New initiation of opioids, benzodiazepines and antipsychotics following hospitalization for COVID-19.

BACKGROUND: Patients newly initiated on opioids (OP), benzodiazepines (BZD), and antipsychotics (AP) during hospitalization are often prescribed these on discharge. Implications of this practice on outcomes remains unexplored. OBJECTIVE: To explore the prevalence and risk factors of new initiation of select OP, BZD and AP among patients requiring in-patient stays. Test the hypothesis that new prescriptions are associated with higher odds of readmission or death within 28 days of discharge. DESIGN: Single center retrospective cohort study. SETTING AND PARTICIPANTS: Patients admitted to a tertiary-level medical center with either a primary diagnosis of RT-PCR positive for COVID-19 or high index of clinical suspicion thereof. INTERVENTION: None. MAIN OUTCOME AND MEASURES: Exposure was the new initiation of select common OP, BZD, and AP which were continued on hospital discharge. Outcome was a composite of 28-day readmission or death following index admission. Multivariable logistic regression was used to assess patient mortality or readmission within 28 days of discharge associated with new prescriptions at discharge. RESULTS: One thousand three hundred and nineteen patients were included in the analysis. 11.3% (149/1319) were discharged with a new prescription of select OP, BZD, or AP either alone or in combination. OP (110/149) were most prescribed followed by BZD (41/149) and AP (22/149). After adjusting for unbalanced confounders, new prescriptions (adjusted odds ratio: 2.44, 95% confidence interval: 1.42-4.12; p = .001) were associated with readmission or death within 28 days of discharge. One in nine patients admitted with a diagnosis of COVID-19 or high clinical suspicion thereof were discharged with a new prescription of either OP, BZD or AP. New prescriptions were associated with higher odds of 28-day readmission or death. Strengthening medication reconciliation processes focused on these classes may reduce avoidable harm.

DANGER Signals Activate G -Protein Receptor Kinases Suppressing Neutrophil Function and Predisposing to Infection After Tissue Trauma.

OBJECTIVE: Injured tissue predisposes the subject to local and systemic infection. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition. BACKGROUND: Injury mobilizes primitive "DANGER signals" [danger-associated molecular patterns (DAMPs)] activating innate immunocyte (neutrophils, PMN) signaling and function. Mitochondrial formyl peptides activate G -protein coupled receptors (GPCR) like formyl peptide receptor-1. Mitochondrial DNA and heme activate toll-like receptors (TLR9 and TLR2/4). GPCR kinases (GRKs) can regulate GPCR activation. METHODS: We studied human and mouse PMN signaling elicited by mitochondrial DAMPs (GPCR surface expression; protein phosphorylation, or acetylation; Ca 2+ flux) and antimicrobial functions [cytoskeletal reorganization, chemotaxis (CTX), phagocytosis, bacterial killing] in cellular systems and clinical injury samples. Predicted rescue therapies were assessed in cell systems and mouse injury-dependent pneumonia models. RESULTS: Mitochondrial formyl peptides activate GRK2, internalizing GPCRs and suppressing CTX. Mitochondrial DNA suppresses CTX, phagocytosis, and killing through TLR9 through a novel noncanonical mechanism that lacks GPCR endocytosis. Heme also activates GRK2. GRK2 inhibitors like paroxetine restore functions. GRK2 activation through TLR9 prevented actin reorganization, implicating histone deacetylases (HDACs). Actin polymerization, CTX, bacterial phagocytosis, and killing were also rescued, therefore, by the HDAC inhibitor valproate. Trauma repository PMN showed GRK2 activation and cortactin deacetylation, which varied with severity and was most marked in patients developing infections. Either GRK2 or HDAC inhibition prevented loss of mouse lung bacterial clearance, but only the combination rescued clearance when given postinjury. CONCLUSIONS: Tissue injury-derived DAMPs suppress antimicrobial immunity through canonical GRK2 activation and a novel TLR-activated GRK2-pathway impairing cytoskeletal organization. Simultaneous GRK2/HDAC inhibition rescues susceptibility to infection after tissue injury.

Adaptive Support Ventilation and Lung-Protective Ventilation in ARDS.

BACKGROUND: Adaptive support ventilation (ASV) is a partially closed-loop ventilation mode that adjusts tidal volume (VT) and breathing frequency (f) to minimize mechanical work and driving pressure. ASV is routinely used but has not been widely studied in ARDS. METHODS: The study was a crossover study with randomization to intervention comparing a pressure-regulated, volume-targeted ventilation mode (adaptive pressure ventilation [APV], standard of care at Beth Israel Deaconess Medical Center) set to VT 6 mL/kg in comparison with ASV mode where VT adjustment is automated. Subjects received standard of care (APV) or ASV and then crossed over to the alternate mode, maintaining consistent minute ventilation with 1-2 h in each mode. The primary outcome was VT corrected for ideal body weight (IBW) before and after crossover. Secondary outcomes included driving pressure, mechanics, gas exchange, mechanical power, and other parameters measured after crossover and longitudinally. RESULTS: Twenty subjects with ARDS were consented, with 17 randomized and completing the study (median PaO2 /FIO2 146.6 [128.3-204.8] mm Hg) and were mostly passive without spontaneous breathing. ASV mode produced marginally larger VT corrected for IBW (6.3 [5.9-7.0] mL/kg IBW vs 6.04 [6.0-6.1] mL/kg IBW, P = .035). Frequency was lower with patients in ASV mode (25 [22-26] breaths/min vs 27 [22-30)] breaths/min, P = .01). In ASV, lower respiratory-system compliance correlated with smaller delivered VT/IBW (R2 = 0.4936, P = .002). Plateau (24.7 [22.6-27.6] cm H2O vs 25.3 [23.5-26.8] cm H2O, P = .14) and driving pressures (12.8 [9.0-15.8] cm H2O vs 11.7 [10.7-15.1] cm H2O, P = .29) were comparable between conventional ventilation and ASV. No adverse events were noted in either ASV or conventional group related to mode of ventilation. CONCLUSIONS: ASV targeted similar settings as standard of care consistent with lung-protective ventilation strategies in mostly passive subjects with ARDS. ASV delivered VT based upon respiratory mechanics, with lower VT and mechanical power in subjects with stiffer lungs.

MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study.

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure. Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO2/FiO2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.