Benjamin D. Singer

Prompting physicians to address a daily checklist and process of care and clinical outcomes: A single-site study

RATIONALE Checklists may reduce errors of omission for critically ill patients. OBJECTIVES To determine whether prompting to use a checklist improves process of care and clinical outcomes. METHODS We conducted a cohort study in the medical intensive care unit (MICU) of a tertiary care university hospital. Patients admitted to either of two independent MICU teams were included. Intervention team physicians were prompted to address six parameters from a daily rounding checklist if overlooked during morning work rounds. The second team (control) used the identical checklist without prompting. MEASUREMENTS AND MAIN RESULTS One hundred and forty prompted group patients were compared with 125 control and 1,283 preintervention patients. Compared with control, prompting increased median ventilator-free duration, decreased empirical antibiotic and central venous catheter duration, and increased rates of deep vein thrombosis and stress ulcer prophylaxis. Prompted group patients had lower risk-adjusted ICU mortality compared with the control group (odds ratio, 0.36; 95% confidence interval, 0.13-0.96; P = 0.041) and lower hospital mortality compared with the control group (10.0 vs. 20.8%; P = 0.014), which remained significant after risk adjustment (odds ratio, 0.34; 95% confidence interval, 0.15-0.76; P = 0.008). Observed-to-predicted ICU length of stay was lower in the prompted group compared with control (0.59 vs. 0.87; P = 0.02). Checklist availability alone did not improve mortality or length of stay compared with preintervention patients. CONCLUSIONS In this single-site, preliminary study, checklist-based prompting improved multiple processes of care, and may have improved mortality and length of stay, compared with a stand-alone checklist. The manner in which checklists are implemented is of great consequence in the care of critically ill patients.

Regulatory T cells as immunotherapy

Regulatory T cells (Tregs) suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed an intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes – autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation – may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease.

Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

First-year residents outperform third-year residents after simulation-based education in critical care medicine.

Introduction Previous research shows that gaps exist in internal medicine residents’ critical care knowledge and skills. The purpose of this study was to compare the bedside critical care competency of first-year residents who received a simulation-based educational intervention plus clinical training with third-year residents who received clinical training alone. Methods During their first 3 months of residency, a group of first-year residents completed a simulation-based educational intervention. A group of traditionally trained third-year residents who did not receive simulation-based training served as a comparison group. Both groups were evaluated using a 20-item clinical skills assessment at the bedside of a patient receiving mechanical ventilation at the end of their medical intensive care unit rotation. Scores on the skills assessment were compared between groups. Results Simulator-trained first-year residents (n = 40) scored significantly higher compared with traditionally trained third-year residents (n = 27) on the bedside assessment (91.3% [95% confidence interval, 88.2%–94.3%] vs. 80.9% [95% confidence interval, 76.8%–85.0%]; P < 0.001). Conclusions First-year residents who completed a simulation-based educational intervention demonstrated higher clinical competency compared with third-year residents who did not undergo simulation training. Critical care competency cannot be assumed after clinical intensive care unit rotations; simulation-based curricula can help ensure residents are proficient to care for critically ill patients.

Foxp3 + regulatory T cells promote lung epithelial proliferation

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3+ regulatory T cells (Foxp3+ Treg cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3+ Treg cells in the lung during the course of resolution. To dissect the role that Foxp3+ Treg cells exert on epithelial proliferation, we depleted Foxp3+ Treg cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3+ Treg numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3+ Treg cells enhanced epithelial proliferation. Moreover, Foxp3+ Treg cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3+ Treg cells in repair of the lung epithelium.

Basic Invasive Mechanical Ventilation

Invasive mechanical ventilation is a lifesaving intervention for patients with respiratory failure. The most commonly used modes of mechanical ventilation are assist-control, synchronized intermittent mandatory ventilation, and pressure support ventilation. When employed as a diagnostic tool, the ventilator provides data on the static compliance of the respiratory system and airway resistance. The clinical scenario and the data obtained from the ventilator allow the clinician to provide effective and safe invasive mechanical ventilation through manipulation of the ventilator settings. While life-sustaining in many circumstances, mechanical ventilation may also be toxic and should be withdrawn when clinically appropriate.

Progress toward improving medical school graduates' skills via a "boot camp" curriculum.

Introduction Medical school graduates are expected to possess a broad array of clinical skills. However, concerns have been raised regarding the preparation of medical students to enter graduate medical education. We designed a simulation-based “boot camp” experience for students entering internal medicine residency and compared medical student performance with the performance of historical controls who did not complete boot camp. Methods This was a cohort study of a simulation-based boot camp educational intervention. Twenty medical students completed 2 days (16 hours) of small group simulation-based education and individualized feedback and skills assessment. Skills included (a) physical examination techniques (cardiac auscultation); technical procedures including (b) paracentesis and (c) lumbar puncture; (d) recognition and management of patients with life-threatening conditions (intensive care unit clinical skills/mechanical ventilation); and (e) communication with patients and families (code status discussion). Student posttest scores were compared with baseline scores of postgraduate year 1 (PGY-1) historical controls to assess the effectiveness of the intervention. Results Boot camp–trained medical students performed significantly better than PGY-1 historical controls on each simulated skill (P < 0.01). Results remained significant after controlling for age, sex, and US Medical Licensing Examination step 1 and 2 scores (P < 0.001). Conclusions A 2-day simulation-based boot camp for graduating medical students boosted a variety of clinical skills to levels significantly higher than PGY-1 historical controls. Simulation-based education shows promise to help ensure that medical school graduates are prepared to begin postgraduate training.

Molecular and physiological manifestations and measurement of aging in humans.

Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time‐dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age‐related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well‐described molecular and cellular hallmarks and discuss physiological changes of aging at the organ‐system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging.

Retention of critical care skills after simulation-based mastery learning.

BACKGROUND Whether cognitive and patient care skills attained during simulation-based mastery learning (SBML) are retained is largely unknown. OBJECTIVE We studied retention of intensive care unit (ICU) clinical skills after an SBML boot camp experience. METHODS Forty-seven postgraduate year (PGY)-1 residents completed SBML intervention designed to increase procedural, communication, and patient care skills. The intervention included ICU skills such as ventilator and hemodynamic parameter management. Residents were required to meet or exceed a minimum passing score (MPS) on a clinical skills examination before starting actual patient care. Skill retention was assessed in 42 residents who rotated in the medical ICU. Residents received a standardized 15-minute booster teaching session reviewing key concepts during the first week of the rotation. During the fourth week of their rotation, PGY-1 residents completed a clinical skills examination at the bedside of an actual ICU patient. Group mean examination scores and the proportion of subjects who met or exceeded the MPS at each testing occasion were compared. RESULTS Residents scored a mean 90% (SD  =  6.5%) on the simulated skills examination immediately after training. Residents retained skills obtained through SBML as the mean score at bedside follow-up testing was 89% (SD  =  8.9%, P  =  .36). Thirty-seven of 42 (88%) PGY-1 residents met or exceeded the MPS at follow-up. CONCLUSION SBML leads to substantial retention of critical care knowledge, and patient care skills PGY-1 boot camp is a highly efficient and effective model that can be administered at the beginning of the academic year.

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming.

Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.