Combined Use of Alkaline Agents With Low-Flow Extracorporeal Carbon Dioxide Removal in Carbon Dioxide Inhalation Models Preserving Inspiratory Efforts.

Background: Low-flow extracorporeal CO 2 removal (ECCO 2 R), managed using a renal replacement platform, is useful in achieving lung-protective ventilation with low tidal volume. However, its capacity for CO 2 elimination is limited. Whether this system is valuable in reducing strong inspiratory efforts in respiratory failure is unclear. The combined use of alkaline agents with low-flow ECCO 2 R might be useful in hypercapnic subjects preserving inspiratory efforts. Methods: This study examined the effects of low-flow ECCO 2 R on respiratory status and investigated the effects of NaHCO 3 , trometamol, and saline on respiratory status during low-flow ECCO 2 R in CO 2 inhalation models. Results: Although low-flow ECCO 2 R did not significantly change the respiratory rate (92.2% ± 24.3% [mean ± standard deviation] of that before ECCO 2 R), it reduced minute ventilation (MV) (78.9% ± 13.5% of that before ECCO 2 R). The addition of NaHCO 3 improved acidemia but did not change MV compared with that of the saline group (0.451 ± 0.026 L/min/kg body weight [BW] vs. 0.556 ± 0.138 L/min/kg BW, respectively). The addition of trometamol improved acidemia and reduced MV compared with that of the saline group (0.381 ± 0.050 L/min/kg BW vs. 0.556 ± 0.138 L/min/kg BW, respectively). The total amounts of CO 2 removed during ECCO 2 R in the NaHCO 3 group were lower than those in the saline and trometamol groups. Conclusion: The low-flow ECCO 2 R reduced MV in subjects preserving spontaneous breathing efforts with CO 2 overload. The addition of NaHCO 3 improved acidemia but did not change MV, whereas the addition of trometamol improved acidemia and reduced MV.

Time definition of reintubation most relevant to patient outcomes in critically ill patients: a multicenter cohort study.

BACKGROUND: Reintubation is a common complication in critically ill patients requiring mechanical ventilation. Although reintubation has been demonstrated to be associated with patient outcomes, its time definition varies widely among guidelines and in the literature. This study aimed to determine the association between reintubation and patient outcomes as well as the consequences of the time elapsed between extubation and reintubation on patient outcomes. METHODS: This was a multicenter retrospective cohort study of critically ill patients conducted between April 2015 and March 2021. Adult patients who underwent mechanical ventilation and extubation in intensive care units (ICUs) were investigated utilizing the Japanese Intensive Care PAtient Database. The primary and secondary outcomes were in-hospital and ICU mortality. The association between reintubation and clinical outcomes was studied using Cox proportional hazards analysis. Among the patients who underwent reintubation, a Cox proportional hazard analysis was conducted to evaluate patient outcomes according to the number of days from extubation to reintubation. RESULTS: Overall, 184,705 patients in 75 ICUs were screened, and 1849 patients underwent reintubation among 48,082 extubated patients. After adjustment for potential confounders, multivariable analysis revealed a significant association between reintubation and increased in-hospital and ICU mortality (adjusted hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.359-1.700, and adjusted HR 1.325, 95% CI 1.076-1.633, respectively). Among the reintubated patients, 1037 (56.1%) were reintubated within 24 h after extubation, 418 (22.6%) at 24-48 h, 198 (10.7%) at 48-72 h, 111 (6.0%) at 72-96 h, and 85 (4.6%) at 96-120 h. Multivariable Cox proportional hazard analysis showed that in-hospital and ICU mortality was highest in patients reintubated at 72-96 h (adjusted HR 1.528, 95% CI 1.062-2.197, and adjusted HR 1.334, 95% CI 0.756-2.352, respectively; referenced to reintubation within 24 h). CONCLUSIONS: Reintubation was associated with a significant increase in in-hospital and ICU mortality. The highest mortality rates were observed in patients who were reintubated between 72 and 96 h after extubation. Further studies are warranted for the optimal observation of extubated patients in clinical practice and to strengthen the evidence for mechanical ventilation.

Factors Associated With Prolonged Ventilation in Patients Receiving Prone Positioning Protocol With Muscle Relaxants for Severe COVID-19 Pneumonia.

BACKGROUND: Prone positioning and neuromuscular blocking agents (NMBAs) are frequently used to treat severe respiratory failure from COVID-19 pneumonia. Prone positioning has shown to improve mortality, whereas NMBAs are used to prevent ventilator asynchrony and reduce patient self-inflicted lung injury. However, despite the use of lung-protective strategies, high death rates in this patient population have been reported. METHODS: We retrospectively examined the factors affecting prolonged mechanical ventilation in subjects receiving prone positioning plus muscle relaxants. The medical records of 170 patients were reviewed. Subjects were divided into 2 groups according to ventilator-free days (VFDs) at day 28. Whereas subjects with VFDs < 18 d were defined as prolonged mechanical ventilation, subjects with VFDs ≥18 d were defined as short-term mechanical ventilation. Subjects' baseline status, status at ICU admission, therapy before ICU admission, and treatment in the ICU were studied. RESULTS: Under the proning protocol for COVID-19, the mortality rate in our facility was 11.2%. The prognosis may be improved by avoiding lung injury in the early stages of mechanical ventilation. According to multifactorial logistic regression analysis, persistent SARS-CoV-2 viral shedding in blood (P = .03), higher daily corticosteroid use before ICU admission (P = .007), delayed recovery of lymphocyte count (P < .001), and higher maximal fibrinogen degradation products (P = .039) were associated with prolonged mechanical ventilation. A significant relationship was found between daily corticosteroid use before admission and VFDs by squared regression analysis (y = -0.00008522x2 + 0.01338x + 12.8; x: daily corticosteroids dosage before admission [prednisolone mg/d]; y: VFDs/28 d, R2 = 0.047, P = .02). The peak point of the regression curve was 13.4 d at 78.5 mg/d of the equivalent prednisolone dose, which corresponded to the longest VFDs. CONCLUSIONS: Persistent SARS-CoV-2 viral shedding in blood, high corticosteroid dose from the onset of symptoms to ICU admission, slow recovery of lymphocyte counts, and high levels of fibrinogen degradation products after admission were associated with prolonged mechanical ventilation in subjects with severe COVID-19 pneumonia.

Personalized ventilatory strategy based on lung recruitablity in COVID-19-associated acute respiratory distress syndrome: a prospective clinical study.

BACKGROUND: Heterogeneity is an inherent nature of ARDS. Recruitment-to-inflation ratio has been developed to identify the patients who has lung recruitablity. This technique might be useful to identify the patients that match specific interventions, such as higher positive end-expiratory pressure (PEEP) or prone position or both. We aimed to evaluate the physiological effects of PEEP and body position on lung mechanics and regional lung inflation in COVID-19-associated ARDS and to propose the optimal ventilatory strategy based on recruitment-to-inflation ratio. METHODS: Patients with COVID-19-associated ARDS were consecutively enrolled. Lung recruitablity (recruitment-to-inflation ratio) and regional lung inflation (electrical impedance tomography [EIT]) were measured with a combination of body position (supine or prone) and PEEP (low 5 cmH2O or high 15 cmH2O). The utility of recruitment-to-inflation ratio to predict responses to PEEP were examined with EIT. RESULTS: Forty-three patients were included. Recruitment-to-inflation ratio was 0.68 (IQR 0.52-0.84), separating high recruiter versus low recruiter. Oxygenation was the same between two groups. In high recruiter, a combination of high PEEP with prone position achieved the highest oxygenation and less dependent silent spaces in EIT (vs. low PEEP in both positions) without increasing non-dependent silent spaces in EIT. In low recruiter, low PEEP in prone position resulted in better oxygenation (vs. both PEEPs in supine position), less dependent silent spaces (vs. low PEEP in supine position) and less non-dependent silent spaces (vs. high PEEP in both positions). Recruitment-to-inflation ratio was positively correlated with the improvement in oxygenation and respiratory system compliance, the decrease in dependent silent spaces, and was inversely correlated with the increase in non-dependent silent spaces, when applying high PEEP. CONCLUSIONS: Recruitment-to-inflation ratio may be useful to personalize PEEP in COVID-19-associated ARDS. Higher PEEP in prone position and lower PEEP in prone position decreased the amount of dependent silent spaces (suggesting lung collapse) without increasing the amount of non-dependent silent spaces (suggesting overinflation) in high recruiter and in low recruiter, respectively.

Control of blood glucose levels by an artificial pancreas in patients with severe coronavirus disease 2019 pneumonia.

BACKGROUND: Many patients with severe coronavirus disease 2019 (COVID-19) pneumonia experience hyperglycemia. It is often difficult to control blood glucose (BG) levels in such patients using standard intravenous insulin infusion therapy. Therefore, we used an artificial pancreas. This study aimed to compare the BG status of the artificial pancreas with that of standard therapy. METHODS: Fifteen patients were included in the study. BG values and the infusion speed of insulin and glucose by the artificial pancreas were collected. Arterial BG and administration rates of insulin, parenteral sugar, and enteral sugar were recorded during the artificial pancreas and standard therapy. The target BG level was 200 mg/dl. RESULTS: Arterial BG was highly correlated with BG data from the artificial pancreas. A higher BG slightly increased the difference between the BG data from the artificial pancreas and arterial BS. No significant difference in arterial BG was observed between the artificial pancreas and standard therapy. However, the standard deviation with the artificial pancreas was smaller than that under standard therapy (p < 0.0001). More points within the target BG range were achieved with the artificial pancreas (180-220 mg/dl) than under standard therapy. The hyperglycemic index of the artificial pancreas (8.7 ± 15.6 mg/dl) was lower than that of standard therapy (16.0 ± 21.5 mg/dl) (p = 0.0387). No incidence of hypoglycemia occurred under the artificial pancreas. CONCLUSIONS: The rate of achieving target BG was higher using artificial pancreas than with standard therapy. An artificial pancreas helps to control BG in critically ill patients.

Association between tracheostomy and survival in patients with coronavirus disease 2019 who require prolonged mechanical ventilation for more than 14 days: A multicenter cohort study.

OBJECTIVE: Tracheostomy is a common procedure with potential prognostic advantages for patients who require prolonged mechanical ventilation (PMV). Early recommendations for patients with coronavirus disease 2019 (COVID-19) suggested delayed or limited tracheostomy considering the risk for viral transmission to clinicians. However, updated guidelines for tracheostomy with appropriate personal protective equipment have revised its indications. This study aimed to evaluate the association between tracheostomy and prognosis in patients with COVID-19 requiring PMV. METHODS: This was a multicenter, retrospective cohort study using data from the nationwide Japanese Intensive Care PAtient Database. We included adult patients aged ≥16 years who were admitted to the intensive care unit (ICU) due to COVID-19 and who required PMV (for >14 days or until performance of tracheostomy). The primary outcome was hospital mortality, and the association between implementation of tracheostomy and patient prognosis was assessed using weighted Cox proportional hazards regression analysis with inverse probability of treatment weighting (IPTW) using the propensity score to address confounders. RESULTS: Between January 2020 and February 2021, 453 patients with COVID-19 were observed. Data from 109 patients who required PMV were analyzed: 66 (60.6%) underwent tracheostomy and 38 (34.9%) died. After adjusting for potential confounders using IPTW, tracheostomy implementation was found to significantly reduce hospital mortality (hazard ratio [HR]: 0.316, 95% confidence interval [CI]: 0.163-0.612). Patients who underwent tracheostomy had a similarly decreased ICU and 28-day mortality (HR: 0.269, 95% CI: 0.124-0.581; HR 0.281, 95% CI: 0.094-0.839, respectively). A sensitivity analysis using different definitions of PMV duration consistently showed reduced mortality in patients who underwent tracheostomy. CONCLUSION: The implementation of tracheostomy was associated with favorable patient prognosis among patients with COVID-19 requiring PMV. Our findings support proactive tracheostomy in critically ill patients with COVID-19 requiring mechanical ventilation for >14 days.

Timing of tracheostomy and patient outcomes in critically ill patients requiring extracorporeal membrane oxygenation: a single-center retrospective observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an integral method of life support in critically ill patients with severe cardiopulmonary failure; however, such patients generally require prolonged mechanical ventilation and exhibit high mortality rates. Tracheostomy is commonly performed in patients on mechanical ventilation, and its early implementation has potential advantages for favorable patient outcomes. This study aimed to investigate the association between tracheostomy timing and patient outcomes, including mortality, in patients requiring ECMO. METHODS: We conducted a single-center retrospective observational study of consecutively admitted patients who were supported by ECMO and underwent tracheostomy during intensive care unit (ICU) admission at a tertiary care center from April 2014 until December 2021. The primary outcome was hospital mortality. Using the quartiles of tracheostomy timing, the patients were classified into four groups for comparison. The association between the quartiles of tracheostomy timing and mortality was explored using multivariable logistic regression models. RESULTS: Of the 293 patients treated with ECMO, 98 eligible patients were divided into quartiles 1 (≤ 15 days), quartile 2:16-19 days, quartile 3:20-26 days, and 4 (> 26 days). All patients underwent surgical tracheostomy and 35 patients underwent tracheostomy during ECMO. The complications of tracheostomy were comparable between the groups, whereas the duration of ECMO and ICU length of stay increased significantly as the quartiles of tracheostomy timing increased. Patients in quartile 1 had the lowest hospital mortality rate (19.2%), whereas those in quartile 4 had the highest mortality rate (50.0%). Multivariate logistic regression analysis showed a significant association between the increment of the quartiles of tracheostomy timing and hospital mortality (adjusted odds ratio for quartile increment:1.55, 95% confidence interval 1.03-2.35, p for trend = 0.037). CONCLUSIONS: The timing of tracheostomy in patients requiring ECMO was significantly associated with patient outcomes in a time-dependent manner. Further investigation is warranted to determine the optimal timing of tracheostomy in terms of mortality.

Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis.

Maintenance of bone integrity is mediated by the balanced actions of osteoblasts and osteoclasts. Because macroautophagy/autophagy regulates osteoblast mineralization, osteoclast differentiation, and their secretion from osteoclast cells, autophagy deficiency in osteoblasts or osteoclasts can disrupt this balance. However, it remains unclear whether upregulation of autophagy becomes beneficial for suppression of bone-associated diseases. In this study, we found that genetic upregulation of autophagy in osteoblasts facilitated bone formation. We generated mice in which autophagy was specifically upregulated in osteoblasts by deleting the gene encoding RUBCN/Rubicon, a negative regulator of autophagy. The rubcnflox/flox;Sp7/Osterix-Cre mice showed progressive skeletal abnormalities in femur bones. Consistent with this, RUBCN deficiency in osteoblasts resulted in elevated differentiation and mineralization, as well as an increase in the elevated expression of key transcription factors involved in osteoblast function such as Runx2 and Bglap/Osteocalcin. Furthermore, RUBCN deficiency in osteoblasts accelerated autophagic degradation of NOTCH intracellular domain (NICD) and downregulated the NOTCH signaling pathway, which negatively regulates osteoblast differentiation. Notably, osteoblast-specific deletion of RUBCN alleviated the phenotype in a mouse model of osteoporosis. We conclude that RUBCN is a key regulator of bone homeostasis. On the basis of these findings, we propose that medications targeting RUBCN or autophagic degradation of NICD could be used to treat age-related osteoporosis and bone fracture.Abbreviations: ALPL: alkaline phosphatase, liver/bone/kidney; BCIP/NBT: 5-bromo-4-chloro-3'-indolyl phosphate/nitro blue tetrazolium; BMD: bone mineral density; BV/TV: bone volume/total bone volume; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NICD: NOTCH intracellular domain; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; SERM: selective estrogen receptor modulator; TNFRSF11B/OCIF: tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin).

Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.

Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell-related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.

Advanced cuff pressure control ventilation (ACPCV); a bench study of a new concept of mechanical ventilation.

The concept of advanced cuff pressure control ventilation (ACPCV) is that the endotracheal tube (ETT) cuff volume could be controlled and allowed to exhale the gas through the vocal cords. The potential advantages of ACPCV are reduction of dead space, reduction of expiratory airway resistance, and preservation of vocal cord function. We developed the ACPCV system and investigated its performance in bench studies. The ETT cuff volume was regulated via four steps, depending on airway pressure and tracheal pressure. Two ventilatory settings were examined under several rates of spontaneous breathing efforts. Imposed expiratory resistance (RE), imposed expiratory work of breathing (WOB), and auto-PEEP of ACPCV were compared with continuous mandatory ventilation (CMV). RE of ACPCV (2.6 ± 0.5 cm H2O/l/s) was significantly lower than that of CMV (11.6 ± 1.6 cm H2O/l/s) (p < 0.001). Expiratory WOB of ACPCV (0.25 ± 0.02 J/l) was significantly lower than that of CMV (0.54 ± 0.10 J/l) (p < 0.001). Auto-PEEP of ACPCV (-0.6 ± 0.2 cm H2O) was significantly lower than that of CMV (1.1 ± 0.7 cm H2O) (p < 0.001). ACPCV can significantly reduce RE and expiratory WOB by controlling the ETT cuff volume in synchronisation with mechanical ventilation.

Effects of Ventilatory Settings on Pendelluft Phenomenon During Mechanical Ventilation.

BACKGROUND: Pendelluft phenomenon is defined as the displacement of gas from a more recruited nondependent (ND) lung region to a less recruited dependent (D) lung region. This phenomenon may cause lung injury. Thus, a lung model for pendelluft was established, and the effects of ventilatory settings on pendelluft were examined. METHODS: Two sets of the twin-bellows-type training test lung (TTL) model were utilized. One set of bellows simulated the diaphragm, and the other simulated the lung. One TTL model represented the ND region, and the other represented the D region. The lung bellows were connected to each other and were ventilated with 1 ventilator. The diaphragm bellows were ventilated with 2 synchronized ventilators that regulated pleural pressure levels. We simulated pendelluft by applying different pleural pressure levels to the D and ND bellows. The increment of the tidal volume in the D region from the "no breathing effort" condition was defined as the pendelluft volume. The effects of ventilator settings, such as ventilatory modes, triggering sensitivity, inspiratory pressurization, and inspiratory cycling-off, were examined. The changes in tidal volumes in the D region based on the control settings were compared to assess the severity of pendelluft. RESULTS: The gas flow from the D region to the ND region was found to be essential in pendelluft, but the severity of this phenomenon was not always proportional to gas flows. The severity increased with the increase in the differences in pleural pressure levels between the ND and D regions, and it was amplified by the difference in lung mechanics between the ND and D regions. However, the ventilator settings had minimal effect on the severity of pendelluft. CONCLUSIONS: The pendelluft was affected by the heterogeneity of lung mechanics and pleural pressure. Furthermore, a minimal association was observed between the ventilator settings and the severity of pendelluft.

Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy.

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.