Proning in COVID-19 Acute Respiratory Distress Syndrome: Role of Paralytics.

Although proning is beneficial to acute respiratory distress syndrome, impressions vary about its efficacy. Some providers believe that paralysis is required to facilitate proning. We studied impact of paralysis on prone-induced gas exchange improvements and provider attitudes regarding paralytics. DESIGN: Observational. SETTING: University of California San Diego. PATIENTS: Intubated COVID acute respiratory distress syndrome patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 1) Changes in Pao2:Fio2 and Spo2:Fio2 ratios before and after proning with and without paralytics, 2) adverse events during proning with and without paralytics, and 3) nurse and physician attitudes about efficacy/safety of proning with and without paralytics. Gas-exchange improvement with proning was similar with and without paralytics (with no serious adverse events). Survey results showed similar attitudes between nurses and physicians about proning efficacy but differing attitudes about the need for paralytics with proning. CONCLUSIONS: Findings support use of proning and may help in design of randomized trials to assess paralytics in acute respiratory distress syndrome management.

A Comparison of Intubation and Airway Complications Between COVID-19 and Non-COVID-19 Critically Ill Subjects.

Introduction The number of subjects infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the western hemisphere increased exponentially in the later months of 2020. With this increase in infection, the number of subjects requiring advanced ventilatory support increased concomitantly. We decided to compare the survival rates between coronavirus disease 2019 (COVID-19) subjects versus non-COVID-19 subjects undergoing intubation in the intensive care unit (ICU). We hypothesized that COVID-19 subjects would have lower rates of survival post-intubation. Methods We screened all subjects admitted to the adult critical care unit between January 2020 and June 2020 to determine if they met the inclusion criteria. These subjects were required to be spontaneously ventilating upon admission and eventually required intubation. Subjects were selected from our electronic health record (EHR) system EPIC© (Epic Systems, Verona, WI) through a retrospective ICU admission analysis. We identified and included 267 non-COVID-19 subjects and 56 COVID-19 subjects. Our primary outcome of interest was intubation-related mortality. We defined intubation mortality as unexpected death (within 48 hours of intubation). Our secondary outcomes were the length of stay in the ICU, length of time requiring ventilator support, and proportion of subjects requiring tracheostomy placement. Results Compared to non-coronavirus disease (COVID) subjects, COVID subjects were more likely to be intubated for acute respiratory distress. COVID subjects had longer stays in the ICU and longer ventilator duration than non-COVID subjects. COVID-positive subjects had a decreased hazard ratio for mortality (HR = 0.42, 95% CI: 0.20-0.87, P < 0.05) and increased chances of survival compared to non-COVID subjects. Conclusions We showed the rates of intubation survival were no different between the COVID and non-COVID groups. We attribute this finding to intubation preparation, a multidisciplinary team approach, and having the most experienced provider lead the intubation process.

Maternal SARS-CoV-2 exposure alters infant DNA methylation.

Background: Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferred in utero to offspring. We hypothesised that in utero exposure to SARS-CoV-2 in humans may alter infant DNA methylation, particularly in genes associated with neurodevelopment. We aimed to test this hypothesis in a pilot sample of children in Victoria, Australia, who were exposed in utero to SARS-CoV-2. Methods: DNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-2 in utero exposed and (n = 4) non-exposed infants and methylation status assessed across 850,000 methylation sites using an Illumina EPIC BeadChip. We also conducted an exploratory enrichment analysis using Gene Ontology annotations. Results: 1962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value <0.00083). Two significant differentially methylated regions were identified; a hypomethylated intergenic region located in chromosome 6p proximal to the genes ZP57 and HLA-F (fwer <0.004), and a hypomethylated region in the promoter and body of the gene GAREM2 (fwer <0.036). Gene network enrichment analysis revealed differential methylation in genes corresponding to pathways relevant to neurodevelopment, including the ERBB pathway. Conclusion: These pilot data suggest that exposure to SARS-CoV-2 in utero differentially alters methylation of genes in pathways that play a role in human neurodevelopment.

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.

Intrapulmonary Shunt and Alveolar Dead Space in a Cohort of Patients with Acute COVID-19 Pneumonitis and Early Recovery.

BACKGROUND: Pathological evidence suggests that COVID-19 pulmonary infection involves both alveolar damage (causing shunt) and diffuse micro-vascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar deadspace in moderate COVID-19 during acute illness and recovery. METHODS: We studied 30 patients (22 males, age: 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled O2 and CO2 concentrations were measured, yielding alveolar-arterial differences for each gas (AaPO2, aAPCO2) from which shunt and alveolar dead space were computed. MEASUREMENTS AND MAIN RESULTS: For acute COVID-19 patients, group mean (range) for AaPO2 was 41.4 (-3.5 to 69.3) mmHg; aAPCO2 was 6.0 (-2.3 to 13.4) mmHg. Both shunt (% cardiac output) at 10.4 (0 to 22.0)%, and alveolar dead space (% tidal volume) at 14.9 (0 to 32.3)% were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4 (0 to 6.1)% and alveolar dead space was 8.5 (0 to 22.4)% (both p<0.05 versus acute); shunt was marginally elevated for 2 patients, however, 5 (30%) had elevated alveolar dead space. CONCLUSIONS: We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks, however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.

A prospective, longitudinal, case-control study to evaluate the neurodevelopment of children from birth to adolescence exposed to COVID-19 in utero.

BACKGROUND: The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk. METHODS: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women's Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. DISCUSSION: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

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.

Supportive Care in Patients with Critical Coronavirus Disease 2019.

Specific therapies for the treatment of coronavirus disease 2019 (COVID-19) have limited efficacy in the event a patient worsens clinically and requires admission to the intensive care unit (ICU). Thus, providing quality supportive care is essential to the overall management of patients with critical COVID-19. Patients with respiratory failure not requiring intubation should be supported with noninvasive positive pressure ventilation, continuous positive airway pressure, or high flow oxygenation. Use of these respiratory modalities may prevent patients from subsequently requiring intubation. Basic components of supportive care for the critically ill should be applied equally to patients with COVID-19 in the ICU.

Community of Inquiry framework to evaluate an online obstetric and neonatal emergency simulation workshop for health professional students in India.

BACKGROUND: We transitioned our obstetric neonatal emergency simulation (ONE-Sim) workshops to an online format during the COVID-19 pandemic. In this study, we evaluated key learning acquired by undergraduate medical and nursing students attending the online ONE-Sim workshops from a low- and middle-income country (LMIC). METHODS: Student perception of online workshops was collected using electronic questionnaires. Data was analysed using thematic analysis by employing the Community of Inquiry (CoI) framework. RESULTS: One hundred sixty medical and nursing students who attended the online ONE-Sim workshops completed the questionnaires. There was evidence in the data to support all three aspects of the CoI framework-social, cognitive and teacher presence. CONCLUSIONS: The use of the CoI framework helped to describe key learning from online interprofessional simulation workshops conducted for a LMIC.

Breath-holding physiology, radiological severity and adverse outcomes in COVID-19 patients: A prospective validation study.

BACKGROUND AND OBJECTIVE: COVID-19 remains a major cause of respiratory failure, and means to identify future deterioration is needed. We recently developed a prediction score based on breath-holding manoeuvres (desaturation and maximal duration) to predict incident adverse COVID-19 outcomes. Here we prospectively validated our breath-holding prediction score in COVID-19 patients, and assessed associations with radiological scores of pulmonary involvement. METHODS: Hospitalized COVID-19 patients (N = 110, three recruitment centres) performed breath-holds at admission to provide a prediction score (Messineo et al.) based on mean desaturation (20-s breath-holds) and maximal breath-hold duration, plus baseline saturation, body mass index and cardiovascular disease. Odds ratios for incident adverse outcomes (composite of bi-level ventilatory support, ICU admission and death) were described for patients with versus without elevated scores (>0). Regression examined associations with chest x-ray (Brixia score) and computed tomography (CT; 3D-software quantification). Additional comparisons were made with the previously-validated '4C-score'. RESULTS: Elevated prediction score was associated with adverse COVID-19 outcomes (N = 12/110), OR[95%CI] = 4.54[1.17-17.83], p = 0.030 (positive predictive value = 9/48, negative predictive value = 59/62). Results were diminished with removal of mean desaturation from the prediction score (OR = 3.30[0.93-11.72]). The prediction score rose linearly with Brixia score (ß[95%CI] = 0.13[0.02-0.23], p = 0.026, N = 103) and CT-based quantification (ß = 1.02[0.39-1.65], p = 0.002, N = 45). Mean desaturation was also associated with both radiological assessment. Elevated 4C-scores (≥high-risk category) had a weaker association with adverse outcomes (OR = 2.44[0.62-9.56]). CONCLUSION: An elevated breath-holding prediction score is associated with almost five-fold increased adverse COVID-19 outcome risk, and with pulmonary deficits observed in chest imaging. Breath-holding may identify COVID-19 patients at risk of future respiratory failure.

Intensivist and COVID-19 in the United States of America: a narrative review of clinical roles, current workforce, and future direction.

COVID-19 continues to spread across borders and has proven to be a challenge for the existing healthcare system. The demand for intensivists has dramatically increased in the United States, in the backdrop of an expected lack of intensivists in many States even before the pandemic. One proposal has been to organize multidisciplinary teams functioning under one intensivist, as this approach would make use of the existing healthcare force and lessen the burden on intensivists. Another recommendation is the adaptation of Tele-ICUs, which have demonstrated constructive outcomes in the past. Moreover, ensuring the provision of all types of personal protective equipment, adequate testing and, other provisions such as mental health support, financial incentives for intensivists should be prioritized. More intensivists should be trained for the future, for which better institutional policies are essential.

The impact of different CPAP delivery approaches on nightly adherence and discontinuation rate in patients with obstructive sleep apnea.

STUDY OBJECTIVES: The impact of direct mail order sales of positive airway pressure (PAP) devices, accentuated by the coronavirus disease 2019 (COVID-19) pandemic, on PAP adherence in patients with obstructive sleep apnea remains unclear. In this study we compared the impact of different modes of continuous positive airway pressure delivery on adherence and daytime symptoms. We hypothesized that adherence would not be affected by remote PAP setup, aided by telehealth technology. METHODS: Three groups were studied: 1) standard group PAP setup (3-4 people); 2) direct home shipment of PAP, followed by telehealth interactions; 3) direct home shipment of PAP, during the COVID-19 pandemic where delivery choice was removed. Demographics, sleepiness, PAP data, and insurance information were also compared. RESULTS: A total of 666 patients were studied in 3 groups. 1) Standard group PAP setup had 225 patients and adherence with PAP (% of nights used more than 4 hours) was 65.3 ± 2.1%. 2) Direct home shipment of PAP group had 231 patients, and adherence was 54.2 ± 2.4%. 3) Direct mailed PAP units during the COVID-19 pandemic group had 210 patients, and adherence was 55.9 ± 2.5%. Adherence was lower in both groups receiving home shipments compared to those in groups in-center (analysis of variance, Tukey, P = .002). Discontinuation of PAP was less in the in-center group setup patients (χ2 = 10.938 P ≤ .001). CONCLUSIONS: Patients receiving direct home PAP shipments had lower adherence and were more likely to discontinue PAP compared to standard in-person setup. CITATION: Stanchina M, Lincoln J, Prenda S, et al. The impact of different CPAP delivery approaches on nightly adherence and discontinuation rate in patients with obstructive sleep apnea. J Clin Sleep Med. 2022;18(8):2023-2027.

Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA).

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Impact of the COVID-19 pandemic and multiple community lockdowns on total live birth rates and preterm births in Melbourne, Australia.

We evaluated the impact of the COVID-19 pandemic and Melbourne's multiple community lockdowns (between 2020-21) on total live birth rates and preterm births in a large health network. Analysis revealed a decrease in total live birth rates following easing of initial lockdowns, and a sharp increase in births at one stage in between lockdowns. The proportion and number of preterm births (<37 weeks gestation) decreased at the start of initial lockdowns with the strongest decrease after the end of the second lockdown period. Births <34 weeks gestation also decreased during lockdowns, but no significant change was identified for births <28 weeks gestation.

Using pulmonary gas exchange to estimate shunt and deadspace in lung disease: theoretical approach and practical basis.

The common pulmonary consequence of SARS-CoV-2 infection is pneumonia, but vascular clot may also contribute to COVID pathogenesis. Imaging and hemodynamic approaches to identifying diffuse pulmonary vascular obstruction (PVO) in COVID (or acute lung injury generally) are problematic particularly when pneumonia is widespread throughout the lung and hemodynamic consequences are buffered by pulmonary vascular recruitment and distention. Although stimulated by COVID-19, we propose a generally applicable bedside gas exchange approach to identifying PVO occurring alone or in combination with pneumonia, addressing both its theoretical and practical aspects. It is based on knowing that poorly (or non) ventilated regions, as occur in pneumonia, affect O2 more than CO2, whereas poorly (or non) perfused regions, as seen in PVO, affect CO2 more than O2. Exhaled O2 and CO2 concentrations at the mouth are measured over several ambient-air breaths, to determine mean alveolar Po2 and Pco2. A single arterial blood sample is taken over several of these breaths for arterial Po2 and Pco2. The resulting alveolar-arterial Po2 and Pco2 differences (AaPo2, aAPco2) are converted to corresponding physiological shunt and deadspace values using the Riley and Cournand 3-compartment model. For example, a 30% shunt (from pneumonia) with no alveolar deadspace produces an AaPO2 of almost 50 torr, but an aAPco2 of only 3 torr. In contrast, a 30% alveolar deadspace (from PVO) without shunt leads to an AaPO2 of only 12 torr, but an aAPco2 of 9 torr. This approach can identify and quantify physiological shunt and deadspace when present singly or in combination.NEW & NOTEWORTHY Identifying pulmonary vascular obstruction in the presence of pneumonia (e.g., in COVID-19) is difficult. We present here conversion of bedside measurements of arterial and alveolar Po2 and Pco2 into values for shunt and deadspace-when both coexist-using Riley and Cournand's 3-compartment gas exchange model. Deadspace values higher than expected from shunt alone indicate high ventilation/perfusion ratio areas likely reflecting (micro)vascular obstruction.