E-cigarette Use, or Vaping, Practices and Characteristics Among Persons with Associated Lung Injury - Utah, April-October 2019.

In August 2019, the Utah Department of Health (UDOH) received reports from health care providers of several cases of lung injury in persons who reported use of electronic cigarette (e-cigarette), or vaping, products (1,2). To describe the characteristics of medical care, potentially related conditions, and exposures among 83 patients in Utah, detailed medical abstractions were completed for 79 (95%) patients. Among patients receiving chart abstractions, 70 (89%) were hospitalized, 39 (49%) required breathing assistance, and many reported preexisting respiratory and mental health conditions. Interviews were conducted by telephone or in person with 53 (64%) patients or their proxies, and product samples from eight (15%) of the interviewed patients or proxies were tested. Among 53 interviewed patients, all of whom reported using e-cigarette, or vaping, products within 3 months of acute lung injury, 49 (92%) reported using any products containing tetrohydrocannabinol (THC), the principal psychoactive component of cannabis; 35 (66%) reported using any nicotine-containing products, and 32 (60%) reported using both. As reported in Wisconsin and Illinois (1), most THC-containing products were acquired from informal sources such as friends or illicit in-person and online dealers. THC-containing products were most commonly used one to five times per day, whereas nicotine-containing products were most commonly used >25 times per day. Product sample testing at the Utah Public Health Laboratory (UPHL) showed evidence of vitamin E acetate in 17 of 20 (89%) THC-containing cartridges, which were provided by six of 53 interviewed patients. The cause or causes of this outbreak is currently unknown (2); however, the predominant use among patients of e-cigarette, or vaping, products with prefilled THC-containing cartridges suggests that the substances in these products or the way in which they are heated and aerosolized play an important role in the outbreak. At present, persons should not use e-cigarette, or vaping, products that contain THC. In addition, because the specific cause or causes of lung injury are not yet known and while the investigation continues, persons should consider refraining from use of all e-cigarette, or vaping, products.

Empirical Consequences of Current Recommendations for the Design and Interpretation of Noninferiority Trials.

BACKGROUND: Noninferiority trials are increasingly common, though they have less standardized designs and their interpretation is less familiar to clinicians than superiority trials. OBJECTIVE: To empirically evaluate a cohort of noninferiority trials to determine 1) their interpretation as recommended by CONSORT, 2) choice of alpha threshold and its sidedness, and 3) differences between methods of analysis such as intention-to-treat and per-protocol. DESIGN: We searched MEDLINE for parallel-group randomized controlled noninferiority trials published in the five highest-impact general medical journals between 2011 and 2016. MAIN MEASURES: Data abstracted included trial design parameters, results, and interpretation of results based on CONSORT recommendations. KEY RESULTS: One hundred sixty-three trials and 182 noninferiority comparisons were included in our analysis. Based on CONSORT-recommended interpretation, 79% of experimental therapies met criteria for noninferiority, 13% met criteria for superiority, 20% were declared inconclusive, and 2% met criteria for inferiority. However, for 12% of trials, the experimental therapy was statistically significantly worse than the active control, but CONSORT recommended an interpretation of inconclusive or noninferior. A two-sided alpha equivalent of greater than 0.05 was used in 34% of the trials, and in five of these trials, the use of a standard two-sided alpha of 0.05 led to changes in the interpretation of results that disfavored the experimental therapy. In four of the five comparisons where different methods of analysis (e.g., intention-to-treat and per-protocol) yielded different results, the intention-to-treat analysis was the more conservative. In 11% of trials, a secondary advantage of the new therapy was neither reported nor could it be inferred by reviewers. CONCLUSIONS: In this cohort, the design and interpretation of noninferiority trials led to significant and systematic bias in favor of the experimental therapy. Clinicians should exercise caution when interpreting these trials. Future trials may be more reliable if design parameters are standardized.

Effect sizes in ongoing randomized controlled critical care trials.

BACKGROUND: An important limitation of many critical care trial designs is that they hypothesize large, and potentially implausible, reductions in mortality. Interpretation of trial results could be improved by systematic assessment of the plausibility of trial hypotheses; however, such assessment has not been attempted in the field of critical care medicine. The purpose of this study was to determine clinicians' views about prior probabilities and plausible effect sizes for ongoing critical care trials where the primary endpoint is landmark mortality. METHODS: We conducted a systematic review of clinical trial registries in September 2015 to identify ongoing critical care medicine trials where landmark mortality was the primary outcome, followed by a clinician survey to obtain opinions about ten large trials. Clinicians were asked to estimate the probability that each trial would demonstrate a mortality effect equal to or larger than that used in its sample size calculations. RESULTS: Estimates provided by individual clinicians varied from 0% to 100% for most trials, with a median estimate of 15% (IQR 10-20%). The median largest absolute mortality reduction considered plausible was 4.5% (IQR 3.5-5%), compared with a median absolute mortality reduction used in sample size calculations of 5% (IQR 3.6-10%) (P = 0.27). CONCLUSIONS: For some of the largest ongoing critical care trials, many clinicians regard prior probabilities as low and consider that plausible effects on absolute mortality are less than 5%. Further work is needed to determine whether pooled estimates obtained by surveying clinicians are replicable and accurate or whether other methods of estimating prior probability are preferred.

Chylothorax in a Young Woman With Crohn Disease.

Chylothorax, which accounts for 1% to 3% of pleural effusions, typically results from either surgery (traumatic) or underlying malignancy (nontraumatic). Less common causes of nontraumatic chylothorax are numerous and include congenital lymphatic abnormalities, connective tissue diseases, cirrhosis, and infection, among others.1 We describe what appears to be the first reported case of chylothorax caused by chylous ascites in Crohn disease. This case highlights the importance of using diagnostic evidence to link new symptoms to preexisting diseases whenever possible, as well as the systemic nature of Crohn disease.

Bicarbonate as a predictor of successful insulin transition in critically ill patients with diabetic ketoacidosis: A retrospective cohort study.

BACKGROUND: Treatment of diabetic ketoacidosis with intravenous insulin is effective but resource intensive. Treatment guidelines recommend transitioning to subcutaneous insulin when the anion gap closes, but transition failures due to recrudescent ketoacidosis are common despite adherence to treatment protocols following such guidance. STUDY OBJECTIVE: The primary objective of our study was to evaluate the ability of serum bicarbonate levels of ≤16 mEq/L to predict intravenous to subcutaneous transition failures among those with a normal anion gap at the time of transition. DESIGN AND SETTING: This retrospective cohort study evaluated critically ill adult patients with a primary diagnosis of diabetic ketoacidosis. Historical patient data were obtained by manual chart review. The primary outcome was transition failure, defined as the re-initiation of intravenous insulin within 24 h of transitioning to subcutaneous insulin. Odds ratios were calculated using generalized estimating equations with a logit link and weighted by standardized inverse probability weights to assess the predictive value of serum bicarbonate levels. MAIN RESULTS: The primary analysis included 93 patients with a total of 118 distinct transitions. In the adjusted analysis, patients whose anion gap had normalized but had a serum bicarbonate of ≤16 mEq/L were significantly more likely to experience a transition failure (odds ratio = 4.74, 95% confidence interval: 1.24-18.1, p = 0.02). The results of the unadjusted analysis were similar. CONCLUSIONS: In patients with a normal anion gap at the time of insulin transition, serum bicarbonate levels of ≤16 mEq/L were associated with significantly increased odds of transition failure.

The association between body mass index, processes of care, and outcomes from mechanical ventilation: a prospective cohort study.

OBJECTIVE: To determine the association between excess weight and processes of care and outcomes for critically ill adults. DESIGN: Prospective cohort study. SETTING: Three medical intensive care units at two hospitals. PATIENTS: Five hundred eighty mechanically ventilated adult patients admitted between February 1, 2006 and January 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After adjusting weight based on the recorded fluid balance before enrollment, 21.9% of subjects were categorized into different body mass index categories than without this adjustment. We used a competing risk analysis with events of interest considered death during hospitalization and successful liberation from mechanical ventilation. We found no statistically significant difference between body mass index categories (<25 kg/m² vs. 25 to <30 kg/m² vs. ≥30 kg/m²) in the competing risks analyses when the results were unadjusted or adjusted for severity of illness and comorbidities. When the analyses were adjusted for the use of continuous infusions of opioids and/or sedatives and ventilator parameters (tidal volume per ideal body weight, positive end-expiratory pressure, and airway pressure), subjects with an overweight fluid-balance-adjusted body mass index had significantly lower hazard ratios for dying while hospitalized (adjusted hazard ratio 0.68 [95% confidence interval 0.47-0.99], p=.044), and those with an obese fluid-adjusted body mass index had significantly higher hazard ratios for successful extubation (adjusted hazard ratio 1.53 [95% confidence interval 1.14-2.06], p=.005). An analysis of longer-term mortality found lower adjusted hazard ratios for subjects with overweight (adjusted hazard ratio 0.74 [95% confidence interval 0.56-0.96]) and obese (adjusted hazard ratio 0.74 [95% confidence interval 0.59-0.94]) fluid-balance-adjusted body mass indices. CONCLUSIONS: Processes of provided care may affect the observed association between excess weight and outcomes for critically ill adults and should be considered when making inferences about observed results. It is unknown if disparities in processes of care are due to clinically justified reasons for variation, bias against heavier patients, or other reasons.

Analysis of Physicians' Probability Estimates of a Medical Outcome Based on a Sequence of Events.

Importance: The probability of a conjunction of 2 independent events is the product of the probabilities of the 2 components and therefore cannot exceed the probability of either component; violation of this basic law is called the conjunction fallacy. A common medical decision-making scenario involves estimating the probability of a final outcome resulting from a sequence of independent events; however, little is known about physicians' ability to accurately estimate the overall probability of success in these situations. Objective: To ascertain whether physicians are able to correctly estimate the overall probability of a medical outcome resulting from 2 independent events. Design, Setting, and Participants: This survey study consisted of 3 separate substudies, in which 215 physicians were asked via internet-based survey to estimate the probability of success of each of 2 components of a diagnostic or prognostic sequence as well as the overall probability of success of the 2-step sequence. Substudy 1 was performed from April 2 to 4, 2021, substudy 2 from November 2 to 11, 2021, and substudy 3 from May 13 to 19, 2021. All physicians were board certified or board eligible in the primary specialty germane to the substudy (ie, obstetrics and gynecology for substudies 1 and 3 and pulmonology for substudy 2), were recruited from a commercial survey service, and volunteered to participate in the study. Exposures: Case scenarios presented in an online survey. Main Outcomes and Measures: Respondents were asked to provide their demographic information in addition to 3 probability estimates. The first substudy included a scenario describing a brow presentation discovered during labor; the 2 conjuncts were the probabilities that the brow presentation would resolve and that the delivery would be vaginal. The second substudy involved a diagnostic evaluation of an incidentally discovered pulmonary nodule; the 2 conjuncts were the probabilities that the patient had a malignant condition and that a technically successful transthoracic needle biopsy would reveal a malignant condition. The third substudy included a modification of the first substudy in an attempt to debias the conjunction fallacy prevalent in the first substudy. Respondents' own probability estimates of the individual events were used to calculate the mathematically correct conjunctive probability. Results: Among 215 respondents, the mean (SD) age was 54.0 (9.5) years; 142 respondents (66.0%) were male. Data on race and ethnicity were not collected. A total of 168 physicians (78.1%) estimated the probability of the 2-step sequence to be greater than the probability of at least 1 of the 2 component events. Compared with the product of their 2 estimated components, respondents overestimated the combined probability by 12.8% (95% CI, 9.6%-16.1%; P < .001) in substudy 1, 19.8% (95% CI, 16.6%-23.0%; P < .001) in substudy 2, and 18.0% (95% CI, 13.4%-22.5%; P < .001) in substudy 3, results that were mathematically incoherent (ie, formally illogical and mathematically incorrect). Conclusions and Relevance: In this survey study of 215 physicians, respondents consistently overestimated the combined probability of 2 events compared with the probability calculated from their own estimates of the individual events. This biased estimation, consistent with the conjunction fallacy, may have substantial implications for diagnostic and prognostic decision-making.

Common things are common, but what is common? Incorporating probability information into differential diagnosis.

The well-known clinical axiom declaring that 'common things are common' attests to the pivotal role of probability in diagnosis. Despite the popularity of this and related axioms, there is no operationalized definition of a common disease, and no practicable way of incorporating actual disease frequencies into differential diagnosis. In this essay, we aim to disambiguate the definition of a common (or rare) disease and show that incidence-not prevalence-is the proper metric of disease frequency for differential diagnosis. We explore how numerical estimates of disease frequencies based on incidence can be incorporated into differential diagnosis as well as the inherent limitations of this method. These concepts have important implications for diagnostic decision making and medical education, and hold promise as a method to improve diagnostic accuracy.

Insurance type and sepsis-associated hospitalizations and sepsis-associated mortality among US adults: a retrospective cohort study.

INTRODUCTION: Socio-demographic and clinical factors associated with increased sepsis risk, including older age, non-white race and specific co-morbidities, are more common among patients with Medicare or Medicaid or no health insurance. We hypothesized that patients with Medicare and/or Medicaid or without health insurance have a higher risk of sepsis-associated hospitalization or sepsis-associated death than those with private health insurance. METHODS: We performed a retrospective cohort study of records from the 2003 Nationwide Inpatient Sample. We stratified the study cohort by Medicare age-qualification (18 to 64 and 65+ years old). We examined the association between insurance category and sepsis diagnosis and death among admissions involving sepsis. We used validated diagnostic codes to determine the presence of sepsis, co-morbidities and organ dysfunction and to provide risk-adjustment. RESULTS: Among patients 18 to 64 years old, those with Medicaid (adjusted odds ratio (AOR) 1.50), Medicare (AOR 1.96), Medicaid + Medicare (AOR 2.22) and the uninsured (AOR 1.18) had significantly higher risk-adjusted odds of a sepsis-associated admission than those with private insurance (all P < 0.0001). Those with Medicaid (AOR 1.17, P < 0.001) and those without insurance (AOR 1.45, P < 0.001) also had significantly higher adjusted odds of sepsis-associated hospital mortality than those with private insurance. Among those 65+ years old, those with Medicaid (AOR 1.43), Medicare alone (AOR 1.13) or Medicaid + Medicare (AOR 1.62) had significantly higher risk-adjusted odds of sepsis-associated admission than those with private insurance and Medicare (all P < 0.0001). Among sepsis patients 65+, uninsured patients had significantly higher risk-adjusted odds (AOR 1.45, P = 0.0048) and those with Medicare alone had significantly lower risk-adjusted odds (AOR 0.92, P = 0.0072) of hospital mortality than those with private insurance and Medicare. Lack of health insurance remained associated with sepsis-associated mortality after stratification of hospitals into quartiles based on rates of sepsis-associated admissions or mortality in both age strata. CONCLUSIONS: Risks of sepsis-associated hospitalization and sepsis-associated death vary by insurance. These increased risks were not fully explained by the available socio-demographic factors, co-morbidities or hospital rates of sepsis-related admissions or deaths.

Delta inflation: a bias in the design of randomized controlled trials in critical care medicine.

INTRODUCTION: Mortality is the most widely accepted outcome measure in randomized controlled trials of therapies for critically ill adults, but most of these trials fail to show a statistically significant mortality benefit. The reasons for this are unknown. METHODS: We searched five high impact journals (Annals of Internal Medicine, British Medical Journal, JAMA, The Lancet, New England Journal of Medicine) for randomized controlled trials comparing mortality of therapies for critically ill adults over a ten year period. We abstracted data on the statistical design and results of these trials to compare the predicted delta (delta; the effect size of the therapy compared to control expressed as an absolute mortality reduction) to the observed delta to determine if there is a systematic overestimation of predicted delta that might explain the high prevalence of negative results in these trials. RESULTS: We found 38 trials meeting our inclusion criteria. Only 5/38 (13.2%) of the trials provided justification for the predicted delta. The mean predicted delta among the 38 trials was 10.1% and the mean observed delta was 1.4% (P < 0.0001), resulting in a delta-gap of 8.7%. In only 2/38 (5.3%) of the trials did the observed delta exceed the predicted delta and only 7/38 (18.4%) of the trials demonstrated statistically significant results in the hypothesized direction; these trials had smaller delta-gaps than the remainder of the trials (delta-gap 0.9% versus 10.5%; P < 0.0001). For trials showing non-significant trends toward benefit greater than 3%, large increases in sample size (380% - 1100%) would be required if repeat trials use the observed delta from the index trial as the predicted delta for a follow-up study. CONCLUSIONS: Investigators of therapies for critical illness systematically overestimate treatment effect size (delta) during the design of randomized controlled trials. This bias, which we refer to as "delta inflation", is a potential reason that these trials have a high rate of negative results."Absence of evidence is not evidence of absence."

Diagnosis of EVALI: General Approach and the Role of Bronchoscopy.

A 23-year-old man arrives at the ED with a 3-week history of dyspnea, dry cough, fevers, and night sweats. Two weeks previously, he was evaluated in an outpatient clinic and given a course of azithromycin for presumed infectious pneumonia. His symptoms did not improve, and he was seen 1 week later in an urgent care center and given a prescription for doxycycline, which he has been taking without improvement. He states that he feels miserable, has severe nausea and vomiting, and has not eaten in several days. His only medical history is childhood asthma. He reports no surgeries and takes no medications. He has no risk factors for HIV, does not smoke combustible cigarettes or use IV drugs, and has not recently traveled. Examination shows a room air saturation of 89%, a temperature of 38.3°C, and a respiratory rate of 22 breaths/min. Results of his examination are normal, and there are no rales or wheezing heard in the lungs. Chest radiograph shows bilateral, consolidative opacities. WBC count is 14,000, with left shift. Results of biochemistries are normal. Erythrocyte sedimentation rate is 104, and procalcitonin is 0.08. Urine toxicology screen is positive for tetrahydrocannabinol (THC). Asked specifically about vaping and e-cigarette use, he reports that he recently began using THC "carts" that his friend gets from an unknown supplier. What is the diagnosis and what additional steps are necessary to confirm it? Is bronchoscopy indicated?

Clinical, Bronchoscopic, and Imaging Findings of e-Cigarette, or Vaping, Product Use-Associated Lung Injury Among Patients Treated at an Academic Medical Center.

Importance: e-Cigarette, or vaping, product use-associated lung injury (EVALI) has caused more than 2800 illnesses and 68 deaths in the United States. Better characterization of this novel illness is needed to inform diagnosis and management. Objective: To describe the clinical features, bronchoscopic findings, imaging patterns, and outcomes of EVALI. Design, Setting, and Participants: This case series of 31 adult patients diagnosed with EVALI between June 24 and December 10, 2019, took place at an academic medical center in Salt Lake City, Utah. Exposures: e-Cigarette use, also known as vaping. Main Outcomes and Measures: Symptoms, laboratory findings, bronchoscopic results, imaging patterns, and clinical outcomes. Results: Data from 31 patients (median [interquartile range] age, 24 [21-31] years) were included in the study. Patients were primarily men (24 [77%]) and White individuals (27 [87%]) who used e-cigarette products containing tetrahydrocannabinol (THC) (29 [94%]). Patients presented with respiratory (30 [97%]), constitutional (28 [90%]), and gastrointestinal (28 [90%]) symptoms. Serum inflammatory markers were elevated in all patients. Bronchoscopy was performed in 23 of 28 inpatients (82%) and bronchoalveolar lavage (BAL) revealed the presence of lipid-laden macrophages (LLMs) in 22 of 24 cases (91%). BAL samples tested positive for Pneumocystis jirovecii (3 patients [13%]), rhinovirus (2 patients [8%]), human metapneumovirus and Aspergillus (1 patient each [4%]); all except human metapneumovirus were determined to be false-positives or clinically inconsequential. The exclusive or dominant computed tomography (CT) pattern was organizing pneumonia in 23 of 26 cases (89%). Patients received antibiotics (26 [84%]) and corticosteroids (24 [77%]), and all survived; 20 patients (65%) seen in follow-up showed marked improvement, but residual symptoms (13 [65%]), radiographic opacities (8 [40%]), and abnormal pulmonary function tests (8 of 18 [44%]) were common. Conclusions and Relevance: In this case series, patients with EVALI characteristically presented with a flu-like illness with elevated inflammatory markers, LLMs on BAL samples, and an organizing pneumonia pattern on CT imaging. Bronchoscopic testing for infection had a high incidence of false-positive results. Patients had substantial residual abnormal results at early follow-up. These data suggest a limited role for bronchoscopy in typical presentations of EVALI without risk factors for alternative diagnoses and the need for careful longitudinal follow-up.

Results from the national sepsis practice survey: predictions about mortality and morbidity and recommendations for limitation of care orders.

INTRODUCTION: Critically ill patients and families rely upon physicians to provide estimates of prognosis and recommendations for care. Little is known about patient and clinician factors which influence these predictions. The association between these predictions and recommendations for continued aggressive care is also understudied. METHODS: We administered a mail-based survey with simulated clinical vignettes to a random sample of the Critical Care Assembly of the American Thoracic Society. Vignettes represented a patient with septic shock with multi-organ failure with identical APACHE II scores and sepsis-associated organ failures. Vignettes varied by age (50 or 70 years old), body mass index (BMI) (normal or obese) and co-morbidities (none or recently diagnosed stage IIA lung cancer). All subjects received the vignettes with the highest and lowest mortality predictions from pilot testing and two additional, randomly selected vignettes. Respondents estimated outcomes and selected care for each hypothetical patient. RESULTS: Despite identical severity of illness, the range of estimates for hospital mortality (5th to 95th percentile range, 17% to 78%) and for problems with self-care (5th to 95th percentile range, 2% to 74%) was wide. Similar variation was observed when clinical factors (age, BMI, and co-morbidities) were identical. Estimates of hospital mortality and problems with self-care among survivors were significantly higher in vignettes with obese BMIs (4.3% and 5.3% higher, respectively), older age (8.2% and 11.6% higher, respectively), and cancer diagnosis (5.9% and 6.9% higher, respectively). Higher estimates of mortality (adjusted odds ratio 1.29 per 10% increase in predicted mortality), perceived problems with self-care (adjusted odds ratio 1.26 per 10% increase in predicted problems with self-care), and early-stage lung cancer (adjusted odds ratio 5.82) were independently associated with recommendations to limit care. CONCLUSIONS: The studied clinical factors were consistently associated with poorer outcome predictions but did not explain the variation in prognoses offered by experienced physicians. These observations raise concern that provided information and the resulting decisions about continued aggressive care may be influenced by individual physician perception. To provide more reliable and accurate estimates of outcomes, tools are needed which incorporate patient characteristics and preferences with physician predictions and practices.