Outcomes of patients with respiratory failure declined for extracorporeal membrane oxygenation: a prospective observational study.

PURPOSE: Descriptive information on referral patterns and short-term outcomes of patients with respiratory failure declined for extracorporeal membrane oxygenation (ECMO) is lacking. METHODS: We conducted a prospective single-centre observational cohort study of ECMO referrals to Toronto General Hospital (receiving hospital) for severe respiratory failure (COVID-19 and non-COVID-19), between 1 December 2019 and 30 November 2020. Data related to the referral, the referral decision, and reasons for refusal were collected. Reasons for refusal were grouped into three mutually exclusive categories selected a priori: "too sick now," "too sick before," and "not sick enough." In declined referrals, referring physicians were surveyed to collect patient outcome on day 7 after the referral. The primary study endpoints were referral outcome (accepted/declined) and patient outcome (alive/deceased). RESULTS: A total of 193 referrals were included; 73% were declined for transfer. Referral outcome was influenced by age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95 to 0.96; P < 0.01) and involvement of other members of the ECMO team in the discussion (OR, 4.42; 95% CI, 1.28 to 15.2; P < 0.01). Patient outcomes were missing in 46 (24%) referrals (inability to locate the referring physician or the referring physician being unable to recall the outcome). Using available data (95 declined and 52 accepted referrals; n = 147), survival to day 7 was 49% for declined referrals (35% for patients deemed "too sick now," 53% for "too sick before," 100% for "not sick enough," and 50% for reason for refusal not reported) and 98% for transferred patients. Sensitivity analysis setting missing outcomes to directional extreme values retained robustness of survival probabilities. CONCLUSION: Nearly half of the patients declined for ECMO consideration were alive on day 7. More information on patient trajectory and long-term outcomes in declined referrals is needed to refine selection criteria.

RéSUMé: OBJECTIF: On manque d'informations descriptives sur les schémas de références et les devenirs à court terme des patient·es atteint·es d'insuffisance respiratoire n'ayant pas pu recevoir une oxygénation par membrane extracorporelle (ECMO). MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective monocentrique sur les références vers l'ECMO à l'Hôpital général de Toronto (hôpital d'accueil) pour insuffisance respiratoire grave (COVID-19 et non-COVID-19), entre le 1er décembre 2019 et le 30 novembre 2020. Les données relatives à la référence, à la décision de référence et aux motifs du refus ont été recueillies. Les motifs de refus ont été regroupés en trois catégories mutuellement exclusives sélectionnées a priori : « Trop malade maintenant ¼, « Trop malade avant ¼ et « Pas assez malade ¼. En ce qui concerne les références refusées, un sondage envoyé aux médecins traitant·es avait pour objectif de recueillir les devenirs des patient·es le jour 7 suivant la référence. Les critères d'évaluation principaux de l'étude étaient le résultat de la référence (accepté/refusé) et le devenir des patient·es (vivant·e/décédé·e). RéSULTATS: Au total, 193 références ont été incluses; le transfert a été refusé dans 73 % des cas. L'acceptation ou le refus de la référence était influencé par l'âge (rapport de cotes [RC], 0,97; intervalle de confiance [IC] à 95 %, 0,95 à 0,96; P < 0,01) et la participation d'autres membres de l'équipe ECMO à la discussion (RC, 4,42; IC 95 %, 1,28 à 15,2; P < 0,01). Les devenirs des patient·es étaient manquants pour 46 (24 %) des personnes référées (incapacité de localiser les médecins traitant·es ou incapacité des médecins de se souvenir du devenir). À l'aide des données disponibles (95 références refusées et 52 références acceptées; n = 147), la survie jusqu'au jour 7 était de 49 % pour les références refusées (35 % pour la patientèle jugée « trop malade maintenant ¼, 53 % pour celle « trop malade avant ¼, 100 % pour celle « pas assez malade ¼ et 50 % pour les cas où la raison du refus n'était pas déclarée) et 98 % pour les patient·es transféré·es. L'analyse de sensibilité établissant les résultats manquants à des valeurs extrêmes directionnelles a conservé la robustesse des probabilités de survie. CONCLUSION: Près de la moitié des patient·es pour lesquel·les un traitement sous ECMO a été refusé étaient en vie au jour 7. Davantage d'informations concernant la trajectoire et les devenirs à long terme des patient·es refusé·es sont nécessaires pour parfaire les critères de sélection.

Thrombopoietin participates in platelet activation in COVID-19 patients.

BACKGROUND: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of target-organ damage. Thrombopoietin (THPO), a growth factor essential to megakariocyte proliferation, is known to prime platelet activation and leukocyte-platelet interaction. In addition, THPO concentrations increase in several critical diseases, such as acute cardiac ischemia and sepsis, thus representing a potential diagnostic and prognostic biomarker. Furthermore, several data suggest that interleukin (IL)-6 is one of the most important inflammatory mediators involved in these phenomena, which led to explore the potential therapeutic role of IL-6 inhibitors. In this prospective cohort study, we aimed to study THPO and IL-6 concentrations in COVID-19 patients at the time of first clinical evaluation in the Emergency Department (ED), and to investigate their potential use as diagnostic and prognostic biomarkers. In addition, we sought to explore the role of THPO contained in plasma samples obtained from COVID-19 patients in priming in vitro platelet activation and leukocyte-platelet interaction. METHODS: We enrolled 66 patients presenting to the ED with symptoms suggestive of COVID-19, including 47 with confirmed COVID-19 and 19 in whom COVID-19 was excluded (Non-COVID-19 patients). As controls, we also recruited 18 healthy subjects. In vitro, we reproduced the effects of increased circulating THPO on platelet function by adding plasma from COVID-19 patients or controls to platelet-rich plasma or whole blood obtained by healthy donors, and we indirectly studied the effect of THPO on platelet activation by blocking its biological activity. FINDINGS: THPO levels were higher in COVID-19 patients than in both Non-COVID-19 patients and healthy subjects. Studying THPO as diagnostic marker for the diagnosis of COVID-19 by receiver-operating-characteristic (ROC) statistics, we found an area under the curve (AUC) of 0.73, with an optimal cut-off value of 42.60 pg/mL. IL-6 was higher in COVID-19 patients than in healthy subjects, but did not differ between COVID-19 and Non-COVID-19 patients. THPO concentrations measured at the time of diagnosis in the ED were also higher in COVID-19 patients subsequently developing a severe disease than in those with mild disease. Evaluating THPO as biomarker for severe COVID-19 using ROC analysis, we found an AUC of 0.71, with an optimal cut-off value of 57.11 pg/mL. IL-6 was also higher in severe than in mild COVID-19 patients, with an AUC for severe COVID-19 of 0.83 and an optimal cut-off value of 23 pg/ml. THPO concentrations correlated with those of IL-6 (r=0.2963; p=0.043), and decreased 24 h after the administration of tocilizumab, an IL-6 receptor blocking antibody, showing that the increase of THPO levels depends on IL-6-stimulated hepatic synthesis. In vitro, plasma obtained from COVID-19 patients, but not from healthy subjects, primed platelet aggregation and leukocyte-platelet binding, and these effects were reduced by inhibiting THPO activity. INTERPRETATION: Increased THPO may be proposed as an early biomarker for the diagnosis of COVID-19 and for the identification of patients at risk of developing critical illness. Elevated THPO may contribute to enhance platelet activation and leukocyte-platelet interaction in COVID-19 patients, thus potentially participating in immunothrombosis/thromboinflammation. FUNDING: This work was supported by Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST) ex 60% to GM and EL.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection.

BACKGROUND: Patients who present to an emergency department with respiratory symptoms are often conservatively triaged in favour of hospitalization. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalization in order to improve the precision of clinical decision-making in the emergency department. PATIENTS AND METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from emergency departments in an international multicentre study: Canada (n=310), Italy (n=131), and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed COVID-19 patients (n=245). An inflammatory profile was determined using a rapid, 50-minute, biomarker panel: Rapid Acute Lung Injury Diagnostic (RALI-Dx), which measures IL-6, IL-8, IL-10, sTNFR1, and sTREM1. RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalization across all three sites. A machine learning algorithm that was applied to predict hospitalization using RALI-Dx biomarkers had an area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy), and 86±3% (Brazil). Model performance in COVID-19 patients was 82±3% and 87±7% for patients with a confirmed pneumonia diagnosis. CONCLUSIONS: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions and represents an important diagnostic adjunct to advance emergency department decision-making protocols.

Physical Rehabilitation Before and After Lung Transplantation for COVID-19 ARDS: A Case Report

Purpose: To describe the functional trajectory and physical rehabilitation of an individual who underwent lung transplantation for COVID-19 acute respiratory distress syndrome (ARDS). Client Description: A previously healthy 60-year-old man admitted to critical care pre-transplantation and followed six months post-transplant. Intervention: Physical rehabilitation in the critical care, acute ward and in-patient rehabilitation settings. Measures and Outcome: Despite a successful surgery, a long and complex acute care admission contributed to a slow and variable functional recovery. Significant functional limitations and physical frailty were present in the early post-transplant period. Implications: Little is known of the effects of COVID-19 superimposed upon lung transplantation on muscle function, exercise capacity, and physical activity. Future research should include case series to further understand the functional deficits and trajectory of recovery in this emerging clinical population. Standard core outcome measures should be identified for this population to enable synthesis of findings and inform short- and long-term rehabilitation strategies.

Interferon-stimulated and metallothionein-expressing macrophages are associated with acute and chronic allograft dysfunction after lung transplantation.

BACKGROUND: Lung transplant recipients experience episodes of immune-mediated acute lung allograft dysfunction (ALAD). ALAD episodes are a risk factor for chronic lung allograft dysfunction (CLAD), the major cause of death after lung transplantation. Our objective was to determine key cellular elements in dysfunctional lung allografts, with a focus on macrophages. METHODS: We have applied single-cell RNA sequencing (scRNAseq) to bronchoalveolar lavage cells from stable and ALAD patients and to cells from explanted CLAD lung tissue. RESULTS: We identified 2 alveolar macrophage (AM) subsets uniquely represented in ALAD. Using pathway analysis and differentially expressed genes, we annotated these as pro-inflammatory interferon-stimulated gene (ISG) and metallothionein-mediated inflammatory (MT) AMs. Functional analysis of an independent set of AMs in vitro revealed that ALAD AMs exhibited a higher expression of CXCL10, a marker of ISG AMs, and increased secretion of pro-inflammatory cytokines compared to AMs from stable patients. Using publicly available bronchoalveolar lavage scRNAseq datasets, we found that ISG and MT AMs are associated with more severe inflammation in COVID-19 patients. Analysis of cells from 4 explanted CLAD lungs revealed similar macrophage populations. Donor and recipient cells were identified using expressed single nucleotide variations. We demonstrated contributions of donor and recipient cells to all AM subsets early post-transplant, with loss of donor-derived cells over time. CONCLUSIONS: Our data reveal extensive heterogeneity among lung macrophages after lung transplantation and indicates that specific sub-populations may be associated with allograft dysfunction, raising the possibility that these cells may represent important therapeutic targets.

Personalized Ventilation to Multiple Patients Using a Single Ventilator: Description and Proof of Concept.

OBJECTIVES: To design and test a ventilator circuit that can be used for ventilation of two or more patients with a single ventilator, while allowing individualization of tidal volume, fractional concentration of oxygen, and positive end-expiratory pressure to each patient, irrespective of the other patient's respiratory system mechanics. DESIGN: Description and proof of concept studies. SETTINGS: Respiratory therapy laboratory. SUBJECTS: Ventilation of mechanical test lungs. INTERVENTIONS: Following a previously advocated design, we used components readily available in our hospital to assemble two "bag-in-a-box" breathing circuits. Each patient circuit consisted of a flexible bag in a rigid container connected via one-way valve to a test lung, along with an inline positive end-expiratory pressure valve, connected to the ventilator's expiratory limb. Compressed gas fills the bags during "patient" exhalation. During inspiration, gas from the ventilator, in pressure control mode, enters the containers and displaces gas from the bags to the test lungs. We varied tidal volume, "respiratory system" compliance, and positive end-expiratory pressure in one lung and observed the effect on the tidal volume of the other. MEASUREMENTS AND MAIN RESULTS: We were able to obtain different tidal volume, dynamic driving pressure, and positive end-expiratory pressure in the two lungs under widely different compliances in both lungs. Complete obstruction, or disconnection at the circuit connection to one test lung, had minimal effect (< 5% on average) on the ventilation to the co-ventilated lung. CONCLUSIONS: A secondary circuit "bag-in-the-box" system enables individualized ventilation of two lungs overcoming many of the concerns of ventilating more than one patient with a single ventilator.

A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide.

Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb <6%. Both groups were ventilated continuously for 6 hours, then the animals were weaned from sedation, mechanical ventilation and followed for 3 days. During treatment, and on the third post-operative day, physiologic assessments were performed to monitor lung function and other significative markers were assessed for potential pulmonary or systemic injury. No significant change in lung function, or inflammatory markers were observed during the study period. Both gas exchange function, lung tissue cytokine analysis and histology were similar between treated and control animals. During treatment, levels of metHb were maintained <6% by administration of MB, and NO2 remained <5 ppm. Additionally, considering extrapulmonary effects, no significant changes were observed in biochemistry markers. Our findings showed that high-dose iNO delivered continuously over 6 hours with adjuvant MB is clinically feasible and safe. These findings support the development of investigations of continuous high-dose iNO treatment of respiratory tract infections, including SARS-CoV-2.

Maintaining technical proficiency in senior surgical fellows during the COVID-19 pandemic through virtual teaching.

BACKGROUND: The novel coronavirus (COVID-19) pandemic has resulted in a severe reduction in operative opportunities for trainees. We hypothesized that augmenting independent practice with a bench model of vascular anastomoses using regular videoconferences and individual feedback would provide a meaningful benefit in the maintenance of technical skills in senior lung transplant surgical fellows. METHODS: A lung transplantation virtual technical skills course was developed, and surgical fellows were provided with a bench model and surgical instruments. Using a virtual communication platform, teaching sessions were held twice weekly, and fellows performed an anastomosis on camera. Video recordings were reviewed and critiqued by attending staff. At the end of the 3-month course, participants were surveyed about their experience. Warm ischemic time was compared between the fellows' 5 most recent cases before and after the pandemic. RESULTS: Seven senior surgical fellows participated and provided feedback. The fellows had graduated medical school an average of 14 years before fellowship, and spent an average of 5 hours (range, 1.3-15 hours) of home practice. Five of the 7 participants (71%) reported improvement in their technical skills and increased confidence in performing lung transplantation. No significant difference in average warm ischemic time in procedures performed by fellows was identified (70.3 minutes prepandemic vs 68.3 minutes postpandemic; P = .68). CONCLUSIONS: A program of virtual technical skills teaching, individual video coaching, and independent practice has provided a benefit in maintaining technical skills in lung transplant surgical fellows during the COVID-19 pandemic, when equivalent operative experience was unavailable. Lessons learned from this exceptional time can be used to create simulation curricula for senior trainees.

Telerehabilitation for Lung Transplant Candidates and Recipients During the COVID-19 Pandemic: Program Evaluation.

BACKGROUND: The COVID-19 pandemic resulted in a rapid shift from center-based rehabilitation to telerehabilitation for chronic respiratory disease and lung transplantation due to infection control precautions. Clinical experience with this delivery model on a large scale has not been described. OBJECTIVE: The aim of this study is to describe usage and satisfaction of providers and lung transplant (LTx) candidates and recipients and functional outcomes following the broad implementation of telerehabilitation with remote patient monitoring during the first wave of the COVID-19 pandemic. METHODS: This study was a program evaluation of providers, LTx candidates, and early LTx recipients who used a web-based, remote monitoring app for at least four weeks between March 16 and September 1, 2020, to participate in telerehabilitation. Within-subjects analysis was performed for physical activity, Self-efficacy For Exercise (SEE) scale score, aerobic and resistance exercise volumes, 6-minute walk test results, and Short Physical Performance Battery (SPPB) results. RESULTS: In total, 78 LTx candidates and 33 recipients were included (57 [51%] males, mean age 58 [SD 12] years, 58 [52%] with interstitial lung disease, 34 [31%] with chronic obstructive pulmonary disease). A total of 50 (64%) LTx candidates and 17 (51%) LTx recipients entered ≥10 prescribed exercise sessions into the app during the study time frame. In addition, 35/42 (83%) candidates agreed the app helped prepare them for surgery and 18/21 (85%) recipients found the app helpful in their self-recovery. The strongest barrier perceived by physiotherapists delivering the telerehabilitation was patient access to home exercise and monitoring equipment. Between the time of app registration and ≥4 weeks on the waiting list, 26 LTx candidates used a treadmill, with sessions increasing in mean duration (from 16 to 22 minutes, P=.002) but not speed (from 1.7 to 1.75 mph, P=.31). Quadriceps weight (pounds) for leg extension did not change (median 3.5, IQR 2.4-5 versus median 4.3, IQR 3-5; P=.08; n=37). On the Rapid Assessment of Physical Activity questionnaire (RAPA), 57% of LTx candidates scored as active, which improved to 87% (P=.02; n=23). There was a decrease in pretransplant 6-minute walk distance (6MWD) from 346 (SD 84) meters to 307 (SD 85) meters (P=.002; n=45) and no change in the SPPB result (12 [IQR 9.5-12] versus 12 [IQR 10-12]; P=.90; n=42). A total of 9 LTx recipients used a treadmill that increased in speed (from 1.9 to 2.7 mph; P=.003) between hospital discharge and three months posttransplant. Quadriceps weight increased (3 [IQR 0-3] pounds versus 5 [IQR 3.8-6.5] pounds; P<.001; n=15). At three months posttransplant, 76% of LTx recipients scored as active (n=17), with a high total SEE score of 74 (SD 11; n=12). In addition, three months posttransplant, 6MWD was 62% (SD 18%) predicted (n=8). CONCLUSIONS: We were able to provide telerehabilitation despite challenges around exercise equipment. This early experience will inform the development of a robust and equitable telerehabilitation model beyond the COVID-19 pandemic.

Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context.

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.

How Hospitals Can Save Lives and Themselves: Lessons on Patient Flow From the COVID-19 Pandemic.

COVID-19 has strained hospital capacity, detracted from patient care, and reduced hospital income. This article lays out a tested strategy that surgical and hospital leaders can use to overcome clinical and financial strain, emphasizing the experience at 2 leading North American medical centers. By classifying the time and resource needs of surgical patients and smoothing the flow of surgical admissions over all days of the week, hospitals can dramatically improve hospital efficiency, the quality of care and timely access to care for emergent and urgent surgeries. Through and beyond the time of COVID, smoothing the flow of surgical patients is a key means to restore hospital vitality and improve the care of all patients.

Alpha-1 Antitrypsin for COVID-19 Treatment: Dual Role in Antiviral Infection and Anti-Inflammation.

Many drugs have been approved for clinical trials for the treatment of COVID-19 disease, focusing on either antiviral or anti-inflammatory approaches. Combining antiviral and anti-inflammatory drugs or therapies together may be more effective. Human alpha-1 antitrypsin (A1AT) is a blood circulating glycoprotein that is best known as a protease inhibitor. It has been used to treat emphysema patients with A1AT deficiency for decades. We and others have demonstrated its role in reducing acute lung injury by inhibiting inflammation, cell death, coagulation, and neutrophil elastase activation. Recently, A1AT has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by inhibiting transmembrane serine protease 2 (TMPRSS2), a protease involved in the entry of SARS-CoV-2 into host cells. This dual role of both antiviral infection and anti-inflammation makes A1AT a unique and excellent candidate for COVID-19 treatment. Three clinical trials of A1AT for COVID-19 treatment have recently been approved in several countries. It is important to determine whether A1AT can prevent the progress from moderate to severe lung injury and eventually to be used to treat COVID-19 patients with acute respiratory distress syndrome.

COVID-19 Guidance for Triage of Operations for Thoracic Malignancies: A Consensus Statement From Thoracic Surgery Outcomes Research Network.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.