Biological Stress Responses to Acute Respiratory Distress Syndrome and Treatment Strategy

急性呼吸窮迫症候群の主病態は，高度の炎症に伴い肺胞隔壁の透過性が亢進することにより もたらされる非心原性肺水腫である．外傷，熱傷，敗血症などの重症病態を背景疾患にも ち，免疫応答により代謝変動をきたし，体内のあらゆる部位で蛋白，炭水化物，脂質の代謝 に影響を及ぼす．中でも骨格筋の異化反応（破壊）は最も重要な代謝変動である．骨格筋の 萎縮は，高齢者の感染症リスクの増加，入院期間の延長，死亡率と関連している．栄養療法 と早期運動療法の組み合わせが，最大の効果をもたらすと考えられている．

A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling.

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

Extracorporeal Membrane Oxygenation for Secondary Organizing Pneumonia after Severe SARS-CoV-2 Infection: A Case Report.

(Background) COVID-19 is caused by SARS-CoV-2 infection and may result in unfavorable outcomes. A recent large-scale study showed that treatment with dexamethasone leads to favorable outcomes in patients with severe COVID-19, and the use of extracorporeal membrane oxygenation (ECMO) has also been shown to improve outcomes. Recently, secondary organizing pneumonia (SOP) has been reported after SARS-CoV-2 infection, but the diagnostic and treatment strategies are still unclear. (Case presentation) Here, we report a patient with severe COVID-19 who developed SOP even after the use of dexamethasone, for whom the introduction of ECMO on the 19th day after hospitalization led to a favorable outcome. (Conclusions) Life-threatening SOP may evolve even after the use of dexamethasone, and the late-phase introduction of ECMO may save such patients with COVID-19.

Roles of Early Mobilization Program in Preventing Muscle Weakness and Decreasing Psychiatric Disorders in Patients with Coronavirus Disease 2019 Pneumonia: A Retrospective Observational Cohort Study.

Although many coronavirus 2019 patients have experienced persistent symptoms and a long-term decline in quality of life after discharge, the details of these persistent symptoms and the effect of early rehabilitation are still unclear. We conducted a single-center, retrospective observational study to investigate the prevalence of persistent symptoms three months after discharge from the intensive care unit by checking the medical records. All patients received an early mobilization program. Four out of 13 patients (31%) had postintensive care syndrome. No patients had muscle weakness, and 11 patients (85%) returned to their previous work. However, psychiatric disorder, such as anxiety (23%) and posttraumatic stress disorder (15%), were observed. Eleven patients claimed persistent symptoms, including fatigue and numbness in the extremities. Our results suggest that the implementation of an early rehabilitation program plays some role in preventing muscle weakness and that decreasing psychiatric disorders should be a next target of patient care in the intensive care unit.

Roles of Electrical Impedance Tomography in Determining a Lung Protective Strategy for Acute Respiratory Distress Syndrome in the Era of Coronavirus Disease 2019.

Electrical impedance tomography (EIT) is noninvasive and can be used at the bedside for real-time evaluation to identify ventilation distribution of infected lungs. This review briefly describes the basic principle of EIT and summarizes the latest findings on its potential contribution to lung protective strategies in coronavirus disease 2019 patients. Additionally, experimental approaches for detecting the distribution of pulmonary blood flow in coronavirus disease 2019 patients are presented. The findings underscore the role of EIT in determining lung protective strategies for coronavirus disease 2019-associated acute respiratory distress syndrome.

Personalisation of Therapies in COVID-19 Associated Acute Respiratory Distress Syndrome, Using Electrical Impedance Tomography.

INTRODUCTION: Each patient suffering from severe coronavirus COVID-19-associated acute respiratory distress syndrome (ARDS), requiring mechanical ventilation, shows different lung mechanics and disease evolution. Therefore, lung protective strategies should be personalised for the individual patient. CASE PRESENTATION: A 64-year-old male patient was intubated ten days after the symptoms of COVID-19 infection presented. He was placed in the prone position for sixteen hours, resulting in a marked improvement in oxygenation. However, after being returned to the supine position, his SpO2 rapidly dropped from 98% to 91%, and electrical impedance tomography showed less ventilation at the dorsal region and a ventral shift of ventilation distribution. An incremental and decremental PEEP trial under electrical impedance tomography monitoring was carried out, confirming that the dependent lung regions were recruited with increased pressures and homogenous ventilation distribution could be provided with 14 cmH2O of PEEP. The optimal settings were reassessed next day after returning from the second session of the prone position. After four prone position-sessions in five days, oxygenation was stabilised and eventually the patient was discharged. CONCLUSIONS: Patients with COVID-19 associated ARDS require individualised ventilation support depending on the stage of their disease. Daily PEEP trial monitored by electrical impedance tomography can provide important information to tailor the respiratory therapies.

Utility of SpO2/FiO2 ratio for acute hypoxemic respiratory failure with bilateral opacities in the ICU.

Acute hypoxemic respiratory failure (AHRF) with bilateral opacities causes fatalities in the intensive care unit (ICU). It is often difficult to identify the causes of AHRF at the time of admission. The SpO2 to FiO2 (S/F) ratio has been recently used as a non-invasive and alternative marker of the PaO2/FiO2 (P/F) ratio in acute respiratory failure. This retrospective cohort study was conducted from October 2010 to March 2019 at the Showa University Hospital, Tokyo, Japan. We enrolled 94 AHRF patients who had bilateral opacities and received mechanical ventilation in ICU to investigate their prognostic markers including S/F ratio. Significant differences were observed for APACHE II, S/F ratio, PaO2/FiO2 (P/F) ratio, and ventilator-free-days at day 28 for ICU mortality, and for age, S/F ratio, P/F ratio, duration of mechanical ventilation, and ventilator-free days at day 28 for hospital mortality. Multivariate logistic regression analysis showed that the S/F ratio was significantly and independently associated with the risk of death during in ICU (p = 0.003) and hospitalization (p = 0.002). The area under the receiver operating characteristic curves (AUC) based on the S/F ratio were significantly greater than those based on simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) for ICU mortality (0.785 in S/F ratio vs. 0.575 in SAPS II, p = 0.012; 0.785 in S/F ratio vs 0.594 in SOFA, p = 0.021) and for hospital mortality (0.701 in S/F ratio vs. 0.502 in SAPS II, p = 0.012; 0.701 in S/F ratio vs. 0.503 in SOFA, p = 0.005). In the subanalysis for bacterial pneumonia and interstitial lung disease groups, the AUC based on the S/F ratio was the greatest among all prognostic markers, including APACHE II, SAPS II, and SOFA. The S/F ratio may be a useful and noninvasive predictive prognostic marker for acute hypoxemic respiratory failure with bilateral opacities in the ICU.

[X. Critical care management of patients with COVID-19 pneumonia]

The epidemic of a novel coronavirus infection caused by SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has had a major impact on intensive care settings around the world. This article describes practical intensive care management, focusing on the pathogenesis of the disease and its treatment, which is gradually being elucidated, based on the experience at our own institution.