Mechanical Ventilation Training Curriculum for Pulmonary Critical Care Fellows during the COVID-19 Pandemic.

Background: Mechanical ventilation (MV) management is an essential skill for pulmonary and critical care medicine (PCCM) fellows to master during training. The unprecedented emergence of the coronavirus disease (COVID-19) pandemic highlighted the need for advanced operator competency in MV to improve patients' outcomes. Objective: We aimed to create a standardized case-based curriculum using a blended approach of high-fidelity simulation, rapid-cycle deliberate practice, video didactics, and hands-on small group sessions for rapid accumulation of knowledge and hands-on skills for PCCM fellows before caring for critically ill patients during the COVID-19 pandemic. Methods: The MV curriculum consisted of the following steps: 1) baseline written knowledge test with 15 multiple-choice questions covering MV, the latest evidence-based practices, and pathophysiology of COVID-19; 2) baseline confidence survey using a 5-point Likert scale; 3) a one-on-one session using a high-fidelity simulation manikin, a lung simulator, and a mechanical ventilator to test baseline competencies; 4) a structured debriefing tailored per fellow's 50-point competency assessment checklist from the simulation using rapid-cycle deliberate practice; 5) video didactics; 6) a hands-on session in small groups for basic knobology, waveforms, and modes of MV; 7) a one-on-one simulation reassessment session; 8) a written knowledge posttest; and 9) a post-training confidence survey using a 5-point Likert scale. Results: Eight PCCM fellows completed the training. The mean multiple-choice question score increased from 7.4 ± 2.9 to 10.4 ± 2.4 (P < 0.05), and the simulation scores increased from 17.1 ± 4.4 to 30.8 ± 3.7 (P < 0.05). Comparing the simulation reassessment to the baseline, fellows showed significant improvement (P < 0.05) in assessing indications for MV; implementing rapid sequence intubation for patients with COVID-19; initiating MV and ventilator bundle per best practices; recognizing and managing mucous plugging, ventilator dyssynchrony, and evidence-based treatments for acute respiratory distress syndrome; and developing a care plan for proning. The post-training survey revealed improved learner confidence in all competencies. Conclusion: This pilot MV curriculum using a blended approach was feasible and allowed PCCM fellows to significantly improve their knowledge and hands-on skills, allowing for the appropriate use of MV during the pandemic. Self-reported improvement scores further reinforced this. The emergent need for novice learners may again be necessary for future pandemic settings where standard training models requiring extensive training time are limited.

Graphene oxide classification and standardization.

There is a need to classify and standardize graphene-related materials giving the growing use of this materials industrially. One of the most used and more difficult to classify is graphene oxide (GO). Inconsistent definitions of GO, closely relating it to graphene, are found in the literature and industrial brochures. Hence, although they have very different physicochemical properties and industrial applications, commonly used classifications of graphene and GO definitions are not substantial. Consequently, the lack of regulation and standardization create trust issues among sellers and buyers that impede industrial development and progress. With that in mind, this study offers a critical assessment of 34 commercially available GOs, characterized using a systematic and reliable protocol for accessing their quality. We establish correlations between GO physicochemical properties and its applications leading to rationale for its classification.

Impact of a Multimodal Simulation-based Curriculum on Endobronchial Ultrasound Skills.

Background: Currently there is no consensus on ideal teaching method to train novice trainees in EBUS. Simulation-based procedure training allows direct observation of trainees in a controlled environment without compromising patient safety. Objective: We wanted to develop a comprehensive assessment of endobronchial ultrasound (EBUS) performance of pulmonary fellows and assess the impact of a multimodal simulation-based curriculum for EBUS-guided transbronchial needle aspiration. Methods: Pretest assessment of 11 novice pulmonary fellows was performed using a three-part assessment tool, measuring EBUS-related knowledge, self-confidence, and procedural skills. Knowledge was assessed by 20 multiple-choice questions. Self-confidence was measured using the previously validated EBUS-Subjective Assessment Tool. Procedural skills assessment was performed on Simbionix BRONCH Express simulator and was modeled on a previously validated EBUS-Skills and Task Assessment Tool (EBUS-STAT), to create a modified EBUS-STAT based on internal faculty input via the Delphi method. After baseline testing, fellows participated in a structured multimodal curriculum, which included simulator training, small-group didactics, and interactive problem-based learning sessions, followed by individual debriefing sessions. Posttest assessment using the same three-part assessment tool was performed after 3 months, and the results were compared to study the impact of the new curriculum. Results: The mean knowledge score improved significantly from baseline to posttest (52.7% vs. 67.7%; P = 0.002). The mean EBUS-Subjective Assessment Tool confidence scores (maximum score, 50) improved significantly from baseline to posttest (26 ± 7.6 vs. 35.2 ± 6.3 points; P < 0.001). The mean modified EBUS-STAT (maximum score, 105) improved significantly from baseline to posttest (44.8 ± 10.6 [42.7%] vs. 65.3 ± 11.4 [62.2%]; P < 0.001). There was a positive correlation (r = 0.81) between the experience of the test participants and the modified EBUS-STAT scores. Conclusion: This study suggests a multimodal simulation-based curriculum can significantly improve EBUS-guided transbronchial needle aspiration-related knowledge, self-confidence, and procedural skills among novice pulmonary fellows. A validation study is needed to determine if skills attained via a simulator can be replicated in a clinical setting.

Use of phenytoin for treatment of tacrolimus toxicity with superimposed sepsis.

A 40-year-old woman with a history of chronic graft-versus-host-disease on immunosuppression with tacrolimus presented to the hospital with somnolence, confusion and muscle cramps over a few days. She was found to have hypertension, hyperglycaemia and acute kidney injury with an elevated blood tacrolimus level of greater than 120 ng/mL (reference range 5-15 ng/mL). Discontinuation of tacrolimus with concomitant administration of intravenous phenytoin led to the successful reduction of elevated tacrolimus concentrations and the resolution of her symptoms. Tacrolimus is metabolised by the cytochrome P (CYP) 450 3A enzyme system, and utilisation of CYP 3A inducers to accelerate its clearance may be used as a successful therapy to treat tacrolimus toxicity.

Novel One Lung Ventilation Strategy (OLV) for a Patient with Complete Unilateral Endobronchial Obstruction Causing Hypoxic Respiratory Failure.

BACKGROUND Mechanical ventilation strategies for one lung ventilation (OLV) differ from conventional modalities in that it can adapt to greater degrees of ventilation/perfusion (V/Q) mismatch. We present a case of cancer causing complete unilateral endobronchial obstruction with refractory hypoxia that improved with OLV strategy. CASE REPORT Our patient was an elderly male, admitted to our intensive care unit (ICU) on mechanical ventilation with worsening hypoxic respiratory failure secondary to lung mass and post-obstructive atelectasis. The patient developed refractory hypoxia on high conventional ventilator settings. Chest x-ray (CXR) showed opacification on left lung with ipsilateral mediastinal shift. Bronchoscopy revealed complete obstruction of the left main stem bronchus by a fungating mass. OLV strategy was then implemented. The patient had improved hypoxia despite unchanged CXR. CONCLUSIONS We propose that ventilating a patient with a complete unilateral endobronchial obstruction is physiologically similar to ventilating a patient with OLV. In such cases, OLV strategies may improve refractory hypoxia by minimizing V/Q mismatch and should be considered.

New insight into the role of MMP14 in metabolic balance.

Membrane-anchored matrix metalloproteinase 14 (MMP14) is involved broadly in organ development through both its proteolytic and signal-transducing functions. Knockout of Mmp14 (KO) in mice results in a dramatic reduction of body size and wasting followed by premature death, the mechanism of which is poorly understood. Since the mammary gland develops after birth and is thus dependent for its functional progression on systemic and local cues, we chose it as an organ model for understanding why KO mice fail to thrive. A global analysis of the mammary glands' proteome in the wild type (WT) and KO mice provided insight into an unexpected role of MMP14 in maintaining metabolism and homeostasis. We performed mass spectrometry and quantitative proteomics to determine the protein signatures of mammary glands from 7 to 11 days old WT and KO mice and found that KO rudiments had a significantly higher level of rate-limiting enzymes involved in catabolic pathways. Glycogen and lipid levels in KO rudiments were reduced, and the circulating levels of triglycerides and glucose were lower. Analysis of the ultrastructure of mammary glands imaged by electron microscopy revealed a significant increase in autophagy signatures in KO mice. Finally, Mmp14 silenced mammary epithelial cells displayed enhanced autophagy. Applied to a systemic level, these findings indicate that MMP14 is a crucial regulator of tissue homeostasis. If operative on a systemic level, these findings could explain how Mmp14KO litter fail to thrive due to disorder in metabolism.

Preliminary noise reduction efforts in a medical intensive care unit.

Noise is a significant contributor to sleep disruption in the intensive care unit (ICU) that may result in increased patient morbidity such as delirium and prolonged length of stay in ICU. We conducted a pre-post intervention study in a 24-bed tertiary care academic medical ICU to reduce the mean noise levels. Baseline dosimeter recordings of ICU noise levels demonstrated a mean noise level of 54.2 A-weighted decibels (dBA) and peak noise levels of 109.9 dBA, well above the Environmental Protection Agency's recommended levels. There were 1735 episodes of "defects" (maximum noise levels > 60 dBA). Following implementation of multipronged interventions, although the mean noise levels did not change significantly between pre- and post-intervention (54.2 vs 53.8 dBA; p = 0.96), there was a significant reduction in the number of "defects" post-intervention (1735 vs 1289, p ≤ 0.000), and the providers felt that the patients were sleeping longer in the ICU post-intervention.

Circulatory Support with Venoarterial ECMO Unsuccessful in Aiding Endogenous Diltiazem Clearance after Overdose.

Introduction. In cardiovascular collapse from diltiazem poisoning, extracorporeal membrane oxygenation (ECMO) may offer circulatory support sufficient to preserve endogenous hepatic drug clearance. Little is known about patient outcomes and diltiazem toxicokinetics in this setting. Case Report. A 36-year-old woman with a history of myocardial bridging syndrome presented with chest pain for which she self-medicated with 2.4 g of sustained release diltiazem over the course of 8 hours. Hemodynamics and mentation were satisfactory on presentation, but precipitously deteriorated after ICU transfer. She was given fluids, calcium, vasopressors, glucagon, high-dose insulin, and lipid emulsion. Due to circulatory collapse and multiorgan failure including ischemic hepatopathy, she underwent transvenous pacing and emergent initiation of venoarterial ECMO. The peak diltiazem level was 13150 ng/mL (normal 100-200 ng/mL) and it remained elevated at 6340 ng/mL at hour 90. Unfortunately, the patient developed multiple complications which resulted in her death on ICU day 9. Conclusion. This case describes the unsuccessful use of ECMO for diltiazem intoxication. Although past reports suggest that support with ECMO may facilitate endogenous diltiazem clearance, it may be dependent on preserved hepatic function at the time of cannulation, a factor not present in this case.

The use of ECMO in HIV/AIDS with Pneumocystis jirovecii Pneumonia: a case report and review of the literature.

There are few reports of extracorporeal membrane oxygenation (ECMO) therapy for respiratory failure because of Pneumocystis jirovecii pneumonia (PJP) in patients with acquired immunodeficiency syndrome (AIDS). None of the cases reported involvement of immune reconstitution inflammatory syndrome (IRIS), a paradoxical clinical worsening after the initiation of antiretroviral therapy (ART) in ART-naïve patients because of an exaggerated systemic inflammation with cell count recovery. We present a patient with newly diagnosed AIDS and PJP pneumonia that progressed to acute respiratory distress syndrome (ARDS) secondary to probable IRIS for which veno-venous ECMO was initiated. He transitioned to conventional ventilator after 57 days of ECMO therapy. However, he did not survive to hospital discharge. Combined with four previously reported cases of ARDS in human immunodeficiency virus patients secondary to PJP treated with ECMO, three of the five patients survived to ECMO decannulation. Extracorporeal membrane oxygenation is considered an accepted modality for adult patients with respiratory and/or cardiac failure refractory to maximal medical therapy. As ECMO becomes increasingly utilized in clinical practice, there is ongoing controversy regarding the appropriate selection of patients. In the past, contraindications to ECMO included immunocompromised states and conditions with known poor prognosis. The cases herein suggest the indications and contraindications warrant further discussion and research.

Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study.

BACKGROUND: The surviving sepsis guidelines recommend early aggressive fluid resuscitation within 6 h of sepsis onset. Although rapid fluid administration may offer benefit, studies on the timing of resuscitation are lacking. We hypothesized that there is an association between quicker, adequate fluid resuscitation and patient outcome from sepsis onset time. METHODS: This is a retrospective cohort study of consecutive adults with severe sepsis and septic shock admitted to a quaternary care medical ICU between January 2007 and December 2009. Data were collected from a previously validated electronic medical database. Multivariate regression modeling was performed, adjusting for age, admission weight, Sequential Organ Failure Assessment score, APACHE (Acute Physiology and Chronic Health Examination) III score, and total fluid administration within the first 6 h of sepsis onset time. RESULTS: Of 651 patients with severe sepsis and septic shock screened, 594 had detailed fluid data. In a univariate analysis, the median amount of fluid within the first 3 h for survivors at discharge was 2,085 mL (940-4,080 mL) and for nonsurvivors, 1,600 mL (600-3,010 mL; P = .007). In comparison, during the latter 3 h, the median amount was 660 mL (290-1,485 mL) vs 800 mL (360-1,680 mL; P = .09), respectively. After adjusting for confounders, the higher proportion of total fluid received within the first 3 h was associated with decreased hospital mortality (OR, 0.34; 95% CI, 0.15-0.75; P = .008). CONCLUSIONS: Earlier fluid resuscitation (within the first 3 h) is associated with a greater number of survivors with severe sepsis and septic shock.

Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney.

The endoplasmic reticulum (ER) stress response is activated in the diabetic kidney and functions to reduce ER protein accumulation and improve cellular function. We previously showed that tribbles homolog 3 (TRB3), an ER stress-associated protein, is upregulated in the diabetic kidney. Here, we investigated whether absence of TRB3 alters outcomes in diabetic nephropathy. Type 1 diabetes was induced in TRB3 wild-type and knockout ((-/-)) mice by low-dose streptozotocin, and the mice were followed for 12 weeks. Diabetic TRB3(-/-) mice developed higher levels of albuminuria and increased expression of inflammatory cytokine and chemokine mRNA in renal cortices relative to wild-type littermates, despite similar hyperglycemia. Diabetic TRB3(-/-) mice also expressed higher levels of ER stress-associated molecules in both the renal cortices and glomeruli. This change was associated with higher renal cortical phosphorylation of AKT at serine 473 (Ser(473)), which is the AKT site phosphorylated by mammalian target of rapamycin complex-2 (mTORC2). We show in renal tubular cells that TRB3 binds to mTOR and the rapamycin-insensitive companion of mTOR (Rictor), a protein specific to mTORC2. Finally, we demonstrate in murine tubular cells that TRB3 can inhibit secretion of IL-6. Thus, TRB3 reduces albuminuria and inflammatory gene expression in diabetic kidney disease by a mechanism that may involve inhibition of the mTORC2/AKT pathway and may prove to be a novel therapeutic target.

Podocytes express IL-6 and lipocalin 2/ neutrophil gelatinase-associated lipocalin in lipopolysaccharide-induced acute glomerular injury.

BACKGROUND/AIMS: Acute kidney injury (AKI) contributes to significant morbidity and mortality in the intensive care unit (ICU). Plasma levels of interleukin (IL)-6 predict the development of AKI and are associated with higher mortality in ICU patients with AKI. Most studies in AKI have focused on the tubulo-interstitium, despite evidence of glomerular involvement. In the following study, our goals were to investigate the expression of IL-6 and its downstream mediators in septic-induced AKI. METHODS: Podocytes were treated in vitro with lipopolysaccharide (LPS) and mice were treated with LPS, and we evaluated IL-6 expression by real-time PCR, ELISA and in situ RNA hybridization. RESULTS: Following LPS stimulation, IL-6 is rapidly and highly induced in cultured podocytes and in vivo in glomeruli and infiltrating leukocytes. Surprisingly, in direct response to exogenous IL-6, podocytes produce lipocalin-2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal). LPS also potently induces Lcn2/Ngal expression in podocytes in culture and in glomeruli in vivo. Intense Lcn2/Ngal expression is also observed in IL-6 knockout mice, suggesting that while IL-6 may be sufficient to induce glomerular Lcn2/Ngal expression, it is not essential. CONCLUSIONS: The glomerulus is involved in septic AKI, and we demonstrate that podocytes secrete key mediators of AKI including IL-6 and Lcn2/Ngal.

Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study.

BACKGROUND: Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible. METHODS AND FINDINGS: We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001). CONCLUSIONS: Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.

Bleeding complications with Drotrecogin alfa activated (Xigris): a retrospective review of 31 operative and 68 non-operative patients with severe sepsis.

We reviewed 100 consecutive patients who received Drotrecogin alfa (activated) (DAA) (Xigris, Eli Lilly, Indianapolis, IN) for the treatment of severe sepsis and compared the incidence of bleeding complications in surgical (n = 30) and nonsurgical cohorts (n = 70). Thirty patients who received DAA therapy for severe sepsis underwent one or more contemporaneous surgical procedures. These were compared with 70 DAA patients who did not undergo surgery. During the course of DAA administration, transfusion of greater than three units of blood, an intracranial hemorrhage, or other bleeding serious adverse event were qualified as bleeding complications. Overall, we identified seven patients who fulfilled the designated bleeding complication criteria, four in the surgical cohort, and three in the nonsurgical cohort. There was no significant difference in the rate of bleeding complications between surgical and nonsurgical cohorts (P = 0.1063). Moreover, there were no mortalities ascribed to bleeding and there were no intracranial hemorrhage events. All bleeding complications were due to a drop in hemoglobin or platelets only, and were treated with transfusion. Our experience demonstrates that there is an equivalent risk of bleeding for surgical patients treated with DAA compared with nonsurgical patients. Additionally, all bleeding complications were amenable to simple transfusion.

Mitochondrial fission proteins regulate programmed cell death in yeast.

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.