Hospital- and Ventilator-associated Pneumonia early after Lung Transplantation: a prospective Study on Incidence, Pathogen Origin and Outcome.

BACKGROUND: Hospital- (HAP) and ventilator-associated pneumonia (VAP) are important complications early (<30 days) after lung transplantation (LT). However, current incidence, associated factors and outcomes are not well reported. METHODS: LT recipients transplanted at our institution (07/2019-01/2020 and 10/2021-11/2022) were prospectively included. We assessed incidence and presentation of pneumonia and evaluated the impact of associated factors using regression models. In addition, we evaluated molecular relatedness of respiratory pathogens collected peri-transplant and at pneumonia occurrence using pulsed-field-gel-electrophoresis (PFGE). RESULTS: In the first 30 days post-LT, 25/270 (9.3%) recipients were diagnosed with pneumonia (68% [17/25] VAP; 32% [8/25] HAP). Median time to pneumonia was 11 days (IQR 7-13). 49% (132/270) of donor and 16% (44/270) of recipient respiratory peri-transplant cultures were positive. However, pathogens associated with pneumonia were not genetically related to either donor or recipient cultures at transplant, as determined by PFGE.Diagnosed pulmonary hypertension (HR 4.42, 95% CI 1.62-12.08) and immunosuppression use (HR 2.87, 95% CI 1.30-6.56) were pre-transplant factors associated with pneumonia.Pneumonia occurrence was associated with longer hospital stay (HR 5.44, 95% CI 2.22-13.37) and VAP with longer ICU stay (HR 4.31, 95% CI: 1.73-10.75) within the first 30 days post-transplant; 30- and 90-day mortality were similar. CONCLUSIONS: Prospectively assessed early pneumonia incidence occurred in around 10% of LT. Populations at increased risk for pneumonia occurrence include LT with pre-transplant pulmonary hypertension and pre-transplant immunosuppression. Pneumonia was associated with increased healthcare use, highlighting the need for further improvements by preferentially targeting higher-risk patients.

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS: Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94). CONCLUSIONS: In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

Implications of High Sensitivity Troponin Levels After Lung Transplantation.

Trends in high-sensitivity cardiac troponin I (hs-cTnI) after lung transplant (LT) and its clinical value are not well stablished. This study aimed to determine kinetics of hs-cTnI after LT, factors impacting hs-cTnI and clinical outcomes. LT recipients from 2015 to 2017 at Toronto General Hospital were included. Hs-cTnI levels were collected at 0-24 h, 24-48 h and 48-72 h after LT. The primary outcome was invasive mechanical ventilation (IMV) >3 days. 206 patients received a LT (median age 58, 35.4% women; 79.6% double LT). All patients but one fulfilled the criteria for postoperative myocardial infarction (median peak hs-cTnI = 4,820 ng/mL). Peak hs-cTnI correlated with right ventricular dysfunction, >1 red blood cell transfusions, bilateral LT, use of EVLP, kidney function at admission and time on CPB or VA-ECMO. IMV>3 days occurred in 91 (44.2%) patients, and peak hs-cTnI was higher in these patients (3,823 vs. 6,429 ng/mL, p < 0.001 after adjustment). Peak hs-cTnI was higher among patients with had atrial arrhythmias or died during admission. No patients underwent revascularization. In summary, peak hs-TnI is determined by recipient comorbidities and perioperative factors, and not by coronary artery disease. Hs-cTnI captures patients at higher risk for prolonged IMV, atrial arrhythmias and in-hospital death.

Echocardiographic Findings in Critically Ill COVID-19 Patients Treated With and Without Extracorporeal Membrane Oxygenation.

OBJECTIVES: To describe echocardiographic findings among mechanically ventilated patients with COVID-19 acute respiratory distress syndrome, comparing those with and without venovenous extracorporeal membrane oxygenation (VV ECMO) support. DESIGN: Single-center, retrospective cohort study. SETTING: Intensive care unit (ICU) of a quaternary academic center. PARTICIPANTS: Patients with COVID-19 admitted between March 2020 and June 2021 receiving mechanical ventilation, with an echocardiogram within 72 hours of admission. INTERVENTIONS: Admission and follow-up echocardiograms during ICU stay. MEASUREMENTS: Patient characteristics and echocardiographic findings were analyzed. Mortality odds ratio (OR) for right ventricular (RV) systolic dysfunction and acute cor pulmonale (ACP) was calculated. MAIN RESULTS: Among 242 patients, 145 (60%) received VV ECMO. Median (IQR) PaO2/FiO2 was 76 (65-95) and 98 (85-140) in ECMO and non-ECMO patients, respectively (p ≤ 0.001). Initial echocardiograms showed no significant differences in left ventricular systolic dysfunction (10% v 15 %, p = 0.31) and RV systolic dysfunction (38% v. 27%, p = 0.27) between ECMO and non-ECMO patients. ACP was more frequent in the ECMO group at baseline (41% v. 26 %, p = 0.02). During the ICU stay, patients on ECMO exhibited a higher prevalence of RV systolic dysfunction (55% v 34%, p = 0.001) and ACP (51% v 26%, p = 0.002). RV systolic dysfunction (OR 1.99; 95% CI 1.09-3.63) and ACP (OR 2.95; 95% CI 1.55-5.62) on the follow-up echocardiograms were associated with higher odds of ICU mortality. CONCLUSIONS: The prevalence of echocardiographic abnormalities, in particular RV dysfunction, was frequent among patients with COVID-19 receiving VV ECMO support and was associated with worse clinical outcomes.

Prone-position decreases airway closure in a patient with ARDS undergoing venovenous extracorporeal membrane oxygenation.

PURPOSE: Airway closure is a interruption of communication between larger and smaller airways. The presence of airway closure during mechanical ventilation may lead to the overestimation of driving pressure (DP), introducing errors in the assessment of respiratory mechanics and in positive end-expiratory pressure (PEEP) setting on the ventilator. Patients with severe acute respiratory distress syndrome (ARDS) may exhibit the airway closure phenomenon, which can be easily diagnosed with a low-flow inflation. Prone positioning is a therapeutic manoeuver proven to reduce mortality in ARDS patients, and has been widely implemented also in patients requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO). To date, the impact of prone positioning on changes in airway closure has not been described. METHODS: We present an image analysis of the pressure waveform during volume-controlled ventilation and low-flow inflations before and after prone positioning in an ARDS patient on VV ECMO. RESULTS: A high airway opening pressure level (23 cmH2O) was detected in the supine position during tidal ventilation. Airway closure was confirmed by using a low-flow inflation. Prone positioning significantly attenuated airway closure, with the airway opening pressure decreasing to 13 cmH2O. After re-supination, airway closure was lower as compared with supine position at baseline (17 cmH2O). CONCLUSION: Prone positioning reduced airway closure in an ARDS patient on VV ECMO support.

Evaluating the Impact of Ex Vivo Lung Perfusion on Organ Transplantation: A Retrospective Cohort Study.

BACKGROUND: Ex vivo lung perfusion (EVLP) sustains and allows advanced assessment of potentially useable donor lungs before transplantation, potentially relieving resource constraints. OBJECTIVE: We sought to characterize the effect of EVLP on organ utilization and patient outcomes. METHODS: We performed a retrospective, before-after cohort study using linked institutional data sources of adults wait-listed for lung transplant and donor organs transplanted in Ontario, Canada between 2005 and 2019. We regressed the annual number of transplants against year, EVLP use, and organ characteristics. Time-to-transplant, waitlist mortality, primary graft dysfunction, tracheostomy insertion, in-hospital mortality, and chronic lung allograft dysfunction were evaluated using propensity score-weighted regression. RESULTS: EVLP availability ( P =0.01 for interaction) and EVLP use ( P <0.001 for interaction) were both associated with steeper increases in transplantation than expected by historical trends. EVLP was associated with more donation after circulatory death and extended-criteria donors transplanted, while the numbers of standard-criteria donors remained relatively stable. Significantly faster time-to-transplant was observed after EVLP was available (hazard ratio=1.64 [1.41-1.92]; P <0.001). Fewer patients died on the waitlist after EVLP was available, but no difference in the hazard of waitlist mortality was observed (HR=1.19 [0.81-1.74]; P =0.176). We observed no difference in the likelihood of chronic lung allograft dysfunction before versus after EVLP was available. CONCLUSIONS: We observed a significant increase in organ transplantation since EVLP was introduced into practice, predominantly from increased acceptance of donation after circulatory death and extended-criteria lungs. Our findings suggest that EVLP-associated increases in organ availability meaningfully alleviated some barriers to transplant.

Association of lung recruitment and change in recruitment-to-inflation ratio from supine to prone position in acute respiratory distress syndrome.

Prone positioning is an evidence-based treatment for patients with moderate-to-severe acute respiratory distress syndrome. Lung recruitment has been proposed as one of the mechanisms by which prone positioning reduces mortality in this group of patients. Recruitment-to-inflation ratio (R/I) is a method to measure potential for lung recruitment induced by a change in positive end-expiratory pressure (PEEP) on the ventilator. The association between R/I and potential for lung recruitment in supine and prone position has not been studied with computed tomography (CT) scan imaging. In this secondary analysis, we sought to investigate the correlation between R/I measured in supine and prone position with CT and the potential for lung recruitment as measured by CT scan. Among 23 patients, the median R/I did not significantly change from supine (1.9 IQR 1.6-2.6) to prone position (1.7 IQR 1.3-2.8) (paired t test p = 0.051) but the individual changes correlated with the different response to PEEP. In supine and in prone position, R/I significantly correlated with the proportion of lung tissue recruitment induced by the change of PEEP. Lung tissue recruitment induced by a change of PEEP from 5 to 15 cmH2O was 16% (IQR 11-24%) in supine and 14.3% (IQR 8.4-22.6%) in prone position, as measured by CT scan analysis (paired t test p = 0.56). In this analysis, PEEP-induced recruitability as measured by R/I correlated with PEEP-induced lung recruitment as measured by CT scan, and could help to readjust PEEP in prone position.

Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis.

Rationale: The most beneficial positive end-expiratory pressure (PEEP) selection strategy in patients with acute respiratory distress syndrome (ARDS) is unknown, and current practice is variable. Objectives: To compare the relative effects of different PEEP selection strategies on mortality in adults with moderate to severe ARDS. Methods: We conducted a network meta-analysis using a Bayesian framework. Certainty of evidence was evaluated using grading of recommendations assessment, development and evaluation methodology. Measurements and Main Results: We included 18 randomized trials (4,646 participants). Compared with a lower PEEP strategy, the posterior probability of mortality benefit from a higher PEEP without lung recruitment maneuver (LRM) strategy was 99% (risk ratio [RR], 0.77; 95% credible interval [CrI], 0.60-0.96, high certainty), the posterior probability of benefit of the esophageal pressure-guided strategy was 87% (RR, 0.77; 95% CrI, 0.48-1.22, moderate certainty), the posterior probability of benefit of a higher PEEP with brief LRM strategy was 96% (RR, 0.83; 95% CrI, 0.67-1.02, moderate certainty), and the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 77% (RR, 1.06; 95% CrI, 0.89-1.22, low certainty). Compared with a higher PEEP without LRM strategy, the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 99% (RR, 1.37; 95% CrI, 1.04-1.81, moderate certainty). Conclusions: In patients with moderate to severe ARDS, higher PEEP without LRM is associated with a lower risk of death than lower PEEP. A higher PEEP with prolonged LRM strategy is associated with increased risk of death when compared with higher PEEP without LRM.

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.

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

BACKGROUND: Patients who present to an emergency department (ED) with respiratory symptoms are often conservatively triaged in favour of hospitalisation. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalisation in order to improve the precision of clinical decision making in the ED. METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from EDs 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 coronavirus disease 2019 (COVID-19) patients (n=245). An inflammatory profile was determined using a rapid, 50-min, biomarker panel (RALI-Dx (Rapid Acute Lung Injury Diagnostic)), which measures interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1). RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalisation across all three sites. A machine learning algorithm that was applied to predict hospitalisation using RALI-Dx biomarkers had a mean±sd area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy) and 86±3% (Brazil). Model performance was 82±3% for COVID-19 patients 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 ED decision-making protocols.