Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients.

Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients.

Multiple studies have identified an association between neutrophils and COVID-19 disease severity; however, the mechanistic basis of this association remains incompletely understood. Here we collected 781 longitudinal blood samples from 306 hospitalized COVID-19 + patients, 78 COVID-19 âˆ' acute respiratory distress syndrome patients, and 8 healthy controls, and performed bulk RNA-sequencing of enriched neutrophils, plasma proteomics, cfDNA measurements and high throughput antibody profiling assays to investigate the relationship between neutrophil states and disease severity or death. We identified dynamic switches between six distinct neutrophil subtypes using non-negative matrix factorization (NMF) clustering. At days 3 and 7 post-hospitalization, patients with severe disease had an enrichment of a granulocytic myeloid derived suppressor cell-like state gene expression signature, while non-severe patients with resolved disease were enriched for a progenitor-like immature neutrophil state signature. Severe disease was associated with gene sets related to neutrophil degranulation, neutrophil extracellular trap (NET) signatures, distinct metabolic signatures, and enhanced neutrophil activation and generation of reactive oxygen species (ROS). We found that the majority of patients had a transient interferon-stimulated gene signature upon presentation to the emergency department (ED) defined here as Day 0, regardless of disease severity, which persisted only in patients who subsequently died. Humoral responses were identified as potential drivers of neutrophil effector functions, as enhanced antibody-dependent neutrophil phagocytosis and reduced NETosis was associated with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirmed that while patient-derived IgG antibodies mostly drove neutrophil phagocytosis and ROS production in healthy donor neutrophils, patient-derived IgA antibodies induced a predominant NETosis response. Overall, our study demonstrates neutrophil dysregulation in severe COVID-19 and a potential role for IgA-dominant responses in driving neutrophil effector functions in severe disease and mortality.

Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro.

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.

Pleural Pressure Targeted Positive Airway Pressure Improves Cardiopulmonary Function in Spontaneously Breathing Patients With Obesity.

BACKGROUND: Increased pleural pressure affects the mechanics of breathing of people with class III obesity (BMI > 40 kg/m2). RESEARCH QUESTION: What are the acute effects of CPAP titrated to match pleural pressure on cardiopulmonary function in spontaneously breathing patients with class III obesity? STUDY DESIGN AND METHODS: We enrolled six participants with BMI within normal range (control participants, group I) and 12 patients with class III obesity (group II) divided into subgroups: IIa, BMI of 40 to 50 kg/m2; and IIb, BMI of ≥ 50 kg/m2. The study was performed in two phases: in phase 1, participants were supine and breathing spontaneously at atmospheric pressure, and in phase 2, participants were supine and breathing with CPAP titrated to match their end-expiratory esophageal pressure in the absence of CPAP. Respiratory mechanics, esophageal pressure, and hemodynamic data were collected, and right heart function was evaluated by transthoracic echocardiography. RESULTS: The levels of CPAP titrated to match pleural pressure in group I, subgroup IIa, and subgroup IIb were 6 ± 2 cmH2O, 12 ± 3 cmH2O, and 18 ± 4 cmH2O, respectively. In both subgroups IIa and IIb, CPAP titrated to match pleural pressure decreased minute ventilation (IIa, P = .03; IIb, P = .03), improved peripheral oxygen saturation (IIa, P = .04; IIb, P = .02), improved homogeneity of tidal volume distribution between ventral and dorsal lung regions (IIa, P = .22; IIb, P = .03), and decreased work of breathing (IIa, P < .001; IIb, P = .003) with a reduction in both the work spent to initiate inspiratory flow as well as tidal ventilation. In five hypertensive participants with obesity, BP decreased to normal range, without impairment of right heart function. INTERPRETATION: In ambulatory patients with class III obesity, CPAP titrated to match pleural pressure decreased work of breathing and improved respiratory mechanics while maintaining hemodynamic stability, without impairing right heart function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02523352; URL: www.clinicaltrials.gov.

High Pleural Pressure Prevents Alveolar Overdistension and Hemodynamic Collapse in Acute Respiratory Distress Syndrome with Class III Obesity. A Clinical Trial.

Rationale: Obesity is characterized by elevated pleural pressure (Ppl) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine the effects of a lung recruitment maneuver (LRM) in the presence of elevated Ppl on hemodynamics, left and right ventricular pressure, and pulmonary vascular resistance. We hypothesized that elevated Ppl protects the cardiovascular system against high airway pressure and prevents lung overdistension.Methods: First, an interventional crossover trial in adult subjects with ARDS and a body mass index ≥ 35 kg/m2 (n = 21) was performed to explore the hemodynamic consequences of the LRM. Second, cardiovascular function was studied during low and high positive end-expiratory pressure (PEEP) in a model of swine with ARDS and high Ppl (n = 9) versus healthy swine with normal Ppl (n = 6).Measurements and Main Results: Subjects with ARDS and obesity (body mass index = 57 ± 12 kg/m2) after LRM required an increase in PEEP of 8 (95% confidence interval [95% CI], 7-10) cm H2O above traditional ARDS Network settings to improve lung function, oxygenation and [Formula: see text]/[Formula: see text] matching, without impairment of hemodynamics or right heart function. ARDS swine with high Ppl demonstrated unchanged transmural left ventricular pressure and systemic blood pressure after the LRM protocol. Pulmonary arterial hypertension decreased (8 [95% CI, 13-4] mm Hg), as did vascular resistance (1.5 [95% CI, 2.2-0.9] Wood units) and transmural right ventricular pressure (10 [95% CI, 15-6] mm Hg) during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized the [Formula: see text]/[Formula: see text] ratio.Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. In addition, patients with ARDS and class III obesity hemodynamically tolerate LRM with high airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT02503241).

Acute Myocardial Infarction Complicated by Cardiogenic Shock: Analysis of the Position Statement From the European Society of Cardiology Acute Cardiovascular Care Association, With Perioperative Implications.

Effective management of cardiogenic shock (CS) is hampered by a lack of evidence-based information. This is a high-mortality condition, without clear, evidence-based guidelines for perioperative management, specifically-a lack of target endpoints for treatment (e.g.: mean arterial pressure or oxygenation), utility of regional care systems or the benefits of palliative care. The Acute Cardiovascular Care Association (ACCA) of the European Society of Cardiology (ESC) recently published a position statement that aimed to offer contemporary guidance on the diagnosis and treatment of acute myocardial infarction (AMI) complicated by CS. Herein, we review this complex clinical topic and review the ACCA statement on AMI associated with CS, with a focus on relevance to perioperative management.

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19.

A recent estimate suggests that one in five deaths globally are associated with sepsis 1 . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity 2,3 and our lack of insight into sepsis immunopathology 4 . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis 5-8 . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data 9 . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.

Acute heart failure after liver transplantation: A narrative review.

Acute heart failure (AHF) is an under recognized yet potentially lethal complication after liver transplantation (LT) surgery. The increase in incidence of liver transplantation amongst high-risk patients and the leniency in the criteria for transplantation, predisposes these patients to postoperative AHF and the antecedent morbidity and mortality. The inability of conventional preoperative cardiovascular testing to accurately identify patients at risk for post-LT AHF poses a considerable challenge to clinicians caring for these patients. Even if high-risk patients are identified, there is considerable ambiguity in the candidacy for transplantation as well as optimization strategies that could potentially prevent the development of AHF in the postoperative period. The intraoperative and postoperative management of patients who develop AHF is also challenging and requires a well-coordinated multidisciplinary approach. The use of mechanical circulatory support in patients with refractory heart failure has the potential to improve outcomes but its use in this complex patient population can be associated with significant complications and requires a stringent risk-benefit analysis on a case-by-case basis.

A lung rescue team improves survival in obesity with acute respiratory distress syndrome.

BACKGROUND: Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. METHODS: In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012-2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015-2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. RESULTS: The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13-0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74). CONCLUSION: Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Deficit Accumulation and Phenotype Assessments of Frailty Both Poorly Predict Duration of Hospitalization and Serious Complications after Noncardiac Surgery.

BACKGROUND: Frailty is associated with adverse postoperative outcomes, but it remains unclear which measure of frailty is best. This study compared two approaches: the Modified Frailty Index, which is a deficit accumulation model (number of accumulated deficits), and the Hopkins Frailty Score, which is a phenotype model (consisting of shrinking, weakness, exhaustion, slowness, and low physical activity). The primary aim was to compare the ability of each frailty score to predict prolonged hospitalization. Secondarily, the ability of each score to predict 30-day readmission and/or postoperative complications was compared. METHODS: This study prospectively enrolled adults presenting for preanesthesia evaluation before elective noncardiac surgery. The Hopkins Frailty Score and Modified Frailty Index were both determined. The ability of each frailty score to predict the primary outcome (prolonged hospitalization) was compared using a ratio of root-mean-square prediction errors from linear regression models. The ability of each score to predict the secondary outcome (readmission and complications) was compared using ratio of root-mean-square prediction errors from logistic regression models. RESULTS: The study included 1,042 patients. The frailty rates were 23% (Modified Frailty Index of 4 or higher) and 18% (Hopkins Frailty Score of 3 or higher). In total, 12.9% patients were readmitted or had postoperative complications. The error of the Modified Frailty Index and Hopkins Frailty Score in predicting the primary outcome was 2.5 (95% CI, 2.2, 2.9) and 2.6 (95% CI, 2.2, 3.0) days, respectively, and their ratio was 1.0 (95% CI, 1.0, 1.0), indicating similarly poor prediction. Similarly, the error of respective frailty scores in predicting the probability of secondary outcome was high, specifically 0.3 (95% CI, 0.3, 0.4) and 0.3 (95% CI, 0.3, 0.4), and their ratio was 1.00 (95% CI, 1.0, 1.0). CONCLUSIONS: The Modified Frailty Index and Hopkins Frailty Score were similarly poor predictors of perioperative risk. Further studies, with different frailty screening tools, are needed to identify the best method to measure perioperative frailty.

Independent lung ventilation: Implementation strategies and review of literature.

Independent lung ventilation, though infrequently used in the critical care setting, has been reported as a rescue strategy for patients in respiratory failure resulting from severe unilateral lung pathology. This involves isolating and ventilating the right and left lung differently, using separate ventilators. Here, we describe our experience with independent lung ventilation in a patient with unilateral diffuse alveolar hemorrhage, who presented with severe hypoxemic respiratory failure despite maximal ventilatory support. Conventional ventilation in this scenario leads to preferential distribution of tidal volume to the non-diseased lung causing over distension and inadvertent volume trauma. Since each lung has a different compliance and respiratory mechanics, instituting separate ventilation strategies to each lung could potentially minimize lung injury. Based on review of literature, we provide a detailed description of indications and procedures for establishing independent lung ventilation, and also provide an algorithm for management and weaning a patient from independent lung ventilation.

Transvenous Lead Extraction: A Clinical Commentary for Anesthesiologists.

With increasing use of cardiovascular implantable electronic devices, the need for lead extractions has increased to an annual volume of more than 10,000 extractions worldwide. This article provides a focused clinical commentary on the perioperative management, identification, and treatment of life-threatening complications associated with lead extractions. In addition, a summary of indications, techniques, and lead extraction complications is provided. Although uncommon, lead extractions are associated with a consistent rate of major procedure-related complications and mortality. Major life-threatening complications include vascular laceration, cardiac avulsion, hemothorax, pericardial effusion, and cardiac arrest. Comprehensive preoperative risk assessment and adequate planning and preparedness are crucial to decreasing all procedure-related adverse events. The location of the procedure (electrophysiology suite v hybrid operating room) and the nature of cardiac surgical backup are determined after meticulous risk stratification. In addition to decisions on vascular access, invasive monitoring, and modality of rhythm support, transesophageal echocardiography plays a crucial role in early diagnosis, timely management, and potential prevention of these complications.