Cardiac Magnetic Resonance Studies in a Large Animal Model that Simulates the Cardiac Abnormalities of Human Septic Shock.

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.

Initial Triage and Management of Patients with Acute Aortic Syndromes.

The acute aortic syndromes (AAS) are life-threatening vascular compromises within the aortic wall. These include aortic dissection (AD), intramural hematoma (IMH), penetrating aortic ulcer (PAU), and blunt traumatic thoracic aortic injury (BTTAI). While patients classically present with chest pain, the presentation may be highly variable. Timely diagnosis is critical to initiate definitive treatment and maximize chances of survival. In high-risk patients, treatment should begin immediately, even while diagnostic evaluation proceeds. The mainstay of medical therapy is acute reduction of heart rate and blood pressure. Surgical intervention is often required but is informed by patient anatomy and extent of vascular compromise.

Complex Heart-Lung Ventilator Emergencies in the CICU.

This review aims to enhance the comprehension and management of cardiopulmonary interactions in critically ill patients with cardiovascular disease undergoing mechanical ventilation. Highlighting the significance of maintaining a delicate balance, this article emphasizes the crucial role of adjusting ventilation parameters based on both invasive and noninvasive monitoring. It provides recommendations for the induction and liberation from mechanical ventilation. Special attention is given to the identification of auto-PEEP (positive end-expiratory pressure) and other situations that may impact hemodynamics and patients' outcomes.

Training Paradigms in Critical Care Cardiology: A Scoping Review of Current Literature.

Background: Over the past decade there has been increasing interest in critical care medicine (CCM) training for cardiovascular medicine (CV) physicians either in isolation (separate programs in either order [CV/CCM], integrated critical care cardiology [CCC] training) or hybrid training with interventional cardiology (IC)/heart failure/transplant (HF) with targeted CCC training. Objective: To review the contemporary landscape of CV/CCM, CCC, and hybrid training. Methods: We reviewed the literature from 2000-2022 for publications discussing training in any combination of internal medicine CV/CCM, CCC, and hybrid training. Information regarding training paradigms, scope of practice and training, duration, sequence, and milestones was collected. Results: Of the 2,236 unique citations, 20 articles were included. A majority were opinion/editorial articles whereas two were surveys. The training pathways were classified into - (i) specialty training in both CV (3 years) and CCM (1-2 years) leading to dual American Board of Internal Medicine (ABIM) board certification, or (ii) base specialty training in CV with competencies in IC, HF or CCC leading to a non-ABIM certificate. Total fellowship duration varied between 4-7 years after a three-year internal medicine residency. While multiple articles commented on the ability to integrate the fellowship training pathways into a holistic and seamless training curriculum, few have highlighted how this may be achieved to meet competencies and standards. Conclusions: In 20 articles describing CV/CCM, CCC, and hybrid training, there remains significant heterogeneity on the standardized training paradigms to meet training competencies and board certifications, highlighting an unmet need to define CCC competencies.

Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

BACKGROUND: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. METHODS/EXAMPLES: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. CONCLUSION: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

Liberation From Mechanical Ventilation in the Cardiac Intensive Care Unit.

The prevalence of respiratory failure is increasing in the contemporary cardiac intensive care unit (CICU) and is associated with a significant increase in morbidity and mortality. For patients that survive their initial respiratory decompensation, liberation from invasive mechanical ventilation (IMV) and the decision to extubate requires careful clinical assessment and planning. Therefore, it is essential for the CICU clinician to know how to assess and manage the various stages of IMV liberation, including ventilator weaning, evaluation of extubation readiness, and provide post-extubation care. In this review, we provide a comprehensive approach to liberation from IMV in the CICU, including cardiopulmonary interactions relative to withdrawal from positive pressure ventilation, evaluation of readiness for and assessment of spontaneous breathing trials, sedation management to optimize extubation, strategies for patients at a high risk for extubation failure, and tracheostomy in the cardiovascular patient.

Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients.

Understanding early innate immune responses to coronavirus disease 2019 (COVID-19) is crucial to developing targeted therapies to mitigate disease severity. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection elicits interferon expression leading to transcription of IFN-stimulated genes (ISGs) to control viral replication and spread. SARS-CoV-2 infection also elicits NF-κB signaling which regulates inflammatory cytokine expression contributing to viral control and likely disease severity. Few studies have simultaneously characterized these two components of innate immunity to COVID-19. We designed a study to characterize the expression of interferon alpha-2 (IFNA2) and interferon beta-1 (IFNB1), both type-1 interferons (IFN-1), interferon-gamma (IFNG), a type-2 interferon (IFN-2), ISGs, and NF-κB response genes in the upper respiratory tract (URT) of patients with mild (outpatient) versus severe (hospitalized) COVID-19. Further, we characterized the weekly dynamics of these responses in the upper and lower respiratory tracts (LRTs) and blood of severe patients to evaluate for compartmental differences. We observed significantly increased ISG and NF-κB responses in the URT of mild compared with severe patients early during illness. This pattern was associated with increased IFNA2 and IFNG expression in the URT of mild patients, a trend toward increased IFNB1-expression and significantly increased STING/IRF3/cGAS expression in the URT of severe patients. Our by-week across-compartment analysis in severe patients revealed significantly higher ISG responses in the blood compared with the URT and LRT of these patients during the first week of illness, despite significantly lower expression of IFNA2, IFNB1, and IFNG in blood. NF-κB responses, however, were significantly elevated in the LRT compared with the URT and blood of severe patients during peak illness (week 2). Our data support that severe COVID-19 is associated with impaired interferon signaling in the URT during early illness and robust pro-inflammatory responses in the LRT during peak illness.

Diaphragmatic Function in Cardiovascular Disease: JACC Review Topic of the Week.

In addition to the diaphragm's role as the primary respiratory muscle, it also plays an under-recognized role in cardiac function. It serves as a pump facilitating venous and lymph return, modulating left ventricular afterload hemodynamics and pericardial pressures, as well as regulating autonomic tone. Heart failure (HF) is associated with diaphragmatic changes (ie, muscle fiber atrophy and weakness, increased ratio of type I to type II muscle fibers, and altered muscle metaboreflex) that lead to diaphragmatic dysfunction with subsequent symptomatic manifestations of HF. Herein, it is proposed that targeting the diaphragm in patients with HF via inspiratory muscle training or device-based stimulation can provide a novel treatment pathway for HF. Reviewed are several potential mechanisms through which therapies targeting the diaphragm can be beneficial in HF (ie, improving preload reserve, atrial and ventricular synchrony, and metaboreflex activity; reducing pericardial restraint; and restoring diaphragm strength).

Quantitative Blood Volume Analysis and Hemodynamic Measures of Vascular Compliance in Patients With Worsening Heart Failure.

BACKGROUND: The role of blood volume (BV) expansion vs a change in vascular compliance in worsening heart failure (HF) remains under debate. We aimed to assess the relationship between BV and resting and stress hemodynamics in worsening HF and to further elucidate the significance of BV in cardiac decompensation. METHODS AND RESULTS: Patients with worsening HF underwent radiolabeled indicator-dilution BV analysis and cardiac catheterization. Intravascular volumes and resting/stress hemodynamics were recorded. Provocative stress maneuvers included change in systolic blood pressure (ΔSBP) from lying to standing and Valsalva and intracardiac pressure changes with leg raise. Correlation between BV and invasive hemodynamics were assessed by linear regression. Of 27 patients with worsening HF, patients' characteristics included mean age 61 ± 12 years, 70% male, 19% Black, and mean ejection fraction 29% ± 15%. Of the patients, 13 (48%) had hypervolemia as measured by total BV, which weakly correlated with ΔSBP by position (R2 = 0.009) and Valsalva (R2 = 0.003) and with right atrial (R2 = 0.049) and pulmonary capillary wedge (R2 = 0.047) pressure changes during leg raise. CONCLUSIONS: In patients with worsening HF, BV mildly correlated with intracardiac pressures at rest. Provocative maneuvers intended to test vascular compliance did not correlate with BV, indicating that compliance may serve as a stand-alone metric in HF.

Modeling current practices in critical care comparative effectiveness research.

Objective: To determine whether contemporaneous practices are adequately represented in recent critical care comparative effectiveness research studies. Design: All critical care comparative effectiveness research trials published in the New England Journal of Medicine from April 2019 to March 2020 were identified. To examine studies published in other high impact medical journals during the same period, such trials were subsequently also identified in the Journal of the American Medical Association and The Lancet. All cited sources were reviewed, and the medical literature was searched to find studies describing contemporary practices. Then, the designated control group or the comparable therapies studied were examined to determine if they represented contemporaneous critical care practices as described in the medical literature. Results: Twenty-five of 332 randomised clinical trials published in these three journals during this 1-year period described critical care comparative effectiveness research that met our inclusion criteria. Seventeen characterised current practices before enrolment (using surveys, observational studies and guidelines) and then incorporated current practices into one or more study arm. In the other eight, usual care arms appeared insufficient. Four of these trials randomly assigned patients to one of two fixed approaches at either end of a range of usually titrated care. However, due to randomisation, different subgroups within each arm received care that was inappropriate for their specific clinical conditions. In the other four of these trials, common practices influencing treatment choice were not reflected in the trial design, despite a prior effort to characterise usual care. Conclusion: One-third of critical care comparative effectiveness research trials published in widely read medical journals during a recent year did not include a designated control arm or comparable therapies representative of contemporary practices. Failure to incorporate contemporary practices into critical care comparative effectiveness trials appears to be a widespread design weakness.

How I Teach Auto-PEEP: Applying the Physiology of Expiration.

Teaching complex topics in mechanical ventilation can prove challenging for clinical educators, both at the bedside and in the classroom setting. Some of these topics, such as the topic of auto-positive end-expiratory pressure (auto-PEEP), consist of complicated physiological principles that can be difficult to convey in an organized and intuitive manner. In this entry of "How I Teach," we provide an approach to teaching the concept of auto-PEEP to senior residents and fellows working in the intensive care unit. We offer a framework for educators to effectively present the concepts of auto-PEEP to learners, either at the bedside or in the classroom setting, by summarizing key concepts and including concrete examples of the educational techniques we use. This framework includes specific content we emphasize, how to present this content using a variety of educational resources, assessing learner understanding, and how to modify the topic on the basis of location, time, or resource constraints.

Mechanistic insights into cell-free hemoglobin-induced injury during septic shock.

Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.

Comparative effectiveness research in critically ill patients: risks associated with mischaracterising usual care.

Comparative effectiveness research can help guide the use of common, routine medical practices. However, to be safe and informative, such trials must include at least one treatment arm that accurately portrays current practices. While comparative effectiveness research is widely perceived as safe and to involve no or only minimal risks, these assumptions may not hold true if unrecognised deviations from usual care exist in one or more study arms. For critically ill subjects in particular, such practice deviations may increase the risk of death or injury and undermine safety monitoring. Furthermore, unrecognised unusual care seems likely to corrupt informed consent documents, with underappreciated risks shrouded under the reassuring "comparative effectiveness" research label. At present, oversight measures are inadequate to ensure that research subjects enrolled in comparative effectiveness trials are actually receiving usual and not unusual care. Oversight by governmental and non-governmental entities with appropriate expertise, empowered to ensure that current clinical practice has been properly represented, could help prevent occurrences in clinical trials of unusual care masquerading as usual care.

Driving blind: instituting SEP-1 without high quality outcomes data.

In 2015, the Centers for Medicare and Medicaid Services (CMS) instituted an all-or-none sepsis performance measure bundle (SEP-1) to promote high-quality, cost-effective care. Systematic reviews demonstrated only low-quality evidence supporting most of SEP-1's interventions. CMS has removed some but not all of these unproven components. The current SEP-1 version requires patients with suspected sepsis have a lactate level, blood cultures, broad-spectrum antibiotics and, if hypotensive, a fixed 30 mL/kg fluid infusion within 3 hours, and a repeat lactate if initially elevated within 6 hours. Experts have continued to raise concerns that SEP-1 remains overly prescriptive, lacks a sound scientific basis and presents risks (overuse of antibiotics and inappropriate fluids not titrated to need). To incentivize compliance with SEP-1, CMS now publicly publishes how often hospitals complete all interventions in individual patients. However, compliance measured across hospitals (5 studies, 48-2,851 hospitals) or patients (three studies, 110-851 patients) has been low (approximately 50%) which is not surprising given SEP-1's lack of scientific basis. The largest observational study (1,738 patients) reporting survival rates employing SEP-1 found they were not significantly improved with the measure (P=0.53) as did the next largest study (851 patients, adjusted survival odds ratio 1.36, 95% CI, 0.85 to 2.18). Two smaller observational studies (158 and 450 patients) reported SEP-1 improved unadjusted survival (P≤0.05) but were confounded either by baseline imbalances or by simultaneous introduction of a code sepsis protocol to improve compliance. Regardless, retrospective studies have well known biases related to non-randomized designs, uncontrolled data collection and failure to adjust for unrecognized influential variables. Such low-quality science should not be the basis for a national mandate compelling care for a rapidly lethal disease with a high mortality rate. Instead, SEP-1 should be based on high quality reproducible evidence from randomized controlled trials (RCT) demonstrating its benefit and thereby safety. Otherwise we risk not only doing harm but standardizing it.

In canine bacterial pneumonia circulating granulocyte counts determine outcome from donor cells.

BACKGROUND: In experimental canine septic shock, depressed circulating granulocyte counts were associated with a poor outcome and increasing counts with prophylactic granulocyte colony-stimulating factor (G-CSF) improved outcome. Therapeutic G-CSF, in contrast, did not improve circulating counts or outcome, and therefore investigation was undertaken to determine whether transfusing granulocytes therapeutically would improve outcome. STUDY DESIGN AND METHODS: Twenty-eight purpose-bred beagles underwent an intrabronchial Staphylococcus aureus challenge and 4 hours later were randomly assigned to granulocyte (40-100 × 109 cells) or plasma transfusion. RESULTS: Granulocyte transfusion significantly expanded the low circulating counts for hours compared to septic controls but was not associated with significant mortality benefit (1/14, 7% vs. 2/14, 14%, respectively; p = 0.29). Septic animals with higher granulocyte count at 4 hours (median [interquartile range] of 3.81 3.39-5.05] vs. 1.77 [1.25-2.50]) had significantly increased survival independent of whether they were transfused with granulocytes. In a subgroup analysis, animals with higher circulating granulocyte counts receiving donor granulocytes had worsened lung injury compared to septic controls. Conversely, donor granulocytes decreased lung injury in septic animals with lower counts. CONCLUSION: During bacterial pneumonia, circulating counts predict the outcome of transfusing granulocytes. With low but normal counts, transfusing granulocytes does not improve survival and injures the lung, whereas for animals with very low counts, but not absolute neutropenia, granulocyte transfusion improves lung function.

RBC Storage Lesion Studies in Humans and Experimental Models of Shock.

The finding of toxicity in a meta-analysis of observational clinical studies of transfused longer stored red blood cells (RBC) and ethical issues surrounding aging blood for human studies prompted us to develop an experimental model of RBC transfusion. Transfusing older RBCs during canine pneumonia increased mortality rates. Toxicity was associated with in vivo hemolysis with release of cell-free hemoglobin (CFH) and iron. CFH can scavenge nitric oxide, causing vasoconstriction and endothelial injury. Iron, an essential bacterial nutrient, can worsen infections. This toxicity was seen at commonly transfused blood volumes (2 units) and was altered by the severity of pneumonia. Washing longer-stored RBCs mitigated these detrimental effects, but washing fresh RBCs actually increased them. In contrast to septic shock, transfused longer stored RBCs proved beneficial in hemorrhagic shock by decreasing reperfusion injury. Intravenous iron was equivalent in toxicity to transfusion of longer stored RBCs and both should be avoided during infection. Storage of longer-stored RBCs at 2 °C instead of higher standard temperatures (4-6 °C) minimized the release of CFH and iron. Haptoglobin, a plasma protein that binds CFH and increases its clearance, minimizes the toxic effects of longer-stored RBCs during infection and is a biologically plausible novel approach to treat septic shock.

The Madagascar hissing cockroach as a novel surrogate host for Burkholderia pseudomallei, B. mallei and B. thailandensis.

BACKGROUND: Burkholderia pseudomallei and Burkholderia mallei are gram-negative pathogens responsible for the diseases melioidosis and glanders, respectively. Both species cause disease in humans and animals and have been designated as category B select agents by the Centers for Disease Control and Prevention (CDC). Burkholderia thailandensis is a closely related bacterium that is generally considered avirulent for humans. While it can cause disease in rodents, the B. thailandensis 50% lethal dose (LD50) is typically ≥ 104-fold higher than the B. pseudomallei and B. mallei LD50 in mammalian models of infection. Here we describe an alternative to mammalian hosts in the study of virulence and host-pathogen interactions of these Burkholderia species. RESULTS: Madagascar hissing cockroaches (MH cockroaches) possess a number of qualities that make them desirable for use as a surrogate host, including ease of breeding, ease of handling, a competent innate immune system, and the ability to survive at 37°C. MH cockroaches were highly susceptible to infection with B. pseudomallei, B. mallei and B. thailandensis and the LD50 was <10 colony-forming units (cfu) for all three species. In comparison, the LD50 for Escherichia coli in MH cockroaches was >105 cfu. B. pseudomallei, B. mallei, and B. thailandensis cluster 1 type VI secretion system (T6SS-1) mutants were all attenuated in MH cockroaches, which is consistent with previous virulence studies conducted in rodents. B. pseudomallei mutants deficient in the other five T6SS gene clusters, T6SS-2 through T6SS-6, were virulent in both MH cockroaches and hamsters. Hemocytes obtained from MH cockroaches infected with B. pseudomallei harbored numerous intracellular bacteria, suggesting that this facultative intracellular pathogen can survive and replicate inside of MH cockroach phagocytic cells. The hemolymph extracted from these MH cockroaches also contained multinuclear giant cells (MNGCs) with intracellular B. pseudomallei, which indicates that infected hemocytes can fuse while flowing through the insect's open circulatory system in vivo. CONCLUSIONS: The results demonstrate that MH cockroaches are an attractive alternative to mammals to study host-pathogen interactions and may allow the identification of new Burkholderia virulence determinants. The importance of T6SS-1 as a virulence factor in MH cockroaches and rodents suggests that the primary role of this secretion system is to target evasion of the innate immune system.