Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

OBJECTIVES: To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. METHODS: This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. RESULTS: Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). CONCLUSIONS: Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

Effectiveness of Quetiapine as a Sedative Adjunct in Mechanically Ventilated Adults Without Delirium.

BACKGROUND: Quetiapine is an atypical antipsychotic that is commonly used in the Intensive Care Unit (ICU). The utility of quetiapine as a sedative adjunct has not yet been evaluated, but has been described previously in studies evaluating quetiapine for delirium or delirium prophylaxis. OBJECTIVE: To determine if adjunctive use of quetiapine reduces sedative dosage requirements among mechanically ventilated adults without delirium. METHODS: This retrospective intrapatient comparator study included all mechanically ventilated adults admitted to a medical ICU who received quetiapine between July 1, 2013, and July 1, 2018. The primary outcome was the change in sedative dosage requirements over 24 hours following quetiapine initiation. Secondary outcomes included change in sedative dosage requirements 48 hours postquetiapine initiation, opioid dosage requirements 24 hours postquetiapine initiation, percent time at goal for both pain and sedation scores, depth of sedation, and QTc. RESULTS: A total of 57 patients were included in the study cohort. There was no significant difference in 24-hour cumulative doses of propofol (P = 0.10), dexmedetomidine (P = 0.14), or benzodiazepines (P = 0.14). During the 48-hour treatment period, there was a significant increase in dexmedetomidine requirements (P = 0.03). There were no differences in 24-hour opioid dosage requirements, percent time at goal pain or sedation scores, depth of sedation, or QTc following quetiapine initiation. CONCLUSION AND RELEVANCE: Adjunctive use of quetiapine was not associated with a significant reduction in sedative dosage requirements 24 or 48 hours following initiation among mechanically ventilated adults without delirium.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit.

OBJECTIVE: To evaluate the proportion of patients receiving a hospital discharge prescription for a scheduled enteral opioid following initiation as a weaning strategy from a continuous opioid infusion in the Intensive Care Unit (ICU). DESIGN: Retrospective, observational study. SETTING: Five adult ICUs at a large, quaternary care academic medical center. PATIENTS: Endotracheally intubated, opioid-naive adults receiving a continuous opioid infusion with a concomitant scheduled enteral opioid initiated. Exclusion criteria were receipt of fewer than two enteral opioid doses, documentation of a long-acting opioid as a home medication, the indication for the enteral opioid was not a weaning strategy, death during hospital admission or discharge to hospice. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The proportion of ICU and hospital survivors who received a discharge prescription for a scheduled enteral opioid, total duration of continuous opioid infusion, duration of continuous opioid infusion after initiation of an enteral opioid therapy, total duration of enteral therapy, ICU and hospital length of stay. RESULTS: Of 62 included patients, 19 patients (30.6 percent) received a new prescription for a scheduled enteral opioid at hospital discharge. The median duration of enteral opioid therapy was longer for patients who received a discharge prescription compared to those who did not (20.09 vs 8.89 days, p = 0.02), though the remaining endpoints were not different. CONCLUSIONS: Utilizing scheduled enteral opioids as a weaning strategy from continuous opioid infusions may place patients at risk of ICU-acquired physical dependence on opioids.

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration in the Diagnosis of Breast Cancer Thoracic Metastases and Detection of Receptor Discordance.

BACKGROUND: Metastasis of breast cancer to mediastinal lymph nodes is common and biopsy of suspicious lesions can have important diagnostic, prognostic, and therapeutic implications, particularly with respect to tumor receptor status. Our aim was to show that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can be used for the diagnosis of metastatic breast cancer and demonstrate reliable receptor evaluation that can result in change of therapy. METHODS: A retrospective review of consecutive adult patients undergoing EBUS-TBNA from May 2007 to September 2012 was performed. Data collected for patients with a history of breast cancer included patient demographics, tumor pathology, receptor analysis, imaging, and bronchoscopy or surgical results. RESULTS: Sixty-four patients with a history of breast cancer aged from 31 to 81 years underwent EBUS-TBNA for the evaluation of mediastinal lymphadenopathy of which 16 patients had not been previously treated for their breast cancer with systemic therapy. Eighty suspicious lymph nodes were biopsied measuring 0.8 to 3.1 cm in diameter. Fifty-nine (92%) patients had diagnostic cytology for malignancy or benign lymphoid tissue. Breast malignancy was identified in 33 (52%) patients and 23 (70%) of these had sufficient samples for the evaluation of estrogen, progesterone, and human epidermal growth factor receptor 2 status. Overall 48% of the patients with receptors analyzed had discordance between the primary tumor and metastasis. CONCLUSIONS: EBUS-TBNA is a useful tool for evaluating mediastinal lymphadenopathy in patients with a history of breast cancer and can provide information on the concordance of receptors status between the primary tumor and metastatic sites in the thorax.

Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis.

BACKGROUND: Current treatments for pulmonary arterial hypertension (PAH) have been shown to improve dyspnea, 6-min walk distance (6MWD), and pulmonary hemodynamics, but few studies were designed to compare treatment regimens or assess the impact of treatment on mortality. METHODS: We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids. We searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH. Two investigators abstracted data and rated study quality and applicability. RESULTS: We identified 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insufficient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively). CONCLUSIONS: Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy.

Predictors of short-term mortality in patients undergoing percutaneous dilatational tracheostomy.

PURPOSE: The purpose of the study was to identify the predictors of short-term mortality in patients undergoing percutaneous dilatational tracheostomy (PDT). MATERIALS AND METHODS: Retrospective analysis of data pertaining to adult patients who underwent PDT between July 2005 and June 2008 in an urban, academic, tertiary care medical center was done. Clinical and demographic data were analyzed for 483 patients undergoing PDT via multivariate logistic regression. RESULTS: Mortality data were examined at in-hospital, 14, 30, and 180 days postprocedure. Overall mortality rates were 11% at 14 days, 19% at 30 days, and 40% at 180 days. In-hospital mortality was 30%. CONCLUSIONS: Patients undergoing PDT have significant short-term mortality with 11% dying within 14 days and an in-hospital mortality rate of 30%. We identified an index diagnosis of ventilator-associated pneumonia and trauma to be associated with a higher survival rate, whereas older age, oncological diagnosis, cardiogenic shock, and ventricular-assist devices were associated with higher mortality. There is significant heterogeneity in both underlying diagnosis and patient outcomes, and these factors should be considered when deciding to perform this procedure and discussed with patients/family members to provide a realistic expectation of potential prognosis.