Publications by authors named "Todd A Miano"

37 Publications

Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries.

medRxiv 2021 May 27. Epub 2021 May 27.

Objective: The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis.

Research Design And Methods: A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity.

Results: ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis.

Conclusions: For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.
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http://dx.doi.org/10.1101/2021.05.25.21257799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168398PMC
May 2021

Identification of Distinct Clinical Subphenotypes in Critically Ill Patients With COVID-19.

Chest 2021 May 6. Epub 2021 May 6.

Center for Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Subphenotypes have been identified in patients with sepsis and ARDS and are associated with different outcomes and responses to therapies.

Research Question: Can unique subphenotypes be identified among critically ill patients with COVID-19?

Study Design And Methods: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into discovery and replication cohorts. We used latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality.

Results: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across the discovery (45 centers; n = 2,188) and replication (22 centers; n = 1,112) cohorts. SP1 was characterized by shock, acidemia, and multiorgan dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 showed the highest burden of chronic diseases, whereas SP4 demonstrated limited chronic disease burden and mild physiologic abnormalities. Twenty-eight-day mortality in the discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors. Compared with SP4, the relative risks were as follows: SP1, 1.67 (95% CI, 1.36-2.03); SP2, 1.39 (95% CI, 1.17-1.65); and SP3, 1.39 (95% CI, 1.15-1.67). Findings were similar in the replication cohort.

Interpretation: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.
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http://dx.doi.org/10.1016/j.chest.2021.04.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099539PMC
May 2021

Patients Living With HIV Are Less Likely to Receive Appropriate Statin Therapy for Cardiovascular Disease Risk Reduction.

J Pharm Pract 2021 Mar 8:897190021999790. Epub 2021 Mar 8.

Department of Pharmacy Practice, Jefferson College of Pharmacy, Philadelphia, PA, USA.

Background: Recent studies suggest that statins are underprescribed in patients living with HIV (PLWH) at risk for atherosclerotic cardiovascular disease (ASCVD), but none have assessed if eligible patients receive the correct statin and intensity compared to uninfected controls.

Objectives: The primary objective was to determine whether statin-eligible PLWH are less likely to receive appropriate statin therapy compared to patients without HIV.

Methods: This retrospective study evaluated statin eligibility and prescribing among patients in both an HIV and internal medicine clinic at an urban, academic medical center from June-September 2018 using the American College of Cardiology/American Heart Association guideline on treating blood cholesterol to reduce ASCVD risk. Patients were assessed for eligibility and actual treatment with appropriate statin therapy. Characteristics of patients appropriately and not appropriately treated were compared with chi-square testing and predictors for receiving appropriate statin therapy were determined with logistic regression.

Results: A total of 221/300 study subjects were statin-eligible. Fewer statin-eligible PLWH were receiving the correct statin intensity for their risk benefit group versus the uninfected control group (30.2% vs 67.0%, p < 0.001). In the multivariable logistic regression analysis, PLWH were significantly less likely to receive appropriate statin therapy, while those with polypharmacy were more likely to receive appropriate statin therapy.

Conclusion: Our study reveals that PLWH may be at a disadvantage in receiving appropriate statin therapy for ASCVD risk reduction. This is important given the heightened risk for ASCVD in this population, and strategies that address this gap in care should be explored.
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http://dx.doi.org/10.1177/0897190021999790DOI Listing
March 2021

The authors reply.

Crit Care Med 2021 Mar;49(3):e346-e347

Department of Pharmacy, Shirley Ryan Abilitylab, Chicago, IL.

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http://dx.doi.org/10.1097/CCM.0000000000004870DOI Listing
March 2021

Population-Based Signals of Antidepressant Drug Interactions Associated With Unintentional Traumatic Injury.

Clin Pharmacol Ther 2021 Feb 9. Epub 2021 Feb 9.

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Antidepressants are very widely used and associated with traumatic injury, yet little is known about their potential for harmful drug interactions. We aimed to identify potential drug interaction signals by assessing concomitant medications (precipitant drugs) taken with individual antidepressants (object drugs) that were associated with unintentional traumatic injury. We conducted pharmacoepidemiologic screening of 2000-2015 Optum Clinformatics data, identifying drug interaction signals by performing self-controlled case series studies for antidepressant + precipitant pairs and injury. We included persons aged 16-90 years codispensed an antidepressant and ≥ 1 precipitant drug(s), with an injury during antidepressant therapy. We classified antidepressant person-days as either precipitant-exposed or precipitant-unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to calculate confounder adjusted rate ratios (RRs) and accounted for multiple estimation via semi-Bayes shrinkage. We identified 330,884 new users of antidepressants who experienced an injury. Among such persons, we studied concomitant use of 7,953 antidepressant + precipitant pairs. Two hundred fifty-six (3.2%) pairs were positively associated with injury and deemed potential drug interaction signals; 22 of these signals had adjusted RRs > 2.00. Adjusted RRs ranged from 1.06 (95% confidence interval: 1.00-1.12, P = 0.04) for citalopram + gabapentin to 3.06 (1.42-6.60) for nefazodone + levonorgestrel. Sixty-five (25.4%) signals are currently reported in a seminal drug interaction knowledgebase. We identified numerous new population-based signals of antidepressant drug interactions associated with unintentional traumatic injury. Future studies, intended to test hypotheses, should confirm or refute these potential interactions.
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http://dx.doi.org/10.1002/cpt.2195DOI Listing
February 2021

Effect of Renin-Angiotensin System Inhibitors on the Comparative Nephrotoxicity of NSAIDs and Opioids during Hospitalization.

Kidney360 2020 Jul;1(7):604-613

Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDS) are increasingly important alternatives to opioids for analgesia during hospitalization as health systems implement opioid-minimization initiatives. Increasing NSAID use may increase AKI rates, particularly in patients with predisposing risk factors. Inconclusive data in outpatient populations suggests that NSAID nephrotoxicity is magnified by renin-angiotensin system inhibitors (RAS-I). No studies have tested this in hospitalized patients.

Methods: Retrospective, active-comparator cohort study of patients admitted to four hospitals in Philadelphia, Pennsylvania. To minimize confounding by indication, NSAIDs were compared to oxycodone, and RAS-I were compared to amlodipine. We tested synergistic NSAID+RAS-I nephrotoxicity by comparing the difference in AKI rate between NSAID versus oxycodone in patients treated with RAS-I to the difference in AKI rate between NSAID versus oxycodone in patients treated with amlodipine. In a secondary analysis, we restricted the cohort to patients with baseline diuretic treatment. AKI rates were adjusted for 71 baseline characteristics with inverse probability of treatment-weighted Poisson regression.

Results: The analysis included 25,571 patients who received a median of 2.4 days of analgesia. The overall AKI rate was 23.6 per 1000 days. The rate difference (RD) for NSAID versus oxycodone in patients treated with amlodipine was 4.1 per 1000 days (95% CI, -2.8 to 11.1), and the rate difference for NSAID versus oxycodone in patients treated with RAS-I was 5.9 per 1000 days (95% CI, 1.9 to 10.1), resulting in a nonsignificant interaction estimate: 1.85 excess AKI events per 1000 days (95% CI, -6.23 to 9.92). Analysis in patients treated with diuretics produced a higher, albeit nonsignificant, interaction estimate: 9.89 excess AKI events per 1000 days (95% CI, -5.04 to 24.83).

Conclusions: Synergistic nephrotoxicity was not observed with short-term NSAID+RAS-I treatment in the absence of concomitant diuretics, suggesting that RAS-I treatment may not be a reason to choose opioids in lieu of NSAIDs in this population. Synergistic nephrotoxicity cannot be ruled out in patients treated with diuretics.
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http://dx.doi.org/10.34067/kid.0001432020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643868PMC
July 2020

An Association Between Hyperchloremia and Acute Kidney Injury in Patients With Acute Ischemic Stroke.

Neurohospitalist 2020 Oct 25;10(4):250-256. Epub 2020 Mar 25.

Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA.

Background And Purpose: While an association between hyperchloremia and worse outcomes, such as acute kidney injury and increased mortality, has been demonstrated in hemorrhagic stroke, it is unclear whether the same relationship exists after acute ischemic stroke. This study aims to determine the relationship between moderate hyperchloremia (serum chloride ≥115 mmol/L) and acute kidney injury in patients with ischemic stroke.

Methods: This is a multicenter, retrospective, propensity-matched cohort study of adults admitted for acute ischemic stroke. The primary objective was to determine the relationship between moderate hyperchloremia and acute kidney injury, as defined by the Acute Kidney Injury Network criteria. Secondary objectives included mortality and hospital length of stay.

Results: A total of 407 patients were included in the unmatched cohort (332 nonhyperchloremia and 75 hyperchloremia) and 114 patients (57 in each group) were matched based upon propensity scores. In the matched cohort, hyperchloremia was associated with an increased risk of acute kidney injury (relative risk 1.91 [95% confidence interval 1.01-3.59]) and a longer hospital length of stay (16 vs 12 days; = .03). Mortality was higher in the hyperchloremia group (19.3% vs 10.5%, = .19), but this did not reach statistical significance.

Conclusions: In this study, hyperchloremia after ischemic stroke was associated with increased rates of acute kidney injury and longer hospital length of stay. Further research is needed to determine which interventions may increase chloride levels in patients with acute ischemic stroke and the association between hyperchloremia and clinical outcomes.
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http://dx.doi.org/10.1177/1941874420913715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495694PMC
October 2020

Evaluation of Vasopressor Exposure and Mortality in Patients With Septic Shock.

Crit Care Med 2020 10;48(10):1445-1453

Division of Pulmonary, Critical Care, and Sleep Medicine, New York University, New York, NY.

Objectives: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern.

Design: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents.

Setting: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1).

Patients: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset.

Interventions: None.

Measurements And Main Results: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality.

Conclusions: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.
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http://dx.doi.org/10.1097/CCM.0000000000004476DOI Listing
October 2020

Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids.

J Bone Joint Surg Am 2020 Jul;102(14):1230-1238

Division of Rheumatology (M.D.G. and J.F.B.), Department of Biostatistics, Epidemiology, and Informatics (M.D.G., J.F.B., C.E.L., T.A.M., and S.H.), and the Department of Orthopedic Surgery (S.M.), University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Cyclooxygenase-2 (COX-2) has been found to be important for fracture-healing in animal models, raising concerns about use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors after fractures. We evaluated associations of NSAIDs, COX-2 inhibitors, and opioids with nonunion after long-bone fracture.

Methods: Using private health insurance claims data from Optum's de-identified Clinformatics Data Mart database from January 1, 2000, to September 30, 2015, we identified adults with a single long-bone fracture or commonly paired long-bone fractures who had 1 year of available follow-up data. Using multivariable logistic regression models, we examined associations between NSAID, COX-2-inhibitor, or opioid prescription fills after the fracture and the risk of nonunion within 1 year, defined as a nonunion diagnosis with a procedure to treat the nonunion.

Results: A nonunion diagnosis with a procedure to treat the nonunion was identified after 2,996 (0.9%) of the 339,864 fracture episodes, with rates varying by fracture site. The risk of that outcome was greater in patients who had filled COX-2-inhibitor prescriptions (adjusted odds ratio = 1.84 [95% confidence interval = 1.38 to 2.46]) or opioid prescriptions (1.69 [1.53 to 1.86]), but not in patients who had filled nonselective-NSAID prescriptions (1.07 [0.93 to 1.23]) after the fracture. Results were similar when the outcome definition was changed to just a nonunion diagnosis.

Conclusions: COX-2 inhibitors, but not nonselective NSAIDs, were associated with a greater risk of nonunion after fracture. Opioids were also associated with nonunion risk, although patients filling prescriptions for opioids may have had more severe fractures.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.19.01415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508275PMC
July 2020

The Magnitude of the Warfarin-Amiodarone Drug-Drug Interaction Varies With Renal Function: A Propensity-Matched Cohort Study.

Clin Pharmacol Ther 2020 06 26;107(6):1446-1456. Epub 2020 Mar 26.

Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Amiodarone inhibits warfarin metabolism and is associated with major bleeding during warfarin therapy. Managing this drug-drug interaction (DDI) is challenging because of substantial interpatient variability in DDI magnitude. Because renal dysfunction induces changes in drug metabolism and protein binding that could alter cytochrome P450 inhibition mechanisms, we hypothesized that renal dysfunction alters the impact of the warfarin-amiodarone DDI. We tested this question in a propensity-matched cohort study of hospitalized patients with atrial fibrillation. Patients were queried from an electronic health record database. Renal function was estimated with creatinine clearance (CrCl). Warfarin response was measured with the warfarin sensitivity index (WSI), a dose-normalized international normalized ratio (INR) measure, and was modeled with multilevel mixed-effects linear regression. Time to supratherapeutic INR (> 4) was modeled using Cox regression. Propensity score matching resulted in 4,518 patients administered amiodarone and 4,518 controls. Amiodarone's effect on warfarin response varied threefold across the renal function range, increasing WSI by 36% in patients with normal renal function (CrCl 115 mL/minute), but by only 11.8% in patients with severe renal dysfunction (CrCl 15 mL/minute). Similarly, amiodarone had a strong effect in patients with normal renal function (hazard ratio (HR) 1.80; 1.23, 2.64), but a negligible effect on supratherapeutic INR hazard in patients with severe renal dysfunction (HR 1.01; 0.75, 1.37). These results suggest that renal function is a novel factor that explains substantial variability in the warfarin-amiodarone DDI. This information could inform warfarin dosage adjustment and monitoring and may have implications for the selection of oral anticoagulation agents in patients treated with amiodarone.
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http://dx.doi.org/10.1002/cpt.1819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217725PMC
June 2020

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

Crit Care 2019 12 9;23(1):400. Epub 2019 Dec 9.

Division of Pulmonary, Allergy and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5036 Gates Building, Philadelphia, PA, 19104, USA.

Background: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.

Methods: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.

Measurements And Main Results: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.

Conclusions: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.
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http://dx.doi.org/10.1186/s13054-019-2684-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902425PMC
December 2019

Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury.

Clin Pharmacol Ther 2020 02 20;107(2):462-470. Epub 2019 Oct 20.

Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.
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http://dx.doi.org/10.1002/cpt.1629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980920PMC
February 2020

The Effect of Sedation on Long-Term Psychological Impairment After Extracorporeal Life Support.

J Cardiothorac Vasc Anesth 2020 Mar 2;34(3):663-667. Epub 2019 Aug 2.

Department of Anesthesiology and Critical Care, University of Pennsylvania Health System, Philadelphia, PA. Electronic address:

Objective: This retrospective study aimed to identify the association between long-term psychological impairment and total sedation received during venovenous extracorporeal life support (VV-ECLS) for acute respiratory failure (ARF).

Design: This observational retrospective study compared characteristics between patients with and without long-term psychological morbidity at long-term follow-up after VV-ECLS for ARF.

Setting: A single institutional experience in a quaternary referral academic medical center in the United States.

Patients: Patients who received VV-ECLS for ARF between January 1, 2015, and April 1, 2017, were identified for selection. Presence of psychiatric morbidity (anxiety and/or depression) was determined with the Hospital Anxiety and Depression Subscale battery at long-term follow-up.

Interventions: No interventions were made during this retrospective observational study.

Measurements And Main Results: A total of 42 patients (21 male, 21 female, median age 49 [interquartile range {IQR} 36-57]) completed a telephone interview a median of 14.6 (IQR 7.7-21.1) months after ECLS decannulation. Cohorts were defined as possessing any psychiatric morbidity (anxiety and/or depression) as defined by the Hospital Anxiety and Depression Subscale battery (n = 22 [52%]) versus no psychiatric morbidity (n = 20 [48%]) at long-term follow-up. Patients who had clinically significant psychiatric morbidity received a median of 15.0 (IQR 11.0-17.0) days of continuous intravenous sedation compared with patients who had no psychiatric morbidity, who received a median of 10.0 (IQR 6.5-13.5) days of intravenous sedation; (p = 0.02).

Conclusions: This retrospective analysis identified a significant association between the presence of long-term post-VV-ECLS psychiatric symptoms and the total number of days of intravenous sedation.
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http://dx.doi.org/10.1053/j.jvca.2019.07.147DOI Listing
March 2020

The association of post-lung transplant acute kidney injury with mortality is independent of primary graft dysfunction: A cohort study.

Clin Transplant 2019 10 28;33(10):e13678. Epub 2019 Aug 28.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality.

Methods: We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders.

Results: Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality.

Conclusions: Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.
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http://dx.doi.org/10.1111/ctr.13678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823116PMC
October 2019

Postreperfusion plasma endothelial activation markers are associated with acute kidney injury after lung transplantation.

Am J Transplant 2019 08 23;19(8):2366-2373. Epub 2019 May 23.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity.
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http://dx.doi.org/10.1111/ajt.15402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658345PMC
August 2019

Norepinephrine and Vasopressin Compared With Norepinephrine and Epinephrine in Adults With Septic Shock.

Ann Pharmacother 2019 09 8;53(9):877-885. Epub 2019 Apr 8.

1 Rush University Medical Center, Chicago, IL, USA.

The optimal adjuvant vasopressor to norepinephrine in septic shock remains controversial. To compare durations of shock-free survival between adjuvant vasopressin and epinephrine. A retrospective, single-center, matched cohort study of adults with septic shock refractory to norepinephrine was conducted. Patients receiving norepinephrine not at target mean arterial pressure (MAP; 65 mm Hg) were initiated on vasopressin or epinephrine to raise MAP to target. Vasopressin-exposed patients were matched to epinephrine-exposed patients using propensity scores. Mortality outcomes were examined using multivariable Poisson regression with robust variance estimation. Of 166 patients, 96 (entire cohort) were included in the propensity score-matched cohort. Shock-free survival durations in the first 7 days were similar between epinephrine- and vasopressin-exposed patients in the matched cohort (median = 13.2 hours, interquartile range [IQR] = 0-121.0, vs median = 41.3 hours, IQR = 0-125.9; = 0.51). Seven- and 28-day mortality rates were similar in the matched cohort (7-day: 47.9% vs 39.6%, = 0.35; 28-day: 56.3% vs 58.3%, = 0.84). Mortality rates were similar between epinephrine- and vasopressin-exposed patients in propensity score-matched regression models with and without adjustments at 7 (relative risk [RR] = 1.28, 95% CI = 0.92-1.79; RR = 1.21, 95% CI = 0.81-1.81) and 28 days (RR = 1.04, 95% CI = 0.81-1.34; RR = 0.96, 95% CI = 0.69-1.34). Shock-free survival durations were similar in matched epinephrine- and vasopressin-exposed groups. Adjuvant epinephrine or vasopressin alongside norepinephrine to raise MAP to target requires further investigation.
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http://dx.doi.org/10.1177/1060028019843664DOI Listing
September 2019

Whose Benchmark Is Right? Validating Venous Thromboembolism Events Between Trauma Registries and Hospital Administrative Databases.

J Am Coll Surg 2019 05 15;228(5):752-759.e3. Epub 2019 Feb 15.

Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background: Venous thromboembolism (VTE) events are tracked in trauma registries and by administrative data sets. Both databases are used to assess outcomes, despite having varying processes for data capture.

Study Design: This study was performed at an urban, university-based, Level I trauma center from 2004 to 2014. Retrospective review of the trauma registry and the hospital's administrative database was performed querying for all VTEs. Each VTE was then validated through manual chart review. Confirmed events were those with radiographic evidence of VTE by ultrasound, CT, and/or ventilation-perfusion scan. Sensitivity, specificity, and predictive values were calculated and compared between databases.

Results: There were 19,353 trauma patients admitted during the study period; 656 VTEs were identified in the registry and 890 were identified via administrative data; 527 potential events were identified by both databases; 129 events were only in registry; and 363 were only found in the administrative database. We confirmed 636 of 656 events in registry (positive predictive value, 97%; 95% CI, 95.6% to 98.3%) vs 815 of 890 events in administrative data (positive predictive value, 91.6%; 95% CI, 89.75% to 93.4%; p < 0.001). Sensitivity was higher for administrative (87.2% vs 68.0%; p < 0.001), as 299 confirmed VTE events were not in the registry. Differences between the 2 databases were diminished when the analysis excluded untreated events and those present on admission. Twenty-three percent of validated deep vein thrombosis events in the registry were upper extremity events.

Conclusions: The trauma registry showed higher specificity and lower sensitivity compared with administrative data. The low false-positive rate of the trauma registry supports its validity in VTE outcomes research. Additional investigation is needed to evaluate the relevance of the variable sensitivity, likely due to definitional differences. Supplementation of trauma registry data with administrative data can strengthen its completeness.
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http://dx.doi.org/10.1016/j.jamcollsurg.2019.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487217PMC
May 2019

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

PLoS One 2018 27;13(11):e0207941. Epub 2018 Nov 27.

Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.

Introduction: Patients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium.

Methods: Ninety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism.

Results: Genotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050.

Conclusion: This observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207941PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258533PMC
April 2019

Attributable Risk and Time Course of Colistin-Associated Acute Kidney Injury.

Clin J Am Soc Nephrol 2018 04 15;13(4):542-550. Epub 2018 Mar 15.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Despite colistin's longstanding reported association with nephrotoxicity, the attributable risk and timing of toxicity onset are still unknown. Whether substantial toxicity occurs during the initial 72 hours of exposure has important implications for early treatment decisions. The objective of this study was to compare colistin-exposed patients with a matched control group given other broad spectrum antibiotics.

Design, Setting, Participants, & Measurements: We conducted a retrospective cohort study in patients treated for multidrug-resistant , , or spp. Colistin-exposed patients were matched to unexposed controls using propensity scores. AKI was defined according to the Kidney Disease Improving Global Outcomes creatinine criteria. Incidence rate ratios and risk differences of AKI in the matched cohort were estimated with the generalized estimating equation Poisson regression model. Risk factors for AKI were tested for effect modification in the matched cohort.

Results: The study included 150 propensity-matched pairs with similar types of infection, similar delays to effective treatment, and similar baseline characteristics. Incidence of AKI was 77 of 150 (51%) in the colistin group versus 33 of 150 (22%) in matched controls (risk difference, 29%; 95% confidence interval, 19 to 39), corresponding to a number needed to harm of 3.5. Early toxicity was apparent, because AKI risk was higher in colistin-exposed patients at 72 hours of exposure (incidence rate ratio, 1.9; 95% confidence interval, 1.1 to 3.5). In both groups, hospital mortality in patients who experienced AKI was lower if kidney function returned to baseline during hospitalization. The effect of colistin exposure on AKI risk varied inversely according to baseline hemoglobin concentration.

Conclusions: Colistin is associated with substantial excess AKI that is apparent within the first 72 hours of treatment. Colistin's toxicity varied according to baseline hemoglobin concentration.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_03_15_CJASNPodcast_18_4_M.mp3.
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http://dx.doi.org/10.2215/CJN.06980717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969457PMC
April 2018

The Healthy User Effect in Studies of Statins in the Critically Ill.

Crit Care Med 2018 01;46(1):e95

Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Department of Pharmacy, Cleveland Clinic, Cleveland, OH.

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http://dx.doi.org/10.1097/CCM.0000000000002743DOI Listing
January 2018

Does a Mobile ECLS Program Reduce Mortality for Patients Transported for ECLS Therapy for Severe Acute Respiratory Failure?

J Cardiothorac Vasc Anesth 2018 06 2;32(3):1137-1141. Epub 2017 Sep 2.

Department of Anesthesiology and Critical Care, University of Pennsylvania Health System, Philadelphia, PA.

Objective: To understand if mobile extracorporeal membrane oxygenation reduces patient mortality during and after transport of patients requiring extracorporeal membrane oxygenation for acute respiratory distress syndrome.

Design: Retrospective chart review.

Setting: University affiliated tertiary care hospitals.

Participants: Seventy-seven patients.

Interventions: Introduction of a mobile extracorporeal membrane oxygenation (ECMO) program designed to facilitate the implementation of ECMO at outside hospitals in patients too unstable for transport for ECMO.

Measurements And Main Results: The 28-day in-hospital mortality was significantly lower in the post-mobile group (12/51 [23.5%] v 12/24 [50%], adjusted risk difference: 28.6%, [95% CI 4.7-52.5, p = 0.011]).

Conclusions: These findings suggest that patients with severe acute respiratory failure who require transport to a referral center for extracorporeal life support may benefit from the availability of a mobile extracorporeal life support team.
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http://dx.doi.org/10.1053/j.jvca.2017.08.050DOI Listing
June 2018

Effect of Modafinil on Cognitive Function in Intensive Care Unit Patients: A Retrospective Cohort Study.

J Clin Pharmacol 2018 02 31;58(2):152-157. Epub 2017 Aug 31.

Mercy Medical Center, Springfield, MA, USA.

Modafinil therapy, a nonamphetamine cognition-enhancing agent, holds the potential to improve recovery from cognitive impairment after intensive care unit (ICU) admission. To date, however, there is a paucity of data on modafinil use in the ICU setting. The purpose of this study was to explore the role of modafinil for improvement in cognition in ICU patients. This retrospective cohort study evaluated a total of 60 ICU patients with any ventilatory support who started on modafinil during their ICU stay from January 1, 2010, to March 19, 2016. The requirements of opioids and sedatives, as well as the lowest and average scores of the Glasgow Coma Scale (GCS) and Riker Sedation-Agitation Scale (SAS), were recorded during 48 hours before and after the start of modafinil therapy in 6-hour periods. The average daily modafinil dose of 170 mg was given for a median duration of 9 days. Modafinil administration was associated with a small, nonsignificant increase in GCS by 0.34 points after controlling for age, baseline severity of illness, and changes in sedation and analgesia over time (95%CI, -0.34 to 0.73 points; P = .0743). No major modafinil-associated adverse effects were observed. Modafinil administration did not significantly improve cognitive function in ICU patients within 48 hours of initiation. However, because of lack of robust evidence, the impact of modafinil on overall patient outcomes in the ICU remains unclear and needs further investigation.
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http://dx.doi.org/10.1002/jcph.1002DOI Listing
February 2018

Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury.

Chest 2018 01 18;153(1):133-142. Epub 2017 Aug 18.

Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA; Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA.

Background: Enoxaparin 30 mg twice daily and dalteparin 5,000 units once daily are two common low-molecular-weight heparin (LMWH) thromboprophylaxis regimens used in the trauma population. Pharmacodynamic studies suggest that enoxaparin provides more potent anticoagulation than does dalteparin.

Methods: In 2009, our institution switched its formulary LMWH from enoxaparin to dalteparin followed by a switch back to enoxaparin in 2013. Using a difference in differences design, we contrasted the change in the VTE rate accompanying the LMWH switch with the change in a control group of trauma patients given unfractionated heparin (UFH) during the same period.

Results: The study included 5,880 patients: enoxaparin period (enoxaparin, n = 2,371; UFH, n = 1,539) vs the dalteparin period (dalteparin, n = 1,046; UFH, n = 924). The VTE rate was unchanged in the LMWH group: 3.3/1000 days in the enoxaparin period vs 3.8/1000 days in the dalteparin period: rate ratio (RR), 1.16; 95% CI 0.74-1.81. The rate was also unchanged in the UFH control subjects: 5.7/1,000 days in the enoxaparin period vs 5.2/1,000 days in the dalteparin period: RR, 0.92; 95% CI, 0.61-1.38. After confounding adjustment, the ratio of the change in VTE rate between the LMWH and UFH groups was similar: RR, 1.06; 95% CI 0.71-2.00. A secondary analysis excluding patients with delayed or interrupted prophylaxis (or both) altered this estimate nonsignificantly in favor of enoxaparin: RR, 2.39; 95% CI, 0.80-7.09.

Conclusions: Our results suggest that dalteparin has an effectiveness similar to that of enoxaparin in real-world trauma patients. Future research should investigate how the timing and consistency of prophylaxis affects LMWH effectiveness.
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http://dx.doi.org/10.1016/j.chest.2017.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812768PMC
January 2018

One-Year Experience With a Mobile Extracorporeal Life Support Service.

Ann Thorac Surg 2017 Nov 29;104(5):1509-1515. Epub 2017 Jun 29.

Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Severe acute respiratory distress syndrome is associated with a high mortality rate. The International Extracorporeal Membrane Oxygenation Network recommends regionalization of extracorporeal life support (ECLS) to high-volume centers and development of mobile ECLS teams to rescue patients with severe acute respiratory disease.

Methods: A tertiary medical center developed a mobile team and the infrastructure to support a ECLS transport service available 24 hours a day, 7 days a week. We conducted a retrospective study of all consecutive patients presenting for ECLS for severe acute respiratory distress syndrome from outside hospitals through our mobile ECLS program associated with hemodynamic instability from January 1, 2015, until December 31, 2015.

Results: During the study period, 106 consultations for ECLS were received, and 36 patients were placed on ECLS. Of these 36 ECLS patients, 11 were deemed stable enough for transport before ECLS, and 21 required mobile ECLS by the mobile ECLS, with a survival of 67% (14 of 21). The other 4 ECLS patients were inhouse patients and therefore received ECLS in a nonmobile fashion. In addition, 28 patients were transferred to our hospital who did not receive ECLS. Patient survival increased significantly with increased experience with the program, as the highest mortality rates were early in the program (p = 0.006), and in conjunction with stricter adherence to our exclusion criteria.

Conclusions: The formation of a mobile ECLS program is a complex undertaking that took 2 years of planning to develop. Development of criteria for ECLS implementation can guide appropriate resources utilization and may prevent their use in patients with little to no chance of survival.
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http://dx.doi.org/10.1016/j.athoracsur.2017.03.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650915PMC
November 2017

In Response.

Anesth Analg 2017 08;125(2):706-707

Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, Pulmonary, Allergy, and Critical Care Division Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Division of Cardiothoracic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Department of Pharmacy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Department of Anesthesiology and Critical Care Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Departments of Anesthesiology, Mayo Hospital, Phoenix, Arizona Department of Anesthesiology and Critical Care Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Division of Cardiothoracic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Department of Anesthesiology and Critical Care Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Division of Cardiothoracic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1213/ANE.0000000000002248DOI Listing
August 2017

Diversity in the Emerging Critical Care Workforce: Analysis of Demographic Trends in Critical Care Fellows From 2004 to 2014.

Crit Care Med 2017 May;45(5):822-827

1Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 2Center for Perioperative Outcomes Research and Transformation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 3Center for Healthcare Improvement and Patient Safety, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 4Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA. 5Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program, Indianapolis, IN. 6NIH-NHLBI PRIDE Research in Implementation Science for Equity, San Francisco, CA. 7Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 8Division of General Internal Medicine, Department of Medicine, Perelman School of Medicine, Philadelphia, PA. 9Office of Diversity and Inclusion, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objectives: Diversity in the physician workforce is essential to providing culturally effective care. In critical care, despite the high stakes and frequency with which cultural concerns arise, it is unknown whether physician diversity reflects that of critically ill patients. We sought to characterize demographic trends in critical care fellows, who represent the emerging intensivist workforce.

Design: We used published data to create logistic regression models comparing annual trends in the representation of women and racial/ethnic groups across critical care fellowship types.

Setting: United States Accreditation Council on Graduate Medical Education-approved residency and fellowship training programs.

Subjects: Residents and fellows employed by Accreditation Council on Graduate Medical Education-accredited training programs from 2004 to 2014.

Interventions: None.

Measurements And Main Results: From 2004 to 2014, the number of critical care fellows increased annually, up 54.1% from 1,606 in 2004-2005 to 2,475 in 2013-2014. The proportion of female critical care fellows increased from 29.5% (2004-2005) to 38.3% (2013-2014) (p < 0.001). The absolute number of black fellows increased each year but the percentage change was not statistically significantly different (5.1% in 2004-2005 vs 3.9% in 2013-2014; p = 0.92). Hispanic fellows increased in number from 124 (7.7%) in 2004-2005 to 216 (8.4%) in 2013-2014 (p = 0.015). The number of American Indian/Alaskan Native/Native Hawaiian/Pacific Islander fellows decreased from 15 (1.0%) to seven (0.3%) (p < 0.001). When compared with population estimates, female critical care fellows and those from racial/ethnic minorities were underrepresented in all years.

Conclusions: The demographics of the emerging critical care physician workforce reflect underrepresentation of women and racial/ethnic minorities. Trends highlight increases in women and Hispanics and stable or decreasing representation of non-Hispanic underrepresented minority critical care fellows. Further research is needed to elucidate the reasons underlying persistent underrepresentation of racial and ethnic minorities in critical care fellowship programs.
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http://dx.doi.org/10.1097/CCM.0000000000002322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392161PMC
May 2017

Statistics Myth Busters: Dispelling Common Misperceptions Held by Readers of the Biomedical Literature.

Ann Pharmacother 2017 May 7;51(5):429-438. Epub 2017 Jan 7.

2 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Proficiency in research design and statistical analysis is crucial to the success of a clinical pharmacist. However, new pharmacy graduates and residents may not have received adequate training and education in these areas. During the authors' tenure as clinical pharmacists, several statistical "myths" were consistently maintained by residents and new clinical practitioners. The purpose of this narrative review is to discuss and dispel several of these statistical fallacies. The myths discussed involve 3 common areas of consideration when evaluating any clinical study: assessing the risk of bias from confounding (propensity score analysis and multivariable modeling), interpretation of the main study findings ( P values and hypothesis testing), and secondary evaluations (subgroup analyses). Literature examples are used to illustrate each of the topics. The authors hope that the discussion will augment each pharmacist's knowledge of medical literature interpretation leading to improvements in patient care, education of future residents, and personal research endeavors.
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http://dx.doi.org/10.1177/1060028016686356DOI Listing
May 2017

Veno-Venous Extracorporeal Life Support in Hemodynamically Unstable Patients With ARDS.

Anesth Analg 2017 03;124(3):846-848

From the *Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; †Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ‡Division of Cardiothoracic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; §Department of Pharmacy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ‖Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

When clinicians consider extracorporeal life support (ECLS) for acute respiratory distress syndrome (ARDS) patients with hemodynamic instability, both veno-arterial (VA) and veno-venous (VV) ECLS are therapeutic possibilities. We analyzed 17 patients with ARDS on inotropic or vasopressor support requiring ECLS for refractory hypoxemia. After implementing VV ECLS, pressor requirements (based on norepinephrine equivalents) were significantly lower in all patients (P = .0001 for overall comparison across time points). None of the 17 patients required conversion from VV ECLS to VA ECLS (95% confidence interval 0%-20.0%). In this sample of 17 patients with substantial baseline vasopressor support and hypoxemic respiratory failure, initiation of VV ECLS was associated with reduced pressor requirements. Such a strategy may help avoid complications of VA ECLS in patients with both respiratory and hemodynamic failure.
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http://dx.doi.org/10.1213/ANE.0000000000001646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313331PMC
March 2017

Comparison of Thrombelastography-Derived Fibrinogen Values at Rewarming and Following Cardiopulmonary Bypass in Cardiac Surgery Patients.

Anesth Analg 2016 09;123(3):570-7

From the *Department of Anesthesiology, University of Miami, Miami, Florida; †Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania; and ‡Department of Biostatistics and Epidemiology, Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: The inflated costs and documented deleterious effects of excess perioperative transfusion have led to the investigation of targeted coagulation factor replacement strategies. One particular coagulation factor of interest is factor I (fibrinogen). Hypofibrinogenemia is typically tested for using time-consuming standard laboratory assays. The thrombelastography (TEG)-based functional fibrinogen level (FLEV) provides an assessment of whole blood clot under platelet inhibition to report calculated fibrinogen levels in significantly less time. If FLEV values obtained on cardiopulmonary bypass (CPB) during rewarming are similar to values obtained immediately after the discontinuation of CPB, then rewarming values could be used for preemptive ordering of appropriate blood product therapy.

Methods: Fifty-one cardiac surgery patients were enrolled into this prospective nonrandomized study to compare rewarming fibrinogen values with postbypass values using TEG FLEV assays. Baseline, rewarming, and postbypass fibrinogen values were recorded for all patients using both standard laboratory assay (Clauss method) and FLEV. Mixed-effects regression models were used to examine the change in TEG FLEV values over time. Bland-Altman analysis was used to examine bias and the limits of agreement (LOA) between the standard laboratory assay and FLEVs.

Results: Forty-nine patients were included in the analysis. The mean FLEV value during rewarming was 333.9 mg/dL compared with 332.8 mg/dL after protamine, corresponding to an estimated difference of -1.1 mg/dL (95% confidence interval [CI], -25.8 to 23.6; P = 0.917). Rewarming values were available on average 47 minutes before postprotamine values. Bland-Altman analysis showed poor agreement between FLEV and standard assays: mean difference at baseline was 92.5 mg/dL (95% CI, 71.1 to 114.9), with a lower LOA of -56.5 mg/dL (95% CI, -94.4 to -18.6) and upper LOA of 242.4 mg/dL (95% CI, 204.5 to 280.3). The difference between assays increased after CPB and persisted after protamine administration.

Conclusions: Our results revealed negligible change in FLEV values from the rewarming to postbypass periods, with a CI that does not include clinically meaningful differences. These findings suggest that rewarming samples could be utilized for ordering fibrinogen-specific therapies before discontinuation of CPB. Mean FLEV values were consistently higher than the reference standard at each time point. Moreover, bias was highly heterogeneous among samples, implying a large range of potential differences between assays for any 1 patient.
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http://dx.doi.org/10.1213/ANE.0000000000001465DOI Listing
September 2016

The incidence of un-indicated preoperative testing in a tertiary academic ambulatory center: a retrospective cohort study.

Perioper Med (Lond) 2015 15;4:14. Epub 2015 Dec 15.

Department of Anesthesiology and Critical Care, Perelman School of Medicine, Senior Scholar, Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania USA.

Background: Despite existing evidence and guidelines advocating for appropriate risk stratification, ambulatory surgery in low-risk patients continues to be accompanied by a battery of routine tests prior to surgery. Using a single-center retrospective cohort study, we aimed to quantify the incidence of un-indicated preoperative testing in an academic ambulatory center by utilizing recommendations by the recently developed American Society of Anesthesiology (ASA) "Choosing Wisely" Top-5 list.

Methods: We utilized data from the EPIC medical records of 3111 patients who had ambulatory surgery at the Hospital of the University of Pennsylvania during a 6-month period. Data were abstracted from laboratory studies- complete blood count, electrolyte panel, coagulation studies, and cardiac studies-stress test, and echocardiogram obtained within 30 days prior to surgery. Preoperative tests obtained from each patient were categorized into "indicated" (ASA ≥ 3) and "un-indicated" (ASA 1 and 2) tests, and percentages were reported.

Results: During the study period, 52.9 % (95 % confidence interval (CI) 37.6-66.4) of all patients had at least one un-indicated laboratory test performed preoperatively. Further analysis revealed variation in the incidence of preoperative ordering between tests; 73 % of all complete blood counts (CBCs), 70 % of all metabolic panels, and 49 % of all coagulation studies were considered un-indicated by "Top-5 List" criteria. Stated differently, of the patients included in the sample, 51 % of patients received an un-indicated CBC, 41 % an un-indicated metabolic panel, and 16 % un-indicated coagulation studies. Twelve percent of "any un-indicated preoperative test" were obtained from ASA 1 healthy patients. Of the 587 patients less than 36 years old, 331 (56 %) had at least one test that was deemed un-indicated. Forty-one patients had either an echocardiogram or stress test ordered and performed within 30 days of surgery. Of these, eight (19.5 %) studies were un-indicated as determined by chart review.

Conclusions: The incidence of ordering "at least one un-indicated preoperative test" in low-risk patients undergoing low-risk surgery remains high even in academic tertiary institutions. In the emerging era of optimizing patient safety and financial accountability, further studies are needed to better understand the problem of overuse while identifying modifiable attitudes and institutional influences on perioperative practices among all stakeholders involved. Such information would drive the development of feasible interventions.
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http://dx.doi.org/10.1186/s13741-015-0023-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681056PMC
December 2015