PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Management Strategies for Acute Pulmonary Embolism in the ICU.

TOPIC IMPORTANCE: Acute pulmonary embolism (PE) is a common disease encountered by pulmonologists, cardiologists, and critical care physicians throughout the world. For patients with high-risk acute PE (defined by systemic hypotension) and intermediate high-risk acute PE (defined by the absence of systemic hypotension, but the presence of numerous other concerning clinical and imaging features), intensive care often is necessary. Initial management strategies should focus on optimization of right ventricle (RV) function while decisions about advanced interventions are being considered. REVIEW FINDINGS: We reviewed the existing literature of various vasoactive agents, IV fluids and diuretics, and pulmonary vasodilators in both animal models and human trials of acute PE. We also reviewed the potential complications of endotracheal intubation and positive pressure ventilation in acute PE. Finally, we reviewed the data of venoarterial extracorporeal membrane oxygenation (ECMO) use in acute PE. The above interventions are discussed in the context of the underlying pathophysiologic features of acute RV failure in acute PE with corresponding illustrations. SUMMARY: Norepinephrine is a reasonable first choice for hemodynamic support with vasopressin as an adjunct. IV loop diuretics may be useful if evidence of RV dysfunction or volume overload is present. Fluids should be given only if concern exists for hypovolemia and absence of RV dilatation. Supplemental oxygen administration should be considered even without hypoxemia. Positive pressure ventilation should be avoided if possible. venoarterial ECMO cannulation should be implemented early if ongoing deterioration occurs despite these interventions.

Clinician Prediction of Survival vs Calculated Prediction Scores in Patients Requiring Extracorporeal Membrane Oxygenation.

BACKGROUND: Determining appropriate extracorporeal membrane oxygenation (ECMO) candidacy ensures appropriate utilization of this costly resource. The current ECMO survival prediction scores do not consider clinician assessment of patient viability. This study compared clinician prediction of survival to hospital discharge versus prediction scores. OBJECTIVES: The aim of this study was to compare clinician prediction of patients' survival to hospital discharge versus prognostic prediction scores (Respiratory ECMO Survival Prediction [RESP] or Survival After Veno-Arterial ECMO [SAVE] score) to actual survival. METHODS: This was an observational descriptive study from January 2020 to November 2021 conducted with interviews of nurses, perfusionists, and physicians who were involved during the initiation of ECMO within the first 24 hours of cannulation. Data were retrieved from the medical record to determine prediction scores and survival outcomes at hospital discharge. Accuracy of clinician prediction of survival was compared to the RESP or SAVE prediction scores and actual survival to hospital discharge. RESULTS: Accurate prediction of survival to hospital discharge for veno-venous ECMO by nurses was 47%, 64% by perfusionists, 45% by physicians, and 45% by the RESP score. Accurate predictions of patients on veno-arterial ECMO were correct in 54% of nurses, 77% of physicians, and 14% by the SAVE score. Physicians were more accurate than the SAVE score, P = .021, and perfusionists were significantly more accurate than the RESP score, P = .044. There was no relationship between ECMO specialists' years of experience and accuracy of predications. CONCLUSION: Extracorporeal membrane oxygenation clinicians may have better predictions of survival to hospital discharge than the prediction scores. Further research is needed to develop accurate prediction tools to help determine ECMO eligibility.

Temporal Trends in Methamphetamine Use in Patients Admitted to the Hospital: A Retrospective Cohort Study.

OBJECTIVES: Although methamphetamine use is common, the scope of methamphetamine use and outcomes for patients admitted to the hospital is unclear. This study aims to identify the prevalence of methamphetamine use from January 2012 to January 2022, coingestions, hospital course, and readmission rate of admitted patients. METHODS: This was a retrospective cohort study conducted on patients admitted to our center with the following inclusions: age older than 18 years, positive/"pending confirm" value for methamphetamine on urine drug screen, and/or an International Classification of Diseases , Tenth Revision , code related to stimulant use disorder as an active issue. Urine drug screen data are reported as methamphetamine +/- and polysubstance (PS) +/-. Patient demographics, admission diagnosis, and hospital course were extracted. Statistical tests used included t tests and Mann-Whitney U tests. RESULTS: A total of 19,159 encounters were included, representing 12,057 unique patients. The median (interquartile range) age was 43 (33-54) years. Of all encounters, 35.3% were methamphetamine + and PS -, and 46.3% were methamphetamine + and PS +. Hospitalizations increased from 883 in 2012 to 2532 in 2021. The median (IQR) hospital stay was 48 (48-120) hours. Of all encounters, 16.8% included an intensive care unit (ICU) admission, and the median ICU stay was 42 (21-87) hours. A total of 2988 patients (24.7%) were readmitted within the study period, and 4988 (71.5%) returned within 1 year of the previous encounter. In context of all emergency department admissions from 2013 to 2022, 13.1% had a urine drug screen + for methamphetamine. CONCLUSIONS: Hospitalizations with recent methamphetamine use doubled at our institution from 2012 to 2022. In addition, 1 in 4 is readmitted (typically within 1 year), and a minority requires ICU care.

Composite Angioimmunoblastic T-Cell Lymphoma and Diffuse Large B-Cell Lymphoma Presenting with Distributive Shock.

Diffuse large B-cell lymphoma (DLBCL) and angioimmunoblastic T-cell lymphoma (AITL) are two subtypes of non-Hodgkin lymphoma (NHL). The simultaneous occurrence of DLBCL and AITL in a composite lymphoma is very rare, and there are no established treatment regimens. We present the case of an 85-year-old male admitted to the intensive care unit with distributive shock, lymphocytosis, and lymphadenopathy, who was subsequently diagnosed with composite AITL and DLBCL, and treated with brentuximab vedotin (BV) and rituximab. To our knowledge, this is the first case of composite lymphoma presenting with distributive shock and treated with BV and rituximab, with successful resolution of shock.

Using Cardiohelp, Quadrox, and Nautilus Extracorporeal Membrane Oxygenators as Vascular Access for Hemodialysis, Continuous Renal Replacement Therapy, and Plasmapheresis: A Brief Technical Report.

The use of intermittent hemodialysis (iHD), and continuous renal replacement therapy (CRRT), along with extracorporeal membrane oxygenation (ECMO) in patients with acute kidney injury (AKI) and end-stage renal disease (ESRD) is very common. In this technical report, we describe the methods to perform these dialytic therapies safely and effectively using the ECMO circuit in lieu of a separate dialysis catheter. Specifically, we describe in detail how to connect these kidney replacement therapy modalities to a Quadrox, Nautilus, and Cardiohelp HLS (combined oxygenator and pump) oxygenator. The dialysis (iHD or CRRT) inlet is attached to the post-oxygenators Luer-Lock, whereas the return is attached to the pre-oxygenator Luer-Lock, both with a dual lumen pigtail. We also discuss the technical aspects of performing plasmapheresis in conjunction with ECMO and iHD or CRRT. Finally, we highlight the fact that the reported technique does not require modifying the ECMO cannulas/tubing which helps maximize safety.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study.

OBJECTIVES: To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE). DESIGN: A single-center prospective physiologic study. SETTING: At a single university medical center. PARTICIPANTS: Adult patients with severe COVID-19 ARDS on VV ECMO. INTERVENTIONS: Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV. MAIN MEASUREMENTS AND RESULTS: Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers. CONCLUSIONS: Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

Absolute quantification of plasma mitochondrial DNA by droplet digital PCR marks COVID-19 severity over time during intensive care unit admissions.

Increased plasma mitochondrial DNA concentrations are associated with poor outcomes in multiple critical illnesses, including COVID-19. However, current methods of cell-free mitochondrial DNA quantification in plasma are time-consuming and lack reproducibility. Here, we used next-generation sequencing to characterize the size and genome location of circulating mitochondrial DNA in critically ill subjects with COVID-19 to develop a facile and optimal method of quantification by droplet digital PCR. Sequencing revealed a large percentage of small mitochondrial DNA fragments in plasma with wide variability in coverage by genome location. We identified probes for the mitochondrial DNA genes, cytochrome B and NADH dehydrogenase 1, in regions of relatively high coverage that target small sequences potentially missed by other methods. Serial assessments of absolute mitochondrial DNA concentrations were then determined in plasma from 20 critically ill subjects with COVID-19 without a DNA isolation step. Mitochondrial DNA concentrations on the day of enrollment were increased significantly in patients with moderate or severe acute respiratory distress syndrome (ARDS) compared with those with no or mild ARDS. Comparisons of mitochondrial DNA concentrations over time between patients with no/mild ARDS who survived, patients with moderate/severe ARDS who survived, and nonsurvivors showed the highest concentrations in patients with more severe disease. Absolute mitochondrial DNA quantification by droplet digital PCR is time-efficient and reproducible; thus, we provide a valuable tool and rationale for future studies evaluating mitochondrial DNA as a real-time biomarker to guide clinical decision-making in critically ill subjects with COVID-19.

Outcomes of cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in-hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post-IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single-center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m2, and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Tension pneumomediastinum from opioid inhalation.

Pneumomediastinum is a rare complication of substance use, likely due to a Valsalva maneuver after drug inhalation. There are no previously documented associations between pneumomediastinum and opioid use. A 30-year-old man with a history of recent heroin and fentanyl inhalation presented to the emergency department in respiratory distress requiring intubation. His course was complicated by pneumomediastinum which subsequently developed tension physiology. He required emergent surgical decompression with a "blowhole incision" to his anterior chest. Although a rare complication of polysubstance use, pneumomediastinum can progress to tension physiology, requiring prompt diagnosis and management.

Plasma enzymatic activity, proteomics and peptidomics in COVID-19-induced sepsis: A novel approach for the analysis of hemostasis.

Introduction: Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation). Methods: Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study. Results: Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors. Discussion: The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.