We report a patient who developed sustained hypotension during craniotomy; further, owing to a mediastinal mass, critical tracheal stenosis and brain edema were observed after craniotomy, despite the absence of preoperative symptomatic superior vena cava (SVC) syndrome. A 62-year-old man underwent removal of a suspected metastatic brain tumor. The main brain tumor was speculated to be a metastatic tumor from lung cancer. A subsequent chest CT revealed a large solid tumor in the mediastinum. The maximum reduction in the cross-sectional area of the trachea was estimated to be 50 %. In addition, bilateral innominate veins were completely obstructed, and the superior vena cava was involved in the mass and was completely compressed. The patient did not show any cardiopulmonary symptoms or upper body edema. Intravenous lines were secured at the right extremity. General anesthesia was induced without any complications and was maintained with sevoflurane, remifentanil, and rocuronium. During the surgery, hemodynamic status fluctuated and was unstable. To maintain systolic blood pressure, continuous, massive infusion of noradrenaline was required. After the surgery, the patient was turned to the supine position. Massive facial edema was apparent. In addition, the bilateral upper extremities were significantly swollen. Despite the removal of the main lesion, brain edema was still observed on head CT. Chest CT revealed that the maximum reduction in the cross-sectional area of the trachea was estimated to be >90 %, which necessitated mechanical ventilation with tracheal intubation. On the day following craniotomy, tracheal stenting was performed uneventfully. The patient's trachea was finally extubated, and his respiratory condition did not deteriorate. Although he did not develop SVC syndrome, the patient died from asphyxiation after coughing up blood at home 5 months after the procedure. It was suggested that fluid infusion from the upper extremities owing to the mediastinal tumor caused critical SVC syndrome.

[General anesthesia for a patient with post-polio syndrome].

We gave anesthesia for a patient with post-polio syndrome undergoing laparoscopic sigmoid colectomy. She is a 68-year-old woman and had been diagnosed as post-polio syndrome since she was 55 years of age. Before the operation, paralysis was observed in her right leg. After inducing anesthesia using propofol, muscle relaxation was obtained by rocuronium bromide for intubation. Remifentanil was used during the operation, and good pain relief was obtained by iv-PCA (fentanyl) after operation.

[General anesthetic management of a patient with spinal muscular atrophy type III].

We report a 61-year-old woman (weight 49 kg, height 156 cm) with Kugelberg-Welander disease who was scheduled for bilateral mastectomy under general anesthesia. We administered rocuronium 10 mg (0.20 mg x kg(-1)) for tracheal intubation. After 80 min, train-of-four ratio (TOFR) was 46%. During the operation, we did not administer rocuronium. After surgery, TOFR was 62%. Therefore, we administered sugammadex 100 mg (2 mg x kg(-1)). After 4 min, TOFR became above 90%, and the patient was extubated. There was no respiratory distress, muscle weakness, or neurologic untoward event after the use of sugammadex in the postoperative period. Sugammadex was effective in reversing rocuronium induced neuromuscular block in a patient with Kugelberg-Welander disease.