The influence of continuous renal replacement therapy on 1,3-ß-d-glucan levels in critically ill patients: a single-center retrospective propensity score study.

1,3-ß-d-Glucan (BDG) is commonly used for diagnosing invasive fungal infections (IFIs). While exposure to cellulose-based hemodialyzers is known to cause false-positive BDG results, the impact of modern hemofilters used in continuous renal replacement therapy (CRRT) remains unclear. This retrospective, single-center cohort study aimed to evaluate the effect of CRRT on BDG levels in critically ill patients. We included adult intensive care unit (ICU) patients with ≥1 BDG measurement between December 2019 and December 2020. The primary outcome was the rate of false-positive BDG results in patients exposed to CRRT compared to unexposed patients. Propensity score analysis was performed to control for confounding factors. A total of 103 ICU patients with ≥1 BDG level were identified. Most (72.8%) were medical ICU patients. Forty patients underwent CRRT using hemofilter membranes composed of sodium methallyl sulfonate copolymer (AN 69 HF) (82.5%) and of polyarylethersulfone (PAES) (17.5%). Among the 91 patients without proven IFI, 31 (34.1%) had false-positive BDG results. Univariable analysis showed an association between CRRT exposure and false-positive BDG results. However, the association between CRRT exposure and false-positive BDG results was no longer significant across three propensity score models employed: 1:1 match (n = 32) (odds ratio (OR) 1.65, p = .48), model-adjusted (n = 91) (OR 1.75, p = .38), quintile-adjusted (n = 91) (OR 1.78, p = .36). In this single-center retrospective analysis, exposure to synthetic CRRT membranes did not independently increase the risk of false-positive BDG results. Larger prospective studies are needed to further evaluate the association between CRRT exposure and false-positive BDG results in critically ill patients with suspected IFI.

Rapid implementation of an emergency on-site CKRT dialysate production system during the COVID-19 pandemic.

BACKGROUND: On December 29, 2021, during the delta wave of the Coronavirus Disease 2019 (COVID-19) pandemic, the stock of premanufactured solutions used for continuous kidney replacement therapy (CKRT) at the University of New Mexico Hospital (UNMH) was nearly exhausted with no resupply anticipated due to supply chain disruptions. Within hours, a backup plan, devised and tested 18 months prior, to locally produce CKRT dialysate was implemented. This report describes the emergency implementation and outcomes of this on-site CKRT dialysate production system. METHODS: This is a single-center retrospective case series and narrative report describing and reporting the outcomes of the implementation of an on-site CKRT dialysate production system. All adults treated with locally produced CKRT dialysate in December 2021 and January 2022 at UNMH were included. CKRT dialysate was produced locally using intermittent hemodialysis machines, hemodialysis concentrate, sterile parenteral nutrition bags, and connectors made of 3-D printed biocompatible rigid material. Outcomes analyzed included dialysate testing for composition and microbiologic contamination, CKRT prescription components, patient mortality, sequential organ failure assessment (SOFA) scores, and catheter-associated bloodstream infections (CLABSIs). RESULTS: Over 13 days, 22 patients were treated with 3,645 L of locally produced dialysate with a mean dose of 20.0 mL/kg/h. Fluid sample testing at 48 h revealed appropriate electrolyte composition and endotoxin levels and bacterial colony counts at or below the lower limit of detection. No CLABSIs occurred within 7 days of exposure to locally produced dialysate. In-hospital mortality was 81.8% and 28-day mortality was 68.2%, though illness severity was high, with a mean SOFA score of 14.5. CONCLUSIONS: Though producing CKRT fluid with IHD machines is not novel, this report represents the first description of the rapid and successful implementation of a backup plan for local CKRT dialysate production at a large academic medical center in the U.S. during the COVID-19 pandemic. Though conclusions are limited by the retrospective design and limited sample size of our analysis, our experience could serve as a guide for other centers navigating similar severe supply constraints in the future.

An Intensivist-Led Extracorporeal Membrane Oxygenation Program: Design, Implementation, and Outcomes of the First Five Years.

We describe the development, implementation, and outcomes of an intensivist-led adult extracorporeal life support (ECLS) program using intensivists both to perform venovenous (V-V), venoarterial (V-A), and extracorporeal cardiopulmonary resuscitation (ECPR) cannulations, and to manage patients on ECLS throughout their ICU course. All adults supported with ECLS at the University of New Mexico Hospital (UNMH) from February 1, 2017 to December 31, 2021 were retrospectively analyzed. A total of 203 ECLS cannulations were performed in 198 patients, including 116 V-A cannulations (including 65 during ECPR) and 87 V-V cannulations (including 38 in patients with COVID-19). UNMH intensivists performed 195 cannulations, with 9 cannulation complications. Cardiothoracic surgeons performed 8 cannulations. Overall survival to hospital discharge or transfer was 46.5%. Survival was 32.3% in the ECPR group and 56% in the non-ECPR V-A group. In the V-V cohort, survival was 66.7% in the COVID-19-negative patients and 34.2% in the COVID-19-positive patients. This large series of intensivist-performed ECLS cannulations-including V-A, V-V, and ECPR modalities-demonstrates the successful implementation of a comprehensive intensivist-led ECLS program. With outcomes comparable to those in the literature, our program serves as a model for the initiation and development of ECLS programs in settings with limited access to local subspecialty cardiothoracic surgical services.

Venoarterial extracorporeal membrane oxygenation is an effective management strategy for massive pulmonary embolism patients.

OBJECTIVE: Treatment of massive pulmonary embolism (MPE) is controversial, with mortality rates ranging from 25% to 65%. Patients commonly present with profound shock or cardiac arrest. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used as a form of acute cardiopulmonary support in critically ill patients. We reviewed our institution's pulmonary embolism response team experience using VA-ECMO for patients presenting with advanced shock and/or cardiac arrest from MPE. METHODS: From March 2017 to July 2019 we retrospectively reviewed 17 consecutive patients at our institution with MPE who were placed on VA-ECMO for initial hemodynamic stabilization. RESULTS: The mean patient age and body mass index was 55.8 years and 31.8, respectively. Ten of 17 patients (59%) required cardiopulmonary resuscitation before or during VA-ECMO cannulation. All patients had evidence of profound shock with a mean initial lactate of 8.95 mmol/L, a mean pH of 7.10, and a mean serum creatinine of 1.78 mg/dL. Seventeen of 17 cannulations (100%) were performed percutaneously, with 41% (n = 7) of patients placed on VA-ECMO while awake and using local analgesia. Five of 17 patients (29%) required reperfusion cannulas, with 0% incidence of limb loss. Overall survival was 13 of 17 patients (76%), with causes of death resulting from anoxic brain injury (n = 2), septic shock (n = 1), and cardiopulmonary resuscitation-induced hemorrhage from liver laceration (n = 1). In survivors, 12 of 13 patients (92%) were discharged without evidence of neurologic insult. The median duration of the VA-ECMO run for survivors was 86 hours (range, 45-218 hours). In survivors, the median length of time from ECMO cannulation to lactate clearance (<2.0 mmol/L) was 10 hours and the median length of time from ECMO cannulation to freedom from vasopressors was 6 hours. Three of 13 patients (23%) required concomitant percutaneous thrombectomy and catheter-directed thrombolysis to address persistent right heart dysfunction, with the remaining survivors (77%) receiving VA-ECMO and anticoagulation alone as definitive therapy for their MPE. The median intensive care and hospital length of stay for survivors was 9 and 13 days, respectively. CONCLUSIONS: VA-ECMO was effective at salvaging highly unstable patients with MPE. Survivors had rapid reversal of multiple organ failure with ECMO as their primary therapy. The majority of survivors required ECMO and anticoagulation alone for definitive therapy of their MPE.

Fatal pulmonary hemorrhage due to severe mitral regurgitation during venoarterial extracorporeal membrane oxygenation.

Pulmonary hemorrhage (PH) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been primarily reported in pediatric patients. We report a case of fatal PH during VA-ECMO for cardiogenic shock after myocardial infarction (MI). PH, in this case, was secondary to a triad of aortic insufficiency, left ventricle distension, and severe laminar mitral regurgitation. This case scenario, previously unreported in adults, illustrates the need for the echocardiographic assessment of left-sided heart valves prior to VA-ECMO initiation after MI as well as management considerations for massive PH in this context.

Prognostic Factors for Long-Term Mortality in Critically Ill Patients Treated With Prolonged Mechanical Ventilation: A Systematic Review.

OBJECTIVES: Long-term survival for patients treated with prolonged mechanical ventilation is generally poor; however, patient-level factors associated with long-term mortality are unclear. Our objective was to systematically review the biomedical literature and synthesize data for prognostic factors that predict long-term mortality in prolonged mechanical ventilation patients. DATA SOURCES: We searched PubMed, CINAHL, and Cochrane Library from 1988 to 2015 for studies on prolonged mechanical ventilation utilizing a comprehensive strategy without language restriction. STUDY SELECTION: We included studies of adults 1) receiving mechanical ventilation for more than or equal to 14 days, 2) admitted to a ventilator weaning unit, or 3) received a tracheostomy for acute respiratory failure. We analyzed articles that used a multivariate analysis to identify patient-level factors associated with long-term mortality (≥ 6 mo from when the patient met criteria for receiving prolonged mechanical ventilation). DATA EXTRACTION: We used a standardized data collection tool and assessed study quality with a customized Newcastle-Ottawa Scale. We abstracted the strength of association between each prognostic factor and long-term mortality. Individual prognostic factors were then designated as strong, moderate, weak, or inconclusive based on an a priori previously published schema. DATA SYNTHESIS: A total of 7,411 articles underwent relevance screening; 419 underwent full article review. We identified 14 articles that contained a multivariate analysis. We abstracted 19 patient-level factors that showed association with long-term mortality. Six factors demonstrated strong strength of evidence for association with the primary outcome: age, vasopressor requirement, thrombocytopenia, preexisting kidney disease, failed ventilator liberation, and acute kidney injury ± hemodialysis requirement. All factors, except preexisting kidney disease and failed ventilator liberation, were measured at the time the patients met criteria for prolonged mechanical ventilation. CONCLUSIONS: Despite the magnitude of the public health challenge posed by the prolonged mechanical ventilation population, only 14 articles in the biomedical literature have tested patient-level factors associated with long-term mortality. Further research is needed to inform optimal patient selection for prolonged mechanical ventilation.

Long-term survival of critically ill patients treated with prolonged mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: Prolonged dependence on mechanical ventilation after critical illness is an emerging public health challenge; however, long-term outcomes are incompletely understood. We aimed to systematically analyse long-term survival of critically ill patients treated with prolonged mechanical ventilation. METHODS: We searched PubMed, CINAHL, and the Cochrane Library between 1988 and Nov 6, 2013, with no language restrictions, for studies on prolonged mechanical ventilation. We included studies of adult populations treated with mechanical ventilation for more than 14 days, who were admitted to a ventilator weaning unit, or who had a tracheostomy for acute respiratory failure. We abstracted data with a standardised collection template and assessed study quality (ie, risk of bias) using a customised Newcastle-Ottawa Scale. We did a stratified analysis based on study setting (eg, acute vs post-acute care hospitals), and used a random-effects model to calculate pooled statistics (proportions with 95% CIs) for all outcomes. We did sensitivity analyses based on study quality (ie, high-quality studies only) and country of origin (USA vs non-USA and USA vs UK). The primary outcome was mortality at 1 year. Secondary outcomes were in-hospital mortality, discharge destination among survivors, successful liberation from mechanical ventilation while in hospital, and mortality at timepoints longer than 1 year. FINDINGS: Of 6326 studies identified, 402 underwent full manuscript review, and 124 studies from 16 countries met the inclusion criteria. 39 studies reported mortality at 1 year, which was 59% (95% CI 56-62). Among the 29 high-quality studies, the pooled mortality at 1 year was 62% (95% CI 57-67). Pooled mortality at hospital discharge was 29% (95% CI 26-32). However, only 19% (16-24) were discharged to home and only 50% (47-53) were successfully liberated from mechanical ventilation. For studies in post-acute care hospitals, outcomes were worse in the USA than internationally (mortality at 1 year was 73% [95% CI 67-78] in the USA vs 47% [29-65] in non-USA countries; in-hospital mortality was 31% [26-37] vs 18% [14-24]; and liberation from ventilation was 47% [42-51] vs 63% [59-68]; p<0·0001 for all). INTERPRETATION: Although a high proportion of patients survived to hospital discharge, fewer than half of patients survived beyond 1 year. Future studies should focus on optimum patient selection for prolonged mechanical ventilation and integration of long-term outcome information into clinical decision making. FUNDING: Cooper University Health Care and Cooper Medical School of Rowan University.

A trans-dominant form of Gag restricts Ty1 retrotransposition and mediates copy number control.

UNLABELLED: Saccharomyces cerevisiae and Saccharomyces paradoxus lack the conserved RNA interference pathway and utilize a novel form of copy number control (CNC) to inhibit Ty1 retrotransposition. Although noncoding transcripts have been implicated in CNC, here we present evidence that a truncated form of the Gag capsid protein (p22) or its processed form (p18) is necessary and sufficient for CNC and likely encoded by Ty1 internal transcripts. Coexpression of p22/p18 and Ty1 decreases mobility more than 30,000-fold. p22/p18 cofractionates with Ty1 virus-like particles (VLPs) and affects VLP yield, protein composition, and morphology. Although p22/p18 and Gag colocalize in the cytoplasm, p22/p18 disrupts sites used for VLP assembly. Glutathione S-transferase (GST) affinity pulldowns also suggest that p18 and Gag interact. Therefore, this intrinsic Gag-like restriction factor confers CNC by interfering with VLP assembly and function and expands the strategies used to limit retroelement propagation. IMPORTANCE: Retrotransposons dominate the chromosomal landscape in many eukaryotes, can cause mutations by insertion or genome rearrangement, and are evolutionarily related to retroviruses such as HIV. Thus, understanding factors that limit transposition and retroviral replication is fundamentally important. The present work describes a retrotransposon-encoded restriction protein derived from the capsid gene of the yeast Ty1 element that disrupts virus-like particle assembly in a dose-dependent manner. This form of copy number control acts as a molecular rheostat, allowing high levels of retrotransposition when few Ty1 elements are present and inhibiting transposition as copy number increases. Thus, yeast and Ty1 have coevolved a form of copy number control that is beneficial to both "host and parasite." To our knowledge, this is the first Gag-like retrotransposon restriction factor described in the literature and expands the ways in which restriction proteins modulate retroelement replication.

Ty1 gag enhances the stability and nuclear export of Ty1 mRNA.

Retrotransposon and retroviral RNA delivery to particle assembly sites is essential for their replication. mRNA and Gag from the Ty1 retrotransposon colocalize in cytoplasmic foci, which are required for transposition and may be the sites for virus-like particle (VLP) assembly. To determine which Ty1 components are required to form mRNA/Gag foci, localization studies were performed in a Ty1-less strain expressing galactose-inducible Ty1 plasmids (pGTy1) containing mutations in GAG or POL. Ty1 mRNA/Gag foci remained unaltered in mutants defective in Ty1 protease (PR) or deleted for POL. However, Ty1 mRNA containing a frameshift mutation (Ty1fs) that prevents the synthesis of all proteins accumulated in the nucleus. Ty1fs RNA showed a decrease in stability that was mediated by the cytoplasmic exosome, nonsense-mediated decay (NMD) and the processing body. Localization of Ty1fs RNA remained unchanged in an nmd2Δ mutant. When Gag and Ty1fs mRNA were expressed independently, Gag provided in trans increased Ty1fs RNA level and restored localization of Ty1fs RNA in cytoplasmic foci. Endogenously expressed Gag also localized to the nuclear periphery independent of RNA export. These results suggest that Gag is required for Ty1 mRNA stability, efficient nuclear export and localization into cytoplasmic foci.

Emergency department inter-hospital transfer for post-cardiac arrest care: initial experience with implementation of a regional cardiac resuscitation center in the United States.

OBJECTIVE: The American Heart Association recently recommended regional cardiac resuscitation centers (CRCs) for post-resuscitation care following out-of-hospital cardiac arrest (OHCA). Our objective was to describe initial experience with CRC implementation. METHODS: Prospective observational study of consecutive post-resuscitation patients transferred from community Emergency Departments (EDs) to a CRC over 9 months. Transfer criteria were: OHCA, return of spontaneous circulation (ROSC), and comatose after ROSC. Incoming patients were received and stabilized in the ED of the CRC where advanced therapeutic hypothermia (TH) modalities were applied. Standardized post-resuscitation care included: ED evaluation for cardiac catheterization, TH (33-34 °C) for 24h, 24h/day critical care physician support, and evidence-based neurological prognostication. Prospective data collection utilized the Utstein template. The primary outcome was survival to hospital discharge with good neurological function [Cerebral Performance Category 1 or 2]. RESULTS: Twenty-seven patients transferred from 11 different hospitals were included. The majority (21/27 [78%]) had arrest characteristics suggesting poor prognosis for survival (i.e. asystole/pulseless electrical activity initial rhythm, absence of bystander cardiopulmonary resuscitation, or an unwitnessed cardiac arrest). The median (IQR) time from transfer initiation to reaching TH target temperature was 7(5-13)h. Ten (37%) patients survived to hospital discharge, and of these 9/10 (90% of survivors, 33% of all patients) had good neurological function. CONCLUSIONS: Despite a high proportion of patients with cardiac arrest characteristics suggesting poor prognosis for survival, we found that one-third of CRC transfers survived with good neurological function. Further research to determine if regional CRCs improve outcomes after cardiac arrest is warranted.