Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022).

Background: Coronavirus disease (COVID-19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. Methods: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of recommendations. The first edition of this guideline was released on September 9, 2020, and this is the revised edition (version 5.0; released on July 15, 2022). Clinical questions (CQs) were set for the following 10 drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), casirivimab/imdevimab (CQ9-1), sotrovimab (CQ9-2), molnupiravir (CQ10), and nirmatrelvir/ritonavir (CQ11). Recommendations: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with mild COVID-19 who do not require oxygen, and patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (both GRADE 2B). Corticosteroids are recommended for moderate and severe COVID-19 (GRADE 1B, 1A). However, their administration is not recommended for mild COVID-19 (GRADE 1B). Tocilizumab is suggested for moderate and severe COVID-19 (GRADE 2B, 2C). Anticoagulant administration is recommended for moderate and severe COVID-19 (Good Practice Statement). Baricitinib is suggested for moderate and severe COVID-19 (both GRADE 2C). Casirivimab/imdevimab and sotrovimab are recommended for mild COVID-19 (both GRADE 2C). Molnupiravir and nirmatrelvir/ritonavir are recommended for mild COVID-19 (both GRADE 2C). SARS-CoV-2 mutant strains emerge occasionally, and each time, the treatment policy at clinics is forced to change drastically. We ask health-care professionals in the field to refer to the recommendations in these guidelines and use these to keep up to date with COVID-19 epidemiological information.

Optimal target blood pressure in elderly with septic shock (OPTPRESS) trial: study protocol for a randomized controlled trial.

BACKGROUND: Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis. METHODS: A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80-85 mmHg (high-target) and 65-70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients' condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 µg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization. DISCUSSION: The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.

Efficacy of Higher Positive End-Expiratory Pressure Ventilation Strategy in Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

Previous systematic reviews and meta-analyses assessing the pooled effects of higher positive end-expiratory pressure (PEEP) failed to show significantly reduced mortality in patients with acute respiratory distress syndrome (ARDS). Some new randomized controlled trials (RCTs) have been reported and an updated systematic review is needed to evaluate the use of higher PEEP in patients with ARDS. We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Igaku-Chuo-Zasshi, ICTRP, the National Institute of Health Clinical Trials Register, and the reference list of recent guidelines. We included RCTs to compare the higher PEEP ventilation strategy with the lower strategy in patients with ARDS. Two authors independently assessed the eligibility of the studies and extracted the data. The primary outcomes were 28-day mortality. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) methodology was used to evaluate the certainty of the evidence. Among the 6530 screened records, 16 randomized trials involving 4150 patients were included in our meta-analysis. When comparing higher PEEP versus lower PEEP, the pooled risk ratio (RR) for 28-day mortality was 0.85 (15 studies, n=4108, 95% CI 0.72 to 1.00, I2=58%, low certainty of evidence). Subgroup analysis by study participants with a low tidal volume (LTV) strategy showed an interaction (P for interaction, 0.001). Our study showed that in patients with ARDS, the use of higher PEEP did not significantly reduce 28-day mortality compared to the use of lower PEEP.

ARDS Clinical Practice Guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

Usefulness of low tidal volume ventilation strategy for patients with acute respiratory distress syndrome: a systematic review and meta-analysis.

The effects of lower tidal volume ventilation (LTV) were controversial for patients with acute respiratory distress syndrome (ARDS). This systematic review and meta-analysis aimed to evaluate the use of LTV strategy in patients with ARDS. We performed a literature search on MEDLINE, CENTRAL, EMBASE, CINAHL, "Igaku-Chuo-Zasshi", clinical trial registration sites, and the reference of recent guidelines. We included randomized controlled trials (RCTs) to compare the LTV strategy with the higher tidal volume ventilation (HTV) strategy in patients with ARDS. Two authors independently evaluated the eligibility of studies and extracted the data. The primary outcomes were 28-day mortality. We used the GRADE methodology to assess the certainty of evidence. Among the 19,864 records screened, 13 RCTs that recruited 1874 patients were included in our meta-analysis. When comparing LTV (4-8 ml/kg) versus HTV (> 8 ml/kg), the pooled risk ratio for 28-day mortality was 0.79 (11 studies, 95% confidence interval [CI] 0.66-0.94, I2 = 43%, n = 1795, moderate certainty of evidence). Subgroup-analysis by combined high positive end-expiratory pressure with LTV showed interaction (P = 0.01). Our study indicated that ventilation with LTV was associated with reduced risk of mortality in patients with ARDS when compared with HTV. Trial registration: UMIN-CTR (UMIN000041071).

ARDS clinical practice guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D); we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D); we suggest against routinely implementing NO inhalation therapy (GRADE 2C); and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jrs.or.jp/publication/jrs_guidelines/). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (September 2021).

BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. METHODS: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on September 9, 2020, and this document is the revised edition (version 4.0; released on September 9, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), and casirivimab/imdevimab (CQ9). Two CQs (hydroxychloroquine [CQ3] and ciclesonide [CQ6]) were retrieved in this updated version. RECOMMENDATIONS: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Corticosteroids are recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 1B) and for patients with severe COVID-19 requiring mechanical ventilation/intensive care (GRADE 1A); however, their administration is not recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). Tocilizumab is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant administration is recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization and patients with severe COVID-19 requiring mechanical ventilation/intensive care (good practice statement). Baricitinib is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2C). Casirivimab/imdevimab is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). We hope that these updated clinical practice guidelines will help medical professionals involved in the care of patients with COVID-19.

Japanese rapid/living recommendations on drug management for COVID-19.

The coronavirus disease (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on 9 September, 2020, and this document is the revised edition (version 3.1) (released 30 March, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), hydroxychloroquine (CQ3), corticosteroids (CQ4), tocilizumab (CQ5), ciclesonide (CQ6), and anticoagulants (CQ7). Favipiravir is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Hydroxychloroquine is not recommended for all COVID-19 patients (GRADE 1B). Corticosteroids are recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 1A); however, their use is not recommended for mild COVID-19 patients not requiring supplemental oxygen (GRADE 1B). Tocilizumab is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant therapy is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID-19 patients.

Post-extubation oxygenation strategies in acute respiratory failure: a systematic review and network meta-analysis.

BACKGROUND: High-flow nasal cannula oxygenation (HFNC) and noninvasive positive-pressure ventilation (NPPV) possibly decrease tracheal reintubation rates better than conventional oxygen therapy (COT); however, few large-scale studies have compared HFNC and NPPV. We conducted a network meta-analysis (NMA) to compare the effectiveness of three post-extubation respiratory support devices (HFNC, NPPV, and COT) in reducing the mortality and reintubation risk. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. COT, NPPV, and HFNC use were assessed in patients who were aged ≥ 16 years, underwent invasive mechanical ventilation for > 12 h for acute respiratory failure, and were scheduled for extubation after spontaneous breathing trials. The GRADE Working Group Approach was performed using a frequentist-based approach with multivariate random-effect meta-analysis. Short-term mortality and reintubation and post-extubation respiratory failure rates were compared. RESULTS: After evaluating 4631 records, 15 studies and 2600 patients were included. The main cause of acute hypoxic respiratory failure was pneumonia. Although NPPV/HFNC use did not significantly lower the mortality risk (relative risk [95% confidence interval] 0.75 [0.53-1.06] and 0.92 [0.67-1.27]; low and moderate certainty, respectively), HFNC use significantly lowered the reintubation risk (0.54 [0.32-0.89]; high certainty) compared to COT use. The associations of mortality with NPPV and HFNC use with respect to either outcome did not differ significantly (short-term mortality and reintubation, relative risk [95% confidence interval] 0.81 [0.61-1.08] and 1.02 [0.53-1.97]; moderate and very low certainty, respectively). CONCLUSION: NPPV or HFNC use may not reduce the risk of short-term mortality; however, they may reduce the risk of endotracheal reintubation. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: PROSPERO (registration number: CRD42020139112, 01/21/2020).

A limited sampling strategy for estimation of the area under the plasma concentration-time curve of gefitinib.

PURPOSE: The aim of this study was to develop a limited sampling strategy (LSS) to estimate the area under the concentration-time curve (AUC) of gefitinib using data from 18 patients with non-small-cell lung cancer. METHODS: On day 14 after beginning daily therapy with 250 mg of gefitinib, plasma samples were collected just before (C(0h), 24 hours after the 13th administration) and 1, 2, 4, 6, 8, 12, and 24 hours (C(nh)) after gefitinib administration and were analyzed by high-performance liquid chromatography. RESULTS: The predicted AUC from 0 to 24 hours (AUC0₋24) from the single time point of C(12h) showed the highest correlation with the measured AUC0₋24 of gefitinib (AUC0₋24 = 20.0 · C(12h) + 1348.0; r² = 0.9623; P , 0.0001). The 95% confidence intervals of the slopes and intercepts of the formulae obtained by bootstrap analysis indicated acceptable accuracy and robustness in the prediction of AUC0₋24 using C(0h), C(1h), C(12h), and C(1h) + C(12h). The median AUC0₋24 and C(0h) of gefitinib in patients with diarrhea (n = 8) were higher than those without diarrhea (n = 10) (15,043 versus 8918 ng·h·mL⁻¹, respectively, P = 0.0164 and 542 versus 261 ng/mL, respectively, P = 0.0263). The area under the receiver operator curve was 0.813, giving the best sensitivity (75%) and specificity (90%) at a C(0h) threshold of 398 ng/mL. CONCLUSIONS: Use of the C(12h) single time point is recommended for the gefitinib AUC0₋24 predictive equation; however, total estimation of the AUC0₋24 of gefitinib at the single point of C(0h) was also precise. C(0h) monitoring of gefitinib might be beneficial during gefitinib therapy, because of a high variability in gefitinib exposure among patients taking 250 mg. Further examination of the correlation between clinical evaluation and the gefitinib exposure is necessary.

Intrapulmonary bronchogenic cyst in the thoracic cavity: a case report.

This case report presents an intrapulmonary bronchogenic cyst exhibiting a unique shape. The patient was a 19-year-old man who had been diagnosed with a posterior mediastinal tumor by computed tomography and magnetic resonance imaging, 2 years previously. The imaging revealed that the tumor was located on the left side of the posterior mediastinum and was 45 × 25 mm in size. As the size and shape of the tumor did not change in the 2 years after its detection, surgical extraction was planned. Preoperative diagnosis was, firstly, a neurogenic tumor originating in the posterior mediastinum.Surgical findings revealed that the tumor formed a bridge between the visceral pleura of the left lower lobe and the chest wall, and most of the tumor was located in the thoracic cavity. Pathological diagnosis was intrapulmonary bronchogenic cyst. An intrapulmonary bronchogenic cyst with a unique shape, as observed in this case, is very rare.Although preoperative imaging could predict the tumor size, it could not confirm where the tumor originated. Surgical resection of this type of tumor, which is diagnosed preoperatively as a posterior mediastinal tumor, is a superior strategy for precise diagnosis and treatment.