Rachel K. Wolfson

Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control.

Objective To determine the effect of intravenous glutamine supplementation vs. an isonitrogenous control on infectious morbidity in severely burned patients. Previous clinical studies in seriously ill patients suggest a beneficial effect of glutamine on infectious morbidity, but no trials have examined possible clinical benefits in severely burned patients. Design Prospective, double-blind, randomized trial. Setting Burn intensive care unit of a university hospital. Patients Twenty-six severe burn patients with total burn surface area of 25% to 90% and presence of full-thickness burns. Patients were evaluated for occurrence of bacteremia and antibiotic use during the first 30 days of their burn unit admission. Nutritional status and overall inflammation were also measured. Intervention Either intravenous glutamine or an isonitrogenous control amino acid solution was administered as a continuous infusion during burn intensive care unit stay. Measurements and Main Results The incidence of Gram-negative bacteremia was significantly reduced in the glutamine-supplemented group (8%) vs. control (43%;p < .04). No difference was seen in the incidence of Gram-positive bacteremia or fungemia. Average number of positive blood cultures, antibiotic usage, and mortality rates also were reduced but did not reach statistical significance. Significant improvements in serum transferrin and prealbumin were observed in glutamine-supplemented patients at 14 days after burn injury (p < .01 and .04, respectively). C-reactive protein was also significantly reduced at 14 days after burn injury in the glutamine group (p < .01). Conclusions Significantly fewer bacteremic episodes with Gram-negative organisms occurred in the glutamine-supplemented patients. Glutamine supplementation improved measures of nutrition and decreased measures of overall inflammation. In addition, a trend toward lower mortality rate, decreased overall bacteremia incidence, and antibiotic usage in the glutamine group was observed. Glutamine’s beneficial effects may be a result of improved gut integrity or immune function, but the precise mechanism of glutamine’s protection is unknown.

Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia

Clinical trials have demonstrated that glutamine (GLN) supplementation can decrease infectious morbidity and improve survival in a number of settings of critical illness. The mechanism of this protection remains unclear. The objective of this study was to evaluate the effect of GLN on cytokine release, organ injury, and survival from endotoxin-induced septic shock. Endotoxemia was induced in Male Sprague-Dawley rats by intravenous administration of 5 mg/kg Escherichia coli lipopolysaccharide (LPS). Concomitantly, animals were fluid resuscitated with a lactated ringers (LR) solution and given GLN (0.75 g/kg i.v.) or LR alone. Blood samples were obtained at multiple time points post-LPS injury for cytokine analysis. Survival rates were monitored for 72 h. Organ injury was evaluated in a separate set of animals via pathologic exam of tissues harvested 6 h post-LPS injury. A single dose of GLN significantly attenuated the release of TNF-alpha at 2 h (P < 0.005) and IL-1 beta at 4 h (P < 0.0001). This attenuation of cytokine release was associated with a significant decrease in mortality (P < 0.003). Pathologic exam demonstrated significant protection of both lung and small bowel tissue by GLN. Blood gas values 6-h post-LPS injury showed increased PaO2 and bicarbonate concentration in GLN treated animals. These data indicate that GLN can significantly attenuate pro-inflammatory cytokine release, protect against end-organ damage, and decrease mortality from endotoxemia. GLN confers protection even when administered at the onset of endotoxemia, rather then as pre-treatment. Thus, one explanation for the clinical benefits observed from GLN-supplementation may be related to the attenuation of pro-inflammatory cytokines.

HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption

Acute lung injury (ALI) results from loss of alveolar-capillary barrier integrity and the evolution of high-permeability pulmonary edema resulting in alveolar flooding and significant morbidity and mortality. HMGB1 is a late mediator of sepsis which uniquely participates in the evolution of sepsis and sepsis-induced ALI. The molecular events by which HMGB1 contributes to ALI remain poorly characterized. We characterized the role of HMGB1 in endothelial cell (EC) cytoskeletal rearrangement and vascular permeability, events essential to paracellular gap formation and barrier dysfunction characteristic of ALI. Initial experiments demonstrated HMGB1-mediated dose-dependent (5-20 μg/ml) decreases in transendothelial cell electrical resistance (TER) in the human pulmonary artery EC, a reflection of loss of barrier integrity. Furthermore, HMGB1 produced dose-dependent increases in paracellular gap formation in concert with loss of peripheral organized actin fibers, dissociation of cell-cell junctional cadherins, and the development of central stress fibers, a phenotypic change associated with increased contractile activity and increased EC permeability. Using siRNA strategies directed against known HMGB1 receptors (RAGE, TLR2, TLR4), we systematically determined that the receptor for advanced glycation end products (RAGE) is the primary receptor signaling HMGB1-induced TER decreases and paracellular gap formation via p38 MAP kinase activation and phosphorylation of the actin-binding protein, Hsp27. These studies add to the understanding of HMGB1-induced inflammatory events and vascular barrier disruption and offer the potential for clinical intervention in sepsis-induced ALI.

Extracorporeal membrane oxygenation after stem cell transplant: clinical decision-making in the absence of evidence.

Objective: To discuss the ethical dilemmas that arise in considering innovative therapies for critically ill children when there is little data to support their use. Design: Case report of a 13-yr-old patient after autologous peripheral blood stem cell transplant for stage III neuroblastoma with sepsis and hemodynamic instability who survived to discharge after a 6-day course of extracorporeal membrane oxygenation (ECMO) support. The case serves as a source of discussion of the following: the use of available data in deciding to proceed with an unproved therapy, the approach to conversations to obtain informed consent, and the need for institutional oversight and hypothesis-driven data collection to advance pediatric critical care. Setting: Pediatric intensive care unit at a university hospital. Patient: One adolescent with stage III neuroblastoma. Results: Despite a lack of data to support the use of ECMO in a neutropenic oncology patient after autologous peripheral blood stem cell transplant, our patient had clinical features that suggested he was a reasonable ECMO candidate. His family gave informed consent to use ECMO and he survived. It is ethical to consider and use innovative therapies when patient characteristics are suggestive that the therapy may be successful even in the absence of evidence. This requires physicians’ attention to the best interest of the patient and should occur in the setting of informed consent and rigorous data collection. Conclusions: The boundaries among standard therapy, innovative therapy, and research can be quite fluid. This case illustrates the ethical imperative to consider therapies that may be appropriate for a critically ill child even without evidence predictive of success, to have entry criteria and treatment protocols for such therapies, and to collect data from such experiences to advance the standard of care.

Excessive mechanical stress increases HMGB1 expression in human lung microvascular endothelial cells via STAT3

Ventilator-induced lung injury (VILI) occurs when the lung parenchyma and vasculature are exposed to repetitive and excessive mechanical stress via mechanical ventilation utilized as supportive care for the adult respiratory distress syndrome (ARDS). VILI induces gene expression and systemic release of inflammatory mediators that contribute to the multi-organ dysfunction and morbidity and mortality of ARDS. HMGB1, an intracellular transcription factor with cytokine properties, is a late mediator in sepsis and ARDS pathobiology, however, the role of HMGB1 in VILI remains poorly described. We now report HMGB1 expression in human lung microvessel endothelial cells (ECs) exposed to excessive, equibiaxial mechanical stress, an in vitro correlate of VILI. We determined that high amplitude cyclic stretch (18% CS) increased HMGB1 expression (2-4-fold) via a signaling pathway with critical involvement of the transcription factor, STAT3. Concomitant exposure to 18% CS and oxidative stress (H₂O₂) augmented HMGB1 expression (~13 fold increase) whereas lipopolysaccharide (LPS) challenge increased HMGB1 expression in static EC, but not in 18% CS-challenged EC. In contrast, physiologic, low amplitude cyclic stretch (5% CS) attenuated both oxidative H₂O₂- and LPS-induced increases in HMGB1 expression, suggesting that physiologic mechanical stress is protective. These results indicate that HMGB1 gene expression is markedly responsive to VILI-mediated mechanical stress, an effect that is augmented by oxidative stress. We speculate that VILI-induced HMGB1 expression acts locally to increase vascular permeability and alveolar flooding, thereby exacerbating systemic inflammatory responses and increasing the likelihood of multi-organ dysfunction.

Changing the “Working While Sick” Culture: Promoting Fitness for Duty in Health Care

The recent Ebola outbreak has drawn attention to the threat of spreading communicable disease between patients and health care workers. However, other infectious diseases are much more prevalent: for instance, a disease like influenza represents a more common cause of morbidity and mortality among patients in the United States and is more likely to be transmitted between patients and health care workers. The risk of health care workers infecting patients is real because many health care workers tend to continue working when they are ill, a finding documented in the report by Szymczak and colleagues1 in the September 2015 issue of JAMA Pediatrics. Based on a survey of 536 clinicians, Szymczak et al found 83% reportedly continued to work even while they were ill. More than half (55.6%) reported that they continued working while having acute onset of significant respiratory symptoms, as did 30% with diarrhea and 16% with fevers.1 Prior studies have described this phenomenon, dubbed “presenteeism,” in which health care workers report to work despite feeling ill or not well rested.2 In one prior study, 57.9% of resident physicians reported working while sick at least once.2 The study by Szymczak et al1 confirmed that the problem persists after training is finished, with attending physicians continuing to work while they are ill. Although this commitment to patient care may be commendable, health care workers who are ill impose risks to patients. The contradiction between dedication to patient care and risking transmission of disease to patients requires more in-depth understanding.3 Szymczak et al1 found that 1 reason clinicians continue to work while they are ill relates to their fear of disappointing Related article at jamapediatrics.com JAMA PEDIATRICS

Goals of medical students participating in scholarly concentration programmes

Scholarly concentration (SC) programmes are increasingly common in medical school curricula, fostering student participation in mentored research. Endpoints including publication rates and impact on career path have been reported, but student goals have not been described. We describe how career plans and gender impact the importance of students’ SC‐related goals. Understanding student goals may enhance mentorship of professional development and self‐directed learning skills.

The physician‐scientist pipeline: return on investment

1 Larsen DP, Butler AC, Roediger HL III. Test-enhanced learning in medical education. Med Educ 2008;42 (10):959–66. 2 Kromann CB, Jensen ML, Ringsted C. The effect of testing on skills learning. Med Educ 2009;43 (1):21–7. 3 Dobson J, Linderholm T, Perez J. Retrieval practice enhances the ability to evaluate complex physiology information. Med Educ 2018;52 (5):513–25. 4 Baghdady M, Carnahan H, Lam EWN, Woods NN. Test-enhanced learning and its effect on comprehension and diagnostic accuracy. Med Educ 2014;48 (2):181–8. 5 Dobson JL, Linderholm T. Selftesting promotes superior retention of anatomy and physiology information. Adv Health Sci Educ Theory Pract 2015;20 (1):149–61. 6 Endres T, Renkl A. Mechanisms behind the testing effect: an empirical investigation of retrieval practice in meaningful learning. Front Psychol 2015;6:1054. 7 Rickard TC, Pan SC. A dual memory theory of the testing effect. Psychon Bull Rev 2017. https://doi.org/10.3758/s13423017-1298-4. [Epub ahead of print.] 8 Vasilopoulos T, Chau DF, Bensalem-Owen M, Cibula JE, Fahy BG. Prior podcast experience moderates improvement in electroencephalography evaluation after educational podcast module. Anesth Analg 2015;121 (3):791–7. 9 Spreckelsen C, Juenger J. Repeated testing improves achievement in a blended learning approach for risk competence training of medical students: results of a randomised controlled trial. BMC Med Educ 2017;17 (1):177. 10 Wojcikowski K, Kirk L. Immediate detailed feedback to test-enhanced learning: an effective online educational tool. Med Teach 2013;35 (1):915–9. 11 Tse CS, Pu X. The effectiveness of test-enhanced learning depends on trait test anxiety and workingmemory capacity. J Exp Psychol Appl 2012;18 (3):253–64.

More on Promoting Medical Student Scholarly Research.

On the basis of one study which found an association between publication rate and course component duration, the authors of the review recommend more curricular research time and propose that mandatory and elective components have similar effects. We suggest that many other factors may account for these findings. Furthermore, we suggest a more theoretically informed and contextualized approach to understanding student experiences in research. In a recent study, we found that the impact of a mandatory research component in a researchnaive population, where only 7.4% of students reported prior research experience, could be explained with Self-Determination Theory. Motivation to do research could thus be promoted with targeted educational strategies, without need for more curricular time.

RESPIRATORY ARREST IN A PATIENT WITH MEDIASTINAL MASS- CALL ECMO: 643

JL is a 13 yo asthmatic with 1 week of wheezing which was treated at an outside hospital with prednisone and albuterol. No CXR was done. His symptoms persisted and he was admitted to the University of Chicago Children’s Hospital for persistent dyspnea where his first CXR showed a large mediastinal mass. CT scan confirmed compression of the trachea and both mainstem bronchi. His dyspnea worsened when supine. He had mild inspiratory stridor and expiratory wheezing when upright. Biopsy of supraclavicular lymphadenopathy was planned. On Day 2, JL had a respiratory arrest and a generalized seizure. Bag-valve mask ventilation was begun. JL went emergently to the OR to secure an airway. En route, JL became progressively more difficult to ventilate and oxygenate. In the OR, JL had deep desaturations and was intolerant of any time without positive-pressure ventilation. His arterial pH was 6.6. His right femoral vessels were emergently cannulated and he was put on ECMO. Once ECMO flow was established he was intubated using rigid bronchoscopy. He had fishmouth compression of the trachea from the glottis to the carina. On ECMO, he went urgently to radiation oncology (XRT) for treatment of presumed lymphoma. After XRT he went to the PICU where he had hypotension, poor LV function, and poor RV inflow. A second venous cannula was placed in the right IJ which produced significant improvement in MAP and ECMO flow. Lymph node biopsy taken at that time showed lymphoblastic lymphoma. Radiation and chemotherapy began. JL was on ECMO for 5 days and was extubated 7 days thereafter. The risk of anesthesia in children with mediastinal masses is well described. Several authors suggest cannulation of the femoral vessels prior to anesthesia to facilitate rapid transition to cardiopulmonary bypass if airway obstruction occurs. The inability to overcome JL’s airway obstruction with bag-valve mask ventilation and the compression of his distal trachea prompted the decision to proceed rapidly to ECMO as a lifesaving maneuver.