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Point of Care ultrasound (POCUS) of the lungs, also known as lung ultrasound (LUS), has emerged as a technique that allows for the diagnosis of many respiratory pathologies with greater accuracy and speed compared to conventional techniques such as chest x-ray and auscultation. The goal of this narrative review is to provide a simple and practical approach to LUS for critical care, pulmonary, and anesthesia providers, as well as respiratory therapists and other health care providers to be able to implement this technique into their clinical practice. In this review, we will discuss the basic physics of LUS, provide a hands-on scanning technique, describe LUS findings seen in normal and pathological conditions (such as mainstem intubation, pneumothorax, atelectasis, pneumonia, aspiration, COPD exacerbation, cardiogenic pulmonary edema, ARDS, and pleural effusion) and also review the training necessary to achieve competence in LUS., (© 2024. The Author(s).)

Background: Inspiratory threshold loading (ITL) and associated dyspnoea have been shown to interfere with cognition during cognitive-motor dual tasking. However, ITL has not been compared with another rhythmic muscle activity, such as lower limb pedalling. While ITL has been shown to interfere with cognition, the mechanism of the prefrontal cortex (PFC) during ITL or other rhythmical muscle dual tasking, has not been elucidated. Given the cognitive interference that arises during ITL, we hypothesise that ITL cognitive-motor dual tasking will result in greater cognitive decrements and increased PFC activity compared with the pedalling cognitive-motor dual task., Methods: 30 healthy participants (16 females; median age 23 (interquartile range 23-24) years) were recruited. They performed five 3-min tasks in a single visit in a random order: single tasks were ITL, pedalling and Stroop task and dual tasks were ITL-Stroop and pedalling-Stroop. Participant's PFC activity was assessed bilaterally using functional near-infrared spectroscopy throughout each task. Single- and dual-task cognitive performance was evaluated by measuring Stroop task reaction time and accuracy. Dyspnoea and rating of perceived exertion were evaluated at the end of each task., Results: ITL-Stroop resulted in greater impairments in reaction time (p<0.001), accuracy (p<0.01) and increased medial/dorsolateral PFC activity (p≤0.006) than pedalling-Stroop. ITL-Stroop elicited greater Borg dyspnoea and rating of perceived exertion than pedalling-Stroop (p<0.001), despite pedalling-Stroop having a greater heart rate response (p<0.001)., Conclusion: The heightened cognitive decrements, perceptual response and PFC activity suggest that inspiratory muscle loading and its accompanied dyspnoea results in greater cognitive interference than rhythmic pedalling., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2024.)

Background: Sigh breaths may impact outcomes in acute hypoxemic respiratory failure (AHRF) during assisted mechanical ventilation. We investigated whether sigh breaths may impact mortality in predefined subgroups of patients enrolled in the PROTECTION multicenter clinical trial according to: 1.the physiological response in oxygenation to Sigh (responders versus non-responders) and 2.the set levels of positive end-expiratory pressure (PEEP) (High vs. Low-PEEP). If mortality differed between Sigh and No Sigh, we explored physiological daily differences at 7-days., Results: Patients were randomized to pressure support ventilation (PSV) with Sigh (Sigh group) versus PSV with no sigh (No Sigh group). (1) Sighs were not associated with differences in 28-day mortality in responders to baseline sigh-test. Contrarily-in non-responders-56 patients were randomized to Sigh (55%) and 28-day mortality was lower with sighs (17%vs.36%, log-rank p = 0.031). (2) In patients with PEEP > 8cmH 2 O no difference in mortality was observed with sighs. With Low-PEEP, 54 patients were randomized to Sigh (48%). Mortality at 28-day was reduced in patients randomised to sighs (13%vs.31%, log-rank p = 0.021). These findings were robust to multivariable adjustments. Tidal volume, respiratory rate and ventilatory ratio decreased with Sigh as compared with No Sigh at 7-days. Ventilatory ratio was associated with mortality and successful extubation in both non-responders and Low-PEEP., Conclusions: Addition of Sigh to PSV could reduce mortality in AHRF non-responder to Sigh and exposed to Low-PEEP. Results in non-responders were not expected. Findings in the low PEEP group may indicate that insufficient PEEP was used or that Low PEEP may be used with Sigh. Sigh may reduce mortality by decreasing physiologic dead space and ventilation intensity and/or optimizing ventilation/perfusion mismatch., Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT03201263., (© 2024. The Author(s).)

Background: We previously showed in animals that transpulmonary driving pressure (PL) can be estimated during Neurally Adjusted Ventilatory Assist (NAVA) and Neural Pressure Support (NPS) using a single lower assist maneuver (LAM). The aim of this study was to test the LAM-based estimate of PL (PL&#95;LAM) in patients with acute respiratory failure., Methods: This was a prospective, physiological, and interventional study in intubated patients with acute respiratory failure. During both NAVA and simulated NPS (high and low levels of assist), a LAM was performed every 3 min by manually reducing the assist to zero for one single breath (by default, ventilator still provides 2 cmH 2 O). Following NAVA and NPS SIM periods, patients were sedated and passively ventilated in volume control and pressure control ventilation, to obtain PL during controlled mechanical ventilation (PL&#95;CMV). PL using an esophageal balloon (PL&#95;Pes) was also compared to PL&#95;LAM and PL&#95;CMV. We measured diaphragm electrical activity (Edi), ventilator pressure (PVent), esophageal pressure (Pes) and tidal volume. PL&#95;LAM and PL&#95;Pes were compared to themselves, and to PL&#95;CMV for matching flows and volumes., Results: Ten patients were included in the study. For the group, PL&#95;LAM was closely similar to PL&#95;CMV, with a high correlation (R 2  = 0.88). Bland-Altman analysis revealed a low Bias of 0.28 cmH 2 O, and 1.96SD of 5.26 cmH 2 O. PL&#95;LAM vs PL&#95;Pes were also tightly related (R 2  = 0.77)., Conclusion: This physiological study in patients confirms our previous pre-clinical data that PL&#95;LAM is as good an estimate as PL&#95;Pes to determine PL, in spontaneously breathing patients on assisted mechanical ventilation. Trial registration The study was registered at clinicaltrials.gov (ID NCT05378802) on November 6, 2021., (© 2024. The Author(s).)

Objectives: We sought to evaluate the effectiveness of any antiseizure medication on the incidence of early post-traumatic seizures among adult patients with traumatic brain injury., Data Sources: MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, and LILACS were searched from inception to October 2023., Study Selection: We included randomized trials of adult patients with traumatic brain injury evaluating any antiseizure medication compared with either placebo or another agent., Data Extraction: Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Our main outcome of interest was the occurrence of early seizures (i.e., within 7 d); secondary outcomes included late-seizures and all-cause mortality., Data Synthesis: Bayesian network meta-analyses were used to derive risk ratios (RRs) alongside 95% credible intervals (CrIs). We used Grading of Recommendations Assessment, Development, and Evaluation methodology to rate the certainty in our findings. Overall, ten individual randomized controlled trials (1851 participants) were included. Compared with placebo, phenytoin (RR, 0.28; 95% CrI, 0.13-0.57; moderate certainty) and levetiracetam (RR, 0.20; 95% CrI, 0.07-0.60; moderate certainty) were associated with a reduction in the risk of early seizures. Carbamazepine may be associated with a reduced risk of early seizures, but the evidence is very uncertain (RR, 0.41; 95% CrI, 0.12-1.27; very low certainty). Valproic acid may result in little to no difference in the risk of early seizures, but the evidence is very uncertain (RR, 0.97; 95% CrI, 0.16-9.00; very low certainty). The evidence is very uncertain about the impact of any antiseizure medication on the risk of late seizures or all-cause mortality at longest reported follow-up time., Conclusions: Phenytoin or levetiracetam reduce the risk of early seizures among adult patients with traumatic brain injury. Further research is needed to evaluate required duration of therapy and long-term safety profiles., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Efficacy of inhaled therapy such as Nitric Oxide (iNO) during mechanical ventilation may depend on airway patency. We hypothesized that airway closure and lung collapse, countered by positive end-expiratory pressure (PEEP), influence iNO efficacy. This could support the role of an adequate PEEP titration for inhalation therapy. The main aim of this study was to assess the effect of iNO with PEEP set above or below the airway opening pressure (AOP) generated by airway closure, on hemodynamics and gas exchange in swine models of acute respiratory distress syndrome. Fourteen pigs randomly underwent either bilateral or asymmetrical two-hit model of lung injury. Airway closure and lung collapse were measured with electrical impedance tomography as well as ventilation/perfusion ratio (V/Q). After AOP detection, the effect of iNO (10ppm) was studied with PEEP set randomly above or below regional AOP. Respiratory mechanics, hemodynamics, and gas-exchange were recorded., Results: All pigs presented airway closure (AOP > 0.5cmH 2 O) after injury. In bilateral injury, iNO was associated with an improved mean pulmonary pressure from 49 ± 8 to 42 ± 7mmHg; (p = 0.003), and ventilation/perfusion matching, caused by a reduction in pixels with low V/Q and shunt from 16%[IQR:13-19] to 9%[IQR:4-12] (p = 0.03) only at PEEP set above AOP. iNO had no effect on hemodynamics or gas exchange for PEEP below AOP (low V/Q 25%[IQR:16-30] to 23%[IQR:14-27]; p = 0.68). In asymmetrical injury, iNO improved pulmonary hemodynamics and ventilation/perfusion matching independently from the PEEP set. iNO was associated with improved oxygenation in all cases., Conclusions: In an animal model of bilateral lung injury, PEEP level relative to AOP markedly influences iNO efficacy on pulmonary hemodynamics and ventilation/perfusion match, independently of oxygenation., (© 2024. The Author(s).)

Background: Patients with acute hypoxemic respiratory failure are at high risk of death and prolonged time on the ventilator. Interventions often aim to reduce both mortality and time on the ventilator. Many methods have been proposed for analyzing these endpoints as a single composite outcome (days alive and free of ventilation), but it is unclear which analytical method provides the best performance. Thus, we aimed to determine the analysis method with the highest statistical power for use in clinical trials., Methods: Using statistical simulation, we compared multiple methods for analyzing days alive and free of ventilation: the t, Wilcoxon rank-sum, and Kryger Jensen and Lange tests, as well as the proportional odds, hurdle-Poisson, and competing risk models. We compared 14 scenarios relating to: 1) varying baseline distributions of mortality and duration of ventilation, which were based on data from a registry of patients with acute hypoxemic respiratory failure and 2) the varying effects of treatment on mortality and duration of ventilation., Results and Conclusions: All methods have good control of type 1 error rates (i.e., avoid false positive findings). When data are simulated using a proportional odds model, the t test and ordinal models have the highest relative power (92% and 90%, respectively), followed by competing risk models. When the data are simulated using survival models, the competing risk models have the highest power (100% and 92%), followed by the t test and a ten-category ordinal model. All models struggled to detect the effect of the intervention when the treatment only affected one of mortality and duration of ventilation. Overall, the best performing analytical strategy depends on the respective effects of treatment on survival and duration of ventilation and the underlying distribution of the outcomes. The evaluated models each provide a different interpretation for the treatment effect, which must be considered alongside the statistical power when selecting analysis models., Competing Interests: Dr. Harhay is funded by the Patient-Centered Outcomes Research Institute (Award ME-2020C1-19220) and the U.S. National Institutes of Health/National Heart, Lung, and Blood Institute (grant numbers R00-HL141678 and R01-HL168202). Dr. Urner is supported by a Scholarship of the Interdepartmental Division of Critical Care Medicine, University of Toronto. Dr. Heath is funded by a Canada Research Chair in Statistical Trial Design; Natural Sciences and Engineering Research Council of Canada (award No. RGPIN-2021 03366). Dr. Goligher is funded by an Early Career Investigator Award from the National Sanitarium Association. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: The optimal revascularization strategy in patients with diabetes and multivessel disease in the setting of a non-ST-segment elevation myocardial infarction (NSTEMI) is unknown., Objectives: The purpose of this study was to compare all-cause mortality between coronary artery bypass grafting (CABG) and multivessel percutaneous coronary intervention (PCI) among patients with diabetes and NSTEMI., Methods: All patients with diabetes and multivessel disease admitted for NSTEMI in Ontario, Canada, between April 2009 and March 2020 were included. Those with previous CABG, PCI in the previous 90 days, or shock were excluded. The primary outcome was all-cause mortality. Propensity score matching was used to account for confounding. Patients who had a cardiac surgeon consultation and then received PCI were classified as being potentially ineligible for CABG., Results: The cohort included 4,649 CABG and 6,760 PCI patients (mean age: 67.8 ± 11.5 years; 70.4% males), resulting in 2,385 matched pairs. CABG was associated with reduced all-cause mortality compared to PCI over a median follow-up of 5.5 years (5-year estimates: 23.4% vs 26.5%; HR: 0.89; 95% CI: 0.80-0.98; P  = 0.021). However, no significant differences in mortality were observed between CABG and PCI patients without a surgical consultation (2,130 pairs; HR: 0.97; 95% CI: 0.86-1.08), while CABG was associated with reduced mortality when compared against PCI patients who had received a surgical consultation (388 pairs; HR: 0.72; 95% CI: 0.58-0.88; P  = 0.002)., Conclusions: While CABG was associated with reduced all-cause mortality compared to multivessel PCI in patients with diabetes and NSTEMI, CABG benefit was seen only against PCI patients potentially ineligible for CABG after receiving a preprocedure surgical consultation., Competing Interests: This study is funded in part by a Foundation Grant (FDN 154333) from the 10.13039/501100000024Canadian Institutes of Health Research (CIHR). This study was supported by ICES, which is funded by an annual grant from the Ontario 10.13039/100009647Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Dr Godoy receives the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. Dr Farkouh has received research grants from 10.13039/100002429Amgen, 10.13039/100004325AstraZeneca, 10.13039/501100004191Novo Nordisk, and 10.13039/100004336Novartis; and serves as a consultant to Otitopic. Dr Shah is supported by the 10.13039/501100004191Novo Nordisk Research Chair in Equitable Care of Diabetes and Related Conditions from the University of Toronto. Dr Nicolau has received research grants from 10.13039/100002429Amgen, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, 10.13039/100008322CSL Behring, 10.13039/501100022274Daiichi Sankyo, Dalcor, 10.13039/501100022336Esperion, 10.13039/100014554Janssen, 10.13039/100004336Novartis, 10.13039/501100004191Novo Nordisk, 10.13039/100004339Sanofi, Vifor; and a scholarship from the Brazilian National Council for Scientific and Technological Development (CNPq #303448/2021/0). Dr Fremes has received research support from AMGEN, Boston Scientific, Medtronics, the Canadian Institutes of Health Research and the National Institutes of Health. Dr Lawler has received unrelated royalties from McGraw-Hill Publishing; and is supported by the Fonds de Recherche du Quebec. Dr Wijeysundera is supported by a Canada Research Chair in Structural Heart Disease Policy and Outcomes. Dr Gaudino has received research grants from the 10.13039/100000002National Institutes of Health and the 10.13039/501100000024Canadian Institutes of Health Research. Dr Ko is supported by the Jack Tu Research Chair in Cardiovascular Outcomes Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: During mechanical ventilation, post-insufflation diaphragm contractions (PIDCs) are non-physiologic and could be injurious. PIDCs could be frequent during reverse-triggering, where diaphragm contractions follow the ventilator rhythm. Whether PIDCs happens with different modes of assisted ventilation is unknown. In mechanically ventilated patients with hypoxemic respiratory failure, we aimed to examine whether PIDCs are associated with ventilator settings, patients' characteristics or both., Methods: One-hour recordings of diaphragm electromyography (EAdi), airway pressure and flow were collected once per day for up to five days from intubation until full recovery of diaphragm activity or death. Each breath was classified as mandatory (without-reverse-triggering), reverse-triggering, or patient triggered. Reverse triggering was further subclassified according to EAdi timing relative to ventilator cycle or reverse triggering leading to breath-stacking. EAdi timing (onset, offset), peak and neural inspiratory time (Ti neuro ) were measured breath-by-breath and compared to the ventilator expiratory time. A multivariable logistic regression model was used to investigate factors independently associated with PIDCs, including EAdi timing, amplitude, Ti neuro , ventilator settings and APACHE II., Results: Forty-seven patients (median[25%-75%IQR] age: 63[52-77] years, BMI: 24.9[22.9-33.7] kg/m 2 , 49% male, APACHE II: 21[19-28]) contributed 2 ± 1 recordings each, totaling 183,962 breaths. PIDCs occurred in 74% of reverse-triggering, 27% of pressure support breaths, 21% of assist-control breaths, 5% of Neurally Adjusted Ventilatory Assist (NAVA) breaths. PIDCs were associated with higher EAdi peak (odds ratio [OR][95%CI] 1.01[1.01;1.01], longer Ti neuro (OR 37.59[34.50;40.98]), shorter ventilator inspiratory time (OR 0.27[0.24;0.30]), high peak inspiratory flow (OR 0.22[0.20;0.26]), and small tidal volumes (OR 0.31[0.25;0.37]) (all P ≤ 0.008). NAVA was associated with absence of PIDCs (OR 0.03[0.02;0.03]; P < 0.001). Reverse triggering was characterized by lower EAdi peak than breaths triggered under pressure support and associated with small tidal volume and shorter set inspiratory time than breaths triggered under assist-control (all P < 0.05). Reverse triggering leading to breath stacking was characterized by higher peak EAdi and longer Ti neuro and associated with small tidal volumes compared to all other reverse-triggering phenotypes (all P < 0.05)., Conclusions: In critically ill mechanically ventilated patients, PIDCs and reverse triggering phenotypes were associated with potentially modifiable factors, including ventilator settings. Proportional modes like NAVA represent a solution abolishing PIDCs., (© 2024. The Author(s).)

Importance: In the setting of an active pandemic the impact of public vaccine hesitancy on healthcare workers has not yet been explored. There is currently a paucity of literature that examines how patient resistance to disease prevention in general impacts practitioners., Objectives: The COVID-19 pandemic created unprecedented healthcare challenges with impacts on healthcare workers' wellbeing. Vaccine hesitancy added complexity to providing care for unvaccinated patients. Our study qualitatively explored experiences of healthcare providers caring for unvaccinated patients with severe COVID-19 infection in the intensive care setting., Design: We used interview-based constructivist grounded theory methodology to explore experiences of healthcare providers with critically ill unvaccinated COVID-19 patients., Setting and Participants: Healthcare providers who cared for unvaccinated patients with severe COVID-19 respiratory failure following availability of severe acute respiratory syndrome coronavirus 2 vaccines were recruited from seven ICUs located within two large academic centers and one community-based hospital. We interviewed 24 participants, consisting of eight attending physicians, seven registered nurses, six critical care fellows, one respiratory therapist, one physiotherapist, and one social worker between March 2022 and September 2022 (approximately 1.5 yr after the availability of COVID-19 vaccines in Canada)., Analysis: Interviews were recorded, transcribed, de-identified, and coded to identify emerging themes. The final data was analyzed to generate the thematic framework. Reflexivity was employed to reflect upon and discuss individual pre-conceptions and opinions that may impact collection and interpretation of the data., Results: Healthcare providers maintained dedication toward professionalism during provision of care, at the cost of suffering emotional turmoil from the pandemic and COVID-19 vaccine hesitancy. Evolving sources of stress associated with vaccine hesitancy included ongoing high volumes of critically ill patients, resource shortages, and visitation restrictions, which contributed to perceived emotional distress, empathy loss, and professional dissatisfaction. As a result, there were profound personal and professional consequences for healthcare professionals, with perceived impacts on patient care., Conclusions: Our study highlights struggles of healthcare providers in fulfilling professional duties while navigating emotional stressors unique to vaccine hesitancy. System-based interventions should be explored to help providers navigate biases and moral distress, and to foster resilience for the next major healthcare system strain., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8) + T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8 + T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.

Background: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1β (interleukin-1β); this significantly reduced cardiovascular events. However, whether IL-1β regulates early disease, particularly LDL transcytosis, remains unknown., Methods: We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1β. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1β and LDL to visualize acute LDL deposition in the aortic arch., Results: Exposure to picomolar concentrations of IL-1β induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1β increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1β on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1β, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1β. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1β increased LDL transcytosis in the aortic arch of wild-type but not Ldlr -/- or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1β-induced LDL accumulation in the aorta., Conclusions: IL-1β induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1β may contribute to the acceleration of early disease., Competing Interests: None.

Background: Manual breathing assist technique (MBAT) is a common physical therapy technique used to facilitate airway clearance and improve ventilation and oxygenation. The effects during and immediately after intervention in individuals with chronic obstructive pulmonary disease (COPD) are unknown. This study aimed to investigate the acute effects and potential mechanisms of MBAT on lung volume, dyspnea, and oxygenation in individuals with COPD., Methods: This non-randomized quasi-experimental pre-test/post-test study included participants from pulmonary rehabilitation programs at Tagami Hospital (COPD group) and a community exercise program (Healthy group). During a single session, MBAT was applied during the expiration of every breath for 10 minutes. Dyspnea and lung volumes (tidal volume; VT, inspiratory capacity; IC, inspiratory reserved capacity; IRV, expiratory reserve capacity; ERV) were collected at baseline and after MBAT. Pulse oximetry (SpO2), skeletal muscle oxygenation (SmO2), and oxy- and deoxy-hemoglobin (O2Hb and HHb) using near-infrared spectroscopy (NIRS) were collected at baseline, during, and after MBAT. Between-group comparisons were conducted using the Mann-Whitney U-test and chi-square analyses. Within-group changes before and after MBAT were analyzed using the Wilcoxon signed-rank test. The Kruskal-Wallis test was used to detect differences in NIRS variables in each phase and over time., Results: Thirty participants with COPD, matched for age and sex, were included, with 15 individuals per group. The difference scores of VT, IRV, and IC were significantly higher in the Healthy group than in the COPD group, but improvements in dyspnea and SpO2 were significantly higher in the COPD group. Compared to baseline, ERV decreased significantly in both groups, with dyspnea and SpO2 improving significantly only in the COPD group. Inspiratory accessory muscle ΔO2Hb and ΔHHb were significantly higher and lower (respectively) during MBAT in the COPD group compared to the Healthy group. Additionally, only the COPD group had increased SmO2 during and after MBAT compared to baseline., Conclusions: MBAT in patients with COPD had acute physiological effects in reducing dyspnea by facilitating expiration and decreasing the recruitment of accessory respiratory muscles. MBAT may help individuals with COPD reduce dyspnea before exercise therapy in a pulmonary rehabilitation program., Competing Interests: This work was conducted in accordance with ethical standards. The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To describe presenting diagnoses and rates and causes of death by age category and sex among children with acute illness brought to a district headquarter hospital in Pakistan., Design: Prospective cohort study., Setting: Sanghar district headquarter hospital, Sindh, Pakistan between December 2019 and April 2020 and August 2020 and December 2020., Participants: 3850 children 0-14 years presenting with acute illness to the emergency and outpatient departments and 1286 children admitted to the inpatient department., Outcome Measures: The primary outcome was Global Burden of Disease diagnosis category. Secondary outcomes were 28-day mortality rate, cause of death and healthcare delays, defined as delay in care-seeking, delay in reaching the healthcare facility and delay in appropriate treatment., Results: Communicable diseases were the most common presenting diagnoses among outpatients and among inpatients aged 1 month to 9 years. Non-communicable diseases and nutritional disorders were more common with increasing age. Few children presented with injuries. Newborn period (age <28 days) was associated with increased odds of death (OR 4.34 [95% CI 2.38 to 8.18], p<0.001, reference age 28 days-14 years) and there was no significant difference in odds of death between female vs male children (OR 1.12, 95% CI 0.6 to 2.04, p=0.72). 47 children died in the hospital (3.6%) and three (0.2%) died within 28 days of admission. Most children who died were <28 days old (n=32/50, 64%); leading diagnoses included neonatal sepsis/meningitis (n=13/50, 26%), neonatal encephalopathy (n=7/50, 14%) and lower respiratory tract infections (n=6/50, 12%). Delays in care-seeking (n=15) and in receiving appropriate treatment (n=12) were common., Conclusion: This study adds to sparse literature surrounding the epidemiology of disease and hospital outcomes for children with acute illness seeking healthcare in rural Pakistan and, in particular, among children aged 5-14 years. Further studies should include public and private hospitals within a single region to comprehensively describe patterns of care-seeking and interfacility transfer in district health systems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Ventilation management may differ between COVID-19 ARDS (COVID-ARDS) patients and patients with pre-COVID ARDS (CLASSIC-ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC-ARDS also exist in COVID-ARDS., Methods: Individual patient data analysis of COVID-ARDS and CLASSIC-ARDS patients in six observational studies of ventilation, four in the COVID-19 pandemic and two pre-pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator-free days and alive (VFD-60) at day 60., Results: This analysis included 6702 COVID-ARDS patients and 1415 CLASSIC-ARDS patients. COVID-ARDS patients received lower median V T (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p < 0.001) and higher median PEEP (12.0 [10.0 to 14.0] vs 8.0 [6.0 to 10.0] cm H 2 O; p < 0.001), at lower median ΔP (13.0 [10.0 to 15.0] vs 16.0 [IQR 12.0 to 20.0] cm H 2 O; p < 0.001) and higher median Crs (33.5 [26.6 to 42.1] vs 28.1 [21.6 to 38.4] mL/cm H 2 O; p < 0.001). Following multivariable adjustment, higher ΔP had an independent association with higher 60-day mortality and less VFD-60 in both groups. Higher PEEP had an association with less VFD-60, but only in COVID-ARDS patients., Conclusions: Our findings show important differences in key ventilation parameters and associations thereof with outcomes between COVID-ARDS and CLASSIC-ARDS., Trial Registration: Clinicaltrials.gov (identifier NCT05650957), December 14, 2022., (© 2024. The Author(s).)

Background: Extracorporeal membrane oxygenation (ECMO) represents an important but limited treatment for patients with severe COVID-19. We assessed the effects of an educational intervention on a person's ECMO care preference and examined whether patients and providers had similar ECMO preferences., Methods: In the Video+Survey group, patients watched an educational video about ECMO's purpose, benefits, and risks followed by an assessment of ECMO knowledge and care preferences in seven scenarios varying by hypothetical patient age, function, and comorbidities. Patients in the Survey Only group and providers didn't watch the video. Logistic regression was used to estimate the probability of agreement for each ECMO scenario between the two patient groups and then between all patients and providers., Results: Video+Survey patients were more likely (64% vs. 17%; p = 0.02) to correctly answer all ECMO knowledge questions than Survey Only patients. Patients in both groups agreed that ECMO should be considered across all hypothetical scenarios, with predicted agreement above 65%. In adjusted analyses, patients and providers had similar predicted agreement for ECMO consideration across six of the seven scenarios, but patients showed greater preference (84% vs. 41%, p = 0.003) for the scenario of a functionally dependent 65-year-old with comorbidities than providers., Discussion and Conclusions: An educational video increased a person's ECMO knowledge but did not change their ECMO preferences. Clinicians were less likely than patients to recommend ECMO for older adults, so advanced care planning discussion between patients and providers about treatment options in critically ill patients with COVID-19 is critical., Competing Interests: Dr. Borre reports funding from the National Institutes of Health. Dr. Maciejewski reports research grants from the Veterans Affairs Health Services Research and Development Service (VA HSR&D, RCS 10-391), and ownership of Amgen stock due to his spouse’s employment. Dr. Fan reports personal fees from Alung Technologies, Aerogen, Baxter, GE Healthcare, Inspira, and Vasomune outside the submitted work. Dr. Zhang reports funding from the Duke National Clinician Scholar Program and the Durham Veteran’s Affairs. All other authors have no conflicts of interest to disclose., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The accuracy of a diagnostic test depends on its intrinsic characteristics and the disease incidence. This study aims to depict post-test probability of Pneumocystis pneumonia (PJP), according to results of PCR and Beta-D-Glucan (BDG) tests in patients with acute respiratory failure (ARF)., Materials and Methods: Diagnostic performance of PCR and BDG was extracted from literature. Incidence of Pneumocystis pneumonia was assessed in a dataset of 2243 non-HIV immunocompromised patients with ARF. Incidence of Pneumocystis pneumonia was simulated assuming a normal distribution in 5000 random incidence samples. Post-test probability was assessed using Bayes theorem., Results: Incidence of PJP in non-HIV ARF patients was 4.1% (95%CI 3.3-5). Supervised classification identified 4 subgroups of interest with incidence ranging from 2.0% (No ground glass opacities; 95%CI 1.4-2.8) to 20.2% (hematopoietic cell transplantation, ground glass opacities and no PJP prophylaxis; 95%CI 14.1-27.7). In the overall population, positive post-test probability was 32.9% (95%CI 31.1-34.8) and 22.8% (95%CI 21.5-24.3) for PCR and BDG, respectively. Negative post-test probability of being infected was 0.10% (95%CI 0.09-0.11) and 0.23% (95%CI 0.21-0.25) for PCR and BDG, respectively. In the highest risk subgroup, positive predictive value was 74.5% (95%CI 72.0-76.7) and 63.8% (95%CI 60.8-65.8) for PCR and BDG, respectively., Conclusion: Although both tests yield a high intrinsic performance, the low incidence of PJP in this cohort resulted in a low positive post-test probability. We propose a method to illustrate pre and post-test probability relationship that may improve clinician perception of diagnostic test performance according to disease incidence in predefined clinical settings., (© 2024. The Author(s).)

Background: Lung ultrasonography (LUS) is a non-invasive imaging method used to diagnose and monitor conditions such as pulmonary edema, pneumonia, and pneumothorax. It is precious where other imaging techniques like CT scan or chest X-rays are of limited access, especially in low- and middle-income countries with reduced resources. Furthermore, LUS reduces radiation exposure and its related blood cancer adverse events, which is particularly relevant in children and young subjects. The score obtained with LUS allows semi-quantification of regional loss of aeration, and it can provide a valuable and reliable assessment of the severity of most respiratory diseases. However, inter-observer reliability of the score has never been systematically assessed. This study aims to assess experienced LUS operators' agreement on a sample of video clips showing predefined findings., Methods: Twenty-five anonymized video clips comprehensively depicting the different values of LUS score were shown to renowned LUS experts blinded to patients' clinical data and the study's aims using an online form. Clips were acquired from five different ultrasound machines. Fleiss-Cohen weighted kappa was used to evaluate experts' agreement., Results: Over a period of 3 months, 20 experienced operators completed the assessment. Most worked in the ICU (10), ED (6), HDU (2), cardiology ward (1), or obstetric/gynecology department (1). The proportional LUS score mean was 15.3 (SD 1.6). Inter-rater agreement varied: 6 clips had full agreement, 3 had 19 out of 20 raters agreeing, and 3 had 18 agreeing, while the remaining 13 had 17 or fewer people agreeing on the assigned score. Scores 0 and score 3 were more reproducible than scores 1 and 2. Fleiss' Kappa for overall answers was 0.87 (95% CI 0.815-0.931, p < 0.001)., Conclusions: The inter-rater agreement between experienced LUS operators is very high, although not perfect. The strong agreement and the small variance enable us to say that a 20% tolerance around a measured value of a LUS score is a reliable estimate of the patient's true LUS score, resulting in reduced variability in score interpretation and greater confidence in its clinical use., (© 2024. The Author(s).)

Objective: Survivors of pediatric critical illnesses are at risk of significant long-term organ sequelae. Chronic kidney disease (CKD) is a complication of critical illness (and ICU interventions) associated with growth impairment, cardiovascular disease, and early death. Our objective was to synthesize the evidence on the incidence of CKD among survivors of pediatric critical illness., Data Sources: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Register of Controlled Trials from inception to February 2024., Study Selection: Observational studies reporting the incidence of de novo CKD among survivors of pediatric critical illness., Data Extraction: Two reviewers independently extracted data on study design, setting, population, demographics, diagnostic criteria, and outcome., Data Synthesis: Meta-analysis was used to describe the incidence of CKD among survivors, risk of bias (RoB) assessed using the Joanna Briggs Institute Tool, and strength and reliability of evidence assessed with GRADE (Grading of Recommendations, Assessment, Development, and Evaluations). CKD was quantified as an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2 (outcome 1), eGFR less than 60 mL/min/1.73 m2 (outcome 2), and end-stage renal disease (ESRD) as eGFR less than 15 mL/min per 1.73 m2 (outcome 3). Twelve studies (3642 patients) met selection criteria and reported at least one measure of CKD. The median duration of follow-up was 2, 3.6, and 5 years, respectively, for outcomes 1, 2, and 3. For each threshold, the pooled estimate of CKD incidence was 24% (95% CI, 16-32%) for eGFR less than 90, 14% (95% CI, 6-23%) less than 60, and 4% (95% CI, 0-7%) for ESRD. The overall quality assessment indicated a moderate RoB., Conclusions: Among a heterogenous population of pediatric critical illness survivors, an important minority of survivors developed CKD or ESRD. This study highlights the importance of diagnostic criteria for reporting, a greater focus on postcritical care surveillance and follow-up to identify those with CKD. Further study would facilitate the delineation of high-risk groups and strategies for improved outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Sociodemographic variables influence health outcomes, either directly (ie, gender identity) or indirectly (eg, structural/systemic racism based on ethnoracial group). Identification of how sociodemographic variables can impact the health of critically ill adults is important to guide care and research design for this population. However, despite the growing recognition of the importance of collecting sociodemographic measures that influence health outcomes, insufficient and inconsistent data collection of sociodemographic variables persists in critical care studies. We aim to develop a set of core data variables (CoDaV) for social determinants of health specific to studies involving critically ill adults., Methods and Analysis: We will conduct a scoping review to generate a list of possible sociodemographic measures to be used for round 1 of the modified Delphi processes. We will engage relevant knowledge users (previous intensive care unit patients and family members, critical care researchers, critical care clinicians and research co-ordinators) to participate in the modified Delphi consensus survey to identify the CoDaV. A final consensus meeting will be held with knowledge user representatives to discuss the final CoDaV, how each sociodemographic variable will be collected (eg, level of granularity) and how to disseminate the CoDaV for use in critical care studies., Ethics and Dissemination: The University of Calgary conjoint health research ethics board has approved this study protocol (REB22-1648)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Community-acquired pneumonia (CAP) triggers inflammatory and thrombotic host responses driving morbidity and mortality. Antiplatelet agents may favorably modulate these pathways; however, their role in non-COVID-19 CAP remains uncertain., Objectives: To evaluate the association of antiplatelet agents with mortality in hospitalized patients with non-COVID-19 CAP., Methods: We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) of adult patients hospitalized for non-COVID-19 CAP exposed to antiplatelet agents (acetylsalicylic acid or P2Y12 inhibitors). We searched MEDLINE, Embase, and CENTRAL from inception to August 2023. Our primary outcome was all-cause mortality: meta-analyzed (random-effects models) separately for observational studies and RCTs. For observational studies, we used adjusted mortality estimates., Results: We included 13 observational studies (123,012 patients; 6 reported adjusted mortality estimates) and 2 RCTs (225 patients; both high risk of bias). In observational studies reporting hazard ratio, antiplatelet agents were associated with lower mortality (hazard ratio, 0.65; 95% CI, 0.46-0.91; I  = 85%; 4 studies, 91,430 patients). In studies reporting adjusted odds ratio, antiplatelet agent exposure was associated with reduced odds of mortality (odds ratio, 0.67; 95% CI, 0.45-1.00; 2  = 85%; 4 studies, 91,430 patients). In studies reporting adjusted odds ratio, antiplatelet agent exposure was associated with reduced odds of mortality (odds ratio, 0.67; 95% CI, 0.45-1.00; I  = 54%; 2 studies, 225 patients). By the Grading of Recommendations, Assessment, Development, and Evaluation criteria, the certainty of the evidence was low, primarily due to risk of bias. 2  = 0%; 2 studies, 24,889 patients). Among RCTs, there was a nonsignificant association with mortality (risk ratio, 0.66; 95% CI, 0.20-2.25; I 2  = 54%; 2 studies, 225 patients). By the Grading of Recommendations, Assessment, Development, and Evaluation criteria, the certainty of the evidence was low, primarily due to risk of bias., Conclusion: In hospitalized patients with non-COVID-19 CAP, antiplatelet agents may be associated with reduced mortality compared with usual care or placebo, but the certainty of evidence is low., (© 2024 The Author(s).)

Background: Healthcare inequities for patients with traumatic brain injury (TBI) represent a major priority area for trauma quality improvement. We hypothesized a relationship between health insurance status and timing of withdrawal of life sustaining treatment (WLST) for adults with severe TBI., Methods: This multicenter retrospective observational cohort study utilized data collected between 2017 and 2020. We identified adult (age ≥ 16) patients with isolated severe TBI admitted participating Trauma Quality Improvement Program centers. We determined the relationship between insurance status (public, private, and uninsured) and the timing of WLST using a competing risk survival analysis framework adjusting for baseline, clinical, injury and trauma center characteristics. Multivariable cause-specific Cox regressions were used to compute adjusted hazard ratios (HR) reflecting timing of WLST, accounting for mortality events. We also quantified the between-center residual variability in WLST using the median odds ratio (MOR) and measured insurance status association with access to rehabilitation at discharge., Results: We identified 42,111 adults with isolated severe TBI treated across 509 trauma centers across North America. There were 10,771 (25.6%) WLST events in the cohort and a higher unadjusted incidence of WLST events was evident in public insurance patients compared to private or uninsured groups. After adjustment, WLST occurred earlier for publicly insured (HR 1.07, 95% CI 1.02-1.12) and uninsured patients (HR 1.29, 95% CI 1.18-1.41) compared to privately insured patients. Access to rehabilitation was lower for both publicly insured and uninsured patients compared to patients with private insurance. Accounting for case-mix, the MOR was 1.49 (95% CI 1.43-1.55), reflecting significant residual between-center variation in WLST decision-making., Conclusions: Our findings highlight the presence of disparate WLST practices independently associated with health insurance status. Additionally, these results emphasize between-center variability in WLST, persisting despite adjustments for measurable patient and trauma center characteristics., (© 2024. The Author(s).)

Background: The effects of obesity on pulmonary gas and blood distribution in patients with acute respiratory failure remain unknown. Dual-energy computed tomography (DECT) is a X-ray-based method used to study regional distribution of gas and blood within the lung. We hypothesized that 1) regional gas/blood mismatch can be quantified by DECT; 2) obesity influences the global and regional distribution of pulmonary gas and blood; 3) regardless of ventilation modality (invasive vs. non-invasive ventilation), patients' body mass index (BMI) has an impact on pulmonary gas/blood mismatch., Methods: This single-centre prospective observational study enrolled 118 hypoxic COVID-19 patients (92 male) in need of respiratory support and intensive care who underwent DECT. The cohort was divided into three groups according to BMI: 1. BMI<25 kg/m 2 (non-obese), 2. BMI = 25-40 kg/m 2 (overweight to obese), and 3. BMI>40 kg/m 2 (morbidly obese). Gravitational analysis of Hounsfield unit distribution of gas and blood was derived from DECT and used to calculate regional gas/blood mismatch. A sensitivity analysis was performed to investigate the influence of the chosen ventilatory modality and BMI on gas/blood mismatch and adjust for other possible confounders (i.e., age and sex)., Results: 1) Regional pulmonary distribution of gas and blood and their mismatch were quantified using DECT imaging. 2) The BMI>40 kg/m 2 group had less hyperinflation in the non-dependent regions and more lung collapse in the dependent regions compared to the other BMI groups. In morbidly obese patients, gas and blood were more evenly distributed; therefore, the mismatch was lower than in other patients (30% vs. 36%, p < 0.05). 3) An increase in BMI of 5 kg/m 2 was associated with a decrease in mismatch of 3.3% (CI: 3.67% to -2.93%, p < 0.05). Neither the ventilatory modality nor age and sex affected the gas/blood mismatch ( p > 0.05)., Conclusion: 1) In a hypoxic COVID-19 population needing intensive care, pulmonary gas/blood mismatch can be quantified at a global and regional level using DECT. 2) Obesity influences the global and regional distribution of gas and blood within the lung, and BMI>40 kg/m 2 improves pulmonary gas/blood mismatch. 3) This is true regardless of the ventilatory mode and other possible confounders, i.e., age and sex., Trial Registration: Clinicaltrials.gov, identifier NCT04316884, NCT04474249., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bjarnadóttir, Perchiazzi, Sidenbladh, Larina, Wallin, Larsson, Franzén, Larsson, Sousa, Segelsjö, Hansen, Frithiof, Hultström, Lipcsey and Pellegrini.)

Background: Cardiogenic shock due to acute myocardial infarction (AMI-CS) is associated with significant short- and long-term morbidity and mortality. Despite this, little is known about associated cost., Objectives: The purpose of this study was to evaluate the health care costs and resource use associated with AMI-CS using administrative data from the province of Ontario, Canada., Methods: This was a retrospective cohort study of adult patients with AMI-CS from April 2009 to March 2019. One-year costs following index admission were reported at an individual level. We used generalized linear models to identify factors associated with increased cost. We stratified patients by revascularization strategy to compare cost in each group and examined total cost at a patient level per individual fiscal year., Results: We included 9,789 consecutive patients with AMI-CS across 135 centers in Ontario (mean age 70.5 years; 67.7% male). Mortality in-hospital was 30.2%, and mortality at 2 years was 45.9%. The median inpatient cost per patient was $23,912 (IQR: $12,234-$41,833) with a median total 1-year cost of $37,913 (IQR: $20,113-$66,582). The median 1-year cost was $17,730 (IQR: $9,323-$38,379) for those who died in hospital, and $45,713 (IQR: $29,688-$77,683) for those surviving to discharge, with $12,719 (IQR: $4,262-$35,275) occurring after discharge. Patients who received coronary artery bypass grafting incurred the highest cost among revascularization groups. No significant differences were observed in cost per fiscal year from 2009 to 2019., Conclusions: AMI-CS is associated with significant health care costs, both during the index hospitalization and following discharge. To optimize cost-effectiveness, future therapies should aim to reduce disability in addition to improving mortality., Competing Interests: Dr Brodie has received research support from and consulting for 10.13039/100013410LivaNova; is on the medical advisory boards for Abiomed, Xenios, Medtronic, Inspira, and Cellenkos; and he writes for UpToDate. Dr Fan has received personal fees from ALung Technologies, Aerogen, Baxter, GE Healthcare, Inspira, and Vasomune, outside of the submitted work. Dr Slutsky has received personal fees from Baxter and Xenios, outside of the submitted work. Dr Combes has received personal fees from Getinge, Baxter, and Xenios, outside of the submitted work. Dr Tanuseputro is supported by a Physician Services Incorporated Graham Farquharson Knowledge Translation Fellowship. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and Ministry of Long-term Care (MLTC). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. Parts of this report are based on Ontario Registrar General (ORG) information on deaths, the original source of which is ServiceOntario. The views expressed therein are those of the author and do not necessarily reflect those of ORG or the Ministry of Public and Business Service Delivery. Parts of this material are based on data and/or information compiled and provided by CIHI, Ontario Health (OH), and the Ontario Ministry of Health. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File. This study was further supported by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario. The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOH/MLTC is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, and opinions and statements expressed in the material are those of the authors, and not necessarily those of CIHI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate., Objective: The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model., Methods: Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-β1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis., Results: Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-β1-induced myofibroblast differentiation in silica-exposed mice., Conclusions: This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Objectives: Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock., Data Sources: We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024., Study Selection: We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration., Data Extraction: Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates., Data Synthesis: We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47-0.94], low certainty) and hospital length of stay (mean difference [MD] -2.1 d [95% CI, -1.4 to -2.8], low certainty). MB may also reduce duration of vasopressors (MD -31.1 hr [95% CI, -16.5 to -45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1-14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, -0.2% to 2.0%], very low certainty). We did not find any differences in adverse events., Conclusions: Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed., Registration: Center for Open Science (https://osf.io/hpy4j)., Competing Interests: Dr. Seely holds patents related to multiorgan variability analysis and has shares in Therapeutic Monitoring Systems. Dr. Cook is supported by a Canada Research Chair in Critical Care Knowledge Translation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk., Methods and Analysis: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation., Ethics and Dissemination: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309)., Trial Registration Number: NCT05148715., Competing Interests: Competing interests: CL, FDA, FLam, FLau, F-MC and MC are recipients of research career awards from the Fonds de recherche du Québec-Santé. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. FDA, MW and PC received stipends for their role at Transplant Québec MaS holds research grants from the Canadian Institute of Health Research and the New Frontiers in Research Fund related to organ donation research and received a stipend for his role as the Regional Medical Lead (Donation) from Ontario Health (Trillium Gift of Life Network). MSe, RB, M-HM, MMa, A-JF, BB, AD, EC, SHo, LB, HT, PL, JGB, MKS, KEAB, JZ, SE, GK, AH, SHa, BR, SJWO, DT and MMe declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery., Methods: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (C RS  < 0.6 (mL/Kg)/cmH 2 O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score ( m LIS), a composite measure that integrated daily measurements of C RS , along with oxygen requirements, oxygenation, and X-rays up to day 28. The m LIS score was also hierarchically adjusted for survival and extubation rates., Results: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average m LIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the m LIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in C RS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups., Conclusions: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020., (© 2024. The Author(s).)

Background: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques., Methods: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis., Results: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs., Conclusions: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs., (© 2024. The Author(s).)

Objectives: To estimate the expected value of undertaking a future randomized controlled trial of thresholds used to initiate invasive ventilation compared with usual care in hypoxemic respiratory failure., Perspective: Publicly funded healthcare payer., Setting: Critical care units capable of providing invasive ventilation and unconstrained by resource limitations during usual (nonpandemic) practice., Methods: We performed a model-based cost-utility estimation with individual-level simulation and value-of-information analysis focused on adults, admitted to critical care, receiving noninvasive oxygen. In the primary scenario, we compared hypothetical threshold A to usual care, where threshold A resulted in increased use of invasive ventilation and improved survival compared with usual care. In the secondary scenario, we compared hypothetical threshold B to usual care, where threshold B resulted in decreased use of invasive ventilation and similar survival compared with usual care. We assumed a willingness-to-pay of 100,000 Canadian dollars (CADs) per quality-adjusted life year., Results: In the primary scenario, threshold A was cost-effective compared with usual care due to improved hospital survival (78.1% vs. 75.1%), despite more use of invasive ventilation (62% vs. 30%) and higher lifetime costs (86,900 vs. 75,500 CAD). In the secondary scenario, threshold B was cost-effective compared with usual care due to similar survival (74.5% vs. 74.6%) with less use of invasive ventilation (20.2% vs. 27.6%) and lower lifetime costs (71,700 vs. 74,700 CAD). Value-of-information analysis showed that the expected value to Canadian society over 10 years of a 400-person randomized trial comparing a threshold for invasive ventilation to usual care in hypoxemic respiratory failure was 1.35 billion CAD or more in both scenarios., Conclusions: It would be highly valuable to society to identify thresholds that, in comparison to usual care, either increase survival or reduce invasive ventilation without reducing survival., Competing Interests: Dr. Yarnell was funded by the Canadian Institutes for Health Research Vanier Scholar program, the Eliot Phillipson Clinician Scientist Training Program, and the Clinician Investigator Program of the University of Toronto. Dr. Heath is supported by a Canada Research Chair in Statistical Trial Design and funded by the Discovery Grant Program of the Natural Sciences and Engineering Research Council of Canada (RGPIN-2021-03366). Dr. Sung is supported by the Canada Research Chair in Pediatric Oncology Supportive Care. Dr. Fowler is the H. Barrie Fairley Professor of Critical Care at the University Health Network, Interdepartmental Division of Critical Care Medicine, and University of Toronto. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: We planned to synthesize evidence examining the potential efficacy and safety of performing physical rehabilitation and/or mobilization (PR&M) in adult patients receiving extracorporeal life support (ECLS)., Data Sources: We included any study that compared PR&M to no PR&M or among different PR&M strategies in adult patients receiving any ECLS for any indication and any cannulation. We searched seven electronic databases with no language limitations., Study Selection and Data Extraction: Two reviewers, independently and in duplicate, screened all citations for eligibility. We used the Cochrane Risk of Bias 2 and Cochrane Risk Of Bias In Non-randomized Studies of Interventions tools to assess individual study risk of bias. Although we had planned for meta-analysis, this was not possible due to insufficient data, so we used narrative and tabular data summaries for presenting results. We assessed the overall certainty of the evidence for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation framework., Data Synthesis: We included 17 studies that enrolled 996 patients. Most studies examined venovenous extracorporeal membrane oxygenation (ECMO) and/or venoarterial ECMO as a bridge to recovery in the ICU. We found an uncertain effect of high-intensity/active PR&M on mortality, duration of mechanical ventilation, ICU length of stay, hospital length of stay, or quality of life compared with low-intensity/passive PR&M in patients receiving ECLS (very low certainty due to very serious imprecision). There was similarly an uncertain effect on safety events including clinically important bleeding, spontaneous intracerebral hemorrhage, limb ischemia, accidental decannulation, or ECLS circuit dysfunction (very low certainty due to very serious risk of bias and imprecision)., Conclusions: Based on the currently available summary of evidence, there is an uncertain effect of high-intensity/active PR&M on patient important outcomes or safety in patients receiving ECLS. Despite indirect data from other populations suggesting potential benefit of high-intensity PR&M in the ICU; further high-quality randomized trials evaluating the benefits and risks of physical therapy and/or mobilization in this population are needed., Competing Interests: Dr. Brodie receives research support from and consults for LivaNova. He has been on the medical advisory boards for Xenios, Medtronic, Inspira, and Cellenkos. He is the President-elect of the Extracorporeal Life Support Organization (ELSO) and the Chair of the Executive Committee of the International Extracorporeal Membrane Oxygenation (ECMO) Network, and he writes for UpToDate. Dr. Tonna is supported by a Career Development Award from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23 HL141596) and is the Chair of the Registry Committee of ELSO. Dr. Hodgson sits on the Executive Committee of the International ECMO Network and leads the national ECMO Registry (EXCEL) in Australia and New Zealand. She also led one of the included randomized controlled trials. Dr. Fan reports personal fees from ALung Technologies, Baxter, Getinge, Inspira, Vasomune, and ZOLL Medical outside the submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Reverse triggering (RT) was described in 2013 as a form of patient-ventilator asynchrony, where patient's respiratory effort follows mechanical insufflation. Diagnosis requires esophageal pressure (P es ) or diaphragmatic electrical activity (EA di ), but RT can also be diagnosed using standard ventilator waveforms., Hypothesis: We wondered (1) how frequently RT would be present but undetected in the figures from literature, especially before 2013; (2) whether it would be more prevalent in the era of small tidal volumes after 2000., Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from 1950 to 2017, with key words related to asynchrony to identify papers with figures including ventilator waveforms expected to display RT if present. Experts labelled waveforms. 'Definite' RT was identified when P es or EA di were in the tracing, and 'possible' RT when only flow and pressure waveforms were present. Expert assessment was compared to the author's descriptions of waveforms., Results: We found 65 appropriate papers published from 1977 to now, containing 181 ventilator waveforms. 21 cases of 'possible' RT and 25 cases of 'definite' RT were identified by the experts. 18.8% of waveforms prior to 2013 had evidence of RT. Most cases were published after 2000 (1 before vs. 45 after, p = 0.03). 54% of RT cases were attributed to different phenomena. A few cases of identified RT were already described prior to 2013 using different terminology (earliest in 1997). While RT cases attributed to different phenomena decreased after 2013, 60% of 'possible' RT remained missed., Conclusion: RT has been present in the literature as early as 1997, but most cases were found after the introduction of low tidal volume ventilation in 2000. Following 2013, the number of undetected cases decreased, but RT are still commonly missed. Reverse Triggering, A Missed Phenomenon in the Literature. Critical Care Canada Forum 2019 Abstracts. Can J Anesth/J Can Anesth 67 (Suppl 1), 1-162 (2020). https://doi-org.myaccess.library.utoronto.ca/ https://doi.org/10.1007/s12630-019-01552-z ., (© 2024. The Author(s).)

Background: Tidal expiratory flow limitation (EFL T ) complicates the delivery of mechanical ventilation but is only diagnosed by performing specific manoeuvres. Instantaneous analysis of expiratory resistance (Rex) can be an alternative way to detect EFL T without changing ventilatory settings. This study aimed to determine the agreement of EFL T detection by Rex analysis and the PEEP reduction manoeuvre using contingency table and agreement coefficient. The patterns of Rex were explored., Methods: Medical patients ≥ 15-year-old receiving mechanical ventilation underwent a PEEP reduction manoeuvre from 5 cmH 2 O to zero for EFL T detection. Waveforms were recorded and analyzed off-line. The instantaneous Rex was calculated and was plotted against the volume axis, overlapped by the flow-volume loop for inspection. Lung mechanics, characteristics of the patients, and clinical outcomes were collected. The result of the Rex method was validated using a separate independent dataset., Results: 339 patients initially enrolled and underwent a PEEP reduction. The prevalence of EFL T was 16.5%. EFL T patients had higher adjusted hospital mortality than non-EFL T cases. The Rex method showed 20% prevalence of EFL T and the result was 90.3% in agreement with PEEP reduction manoeuvre. In the validation dataset, the Rex method had resulted in 91.4% agreement. Three patterns of Rex were identified: no EFL T , early EFL T , associated with airway disease, and late EFL T , associated with non-airway diseases, including obesity. In early EFL T , external PEEP was less likely to eliminate EFL T ., Conclusions: The Rex method shows an excellent agreement with the PEEP reduction manoeuvre and allows real-time detection of EFL T . Two subtypes of EFL T are identified by Rex analysis., Trial Registration: Clinical trial registered with www.thaiclinicaltrials.org (TCTR20190318003). The registration date was on 18 March 2019, and the first subject enrollment was performed on 26 March 2019., (© 2024. The Author(s).)

Background and Objective: Collection of biosamples for translational research studies is vital for understanding biological pathways, discovering disease-related biomarkers, and identifying novel therapeutic targets. However, a lack of infrastructure for sample procurement, processing, storage, and shipping may hinder the ability of clinical research units to effectively engage in translational research. The purpose of this study was to identify the barriers to biosampling-based translational research in the critical care setting in Canada., Methods: We administered an online survey to members of the Canadian Critical Care Trials Group (CCCTG), the Canadian Critical Care Translational Biology Group (CCCTBG), and the Canadian Critical Care Research Coordinators Group (CCCRCG). The survey focused on participants' personal experience of biosampling research, research infrastructure, motivating factors, and perceived barriers., Results: We received 59 responses from 31 sites, including 6 community intensive care unit (ICU) sites. The overall response rate was 11.3%. The majority of respondents were research coordinators (44%), followed by clinician-investigators (33.8%), graduate students (10.2%), and PhD-investigators (8.5%). Although most (63.8%) respondents reported an interest in participating in translational research, they also reported that their ICUs were currently contributing to a third of the number of translational studies compared to clinical studies. For respondents with experience in participating in translational research studies, the most common barriers were lack of funding, lack of time, and insufficient research staff. For respondents without previous experience, the perceived facilitators were more interest from their research group, improved training/mentorship, increased funding, and better access to laboratory equipment., Conclusions: Our survey found that the majority of participants were interested in and recognize the value of participating in biosampling-based translational research but lacked funding, time, and research personnel trained in biosampling protocols. Our survey also identified factors that might encourage participation at new sites. Addressing these barriers will be a key step towards increasing translational research capacity across Canada., Competing Interests: No authors have competing interests., (Copyright: © 2024 Cani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)