Sudden Vision Loss.

A 37-year-old woman was referred for evaluation of a retinal detachment in her left eye. Posterior examination results demonstrated a retinal detachment in the posterior pole with shifting fluid and no identifiable retinal break, and there was a thickened choroid with a hyporeflective band on ultrasound biomicroscopy. What would you do next?

Extracorporeal Membrane Oxygenation Selection by Multidisciplinary Consensus: The ECMO Council.

Coronavirus disease 2019 (COVID-19) has increased the demand for extracorporeal membrane oxygenation (ECMO) and introduced distinct challenges to patient selection for ECMO. Standardized processes for patient selection amidst resource limitations are lacking, and data on ECMO consults are underreported. We retrospectively reviewed consecutive adult ECMO consults for acute respiratory failure received at a single academic medical center from April 1, 2020, to February 28, 2021, and evaluated the implementation of a multidisciplinary selection committee (ECMO Council) and standardized framework for patient selection for ECMO. During the 334-day period, there were 202 total ECMO consults; 174 (86.1%) included a diagnosis of COVID-19. Among all consults, 157 (77.7%) were declined and 41 (20.3%) resulted in the initiation of ECMO. Frequent reasons for decline included the presence of multiple relative contraindications (n = 33), age greater than 60 years (n = 32), and resource limitations (n = 27). The ECMO Council deliberated on every case in which an absolute contraindication was not present (n = 96) via an electronic teleconference platform. Utilizing multidisciplinary consensus together with a standardized process for patient selection in ECMO is feasible during a pandemic and may be reliably exercised over time. Whether such an approach is feasible at other centers remains unknown.

Simulation Versus Interactive Mobile Learning for Teaching Extracorporeal Membrane Oxygenation to Clinicians: A Randomized Trial.

OBJECTIVES: Extracorporeal membrane oxygenation has become integral to critical care. Data informing optimal extracorporeal membrane oxygenation education modalities are lacking. We aimed to compare the effect of high-fidelity simulation versus interactive mobile learning on extracorporeal membrane oxygenation knowledge acquisition and retention among clinicians. DESIGN: Observer-blinded, randomized controlled trial. SETTING: A single academic medical center. SUBJECTS: Forty-four critical care clinicians with limited extracorporeal membrane oxygenation experience. INTERVENTIONS: Participants were randomized to receive: 1) simulation: three high-fidelity training scenarios, 2) QuizTime: 15 total multiple-choice questions delivered over 3 weeks via mobile device, or 3) experiential: no formal training. Participants completed a survey, written knowledge examination, and simulation assessment prior to randomization, immediately following the intervention, and 4 month postintervention. MEASUREMENTS AND MAIN RESULTS: The primary outcome was knowledge about extracorporeal membrane oxygenation assessed by score on the immediate postintervention written examination. Secondary outcomes included performance in extracorporeal membrane oxygenation simulation postintervention and 4 months later assessed by a rater blinded to group assignment. Clinicians randomized to simulation (n = 15), QuizTime (n = 14), and experiential (n = 15) had similar baseline characteristics. Adjusting for baseline knowledge, postintervention examination scores were higher in the simulation group (90.0%; interquartile range, 85.0-90.0%) than the QuizTime group (70.0%; interquartile range, 65.0-80.0%; p = 0.0003) and the experiential group (75.0%; interquartile range, 65.0-80.0%; p = 0.001). Scores did not differ between the groups at 4 months (p > 0.05 in all analyses). In postintervention extracorporeal membrane oxygenation simulations, the simulation group demonstrated shorter time to critical action compared with QuizTime (80.0 s [interquartile range, 54.0-111.0 s] vs 300.0 s [interquartile range 85.0-300.0 s]; p = 0.02) and compared with both QuizTime (45.0 s [interquartile range, 34.0-92.5 s] vs 255.5 s [interquartile range, 102.0-300.0 s]; p = 0.008) and experiential (300.0 s [interquartile range, 58.0-300.0 s]; p = 0.009) at 4 months. CONCLUSIONS: Simulation was superior to QuizTime and experiential learning with regard to extracorporeal membrane oxygenation knowledge acquisition. Further studies are needed to ascertain the effect of these interventions on knowledge retention, clinical performance, and patient outcomes.

Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

A call for collaboration and consensus on training for endotracheal intubation in the medical intensive care unit.

Endotracheal intubation (EI) is a potentially lifesaving but high-risk procedure in critically ill patients. While the ACGME mandates that trainees in pulmonary and critical care medicine (PCCM) achieve competence in this procedure, there is wide variation in EI training across the USA. One study suggests that 40% of the US PCCM trainees feel they would not be proficient in EI upon graduation. This article presents a review of the EI training literature; the recommendations of a national group of PCCM, anesthesiology, emergency medicine, and pediatric experts; and a call for further research, collaboration, and consensus guidelines.

Echocardiographic Detection of Occult Diastolic Dysfunction in Pulmonary Hypertension After Fluid Challenge.

Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.

Human PAH is characterized by a pattern of lipid-related insulin resistance.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.

Clinical and genetic associations with prostacyclin response in pulmonary arterial hypertension.

Parenteral prostacyclin therapy is the most efficacious pharmacologic treatment for pulmonary arterial hypertension (PAH), but clinical response is variable. We sought to identify clinical, hemodynamic, and genetic associations with response to prostacyclin therapy. We performed a retrospective analysis of patients within a de-identified electronic health record and associated DNA biobank. Patients with PAH and a right heart catheterization (RHC) in the six months before initiation of a parenteral prostacyclin were included. Responders were defined a priori by attainment of World Health Organization (WHO) functional class (FC) 2 or better at the time of repeat RHC within two years. We performed exploratory analyses to identify genomic associations with prostacyclin response. Of 129 patients identified, 54 met our criteria for "responders." These patients were younger, more likely to be male, and were less likely to have connective tissue disease-related PAH. At follow-up, responders had improved hemodynamics, 6-min walk distance, and long-term survival. Baseline PA oxygen saturation (hazard ratio [HR] 0.568 [0.34-0.95]) and follow-up FC (HR = 2.57 [1.22-5.43]) were associated with survival. Prostacyclin responders were enriched in alleles related to cell development and circulatory system development and pathways related to aldosterone metabolism, cAMP signaling, and vascular smooth muscle contraction ( P < 0.001). Age at treatment initiation, WHO FC at short-term follow-up, and PA O2% are associated with survival in patients with PAH exposed to parenteral prostacyclins. Exploratory genetic analysis yielded associations in biologically relevant pathways in the pathogenesis of PAH.

A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg-1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

End-Tidal Carbon Dioxide as a Prognostic Feature in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized in part by increased dead space ventilation, which can be estimated noninvasively at the bedside by measurement of end-tidal CO2 (ETco2). OBJECTIVES: Prior work has demonstrated that ETco2 is lower in patients with PAH than in control patients, but whether ETco2 has prognostic value is unknown. We hypothesized that lower measurements of ETco2 in patients with PAH correlate with worse long-term outcomes. METHODS: Patients with PAH seen in our referral clinic were prospectively recruited for ETco2 measurement between September 2009 and February 2010. Vital status as of July 2015 was documented using medical records and the Social Security Death Index. RESULTS: Eighty-two patients were followed for a median of 60 months. Twenty-six patients died, and two were lost to follow-up. Patients who died were more likely to be older (58.5 ± 14.9 vs. 47.6 ± 12.2 yr; P < 0.05) and to have shorter 6-minute walk distance (296 ± 127 vs. 401 ± 92 m; P < 0.05). Mean ETco2 in survivors was 30.5 ± 4.8 mm Hg, whereas mean ETco2 in patients who died was 27.1 ± 4.2 mm Hg (P = 0.004). After stratification by median baseline ETco2 of 29 mm Hg, survival in each group was analyzed. Patients with lower ETco2 had shorter survival (P = 0.006). Cox regression analysis with ETco2 as a continuous variable revealed the hazard ratio to be 0.88 (95% confidence interval, 0.80-0.97; P = 0.006). In 52 patients with more than one measurement a median of 17 months apart, ETco2 was unchanged. CONCLUSIONS: Our single-center data suggest that lower ETco2 is associated with shorter survival and that ETco2 is stable over time in patients with PAH.

Update on chronic thromboembolic pulmonary hypertension.

Chronic, unresolved thromboemboli are an important cause of pulmonary hypertension (PH) with specific treatment strategies differing from other types of PH. Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group 4 PH by the World Health Organization. It is a rare, but underdiagnosed, complication of acute pulmonary embolism that does not resolve and results in occlusion of large pulmonary arteries with a fibro-thrombotic material. The etiology of CTEPH remains uncertain, and it is unknown why certain patients with acute pulmonary embolism develop this disorder. The evaluation for CTEPH is an important part of the evaluation for PH in general, and it is crucial not to overlook this diagnosis, as it is the only form of PH that is potentially curable. Patients diagnosed with CTEPH should be referred to an expert center for consideration of pulmonary endarterectomy, and surgical removal of the chronic thromboembolic material. Not all patients with CTEPH are surgical candidates, however, and there are emerging treatments-medical therapy and balloon pulmonary angioplasty-that have shown benefit in this patient population. Without treatment, CTEPH can lead to progressive pulmonary vascular obstruction, right heart failure, and death. Thus, it is important for clinicians to recognize this subtype of PH. In this review, we provide an overview of current understanding of the pathogenesis of CTEPH and highlight recommendations and recent advances in the evaluation and treatment of CTEPH.

Severity of pulmonary hypertension and obesity are not associated with worse functional outcomes after pulmonary thromboendarterectomy.

Predictors of functional outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary thromboendarterectomy (PTE) are important to identify preoperatively. We hypothesized that baseline severity of pulmonary hypertension and obesity would not be associated with 6-month functional outcomes after PTE. Clinical and hemodynamic data were collected on consecutive patients undergoing PTE from 2008 to 2014. Patients were stratified according to baseline pulmonary vascular resistance (PVR) and body mass index (BMI). Six-minute walk distance (6MWD), New York Heart Association functional class (FC), and echocardiography were assessed in each group at baseline and 6 months after PTE. Regression analyses were performed to evaluate for associations between functional outcomes and baseline PVR and BMI. Forty-two patients underwent PTE and had 6-month follow up data. In comparisons of patients with high and low baseline PVR, the baseline characteristics, distribution of disease, 6MWD, and FC were similar. Postoperative hemodynamics for both groups were similar. At 6 months, both groups achieved improvements in FC, and there were no between-group differences in the change in 6MWD or FC. In comparisons of obese and nonobese patients, perioperative and FC improvement were similar; however, obese patients achieved a greater improvement in 6MWD than nonobese patients (P = 0.04). In conclusion, our data suggest that baseline severity of CTEPH and obesity were not associated with worse functional outcome. Further studies are needed to confirm these results, as these findings could have implications for patient selection for PTE.

Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension.

BACKGROUND: The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. METHODS AND RESULTS: We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4±1.3% triglyceride versus 0.22±0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV. CONCLUSIONS: Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation.

Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension and associated right ventricular (RV) dysfunction are important determinants of morbidity and mortality, which are optimally characterized by invasive hemodynamic measurements. OBJECTIVES: This study sought to determine whether metabolite profiling could identify plasma signatures of right ventricular-pulmonary vascular (RV-PV) dysfunction. METHODS: We measured plasma concentrations of 105 metabolites using targeted mass spectrometry in 71 individuals (discovery cohort) who underwent comprehensive physiological assessment with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise. Our findings were validated in a second cohort undergoing invasive hemodynamic evaluations (n = 71), as well as in an independent cohort with or without known pulmonary arterial (PA) hypertension (n = 30). RESULTS: In the discovery cohort, 21 metabolites were associated with 2 or more hemodynamic indicators of RV-PV function (i.e., resting right atrial pressure, mean PA pressure, pulmonary vascular resistance [PVR], and PVR and PA pressure-flow response [ΔPQ] during exercise). We identified novel associations of RV-PV dysfunction with circulating indoleamine 2,3-dioxygenase (IDO)-dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites and confirmed previously described associations with arginine-nitric oxide metabolic pathway constituents. IDO-TM levels were inversely related to RV ejection fraction and were particularly well correlated with exercise PVR and ΔPQ. Multisite sampling demonstrated transpulmonary release of IDO-TMs. IDO-TMs also identified RV-PV dysfunction in a validation cohort with known risk factors for pulmonary hypertension and in patients with established PA hypertension. CONCLUSIONS: Metabolic profiling identified reproducible signatures of RV-PV dysfunction, highlighting both new biomarkers and pathways for further functional characterization.

Parenteral Prostanoid Use at a Tertiary Referral Center: A Retrospective Cohort Study.

BACKGROUND: Evidence-based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many patients with PAH die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize patients with PAH who died without receiving PP. METHODS: We conducted a single-center retrospective cohort analysis of consecutive patients with PAH between 2008 and 2012. Clinical data and cause of death were compared between patients with PAH treated with PP (PAH-PP) and those who were not but were not documented as poor PP candidates (PAH-nonPP). RESULTS: Of the 101 patients who received a diagnosis of PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) whereas 30 were not considered candidates or refused PP therapy. Compared with PAH-PP, PAH-nonPP had a longer 6-min walk distance, had a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be diagnosed as functional class IV, and had significantly lower right atrial pressure. None of the PAH-nonPP died of progressive PAH. CONCLUSIONS: We found that most patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH-related causes. Our data suggest that at large pulmonary hypertension (PH) centers, the vast majority of patients who are appropriate candidates receive PP therapy.

Use of pulmonary arterial hypertension-approved therapy in the treatment of non-group 1 pulmonary hypertension at US referral centers.

Pulmonary hypertension (PH) is a frequent complication of left heart disease and parenchymal lung disease, and it portends increased mortality. A growing number of medications are approved for the treatment of World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH). However, they are not well studied in PH of other etiologies (WHO groups 2-5). We sought to assess treatment approaches used by PAH referral centers in this diverse group of patients. We developed a semiquantitative online survey designed to evaluate the use of PAH-approved therapy by pulmonary vascular disease centers in the United States for management of non-group 1 PH. Thirty of 50 centers completed the survey. Almost all centers (93%) reported using PAH therapy for patients with non-group 1 PH, including 77% with group 2 PH and 80% with group 3 PH. Elevated transpulmonary gradient or pulmonary vascular resistance and the presence of right ventricular (RV) dysfunction were commonly cited as supporting use of PAH therapy in patients with PH secondary to left heart disease. For patients with PH and concomitant parenchymal lung disease, degree of pulmonary function impairment and RV dysfunction were most important in influencing use of PAH therapy. In conclusion, pulmonary vascular disease treatment centers use PAH-approved therapy for patients with WHO group 2-5 PH, mostly relying on hemodynamics and assessment of RV function to identify candidates for therapy. Clinical trials designed to test the efficacy of PAH therapy in PH due to left heart and lung disease are needed, as clinical practice has extended beyond the evidence for these etiologies of PH.

A randomized trial comparing didactics, demonstration, and simulation for teaching teamwork to medical residents.

RATIONALE: Effective teamwork is fundamental to the management of medical emergencies, and yet the best method to teach teamwork skills to trainees remains unknown. OBJECTIVES: In a cohort of incoming internal medicine interns, we tested the hypothesis that expert demonstration of teamwork principles and participation in high-fidelity simulation would each result in objectively assessed teamwork behavior superior to traditional didactics. METHODS: This was a randomized, controlled, parallel-group trial comparing three teamwork teaching modalities for incoming internal medicine interns. Participants in a single-day orientation at the Vanderbilt University Center for Experiential Learning and Assessment were randomized 1:1:1 to didactic, demonstration-based, or simulation-based instruction and then evaluated in their management of a simulated crisis by five independent, blinded observers using the Teamwork Behavioral Rater score. Clinical performance was assessed using the American Heart Association Advanced Cardiac Life Support algorithm and a novel "Recognize, Respond, Reassess" score. MEASUREMENTS AND MAIN RESULTS: Participants randomized to didactics (n = 18), demonstration (n = 17), and simulation (n = 17) were similar at baseline. The primary outcome of average overall Teamwork Behavioral Rater score for those who received demonstration-based training was similar to simulation participation (4.40 ± 1.15 vs. 4.10 ± 0.95, P = 0.917) and significantly higher than didactic instruction (4.40 ± 1.15 vs. 3.10 ± 0.51, P = 0.045). Clinical performance scores were similar between the three groups and correlated only weakly with teamwork behavior (coefficient of determination [Rs(2)] = 0.267, P < 0.001). CONCLUSIONS: Among incoming internal medicine interns, teamwork training by expert demonstration resulted in similar teamwork behavior to participation in high-fidelity simulation and was more effective than traditional didactics. Clinical performance was largely independent of teamwork behavior and did not differ between training modalities.