Introduction: Emergency physicians pursuing critical care training must enter fellowships designed for internal medicine, anesthesiology, or surgery trainees. In this study we aimed to assess how emergency medicine (EM)-trained fellows are perceived by critical care fellowship leadership compared to their peers and to identify specialty-specific strengths and gaps that may inform targeted educational approaches. Methods: We conducted a national, cross-sectional survey of program directors and associate/assistant directors of Accreditation Council of Graduate Medical Education-accredited critical care fellowships. Respondents rated the baseline competence of incoming fellows across 11 core critical care domains using a 5-point Likert scale. We compared competency ratings across residency training backgrounds using linear mixed models, accounting for clustering and adjusting for rater specialty where appropriate. Results: Of 429 distributed surveys, 118 (27.5%) were completed. Our respondents represented internal medicine-based fellowships (63, 53%), surgical fellowships (32, 27%), and anesthesia fellowships (23, 20%). On a 5-point Likert scale ranging from 1 = “Not competent” to 5 = “Very competent,” EM-trained fellows were rated significantly higher than their internal medicine-trained peers in intubation (3.93 vs 1.86, P < .01); vascular access (3.72 vs 2.52, P < .01); point-of-care ultrasound (3.80 vs 2.52, P < .01); surgical critical care (2.39 vs 1.99, P < .01); and neurologic emergencies (2.59 vs 2.10, P < .01). Fellows trained in internal medicine were rated higher in ventilator management (2.54 vs 2.06, P < .01); palliation (3.05 vs 2.08, P < .01); and renal physiology/acid-base disturbances (3.18 vs 2.40, P < .01). Slightly different patterns emerged when comparing EM to surgery and anesthesiology trainees, where EM-trained fellows were rated similarly or lower in procedural domains but demonstrated more robust competence in organ-specific physiology and ultrasonography. These patterns remained largely consistent in sensitivity analyses adjusting for rater specialty. Conclusion: Critical care fellows who trained in EM bring distinct strengths in diagnostics and resuscitation to critical care training, but their educational needs may differ from those of peers within specialty-specific fellowships. Tailoring curricula to address these differences can help ensure all trainees achieve proficiency across core domains.

Introduction: Emergency physicians pursuing critical care training must enter fellowships designed for internal medicine, anesthesiology, or surgery trainees. In this study we aimed to assess how emergency medicine (EM)-trained fellows are perceived by critical care fellowship leadership compared to their peers and to identify specialty-specific strengths and gaps that may inform targeted educational approaches. Methods: We conducted a national, cross-sectional survey of program directors and associate/assistant directors of Accreditation Council of Graduate Medical Education-accredited critical care fellowships. Respondents rated the baseline competence of incoming fellows across 11 core critical care domains using a 5-point Likert scale. We compared competency ratings across residency training backgrounds using linear mixed models, accounting for clustering and adjusting for rater specialty where appropriate. Results: Of 429 distributed surveys, 118 (27.5%) were completed. Our respondents represented internal medicine-based fellowships (63, 53%), surgical fellowships (32, 27%), and anesthesia fellowships (23, 20%). On a 5-point Likert scale ranging from 1 = “Not competent” to 5 = “Very competent,” EM-trained fellows were rated significantly higher than their internal medicine-trained peers in intubation (3.93 vs 1.86, P < .01); vascular access (3.72 vs 2.52, P < .01); point-of-care ultrasound (3.80 vs 2.52, P < .01 ); surgical critical care (2.39 vs 1.99, P < .01); and neurologic emergencies (2.59 vs 2.10, P < .01). Fellows trained in internal medicine were rated higher in ventilator management (2.54 vs 2.06, P < .01); palliation (3.05 vs 2.08, P < .01); and renal physiology/acid-base disturbances (3.18 vs 2.40, P < .01). Slightly different patterns emerged when comparing EM to surgery and anesthesiology trainees, where EM-trained fellows were rated similarly or lower in procedural domains but demonstrated more robust competence in organ-specific physiology and ultrasonography. These patterns remained largely consistent in sensitivity analyses adjusting for rater specialty. Conclusion: Critical care fellows who trained in EM bring distinct strengths in diagnostics and resuscitation to critical care training, but their educational needs may differ from those of peers within specialty-specific fellowships. Tailoring curricula to address these differences can help ensure all trainees achieve proficiency across core domains.

BACKGROUND:Mechanical ventilation can be lifesaving for critically ill patients. However, there is evidence that intensivists' mechanical ventilation management skills are lacking, presenting a potential risk to patient safety. Ventilator waveform interpretation skills of intensivists need to be further studied to address learning gaps among intensivists. OBJECTIVES:We aimed to study the baseline ventilator waveform interpretation and management skills of attending intensivists compared to those of critical care fellows in academic medical institutions in the United States. METHODS:This prospective multi-institutional investigation spanned 7 US cities where the Multi-Institutional Fundamentals of Mechanical Ventilation Course (MFMVC) took place in July and August 2023. Participants included attending intensivists (study group) from academic medical centers and critical care fellows (control group) who participated in the MFMVC. A validated ventilator waveform test was administered pre- and post-MFMVC. The primary outcome was the pretest scores of intensivists compared to fellows. RESULTS:Thirty-three attendings and 136 fellows took the pretest and 29 attendings and 135 fellows took the posttest. Mean ± SD pretest scores out of 100 points were 24.3 ± 22.3 for attendings and 16.9 ± 18.7 for fellows (P = .0503). Posttest scores for attendings (45.6 ± 25.5; delta score, 21.3; P = .0015) and fellows (43.6 ± 24.0; delta score, 26.7; P <.00001) significantly improved. There was no difference in posttest scores between attendings versus fellows (P = .69). CONCLUSIONS:Intensivists' ventilator waveform interpretation and management skills are not different from those of critical care fellows before and after a mechanical ventilation course. These findings highlight a need for targeted educational interventions given the apparent concerning knowledge gaps among intensivists post-fellowship.

Introduction/Purpose:During the septic cardiomyopathy, the mechanism and relationship to outcome of changes in left ventricular (LV) end diastolic volume (EDV) and ejection fraction (EF) remains obscure. We compared serial changes in LVEF and LVEDV to successive alterations in LV wall ultrastructure, water content, and total mass to investigate whether these measures can explain their basis. Methods:We performed cardiac magnetic resonance imaging at 0,6,18,30,42,54, and 92h post-bacterial challenge in a large-animal model (n=57) that mimics human septic cardiomyopathy. LV tissue was obtained for electron microscopy (EM) upon death and 66h in sacrificed survivors. Results:Between 0-6h post-challenge, LV compliance and EDV reached its greatest decline. Non-survivors (n=18) exhibited significantly greater reductions in LVEDV, along with more myocyte edema, mitochondrial swelling and myofilament fragmentation on EM. This increased tissue damage may explain why non-survivors developed worse LV compliance and a greater decline in LVEDV, which persisted until death. From 6-30h, LVEDV significantly improved to baseline in non-survivors, while survivors experienced ∼20% increases (n=39). Concurrently, there was significant LV mass loss and increases in percent water content that were significantly associated with increases in LVEDV. This is consistent with a passive mechanism for rapidly improving LV compliance and EDV. Full recovery of EF required additional days. We hypothesize the prolonged significant mass loss over 5d reflects an active process for remodeling fragmented myofilaments, eliminating myocyte edema, and mitochondrial swelling, ultimately restoring contractile function. Conclusion:The septic cardiomyopathy constitutes a diffuse ultrastructural injury to myocytes with three phases. Initially, there is a decrease in LVEDV, and EF due to myocyte damage within 6h of bacterial challenge; next, the patient sees a passive LVEDV recovery from 6-30h, where LV mass loss increases relative wall percent water content, which facilitates wall compliance and LVEDV; and lastly, the patient sees mass loss beyond 30h consistent with an active repair mechanism of myocytes, returning systolic function to normal. Therefore, EDV changes are a pathophysiological biomarker for sepsis outcomes. A lower LVEDV indicates persistent unrepairable ultrastructure damage with worsening wall compliance and poorer outcomes. LVEDV dilation is a sign of near-full recovery of ultrastructure injury, augmenting wall compliance and improving outcomes. Clinical Implications:We explain herein why septic cardiomyopathy findings don't have clinical implications like heart failure. Septic patients who exhibit signs of heart failure, low LVEF with high EDVs, are doing well - reflecting mild myocyte injury, effective damaged tissues clearance, increased relative LV wall water content, and compliance. This augments the LVEDV, lowering the LVEF. Septic patients who deteriorate rapidly, contrary to heart failure patients, show high/normal LVEF and low/normal LVEDV. Here, the myocyte damage is severe, leading to insufficient wall repair, and this decreased wall compliance persists, preventing the LV from dilating and making LVEDV low which ultimately raises the LVEF.

Controlled clinical trials investigating ongoing questions about extracorporeal membrane oxygenation (ECMO) for patients with the acute respiratory distress syndrome (ARDS), including what the optimal mechanical ventilation (MV) tidal volume (TV) strategies are and whether ECMO potentiates injurious host responses, are difficult. We therefore conducted a systematic literature search and review to characterize studies investigating ECMO in adult animal lung injury models and to determine whether they inform these questions. A systematic literature search with relevant search terms was conducted of four data bases through 2/2/24. Forty-five studies met inclusion criteria, and most parameters examined were represented similarly in studies with (n = 24) or without (n = 21) severe ARDS PaO2/FiO2s levels (≤ 100 mmHg or > 100 mmHg). Overall, while only 11 studies were published from 1971 to 2005, 5, 8, and 11 were published in subsequent 5-year periods up to 2020 and then 10 through 2/2/24 (Figure 1). Most studies investigated pig or sheep models (n = 32), but since 2016, six studies employed rat models. Eighteen studies administered lung lavage alone or with another lung injury challenge (17 with PaO2/FiO2s ≤ 100) and 9 used oleic acid. Although seven studies administered lipopolysaccharide, very different from clinical ARDS only one used a bacterial and none a viral challenge. Thirty-two studies employed V-V ECMO. The most frequent duration of ECMO investigated was 24 h in 16 studies but only 2 studies investigated longer periods (48 and 96 h). Differences in study questions, methodologies and outcome measures precluded formal meta-analysis. However, overall in studies that compared mechanical ventilation alone (MV) to ECMO groups or that compared differing ECMO groups: in 5 studies ECMO supported tidal volume reductions that approached apneic levels in 2; all but 1 of 10 studies indicated that ECMO with or without TV reductions either did not increase or reduced lung injury measures; 2 studies did while 4 did not find that ECMO aggravated molecular or cellular markers of inflammation; and only 2 studies examined host thrombotic responses with ECMO. Animal models to date have addressed important questions facing ECMO use for ARDS, but ones more closely simulating ARDS in patients appear warranted.

Background:Classified by the WHO as one of the 19 most dangerous fungal pathogens, Pneumocystis jirovecii has been associated with increasing outbreaks of Pneumocystis pneumonia (PCP) among solid organ transplant (SOT) recipients worldwide. Mycophenolic acid (MPA), an inosine monophosphate dehydrogenase (IMPDH) inhibitor commonly used as an immunosuppressant to prevent organ rejection, is a risk factor for PCP. However, MPA also displays antifungal activity, potentially protecting against PCP, despite not being used to treat it. Therefore the underlying factors driving these outbreaks remain undefined. Methods:In this international multicenter retrospective observational study, P. jirovecii samples were collected from 96 SOT patients (including 94 from nine separate outbreaks and 84 on MPA therapy) and 67 non-transplant controls (none on MPA), between 1986 and 2020 across six countries in Europe, North America and Asia. All samples underwent extensive targeted sequencing of the P. jirovecii inosine monophosphate dehydrogenase (impdh) gene and multiple genetic markers, with selected samples further analyzed for complete mitogenome and restriction fragment length polymorphisms. Computational modeling was employed to predict the effects of IMPDH mutations on protein structure and MPA binding. Results:Six impdh mutations (including one previously reported) were identified, with frequencies of 4-21% each in SOT patients and 0-1% in controls. These mutations were strongly associated with prior MPA exposure and showed marked geographic segregation and temporal shifts. Four mutations were each linked to multiple distinct genotype profiles, representing separate P. jirovecii strains. Structure modeling predicted that these four mutations reduced protein stability and binding affinity to MPA. Conclusions:This study suggests that the widespread use of MPA in SOT recipients has unexpectedly driven the emergence of multiple impdh mutations in P. jirovecii, each presumably arising independently in multiple strains worldwide. These mutations likely confer drug resistance and provide a selective survival advantage to P. jirovecii in SOT recipients exposed to MPA, thereby facilitating transmission and outbreaks. These findings have significant implications for the prevention and clinical management of PCP in SOT recipients, highlighting a rare example of how antimicrobial resistance can emerge through unexpected pathways, transcending conventional antimicrobial use and emphasizing the need for increased vigilance and strategic adaptation in clinical practice.

Background: Rapid accumulation of knowledge and skills by trainees in the intensive care unit assumes prior mastery of clinically relevant core physiology concepts. However, for many fellows, their foundational physiology knowledge was acquired years earlier during their preclinical medical curricula and variably reinforced during the remainder of their undergraduate and graduate medical training. Objective: We sought to assess the retention of clinically relevant pulmonary physiology knowledge among pulmonary and critical care medicine (PCCM) and critical care medicine (CCM) fellows. Methods: A composite examination was developed from an initial set of questions used in preclinical pulmonary physiology courses at four separate medical schools. These questions passed through multiple rounds of review by various educators to arrive at a set of 15 multiple-choice questions. The test was administered to incoming first-year PCCM and CCM fellows at seven institutions during their 2021 fellowship orientation. Results: Forty-one first-year PCCM (n = 24) and CCM (n = 17) fellows completed the examination, and the proportion correct among the fellows was compared with that of medical students for each item. Although all questions were deemed to be clinically relevant, preclinical medical students significantly outperformed the incoming fellows. Conclusion: These findings suggest considerable decay of clinically relevant pulmonary physiologic knowledge during residency training and point to a need for longitudinal retrieval practice to reinforce these concepts during the course of medical school clerkship years and postgraduate clinical training as well as consideration of dedicated pulmonary physiology curricula for PCCM and CCM fellowship programs.

Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing and obliteration of distal, pre-capillary pulmonary vessels. Yet, noninvasive biomarkers that reflect this disease-defining process are lacking. A systematic review of PAH studies that measured circulating progenitor cells (CPCs) or circulating endothelial cells (CECs) in PAH by flow cytometry was performed to understand how future studies, leveraging state-of-the-art single-cell analyses, can advance the field. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews. Of the 2422 studies identified, 20 met inclusion criteria. Nineteen studies measured CPCs by flow cytometry, only one study examined CECs. A total of 647 PAH patients were included across all 19 CPC studies. Marker schemes chosen to define CPCs, and the methods of flow cytometry used, varied significantly across studies. Meta-analysis of a subgroup of CPC studies (n = 8) similarly identified a significant amount of heterogeneity even amongst studies using the same marker scheme. In conclusion, a systematic review of CPC studies in PAH patients reveals the limitations of the current literature. Future studies should include contemporary risk assessments, disease duration, reporting of comorbid conditions, and serial sampling over time. Furthermore, methods that incorporate best practices for detecting rare cell populations by flow cytometry are essential and should be reported in sufficient detail in future publications. With the emergence of single-cell technologies, future studies of circulating progenitor and endothelial cells in PAH remain relevant and may incorporate several insights from the current review to build upon the existing literature.

Disruption of nicotinamide adenine dinucleotide (NAD) biosynthesis and function during infection may impair host defenses and aggravate inflammatory and oxidative organ injury. Increasingly, studies are investigating whether niacin or NAD metabolite treatment is beneficial in infection and sepsis animal models. We examined whether this preclinical experience supports clinical trials. A systematic review of three data bases was conducted through 2/29/2024 and a meta-analysis was performed comparing niacin or NAD metabolite treatment to control in adult animal models employing microbial challenges. Fifty-six studies met inclusion criteria, with 24 published after 2019. Most studies employed mouse (n = 40 studies) or rat (n = 12) models and administered either a bacterial toxin (n = 28) or bacterial (n = 19) challenge. Four and three studies employed viral or fungal challenges respectively. Studies investigated an NAD metabolite alone (n = 44), niacin alone (n = 9), or both (n = 3), usually administered before or within 24h after challenge (n = 50). Only three and four studies included standard antimicrobial support or started treatment > 24h after challenge respectively. In similar patterns with differing animal types (p ≥ 0.06), compared to control across those studies investigating the parameter, niacin or NAD treatment decreased the odds ratio of mortality [95% confidence interval (CI)] [0.28 (0.17, 0.49)] and in blood or tissue increased antioxidant levels [standardized mean differences (95%CI)] (SMD) [3.61 (2.20,5.02)] and decreased levels of microbes [− 2.44 (− 3.34, − 1.55)], histologic and permeability organ injury scoring [− 1.62 (− 2.27, − 0.98) and − 1.31(− 1.77, − 0.86) respectively], levels of TNFα, IL-6 and IL-1β [− 2.47 (− 3.30, − 1.64), − 3.17 (− 4.74, − 1.60) and − 8.44 (− 12.4, − 4.5) respectively] and myeloperoxidase (MPO) [− 1.60 (− 2.06, − 1.14)], although with significant, primarily quantitative heterogeneity for each (I2 ≥ 53%, p < 0.01) except MPO. Treatment increased blood or tissue NAD+ levels and decreased chemical organ injury measures and oxidation markers but differently comparing species (p ≤ 0.05). Only 2 and 9 survival studies described power analyses or animal randomization respectively and no study described treatment or non-histologic outcome measure blinding. Among survival studies, Egger’s analysis (p = 0.002) suggested publication bias. While suggestive, published animal studies do not yet support clinical trials testing niacin and NAD metabolite treatment for infection and sepsis. Animal studies simulating clinical conditions and with randomized, blinded designs are needed to investigate this potentially promising therapeutic approach.

BACKGROUND:Although mechanical ventilation (MV) is a critical competency in critical care training, standardized methods for assessing MV-related knowledge are lacking. Traditional multiple-choice question (MCQ) development is resource intensive, and prior studies have suggested that generative AI tools could streamline question creation. However, the quality of AI-generated MCQs remains unclear. RESEARCH QUESTION:Are MCQs generated by ChatGPT noninferior to human expert (HE)-created questions in terms of quality and relevance for MV education? STUDY DESIGN AND METHODS:Three key MV topics were selected: Equation of Motion and Ohm's Law, Tau and Auto-PEEP, and Oxygenation. Fifteen learning objectives were used to generate 15 AI-written MCQs via a standardized prompt with ChatGPT-o1 (preview model; made available September 12, 2024). A group of 31 faculty experts, all of whom regularly teach MV, evaluated both AI- and HE-generated MCQs. Each MCQ was assessed based on its alignment with learning objectives, accuracy of chosen answer, clarity of the question stem, plausibility of distractor options, and difficulty level. The faculty members were blinded to the provenance of the MCQ questions. The noninferiority margin was predefined as 15% of the total possible score (-3.45). RESULTS:AI-generated MCQs were statistically noninferior to the HE-written MCQs (95% upper CI, [-1.15, ∞]). In additions, respondents were unable to reliably differentiate AI-generated MCQs from HE-written MCQs (P = .32). INTERPRETATION:Our results suggest that AI-generated MCQs using ChatGPT-o1 are comparable in quality to those written by HEs. Given the time and resource-intensive nature of human MCQ development, AI-assisted question generation may serve as an efficient and scalable alternative for medical education assessment, even in highly specialized domains such as MV.

Background Lung transplantation offers life-saving benefits for patients with end-stage lung disease, however, long-term outcomes remain poor, with a median survival of 6.5 years. Identifying patients at risk for poor post-transplant lung function is crucial for improving outcomes. While peri-operative and demographic factors have previously been studied, the impact of donor-specific antibodies (DSA) on longitudinal post-transplant lung function remains unclear. This study examines the effects of DSA on post-transplant lung function and the risk of baseline lung allograft dysfunction (BLAD). Research question Is DSA development linked to worse longitudinal lung function, higher BLAD rates, and poorer survival compared to DSA-negative patients regardless of the development of clinical AMR? Methods This study included lung transplant recipients from two prospective cohort studies, comparing DSA+ and DSA- patients. All participants underwent serial surveillance and clinically-indicated bronchoscopy, pulmonary function tests, and DSA testing. Statistical analysis included linear mixed models for longitudinal lung function data, multivariable logistic regression for BLAD, and survival analysis using Cox Proportional Hazard models. Results We analyzed 213 patients with a median follow-up of 48.1 months. Among them, 50.7% developed DSA. DSA+ patients showed significantly lower rates of post-transplant spirometric improvement compared to DSA- patients (p=0.008 for %FVC; p=0.02 for %FEV1). After DSA detection, there was a significant decrease in the slopes of %FVC and %FEV1 (p=0.0008 and p=0.0006, respectively). DSA+ patients had a higher risk of developing BLAD (OR 2.14, 95% CI [1.45, 3.17], p=0.0001). Additionally, DSA+ patients had a higher risk of death (HR 2.98, 95% CI [1.79, 4.99], p<0.0001). These findings were consistent even when excluding patients with clinical antibody-mediated rejection (AMR). Interpretation Our study demonstrates that DSA development significantly impairs post-transplant lung function and increases the risk of BLAD even in the absence of clinical AMR. These findings suggest that DSA may serve as a biomarker of BLAD, and could potentially aid in risk stratification following lung transplantation.

Background High levels of catecholamines are cardiotoxic and associated with stress‐induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. Methods and Results Purpose‐bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 μg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine‐stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High‐dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular‐aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800‐fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular‐aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. Conclusions Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion‐induced ischemia. However, epinephrine itself has potentially harmful long‐lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

Background. A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods. This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results. BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: –0.0095 [0.0007] versus –0.0109 [0.0007]; P = 0.15). Conclusions. BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

Nonhuman primate models that closely emulate the disease course, pathogenesis, and supportive care provided to human patients in the modern intensive care unit with bacterial sepsis are urgently needed to study pathogenesis and assess novel therapies. We therefore developed a non-human primate model of septic shock that includes supportive care akin to a modern intensive care unit. In this study, we characterized pathogen kinetics and evaluated the physiologic, immunologic, and pathologic responses in this model of septic shock induced by the clinically relevant pathogen Klebsiella pneumoniae across a three-log dose range. We observed dose-dependent bacteremia and circulating levels of Klebsiella pneumoniae DNA and endotoxin. Tachycardia and hypotension occurred in all animals and the study endpoint occurred in 8 of 12 animals that were euthanized. The infused bacterial dose was significantly associated with the severity of renal insufficiency and coagulopathy. Neutrophil activation evidenced by increased CD11b expression, decreased CD62L expression, and increased circulating levels of myeloperoxidase, lactoferrin, and neutrophil extracellular traps; monocyte activation evidenced by increased circulating levels of interleukin-6, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1; and endothelial activation evidenced by increased circulating levels of syndecan-1 and angiopoietin-II were all consistent with human sepsis. Our model provides an opportunity to study pathogenesis and investigate novel therapeutics for the treatment of bacterial sepsis in the setting of modern supportive care. IMPORTANCE There is currently a disconnect between the efficacy of sepsis therapies in pre-clinical animal models and human clinical trials. Therefore, developing nonhuman primate models that closely mimic human sepsis pathogenesis to study novel host-targeted therapeutics is a priority. In this study, we developed a model of septic shock with a clinically relevant bacteria (Klebsiella pneumoniae) that provides standard supportive care including mechanical ventilation, invasive hemodynamic monitoring, volume resuscitation, vasopressors, antibiotics, and steroids. In a dose-dependent manner, we observed that this model closely emulates the hemodynamic, end-organ dysfunction, and cellular and soluble responses associated with human sepsis. This validated model provides a unique opportunity to study the pathogenesis of acute septic shock and evaluate host-directed therapeutics in a large animal model that closely emulates the modern-day intensive care unit and supportive critical care.

OBJECTIVES:COVID-19 pandemic surges strained hospitals globally. We performed a systematic review to examine measures of pandemic caseload surge and its impact on mortality of hospitalized patients. DATA SOURCES:PubMed, Embase, and Web of Science. STUDY SELECTION:English-language studies published between December 1, 2019, and November 22, 2023, which reported the association between pandemic "surge"-related measures and mortality in hospitalized patients. DATA EXTRACTION:Three authors independently screened studies, extracted data, and assessed individual study risk of bias. We assessed measures of surge qualitatively across included studies. Given multidomain heterogeneity, we semiquantitatively aggregated surge-mortality associations. DATA SYNTHESIS:Of 17,831 citations, we included 39 studies, 17 of which specifically described surge effects in ICU settings. The majority of studies were from high-income countries (n = 35 studies) and included patients with COVID-19 (n = 31). There were 37 different surge metrics which were mapped into four broad themes, incorporating caseloads either directly as unadjusted counts (n = 11), nested in occupancy (n = 14), including additional factors (e.g., resource needs, speed of occupancy; n = 10), or using indirect proxies (e.g., altered staffing ratios, alternative care settings; n = 4). Notwithstanding metric heterogeneity, 32 of 39 studies (82%) reported detrimental adjusted odds/hazard ratio for caseload surge-mortality outcomes, reporting point estimates of up to four-fold increased risk of mortality. This signal persisted among study subgroups categorized by publication year, patient types, clinical settings, and country income status. CONCLUSIONS:Pandemic caseload surge was associated with lower survival across most studies regardless of jurisdiction, timing, and population. Markedly variable surge strain measures precluded meta-analysis and findings have uncertain generalizability to lower-middle-income countries (LMICs). These findings underscore the need for establishing a consensus surge metric that is sensitive to capturing harms in everyday fluctuations and future pandemics and is scalable to LMICs.

Background: Training in mechanical ventilation is a key goal in critical care fellowship education. Web-based simulators offer a cost-effective and readily available alternative to traditional on-site simulators. However, it is unclear how effective they are as teaching tools. In this study, we evaluated the test scores of fellows who underwent mechanical ventilation training by using a web-based simulator compared with fellows who used an on-site simulator during a mechanical ventilation course. Methods: This was a nonrandomized controlled trial conducted as part of a mechanical ventilation course that involved 70 first-year critical care fellows. The course was identical except for the simulation technology used. One group of instructors used a traditional on-site simulator, the ASL 5000 Lung Solution (n = 39). The second group was instructed in using a web-based simulator, VentSim (n = 31). Each fellow completed a pre-course test and a post-course test by using a validated, case-based ventilator waveform examination that consisted of 5 questions with a total possible score of 100. The primary outcome was a comparison of the mean scores on the posttest between the 2 groups. The study was designed as a non-inferiority trial with a predetermined margin of 10 points. Results: There was no significant difference in the mean +/- SD pretest scores between the web-based and the on-site groups (21.1 +/- 12.6 and 26.9 +/- 13.6 respectively; P = .11). The mean +/- SD posttest scores were 45.6 +/- 25.0 for the web-based simulator and 43.4 +/- 16.5 for on-site simulator (mean difference 2.2; one-sided 95% CI -7.0 to infinity; P (non-inferiority) = .02 [non-inferiority confirmed]). Changes in mean +/- SD scores (posttest - pretest) were 25.9 +/- 20.9 for the web-based simulator and 16.5 +/- 15.9 for the on-site simulator (mean difference 9.4, one-sided 95% CI 0.9 to infinity; P (non-inferiority) < .001 [non-inferiority confirmed]). Conclusions: In the education of first-year critical care fellows on mechanical ventilation waveform analysis, a web-based mechanical ventilation simulator was non-inferior to a traditional on-site mechanical ventilation simulator.

Background:Septic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown. Methods:Purpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals. Results:From 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size. Conclusion:Systolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury.