Severe coronavirus disease 2019: Is it acute respiratory distress syndrome?.

The outbreak of coronavirus disease 2019 (COVID-19) poses a major global threat. Although we have learned a lot about COVID-19 from clinical studies and autopsy findings, there is still a lot of confusion. One of the biggest controversies is whether severe COVID-19 can be diagnosed as acute respiratory distress syndrome (ARDS). Severe COVID-19 may meet ARDS Berlin criteria, but it differs from ARDS caused by other etiologies and is characterized by later onset time, relatively normal lung compliance in some cases, significant hypercapnia, lung CT findings, and significant coagulation activation in lungs. Some reports classify COVID-19-related ARDS into different phenotypes, but most of them are based on observational studies, with high bias. To date, we have not fully understood the pathophysiology of COVID-19-related ARDS. Premature phenotyping may mislead mechanical ventilation strategies. We expect evidence from large clinical studies.Copyright © 2021, Peking Union Medical College Hospital. All rights reserved.

Lung Ultrasound versus SpO2-guided as 'Best-PEEP' titration in SARS-CoV2 ARDS

Background: SARS-CoV2 pneumonia with respiratory failure may evolve to ARDS. The effects of high PEEP on respiratory compliance varies in different patients. Our study is based on the high accurancy and sensitivity of Lung Ultrasound (LUS) in evaluating the heterogeneous distribution of aeration loss, and use of LUS to individualize PEEP titration to produce the best lung aeration. Method(s): Retrospective trial on two cohorts of patients (15+15) with SARS-CoV2 ARDS mild-to-moderate(according to Berlin Criteria), aged 18 to 80 y.o. In Group I(GI) PEEP titration was LUS guided, in Group II(GII) titration was SpO2-guided. In GI LUS score was calculated dividing lungs in six regions per hemithorax. Patients were treated with NIV or CPAP Helmet. In GII FiO2 was initially set at 40% and increased if target oxygenation was not met. In GI PEEP was set at 5 cmH2O and guided by LUS aeration. Cases were managed by PEEP values from 7.5-15 cmH2O. Determination of optimal PaO2/FiO2 was the primary outcome. Secondary outcomes were adverse event: incidence of barotrauma/pneumothorax/pneumomediastinum, haemodynamics (MAP and HR), time spent on NIV/ CPAP, length of stay, weaning categories, and mortality at day 28. Result(s): P/F ratio was 282+/-38.6 in GI, and 243+/-43.2 in GII. We didn't detect significant statistical differences between the two groups in terms of mortality (6.2% in Gi vs 6.8% in GII) nor in time to weaning (5+/-6 in GI vs 16+/-4.5 in GII). In-stead there were fewer AE in GI vs GII. Length of stay was reduced with mean value of 4.3 days. Conclusion(s): Compared to SpO2-guided PEEP titration, LUS-based titration was associated with favorable effects on rate of adverse events and length of hospital stay.

Utility of urinary biomarkers for diagnosis of acute kidney injury (AKI) in COVID-19

Introduction: Incidence of AKI reported varies from 0.5% to 37%.These incidence cannot be extrapolated in our patients as the severity of COVID-19 infection, the ethnicity of the patients l, the clinical profile and the healthcare delivery system is different.The aim of this study was to explore whether urinary cell cycle arrest markers and other renal biomarkers have a role in predicting AKI in critically ill patients with COVID-19 and acute respiratory disease Methods: This prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at study entry. Patients aged more than 18 years with moderate or severe respiratory disease as defined by Berlin criteria were subsequently recruited from November 2020 to May 2021. Urine samples were collected on admission to critical care areas for determination of KIM1, NGAL, IL-18,IGF-BP-7, TIMP -2 at the time point of study inclusion, 12h, 24h, 48h, after inclusion. The demographic information, comorbidities, clinical, and laboratory data were recorded. The study outcomes were the development of AKI and mortality during hospitalization. Result(s): [Formula presented] ROC analysis was done to determine the diagnostic performance of the various urinary biomarkers;AUC was 0.655 for normalised IL-18, 0.685 for normalised NGAL, 0.658 for normalised TIM-1, and so on Conclusion(s): AKI was common in critically ill COVID-19 patients. Raised values of urinary biomarkers with clinical information, are useful for the identification of AKI in critically ill COVID-19 patients. No conflict of interestCopyright © 2023

Effectiveness of Non-Invasive Ventilation with Awake Prone in Covid-19 Related-Acute Respiratory Distress Syndrome at Covid-19 Isolation Hospital Muzaffarabad

Background: Despite its widespread usage, invasive positive pressure ventilation (IPPV) has a dismal track record in COVID-19 patients with SARDS. Currently, there is a paucity of evidence supporting the usefulness of noninvasive positive pressure ventilation (NIPPV) in the treatment of severe ARDS, as well as a significant risk of aerosol formation in patients with COVID-19 infection. Objective(s): This study aims to assess the efficacy and safety of NIPPV administration to COVID-19 patients. Method(s): The trial included 130 participants with moderate tosevere ARDS based to the Berlin criteria (PaO2/FiO2 ratio of 200mmHg, GCS > 13, respiratory breathing index (RBI) of 105, and no systemic issues). They were treated with NIPPV with awake proaning up to 12 hours per day at a hospital in Muzaffarabad. The addition of a heat and moisture exchanger (HME) and viral/bacterial filters to the expiratory limb of the ventilator circuit represented a minor improvement. Result(s): In an average of six days, the PaO2/FiO2 ratio indicates that the severity of ARDS has improved from moderate/severe to mild in 64 percent of patients. 36 percent of individuals who had a defined airway experienced IPPV or failure of NIV. During the study period, 1 % the of healthcare workers (HCW) were infected with COVID19. The delivery of NIPPV was associated with claustrophobia, nasal crusting, aspiration, and barotrauma (0.7 percent). Conclusion(s): In selected patients, NIV with awake proaning up to 12 hours per day can be employed to give respiratory support without the need for IPPV, hence eliminating the need for IPPV in those patients. However, larger-scale investigations are required to validate our findings. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Ventilatory Ratio Identifies Organ Failure Risk in Covid-19 Ards Requiring Mechanical Ventilation

INTRODUCTION: Ventilatory ratio (VR) is a simple bedside index of carbon dioxide removal. VR correlates well with physiologic dead space fraction (VD/VT) and clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that high VR would identify COVID-19 ARDS patients with higher risk for death and organ failure. METHOD(S): We conducted a retrospective cohort study of patients admitted to a single hospital in New York, NY, USA from March-July 2020 who had PCR-confirmed SARS-CoV-2 infection, met the Berlin criteria for ARDS, and required tracheostomy for prolonged invasive mechanical ventilation (MV). MV parameters were collected 2-8 hours after intubation. Based on prior studies, a VR>2 was considered to be abnormally elevated. Comparisons were performed using the Wilcoxon rank-sum test or z-test for difference in proportions with alpha=0.05. The primary outcome was 30- day mortality and the secondary outcome was a composite endpoint of death or organ failure defined as requiring renal replacement or extracorporeal membrane oxygenation (ECMO) during the hospitalization. RESULT(S): Of 139 subjects enrolled, 67 (48.2%) had a VR>2. Low and high VR groups had similar baseline characteristics, including age (mean 58 years, SD +/-15.2), body mass index (30.1+/-6.69 kg/m2), simplified acute physiology score II (35.4+/-12.4), sequential organ failure assessment (SOFA) score (5.7+/-2.5), and a 19-point review of systemic disease history. High VR was not significantly associated with mortality (OR 0.92, p=0.827). However, high VR was associated with increased risk for the composite endpoint (OR 1.96, p=0.049) and independently identified patients with a higher risk of organ failure (OR 2.03, p=0.047). High VR was also associated with longer hospital length-of-stay for subjects who survived to discharge (52 vs. 43, p=0.035), more MV-free days within the 30 days after intubation (3.2 vs. 1.8, p=0.029), and higher SOFA score at 10+/-4 days post-intubation (6.2 vs. 4.8, p=0.024). CONCLUSION(S): Ventilatory ratio identifies COVID-ARDS ventilated patients with increased risk for organ failure requiring advanced intervention, as well as patients who may require prolonged mechanical ventilation and hospitalization.

Influence of Inflammatory Markers and Acute Phase Reactants on Pulmonary Dead Space in Covid-19 Ards

INTRODUCTION: Ventilatory ratio (VR) is a bedside index of impaired ventilation that can be used as a surrogate marker for pulmonary dead space fraction (VD/VT). Vasculopathy is hypothesized to increase VD/VT in patients with acute respiratory distress syndrome (ARDS) due to COVID-19. The purpose of this study was to investigate associations between VR and markers of inflammation in critically ill COVID-ARDS patients. METHOD(S): We conducted a retrospective study of patients admitted to an intensive care unit due to SARS-CoV-2 infection. All subjects required invasive mechanical ventilation and met the Berlin criteria for ARDS. Clinical lab values were collected at two timepoints: 2-8 hours after intubation (T1) and 2-24 hours before tracheostomy (T2). VR was split into high (VR>2) and low (VR< 2) groups. Comparisons were performed using student's t, Mann-Whitney, and z tests for difference in proportions with alpha=0.05. RESULT(S): Of the 139 subjects enrolled at T1, 67 (48%) had high VR (>2), with an overall mean VR of 2.08. High VR was significantly associated with leukocyte count (WBC) (13.3 vs. 10.6 x10

Prone Positioning in Severe Ards Due to Covid-19

INTRODUCTION: Studies have shown early application of prone-positioning in ARDS significantly decreased mortality. Our goal is to evaluate the effect of early prone-positioning specifically on COVID ARDS patients. METHOD(S): We performed a multicenter, retrospective observational analysis with a total of 1,335 patients with COVID ARDS that underwent prone positioning. Data was obtained from all HCA facilities within the dates of 1/1/2020- 6/20/2021. ARDS was defined using the Berlin criteria. Logistic regression was used to predict the likelihood of in-hospital all-cause mortality early vs late prone-positioning. Secondary outcomes were the relationship between age of the patient, MAP, days on ventilator and ICU length of stay (ICULOS) likelihood of in-hospital mortality. RESULT(S): From 1/1/2020-6/20/2021, a total of 3,407 patients with COVID ARDS were admitted to the participating facilities. 1,335 patients were included in the final analysis. Patients were mostly between ages 51-80 years old (77%), male (61.5%), white (55.4%), all of them admitted to ICU on mechanical ventilation. In-hospital allcause mortality was significantly lower in the shorter time to prone group (< 16 hours) than the longer time to prone group (>16, >24 hours), (p < 0.001, Exp(B) = 1.119, 95% C.I. [1.088, 1.151]). Mortality rate < 16 hours (46.53%), >16 hours (55%) vs >24 hours (68.1%). Patients that were prone in < 16 hours were less likely to experience an in-hospital mortality than those prone >16 hours (X2 (1, N= 1513) = 19.051, p < 0.001). There was not any statistically significant difference between the 16- and 24-hours group. For each one-day increase in days on the ventilator the likelihood of mortality is 0.978 times as likely. (p < 0.01, Exp(B) = 0.978, 95% C.I. [0.968, 0.989]). Expired rate by time to prone < 16 hours (55.45%) vs >16 hours (79.69%). For each one-year increase in age, patients are 1.045 times as likely to experience an in-hospital mortality (p < 0.001, Exp(B) =1.045, 95% C.I. [1.033,1.056]). CONCLUSION(S): We concluded through logistic regression that the time to prone had a statistically significant relation to in-hospital all-cause mortality and patients with COVID ARDS can benefit from early prone treatment.

Phase 1/2 Study of Agent-797, an Allogeneic Invariant Natural Killer T (Inkt) Cell Therapy, in Subjects with Moderate to Severe Acute Respiratory Distress Syndrome (Ards) Secondary to Sars-Cov-2 (Covid-19)

Background AgenT-797 is a novel allogeneic iNKT cell therapy demonstrating activity in malignances and serious viral infections (i.e., SARS-CoV-2). In response to inflammatory injury, iNKTs home to critical organs, including lungs, dampen proinflammatory cytokines and protect epithelial tissues. INKTs drive response through activation of innate and adaptive immunity, recruitment/trans-activation of NK, B, and T cells, and myeloid cells via contact and soluble mediators. iNKTs represent a novel and attractive potential immunotherapy for viral ARDS. This analysis presents results from an ongoing phase 1/2 study of agenT-797 in mechanically ventilated patients with moderate to severe ARDS secondary to COVID- 19;NCT04582201. Methods As of February 2022, patients on mechanical ventilation with confirmed moderate to severe (Berlin Definition) ARDS, secondary to COVID-19 were treated with a single infusion of agenT-797 at 100, 300, or 1000 x 106 iNKT cells. Primary endpoint was safety and secondarily, time to extubation, prevention of secondary infections, persistence and alloimmunity were evaluated. Clinical benefit was defined as improvement/resolution of viral ARDS evaluated as time to extubation and survival at 30 days post-infusion. Results Twenty evaluable patients were treated with agenT-797 with a median age of 66 years (range 26-77;85% >=65y). Patients enrolled early in pandemic (pre-vaccines) and were heavily pre-treated with remdesivir, steroids and/or tocilizumab. No dose-limiting toxicities were observed. Tolerability was favorable with no cytokine release syndrome (CRS), neurotoxicity, or severe immune-related AEs. One SAE was deemed possibly related to agenT-797 (Dyspnea, Grade 4). The most frequent AEs deemed possibly related was pyrexia (grade 1;n=6). Survival was 70% (14/20) in this predominantly elderly, mechanically ventilated population. Early signals of reduction in ARDS symptoms, rapid extubation, and reduction in secondary infections were observed. AgenT-797 was detected in peripheral blood up to day 6 post-infusion, consistent with a rapid translocation from blood to tissue. Spikes in the blood during D1 and D2 showed a dose-proportional relationship, however, increased dose did not lead to prolonged peripheral persistence. Additional translational and biomarker evaluation is underway. Conclusions In patients with severe viral ARDS secondary to SARS-COV-2, agenT-797 demonstrated encouraging survival and disease mitigating benefit with a favorable tolerability profile. The deep and broad activity observed is likely attributed to iNKT cells' ability to promote viral clearance, home to the lungs, and reduce inflammation. These findings support the potential for a variant-agnostic therapy for patients with viral ARDS, a condition for which there are currently no effective therapies.

METABOLOMIC PROFILING AND PROGNOSTICATION IN COVID-19-RELATED ARDS

SESSION TITLE: Late Breaking Posters in Critical Care SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: The majority of deaths in COVID-19 are due to acute respiratory distress syndrome (ARDS). We recently identified two subphenotypes among patients with COVID-19 related ARDS (C-ARDS) with divergent outcomes and responses to therapies. However, the precise biological processes that distinguish the subphenotypes, remain to be fully elucidated. High-resolution profiling of the metabolome can be used to gain precise insights into disease pathogenesis. The purpose of this study was to use precise, metabolomic profiling at the onset of C-ARDS to identify metabolic alterations and predict hospital mortality. METHODS: This was a retrospective, matched cohort study. Participants were adults with COVID-19 who met Berlin criteria for ARDS on the initial day of mechanical ventilation. All participants had prospectively banked plasma samples collected within one week of intubation. Twenty-five survivors to 90-days were matched on age, sex, and ethnicity to 25 patients who died within 28 days of intubation. Untargeted and targeted metabolomic analysis was performed using mass spectrometry and compared between survivors and non-survivors. Statistical analyses were performed with conditional logistic regression modeling with Bayesian inference. Compounds associated with mortality were identified using a cut-off of Bayes Factor (BF) > 3. Biological clustering analysis was performed using ChemRICH. Competitive modeling by four machine learning models—LASSO, adaptive LASSO, Random Forest, and XGBoost—was used to predict mortality. Three sets of predictors were explored: all metabolites, metabolites with BF > 1, and metabolites with BF > 3. RESULTS: Targeted and untargeted metabolomics of metabolic analytes yielded data for 30 bile acids, 340 biogenic amines, 522 complex lipids, 83 oxylipins, and 133 primary metabolites. Twenty-five compounds were identified with significant differences between survivors and non-survivors. Five compounds had increased levels associated with mortality, and 20 had decreased levels associated with mortality. Biological clustering analysis on these compounds identified four key clusters of compounds—unsaturated and saturated lysophosphatidylcholines, plasmalogens, and saturated ceramides—that were decreased amongst non-survivors. A machine learning-derived signature reflecting these metabolites showed excellent discrimination in predicting mortality, with the best model demonstrating area-under-the-receiver-operating-characteristic curve of 0.91. CONCLUSIONS: Metabolomic analysis identified differential enrichment of lipid metabolites in C-ARDS survivors compared to non-survivors. A machine learning model was able to accurately predict mortality from C-ARDS based on metabolomic profiles. CLINICAL IMPLICATIONS: Improved characterization of the metabolomic derangements in COVID-19 ARDS may lead to an enhanced understanding of drivers of mortality and improve prognostication and precision therapy. DISCLOSURES: No relevant relationships by Thomas Briese No relevant relationships by Xiaoyu Che No relevant relationships by Matthew Cummings No relevant relationships by Oliver Fiehn No relevant relationships by David Furfaro No relevant relationships by Wenhao Gou no disclosure on file for Walter Lipkin;no disclosure on file for Nischay Mishra;No relevant relationships by Max O'Donnell

POSITIVE END-EXPIRATORY PRESSURE (PEEP) INDEX: A NOVEL, BETTER DISCRIMINATION MARKER THAN PAO2/FIO2 FOR RESCUE MEASURES IN COVID-RELATED ARDS

SESSION TITLE: ECMO and ARDS in COVID-19 Infections SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: COVID-related acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. PaO2/Fio2 (PFR) is a prognostic and severity marker for ARDS. Other markers have been posited for ARDS. PEEP Index (PIx) [PEEP/PFR] or [(PEEP*Fio2)/PaO2] could serve as a new discriminatory marker to assess rescue therapies such as proning or ECMO referral. METHODS: Retrospective cohort study of all intubated COVID-19 patients with ARDS hospitalized at our institution between February 5th – May 11th, 2020. ARDS were calculated within first 24 hours of worst PaO2/FIO2 and their associated PEEP with bilateral infiltrates on Chest X-ray manually confirmed within 24hours of intubation fulfilling 2012 Berlin criteria. Outcomes of interest were all-cause in-hospital mortality, need for pronation and paralysis use. Binomial logistic regression with ROC curve were performed for univariate association for outcomes of interest. Cox proportional hazard regression modeling was performed and adjusted for potential confounders. PFR was transformed into a denominator of itself to reflect a direct proportional relationship. RESULTS: Data was analyzed from 113 hospitalized COVID-19 patients with identified ARDS. Mean age was 56.4 (STD 14.4);24% (27/113) were female. Median BMI was 30.3 [IQR 48.5,65.5]. Mean Tidal Volume (Vt) was 430 (STD 54). 64% (72/113) were compliant with low Vt (=<6mL/kg based on IBW). Median PFR 125 [IQR 99,192]. Mortality was 66% (74/113). 44% (50/113) were proned. 62% (70/113) required paralysis. PEEP Index outperformed PFR for discrimination for proning use: AUC 0.73 [95%CI 0.63,0.82], p< 0.005;vs AUC 0.674 [95%CI 0.58,0.77], p= 0.02. PEEP Index performed mildy better than PFR for discrimination of requiring paralytic use in ARDS with AUC 0.68 [95% 0.57,0.78], p< 0.05;vs AUC 0.62 [95%CI 0.51,0.73], p<0.05. APACHE2 score showed poor discrimination for both proning and paralytic use (AUC= 0.46 [95%CI 0.35,0.56];p=0.43 and respectively, AUC=0.45 [95%CI 0.34,0.56];p=0.36). After adjusting for confounders, PEEP Index nor PFR didn’t for predict for mortality (p>0.05);however, our sample was not powered. CONCLUSIONS: PEEP Index (PIx) is a novel tool that can serve as a better discriminatory function to evaluate patients with ARDS in the ICU who will require proning in comparison to traditional used PFR. CLINICAL IMPLICATIONS: PEEP Index (PIx) can serve as an easy alternative calculation to Oxygenation Index (OI) [(FiO2 x PAW) / PaO2] to identify patients that would benefit from early proning and other rescue therapies. Further studies are required to compare and validate PIx and OI prospectively as well as benefit cut-off points between proning and ECMO. DISCLOSURES: No relevant relationships by Perminder Gulani No relevant relationships by Manuel Hache Marliere no disclosure on file for Adarsh Katamreddy;No relevant relationships by Hyomin Lim No relevant relationships by Marzio Napolitano No relevant relationships by Leonidas Palaiodimos No relevant relationships by Anika Sasidharan Nair No relevant relationships by Jee Young You

UNDERSTANDING THE NEED FOR A BROAD DIFFERENTIAL DIAGNOSIS: A CASE OF PNEUMONIC TULAREMIA

SESSION TITLE: Disseminated Bacterial Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Tularemia is a rare infectious disease caused by Francisella Tularensis that typically affects the skin, eyes, lymph nodes, and lungs. There are a variety of forms of tularemia with varying rates of contagiousness and mortality. Respiratory tularemia has a high mortality rate if left untreated and presents with non-specific viral like symptoms occurring in conjunction with respiratory symptoms: cough, hemoptysis, and pleuritic chest pain. In this COVID ARDS era, it is important to evaluate a broad differential diagnosis. Therefore, the authors describe a patient presenting with flu-like respiratory symptoms whom was ultimately was diagnosed with acute respiratory distress syndrome (ARDS) due to F. Tulerensis. CASE PRESENTATION: A 44-year-old male presented with a four-day history of night sweats, shortness of breath, a productive cough which progressed to hemoptysis, and oliguria. Prior to admission, his initial symptoms were treated as chronic sinusitis with varied antibiotics. Social history including tobacco abuse and deer hunting 1 month prior to presentation. Vitals were stable except for tachycardia, hypoxia, and tachypnea. Laboratory findings were significant for AKI, lactic acidosis, mild transaminitis, hyperbilirubinemia, and leukocytosis with predominant neutrophilia. Thoracic CTA showed bilateral diffused pulmonary edema without evidence of pulmonary embolism. Due to the patient's worsening respiratory status, he was intubated for support. The patient progressed to Severe ARDS per Berlin Criteria eventually requiring pronation and continuous paralyzing. Bronchoscopy was performed with bronchial lavage. Bacterial, viral, and fungal cultures did not show growth while vasculitic work-up was negative. Empiric antibiotic treatment did not show improvement until the patient was diagnosed with F. Taularensis via serological testing with an IgM of 20 U/mL, and patient was transitioned to gentamycin. Ultimately, the patient was extubated, transitioned to oral doxycycline, and discharged home. DISCUSSION: Approximately 250 cases of tularemia are reported to CDC each year. Respiratory tularemia has a mortality rate up to 30% if not treated. For this reason, F. tularensis is a potential biological weapon and is categorized as a Group A pathogenic agent. Serological testing may be negative early in disease progression;therefore, early inflammatory markers with clinical suspicion are essential to diagnose the disease early in its course. DNA microarray has high specificity and sensitivity for rapid diagnosis of tularemia while being cost effective. After prompt diagnosis, intravenous aminoglycosides;such as gentamycin or streptomycin;must be started. CONCLUSIONS: In the above case, we illustrate the gradual onset and rapid patient deterioration when treatment is delayed;yet, there is rapid recovery once appropriate treatment is used. Reference #1: 1. Ranjbar, Reza, Payam Behzadi, and Caterina Mammina. "Respiratory tularemia: Francisella tularensis and microarray probe designing.” The open microbiology journal 10 (2016): 176. Reference #2: 2. Akhvlediani, N., I. Burjanadze, D. Baliashvili, T. Tushishvili, M. Broladze, A. Navdarashvili, S. Dolbadze et al. "Tularemia transmission to humans: a multifaceted surveillance approach.” Epidemiology & Infection 146, no. 16 (2018): 2139-2145. Reference #3: 3. Tularemia in British Columbia: A case report and review. Issue: BCMJ, vol. 52, No. 6, July August 2010 (Pages 303- 307). Megan Isaac-Renton, BSc, Muhammad Morshed, PhD, SCCM Eleni Galanis, MD, MPH, FRCPC Sunny Mak, MSc Vicente Loyola, MD, FRCPC, Linda M.N. Hoang, MD, MHSc, FRCPC DISCLOSURES: No relevant relationships by Munish Adhikari No relevant relationships by Ashma Ul Husna No relevant relationships by Yan Jiang No relevant relationships by Divya Kharel No relevant relationships by Gregory Polcha

Testing oxygenated microbubbles via intraperitoneal and intrathoracic routes on a large pig model of LPS-induced acute respiratory distress syndrome.

With a mortality rate of 46% before the onset of COVID-19, acute respiratory distress syndrome (ARDS) affected 200,000 people in the US, causing 75,000 deaths. Mortality rates in COVID-19 ARDS patients are currently at 39%. Extrapulmonary support for ARDS aims to supplement mechanical ventilation by providing life-sustaining oxygen to the patient. A new rapid-onset, human-sized pig ARDS model in a porcine intensive care unit (ICU) was developed. The pigs were nebulized intratracheally with a high dose (4 mg/kg) of the endotoxin lipopolysaccharide (LPS) over a 2 h duration to induce rapid-onset moderate-to-severe ARDS. They were then catheterized to monitor vitals and to evaluate the therapeutic effect of oxygenated microbubble (OMB) therapy delivered by intrathoracic (IT) or intraperitoneal (IP) administration. Post-LPS administration, the PaO2 value dropped below 70 mmHg, the PaO2 /FiO2 ratio dropped below 200 mmHg, and the heart rate increased, indicating rapidly developing (within 4 h) moderate-to-severe ARDS with tachycardia. The SpO2 and PaO2 of these LPS-injured pigs did not show significant improvement after OMB administration, as they did in our previous studies of the therapy on small animal models of ARDS injury. Furthermore, pigs receiving OMB or saline infusions had slightly lower survival than their ARDS counterparts. The OMB administration did not induce a statistically significant or clinically relevant therapeutic effect in this model; instead, both saline and OMB infusion appeared to lower survival rates slightly. This result is significant because it contradicts positive results from our previous small animal studies and places a limit on the efficacy of such treatments for larger animals under more severe respiratory distress. While OMB did not prove efficacious in this rapid-onset ARDS pig model, it may retain potential as a novel therapy for the usual presentation of ARDS in humans, which develops and progresses over days to weeks.

Macklin Effect in the Current Pandemic: A Pathological Sequelae or Ventilator-Associated Lung Injury

Aim and background: SARS-CoV-2 pandemic questioned many basic concepts in medicine. COVID-19 affects many organ systems despite the lung being the primary affected organ. ARDS management is challenging and a new complication during the management adds to the burden. Macklin described a pathophysiological process by which air escaped through the ruptured alveolar basement membrane causing pneumomediastinum. The occurrence of air leak syndromes (ALS) in COVID-19 made us investigate the disease and its association with the complication. Objective: To observe the clinicopathological profile of patients who developed air leak syndrome during the second wave of the pandemic. Materials and methods: A retrospective analysis was conducted on SARSCoV- 2 patients admitted to ICU due to ARDS. The study included patients admitted from March to June 2021 with rTPCR positive test for SARS-CoV-2 illness and diagnosed to have ARDS as defined by the Berlin criteria. We analyzed 195 cases admitted in the ICU who met the above criteria and received protocolised care as per national and institutional guidelines. Cases who received ventilatory support either as HFNO (high flow nasal oxygenation), NIV (noninvasive ventilation), or invasive mechanical ventilation as per ARDS NET protocol and developed ALS were included. Demographic and clinical profiles of patients and laboratory parameters like acute phase reactants, haemogram, and serum creatinine were analysed. Results: 5.6% of patients were diagnosed to have air leak syndrome, which includes subcutaneous emphysema, pneumomediastinum, pneumopericardium, and pneumothorax. 81% of the cases were men. The average age was 44.8 years. 90% of the patients had no pre-existing lung pathology or respiratory comorbidity. 81.8% did not have a documented history of smoking. 63.33% of patients had other preexisting co-morbidities. 27.2% of patients had more than one comorbidity with diabetes mellitus being the most common. The average time to develop air leak syndrome was 6 days. 81% of the patients received mechanical ventilation, 2 patients were only on HFNO. 90% of the patients were prone in view of severe ARDS. From air leak syndromes mentioned above, 72.2% developed pneumothorax, 63.3% of the patients developed subcutaneous emphysema, 54.5% of the patients developed pneumomediastinum, and 9% developed pneumopericardium. 1 patient (9%) developed the complete spectrum of ALS. 63% of the patients developed 2 or more entities of the air leak, i.e., subcutaneous emphysema, pneumomediastinum, pneumopericardium, and pneumothorax. Acute phase reactants were elevated in all patients who developed ALS. There was neutrophil predominance in the haemogram. Only one patient developed AKI. Another compelling finding was the development of secondary infection, the majority was respiratory tract infections (81%) followed by urinary tract infections. Candiduria was observed in 36.6% of patients. The average duration of stay was 21.6 days. The mortality rate was 63%. 4 patients were discharged who had an average time to resolution of 8 days. Conclusion: COVID-19 is majorly a self-limiting disease. Secondary bacterial infection and poor oxygenation was major finding in our study. Development of ALS in a previously normal lung with no preexisting lung pathology points towards the need to conclude ALS and viral pneumonias.

Implementation of a Clinical Decision Support Tool for Improving Adherence to Lung Protective Ventilation Strategies

RATIONALE: Pre-pandemic, ARDS accounted for approximately 10% of all ICU admissions and 25% of ICU patients requiring mechanical ventilation (MV). Surges in severe Covid-19 cases have increased the number of ICU patients requiring MV for ARDS. It has been estimated that only 60% of ARDS cases are identified at any time during the clinical course, and only 34% of ARDS cases are identified when initial criteria are met. Additionally, it is estimated that only 60% of ARDS patients are managed with evidence based MV settings, including low tidal volume ventilation (LTV) of <6 cc/kg ideal body weight, plateau pressure <30 cm H2O, and low driving pressure <15 cm H2O. Adherence to lung protective ventilation strategies have been linked to decreased mortality in ARDS. We implemented a clinical decision support tool (CDST) to aid clinicians in the early recognition of ARDS and aid in implementation of lung protective ventilation strategies. METHODS: From March 2020 to March 2021 we used medical informatics (SickbayTM) to identify ICU patients requiring MV that met criteria for ARDS based on the Berlin Criteria. We monitored documentation of ARDS, MV tidal volume as cc/kg ideal body weight, plateau pressure, driving pressure, MV settings, arterial blood gas values (ABG), and PaO2 / FiO2. From March 2021 to October 2021, we implemented a CDST outlining above variables to aide ICU clinicians in 1) recognition of ARDS and 2) utilization of MV and ABG data to make evidence based MV changes. Lung protective strategies were automatically recorded every two hours via informatics software. The results were analyzed using a chi-squared test. RESULTS: There were 207 patients reviewed preimplementation of the CDST and 88 patients reviewed during implementation of the CDST. Implementation of the CDST resulted in improved detection and documentation of ARDS (63.8% vs 100%, p=.0001), improved adherence to LTV (53.9% vs 64.9%, p = .0005), and improved adherence to low plateau pressure (67.7% vs 71.8%, p=.20). There was a decrease in adherence to low driving pressure (36.6% vs 23.9%, p=.0003).CONCLUSIONS: Implementation of CDST is a low-cost, efficacious measure to aide clinicians in the detection and documentation of ARDS. Using CDST was associated with improved adherence to LTV and low plateau pressure MV strategies. We hypothesize that difficulty with adherence to low driving pressure is related to the respiratory mechanics of Covid-19 ARDS differing from other forms of ARDS. A validation cohort is needed to further support our findings.

Non-Invasive Ventilation versus Invasive Mechanical Ventilation: Results from a Tertiary Care Hospital

Objective: To compare the patient outcome in severe COVID-19 pneumonia between the non-invasive ventilation and invasive mechanical ventilation. Study design: Prospective, observational study Study Setting and Duration: Department of Pulmonology, Bahawal Victoria Hospital, Bahawalpur from January 2021 to June 2021. Methodology: We analyzed 660 patients of severe covid pneumonia. Conscious proning was done in those requiring ≥ 21 L oxygen and oxygen saturation < 90%. We defined typical ARDS according to Berlin criteria. Atypical ARDS did not fulfill set criteria. We divided ARDS into 2 types i-e H and L type. We managed ARDS with either NIV, invasive mechanical ventilation or both. We used multiple regression analysis to predict ICU stay. Results: Out of 660 patients, 285 (43.18%) developed biPAP failure and were subsequently intubated. We observed 273 (41.4%) overall mortality, 175 (64.1%) in IMV and 98 (35.9%) in the NIV group (p<0.0001). invasive mechanical ventilation had statistically significant correlation with mortality and also predicted ICU stay. (p=< 0.001, OR 3.2, p=0.001). Conclusion: NIV therapy is superior to invasive mechanical ventilation in terms of ICU stay and outcome.

Respiratory mechanics and mortality in coronavirus disease 2019 acute respiratory distress syndrome: A retrospective cohort study.

BACKGROUND: The association between commonly monitored respiratory parameters, including compliance and oxygenation and clinical outcomes in acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19) remains unclear, limiting prognostication and the delivery of targeted treatments. Our project aim was to identify if any such associations exist between clinical outcomes and respiratory parameters. METHODS: We performed a retrospective observational cohort study of confirmed COVID-19 positive patients admitted to a single dedicated intensive care unit at a university hospital from March 27 to April 26, 2020. We collected information on baseline clinical and demographic characteristics and initial respiratory parameters. Our primary outcome was in-hospital mortality. RESULTS: A total of 22 patients met criteria for ARDS and were included in our study. Nine of the 22 (40.9%) patients with ARDS died during hospitalization. The initial static respiratory system compliance of survivors was 39 (interquartile range [IQR] 34, 55) and nonsurvivors was 27 (IQR 24, 33, P < 0.01). A lower respiratory system compliance was associated with an increased adjusted odd of in-hospital mortality (odds ratio 1.2, 95% confidence interval 1.01, 1.45 P = 0.04). CONCLUSION: In our cohort of 22 patients mechanically ventilated with ARDS from COVID-19, having lower respiratory system compliance after intubation was associated with an increased risk of in-hospital mortality, consistent with ARDS from non-COVID etiologies.

A Case Report of Rapidly Lethal Acute Respiratory Distress Syndrome Secondary to Coronavirus Disease 2019 Viral Pneumonia.

As of April 2020, the coronavirus 2019 (COVID-19) pandemic has resulted in more than 210,000 deaths globally. The most common cause of death from COVID-19 is acute respiratory failure. We report the case of a 78-year-old female with a history of hypertension, cerebrovascular accident (CVA), type 2 diabetes mellitus, and sarcoidosis, who presented to the emergency department with one day of dyspnea. The patient experienced a rapid decline in respiratory function and was intubated in the intensive care unit (ICU), meeting the Berlin criteria for severe acute respiratory distress syndrome (ARDS). Chest radiography revealed diffuse bilateral coalescent opacities, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA swab test was positive for COVID-19. The patient experienced acute kidney injury with uptrending creatinine levels and remained lethargic and unresponsive throughout her ICU stay, suggestive of potential hypoxic brain injury. In light of the patient's poor clinical status, age, and significant comorbidities, prognosis was conveyed about medical futility and patient's family agreed to terminal extubation and the patient expired peacefully, exactly one week from hospital admission. This case report highlights the speed at which severe ARDS can present and contribute to end-organ dysfunction in COVID-19 patients.

Acute respiratory failure in COVID-19: is it "typical" ARDS?

In December 2019, an outbreak of coronavirus disease 2019 (COVID-19) was identified in Wuhan, China. The World Health Organization (WHO) declared this outbreak a significant threat to international health. COVID-19 is highly infectious and can lead to fatal comorbidities especially acute respiratory distress syndrome (ARDS). Thus, fully understanding the characteristics of COVID-19-related ARDS is conducive to early identification and precise treatment. We aimed to describe the characteristics of COVID-19-related ARDS and to elucidate the differences from ARDS caused by other factors. COVID-19 mainly affected the respiratory system with minor damage to other organs. Injury to the alveolar epithelial cells was the main cause of COVID-19-related ARDS, and endothelial cells were less damaged with therefore less exudation. The clinical manifestations were relatively mild in some COVID-19 patients, which was inconsistent with the severity of laboratory and imaging findings. The onset time of COVID-19-related ARDS was 8-12 days, which was inconsistent with ARDS Berlin criteria, which defined a 1-week onset limit. Some of these patients might have a relatively normal lung compliance. The severity was redefined into three stages according to its specificity: mild, mild-moderate, and moderate-severe. HFNO can be safe in COVID-19-related ARDS patients, even in some moderate-severe patients. The more likely cause of death is severe respiratory failure. Thus, the timing of invasive mechanical ventilation is very important. The effects of corticosteroids in COVID-19-related ARDS patients were uncertain. We hope to help improve the prognosis of severe cases and reduce the mortality.