Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial.

OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. RESULTS: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). CONCLUSIONS: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography. CLINICAL TRIAL REGISTRATION: NCT01939301.

Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.

BACKGROUND: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone. METHODS: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and ß=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy. RESULTS: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO. CONCLUSIONS: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.

Role of physician perception of patient smile on pretest probability assessment for acute pulmonary embolism.

BACKGROUND: Many clinicians use a global visual interpretation of patient appearance to decide if a patient looks sick or not. For patients with suspected acute pulmonary embolism (PE), we tested the relationship between visual appearance of a happy patient facial affect and probability of PE+ on CT pulmonary angiography (CTPA). METHODS: Eligible patients were selected by usual care to undergo CTPA, the criterion standard for PE+ or PE-. Prior to CTPA result, trained study personnel obtained physician pretest probability using the gestalt method (visual analogue scale, 0%-100%), the Wells score (0-12) and physicians' impression of whether the patient smiled during the initial examination (smile+). Patients' faces were also video recorded and analysed with an automated neural network-based algorithm (Noldus FaceReader) for happy affect. RESULTS: Of the 208 patients enrolled, 27 were PE+ and smile+ was more frequent in patients with PE+ than PE-, a finding confirmed by the Noldus. The diagnostic sensitivity and specificity of smile was low, and physicians overestimated presence of an alternative diagnosis more likely to PE with smile+ than smile- patients in patients with true PE. As a result, the area under the receiver operating characteristic curve (AUROC) was lower for the Wells score in smile+ patients. However, the physicians' mean gestalt estimate of PE did not differ with smile status, nor did smile status affect the AUROC for gestalt. CONCLUSIONS: In patients with suspected PE, physician recollection of patients' smile+ was more common in PE+ patients, and was associated with a less accurate Wells score, primarily because physicians overestimated probability of alternative diagnosis. However, the overall diagnostic accuracy of physicians' gestalt did not differ with perceived smile status. These data suggest that the patients' smile had less effect on the numeric gestalt pretest probability assessment than on the binary decision about an alternative diagnosis.

Perception of Physician Empathy Varies With Educational Level and Gender of Patients Undergoing Low-Yield Computerized Tomographic Imaging.

OBJECTIVE: Lack of empathic communication between providers and patients may contribute to low value diagnostic testing in emergency care. Accordingly, we measured the perception of physician empathy and trust in patients undergoing low-value computed tomography (CT) in the emergency department (ED). METHODS: Multicenter study of ED patients undergoing CT scanning, acknowledged by ordering physicians as unlikely to show an emergent condition. Near the end of their visit, patients completed the Jefferson Scale of Patient Perception of Physician Empathy (JSPPPE), Trust in Physicians Survey (TIPS), and the Group Based Medical Mistrust Scale (GBMMS). We stratified results by patient demographics including gender, race, and education. RESULTS: We enrolled 305 participants across 9 sites with diverse geographic, racial, and ethnic representation. The median scores (interquartile ranges) for the JSPPPE, TIPS, and GBMMS for all patients were 29 (24-33.5), 55 (47-62), and 18 (12-29). Compared with white patients, nonwhite patients had similar JSPPPE and TIPS scores but had higher (worse) GBMMS scores. Females had significantly lower JSPPPE and TIPS scores than males, and scores were lower (worse) in females with college degrees. Patients in the lowest tier of educational status had the highest (better) JSPPPE and TIPS scores. Scores were invariant with physician characteristics. CONCLUSION: Among patients undergoing low-value CT scanning in the ED, the degree of patient perception of physician empathy and trust varied based on the patients' level of education and gender. Given this variation, an intervention to increase patient perception of physician empathy should contain individualized strategies to address these subgroups, rather than a one-size-fits-all approach.

Clinical characteristics of children evaluated for suspected pulmonary embolism with D-dimer testing.

BACKGROUND: We sought to determine clinical variables in children tested for suspected pulmonary embolism (PE) that predict PE+ outcome for the development of paediatric PE prediction rule. METHODS: Data were collected by query of a laboratory database for D-dimer from January 2004 to December 2014 for a large multicentre hospital system and the radiology database for pulmonary vascular imaging in children aged 5-17. Using explicit, predefined methods, trained abstractors, determined if D-dimer was sent in the evaluation of PE and then recorded predictor data which was tested for association with PE+ outcome using univariate techniques. RESULTS: D-dimer was ordered in 526 children for clinical suspicion of PE. Thirty-four of 526 were PE+ (6.4%, 95% CI 4.3% to 8.7%). The radiology database identified 17 additional patients with PE (n=51 PE+ total). Children evaluated for PE were primarily in the ED setting (80%), teenagers (88%) and 2:1 female:male. Children with PE had higher mean heart and higher respiratory rate and a lower pulse oximetry and haemoglobin concentration. On univariate analysis, five conditions were more frequent in PE+ compared with no PE: surgery, central line, limb immobility, prior PE or deep vein thrombosis and cancer. CONCLUSIONS: The rate of PE diagnosis in children with D-dimer was 6.4%, similar to that seen in adults; most children with PE are over 13 years and had clinical predictors known to increase probability of PE in symptomatic adults. Future studies should use these criteria to develop a clinical decision rule for PE in children.

Diagnostic accuracy of the D-dimer in children.

BACKGROUND: We sought to measure the diagnostic accuracy of D-dimer in children with suspected pulmonary embolism (PE). METHODS: We queried our electronic medical record for quantitative D-dimer values obtained in all children ages 5-17 over 10 years in our 10-hospital system. Patients who had a D-dimer obtained in the evaluation of PE underwent supervised chart review to extract baseline demographics (age, sex, ethnicity), medical history, laboratory data and imaging results. PE was confirmed by imaging positive for deep vein thrombosis (DVT) or PE and excluded by imaging or no DVT or PE diagnosis within 90 days. RESULTS: Over a 10-year period, we identified 13 792 orders for D-dimer testing in 2554 unique patients. Chart review indicated that 526 (20.6%) unique patients had D-dimer testing performed in the evaluation of PE (Cohen's kappa=0.95, 95% CI 0.85 to 1.0). Most D-dimers (465/526, 88%) were ordered in children aged >12 years. Of these 526 children, 34 (6.4%, 95% CI) had a criterion standard positive for new or recurrent PE. The mean D-dimer value was 2104±1394 ng/mL in the 34/34 PE+ children and 586±962 ng/mL in PE- children with a sensitivity of 34/34 (100%, 89% to 100%) and a specificity of 290/492 (58%, 54% to 63%). The area under the receiver operating characteristic curve was 0.90 ((0.9)87-0.94). CONCLUSIONS: D-dimer is currently ordered in children for suspected PE in the emergency care setting, mostly in teenagers. The observed lower limit 95% CIs of 89% and 54% for diagnostic sensitivity and the specificity, respectively, suggest if used in patients with low-clinical probability, a normal D-dimer can safely exclude PE in children.

Evaluation of the pulmonary embolism rule out criteria (PERC rule) in children evaluated for suspected pulmonary embolism.

BACKGROUND: The pulmonary embolism rule out criteria (PERC) reliably predicts a low probability of PE in adults. We examine the diagnostic accuracy of the objective components of the PERC rule in children previously tested for PE. METHODS: Children aged 5-17 who had a D-dimer or pulmonary vascular imaging ordered from 2004 to 2014 in a large multicenter hospital network were identified by query of administrative databases. Using explicit, predefined methods, trained abstracters selected charts of children clearly tested for PE, collected the 8 objective variables for PERC, and determined PE criterion standard status (image or autopsy confirmed PE or deep vein thrombosis within 30 days by query of the Indiana Network for Patient Care (INPC)). RESULTS: We identified 543 patients, including 56 (10.3%, 95% CI: 7.8-13.1%) who were PE+, with a mean and median age of 15 years. All 8 objective criteria from PERC were negative in 170 patients (31%), including one with PE (false negative rate 0.6%, 0-3.2%). Diagnostic sensitivity and specificity were 98.2% (90.5-100%), and 34.7 (30.5-39.1%), respectively, leading to a likelihood ratio negative = 0.05 (0.1-0.27). When treated as a diagnostic test based upon sum of criteria positive, PERC had good discrimination between PE+ vs PE- with an area under receiver operating characteristic curve 0.81 (0.75-0.86). CONCLUSIONS: In this sample of children and teenagers with suspected PE, the PERC rule was negative in 31%, and demonstrated good overall diagnostic accuracy, including a low false negative rate. These data support the need for a large, prospective diagnostic validation study of PERC in children.

Improving perceptions of empathy in patients undergoing low-yield computerized tomographic imaging in the emergency department.

OBJECTIVE: We assessed emergency department (ED) patient perceptions of how physicians can improve their language to determine patient preferences for 11 phrases to enhance physician empathy toward the goal of reducing low-value advanced imaging. METHODS: Multi-center survey study of low-risk ED patients undergoing computerized tomography (CT) scanning. RESULTS: We enroled 305 participants across nine sites. The statement "I have carefully considered what you told me about what brought you here today" was most frequently rated as important (88%). The statement "I have thought about the cost of your medical care to you today" was least frequently rated as important (59%). Participants preferred statements indicating physicians had considered their "vital signs and physical examination" (86%), "past medical history" (84%), and "what prior research tells me about your condition" (79%). Participants also valued statements conveying risks of testing, including potential kidney injury (78%) and radiation (77%). CONCLUSION: The majority of phrases were identified as important. Participants preferred statements conveying cognitive reassurance, medical knowledge and risks of testing. PRACTICE IMPLICATIONS: Our findings suggest specific phrases have the potential to enhance ED patient perceptions of physician empathy. Further research is needed to determine whether statements to convey empathy affect diagnostic testing rates.

Impact of Patient Affect on Physician Estimate of Probability of Serious Illness and Test Ordering.

PURPOSE: The authors hypothesize patient facial affect may influence clinician pretest probability (PTP) estimate of cardiopulmonary emergency (CPE) and desire to order a computerized tomographic pulmonary angiogram (CTPA). METHOD: This prospective study was conducted at three Indiana University-affiliated hospitals in two parts: collecting videos of patients undergoing CTPA for suspected acute pulmonary embolism watching a humorous video (August 2014-April 2015) and presenting the medical histories and videos to clinicians to determine the impact of patient facial affect on physicians' PTP estimate of CPE and desire to order a CTPA (June-November 2015). Patient outcomes were adjudicated as CPE+ or CPE- by three independent reviewers. Physicians completed a standardized test of facial affect recognition, read standardized medical histories, then viewed videos of the patients' faces. Clinicians marked their PTP estimate of CPE and desire for a CTPA before and after seeing the video on a visual analog scale (VAS). RESULTS: Fifty physicians completed all 73 videos. Seeing the patient's face produced a > 10% absolute change in PTP estimate of CPE in 1,204/3,650 (33%) cases and desire for a CTPA in 1,095/3,650 (30%) cases. The mean area under the receiver operating characteristic curve for CPE estimate was 0.55 ± 0.15, and the change in CPE VAS was negatively correlated with physicians' standardized test scores (r = -0.23). CONCLUSIONS: Clinicians may use patients' faces to make clinically important inferences about presence of serious illness and need for diagnostic testing. However, these inferences may fail to align with actual patient outcomes.