Improving Outcomes in Mechanically Ventilated Adult ICU Patients Following Implementation of the ICU Liberation (ABCDEF) Bundle Across a Large Healthcare System.

OBJECTIVES: To measure how the ICU Liberation Bundle (aka ABCDEF Bundle or the Bundle) affected clinical outcomes in mechanically ventilated (MV) adult ICU patients, as well as bundle sustainability and spread across a healthcare system. DESIGN: We conducted a multicenter, prospective, cohort observational study to measure bundle performance versus patient outcomes and sustainability in 11 adult ICUs at six community hospitals. We then prospectively measured bundle spread and performance across the other 28 hospitals of the healthcare system. SETTING: A large community-based healthcare system. PATIENTS: In 11 study ICUs, we enrolled 1,914 MV patients (baseline n = 925, bundle performance/outcomes n = 989), 3,019 non-MV patients (baseline n = 1,323, bundle performance/outcomes n = 1,696), and 2,332 MV patients (bundle sustainability). We enrolled 9,717 MV ICU patients in the other 28 hospitals to assess bundle spread. INTERVENTIONS: We used evidence-based strategies to implement the bundle in all 34 hospitals. MEASUREMENTS AND MAIN RESULTS: We compared outcomes for the 12-month baseline and bundle performance periods. Bundle implementation reduced ICU length of stay (LOS) by 0.5 days (p = 0.02), MV duration by 0.6 days (p = 0.01), and ICU LOS greater than or equal to 7 days by 18.1% (p < 0.01). Performance period bundle compliance was compared with the preceding 3-month baseline compliance period. Compliance with pain management and spontaneous awakening trial (SAT) and spontaneous breathing trial (SBT) remained high, and reintubation rates remained low. Sedation assessments increased (p < 0.01) and benzodiazepine sedation use decreased (p < 0.01). Delirium assessments increased (p = 0.02) and delirium prevalence decreased (p = 0.02). Patient mobilization and ICU family engagement did not significantly improve. Bundle element sustainability varied. SAT/SBT compliance dropped by nearly half, benzodiazepine use remained low, sedation and delirium monitoring and management remained high, and patient mobility and family engagement remained low. Bundle compliance in ICUs across the healthcare system exceeded that of study ICUs. CONCLUSIONS: The ICU Liberation Bundle improves outcomes in MV adult ICU patients. Evidence-based implementation strategies improve bundle performance, spread, and sustainability across large healthcare systems.

Clinical and Immunologic Correlates of Vasodilatory Shock Among Ebola Virus-Infected Nonhuman Primates in a Critical Care Model.

BACKGROUND: Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. METHODS: Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. RESULTS: We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. CONCLUSIONS: Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.

Long-term survival outcomes of esophageal cancer after minimally invasive Ivor Lewis esophagectomy.

OBJECTIVES: The aim of this study was to determine the long-term overall and disease-free survival and factors associated with overall survival in patients with esophageal cancer undergoing a totally minimally invasive Ivor Lewis esophagectomy (MILE) at a safety-net hospital. METHODS: This was a single-center retrospective review of consecutive patients who underwent MILE from September 2013 to November 2017. Overall and disease-free survival were analyzed by Kaplan-Meier estimates, and hazard ratios (HR) were derived from multivariable Cox regression models. RESULTS: Ninety-six patients underwent MILE during the study period. Overall survival at 1, 3, and 5 years was 83.2%, 61.9%, and 55.9%, respectively. Disease-free survival at 1, 3, and 5 years was 83.2%, 60.6%, and 47.5%, respectively. Overall survival (p < 0.001) and disease-free survival (p < 0.001) differed across pathological stages. By multivariable analysis, increasing age (HR, 1.06; p = 0.02), decreasing Karnofsky performance status score (HR, 0.94; p = 0.002), presence of stage IV disease (HR, 5.62; p = 0.002), locoregional recurrence (HR, 2.94; p = 0.03), and distant recurrence (HR, 4.78; p < 0.001) were negatively associated with overall survival. Overall survival significantly declined within 2 years and was independently associated with stage IV disease (HR, 3.29; p = 0.04) and distant recurrence (HR, 5.78; p < 0.001). CONCLUSION: MILE offers favorable long-term overall and disease-free survival outcomes. Age, Karnofsky performance status score, stage IV, and disease recurrence are shown to be prognostic factors of overall survival. Prospective studies comparing long-term outcomes after different MIE approaches are warranted to validate survival outcomes after MILE.

The Vaginal Microbiome of Nonhuman Primates Can Be Only Transiently Altered to Become Lactobacillus Dominant without Reducing Inflammation.

The vaginal microbiome composition in humans is categorized based upon the degree to which one of four species of Lactobacillus is dominant (Lactobacillus crispatus, community state type I [CST I], Lactobacillus gasseri, CST II, Lactobacillus iners, CST III, and Lactobacillus jensenii, CST V). Women with a vaginal microbiome not dominated by one of the four Lactobacillus species tend to have a more diverse microbiome, CST IV. CSTs I, II, III, and V are common in North America and Europe and are associated with lower incidences of some pathogens, such as human immunodeficiency virus (HIV), human papillomavirus (HPV), and Gardnerella vaginalis. As a result, therapeutic interventions to change the composition of the vaginal microbiomes are under development. However, Homo sapiens is the only mammalian species which has high frequencies of Lactobacillus-dominated vaginal microbiomes. Here, we treated female nonhuman primates (NHPs) with regimens of metronidazole and high levels of L. crispatus to determine how well these animals could be colonized with L. crispatus, how this influenced the immunological milieu, and how Lactobacillus treatment influenced or was influenced by the endogenous vaginal microbiome. We find that NHPs can transiently be colonized with L. crispatus, that beta diversity and not the number of doses of L. crispatus or pretreatment with metronidazole predicts subsequent L. crispatus colonization, that L. crispatus does not alter the local immunological milieu, and that the vaginal microbiome composition was resilient, normalizing by 4 weeks after our manipulations. Overall, this study suggests these animals are not amenable to long-term L. crispatus colonization. IMPORTANCE NHPs have proven to be invaluable animal models for the study of many human infectious diseases. The use of NHPs to study the effect of the microbiome on disease transmission and susceptibility is limited due to differences between the native microbiomes of humans and NHPs. In particular, Lactobacillus dominance of the vaginal microbiome is unique to humans and remains an important risk factor in reproductive health. By assessing the extent to which NHPs can be colonized with exogenously applied L. crispatus to resemble a human vaginal microbiome and examining the effects on the vaginal microenvironment, we highlight the utility of NHPs in analysis of vaginal microbiome manipulations in the context of human disease.

Improved Quality of Care and Efficiency Do Not Always Mean Cost Recovery After Minimally Invasive Ivor Lewis Esophagectomy.

PURPOSE: The aim of this study is to determine the financial impact of clinical complications and outcomes after minimally invasive Ivor Lewis esophagectomy (MILE) at a safety-net hospital. METHODS: This was a single-center retrospective analysis of consecutive patients undergoing MILE from 2013 to 2018. Postoperative complications were classified by Clavien-Dindo grade and associated total and direct recovered costs were assessed. Direct cost and LOS index were defined as the ratio of observed to expected values (>1 denotes above nationwide expectations). Annual outcomes were based on Medicare fiscal years. RESULTS: One hundred twenty-four patients (99 males, mean age 65.7 ± 9.3) were surgically treated for esophageal malignancy (n = 118) and benign disease (n = 6) by MILE between 2014 and 2018. Mean ICU LOS (5.8 ± 6.6 versus 4.3 ± 6.3 days) and LOS index (1.16 versus 0.76) improved from 2014 to 2018. Both direct cost index (1.03 versus 0.99) and indirect costs (43.4% versus 41.4%) decreased over time. However, direct costs recovered (213.6 to 159.0%) and total costs recovered (119.1 to 92.5%) declined during this period. Clinical complications grade was not associated with total costs recovered (p = 0.69). Extent of recovered expenditure was significantly higher from commercial/private payers as compared to government-sponsored payers (p < 0.05). CONCLUSION: Improvement in clinical outcomes and efficiency of care are not reflected by annual recovered expenditure. Furthermore, clinical complications do not correlate with the ability to recover hospital spending. Financial recovery was primary payer dependent. Enhanced collaboration with hospital administration may be needed in an effort to maximize financial fidelity in the presence of good quality of care after highly complex procedures.

Venous thromboembolism prevention compliance: A multidisciplinary educational approach utilizing NSQIP best practice guidelines.

BACKGROUND: Review of our institutional National Surgical Quality Improvement Project (NSQIP) data found higher rate of Venous Thromboembolic Events (VTE) (2.5% vs. 1.1%). Compared to the national benchmark. Our goal was to identify opportunities for quality improvement. METHODS: We compared NSQIP general surgery data from January 2015-December 2016 (period 1) to January 2017-December 2018 (period 2). A multidisciplinary committee was developed and patient centered education implemented to enhance VTE compliance. RESULTS: Over 50% of all the patients who developed VTE were non-compliant with chemical prophylaxis. The majority of non-compliance was due to pain. During period 1 there were 12 VTEs in 482 cases, while in period two, 18 VTEs in 2347 cases (2.5% vs. 0.8%; RR 2.3, 95% CI 1.5-3.7, p < 0.001). Missed chemical prophylaxis decreased from 50 to 17 per week after the intervention. CONCLUSION: A multidisciplinary, patient centered approach to increase VTE prevention decreases VTE rates to below a comparable benchmark.

Serum Albumin Trend Is a Predictor of Mortality in ICU Patients With Sepsis.

INTRODUCTION: Patients admitted to the hospital with sepsis are 8 times more likely to die than patients with other diagnoses. There is no diagnostic test that clearly identifies the presence of the dysregulated host response that is central to sepsis. Researchers have identified serum albumin as a possible predictor of mortality in a number of critically ill patient populations. However, these studies primarily focus on the levels on admission, neglecting the clinically significant decrease that occurs subsequently. The purpose of this study was to examine the relationship between the trend of serum albumin over time and mortality in adults admitted to the intensive care unit (ICU) with sepsis. METHODS: This retrospective, correlational study used existing medical record data. All patients admitted to the ICU at a Midwestern regional medical center with a primary sepsis diagnosis were included in the initial sample. Logistic regression analysis was used to assess the ability of serum albumin to predict mortality. RESULTS: Serum albumin trend, admission serum albumin level, and lowest serum albumin level were significant unique predictors of mortality. The probability of survival decreases by 70.6% when there is a strong negative trend in serum albumin level, by 63.4% when admission serum albumin is ≤2.45 g/dl, and by 76.4% when the lowest serum albumin is ≤1.45 g/dl. CONCLUSION: Clinicians are encouraged to measure serum albumin levels in patients with sepsis. Low serum albumin levels and a strong negative trend in serial measurements should instigate aggressive monitoring and treatment in this population.

Improving Glycemic Control Safely in Non-Critical Care Patients: A Collaborative Systems Approach in Nine Hospitals.

BACKGROUND: Practice variations in insulin management and glycemic adverse events led nine Dignity Health hospitals to initiate a collaborative effort to improve hypoglycemia, uncontrolled hyperglycemia, and glycemic control. METHODS: Non-critical care adult inpatients with ≥4 point-of-care blood glucose (BG) readings in a ≥2-day period were included. Balanced glucometric goals for each hospital were individualized to improve performance by 10%-20% from baseline or achieve top performance derived from Society of Hospital Medicine (SHM) benchmarking studies. Baseline measures (2011) were compared to mature results (postintervention, 2014). Protocols for insulin management and hypoglycemia prevention were piloted at one facility and were then spread to the cohort. Interventions included standardized order sets, education, mentoring from physician experts, feedback of metrics, and measure-vention (coupling measurement of patients "off protocol" with concurrent intervention to correct lapses in care). RESULTS: The day-weighted mean BG for the cohort improved by 11.4 mg/dL (95% confidence interval [CI]: 11.0-11.8]; all nine sites improved. Eight of the sites reduced severe hyperglycemic days, and the percentage of patient-days with any BG > 299 mg/dL for the total cohort improved from 11.6% to 8.8% (relative risk, 0.76 [95% CI: 0.74-0.78]). The percentage of patient-days with any BG < 70 mg/dL remained unchanged at 3.6%. Eight of the sites either reduced hypoglycemia by 20% or achieved SHM best-quartile rates. CONCLUSION: Multihospital improvements in glycemic control and severe hyperglycemia without significant increases in hypoglycemia are feasible using portable low-cost toolkits and metrics.

IMPROVING GLYCEMIC CONTROL SAFELY IN CRITICAL CARE PATIENTS: A COLLABORATIVE SYSTEMS APPROACH IN NINE HOSPITALS.

OBJECTIVE: Safely improve glycemic control in the critical care units of nine hospitals. METHODS: Critical care adult inpatients from nine hospitals with ≥4 point-of-care blood glucose (BG) readings over ≥2 days were targeted by collaborative improvement efforts to reduce hyper- and hypoglycemia. Balanced glucometric goals for each hospital were set targeting improvement from baseline or goals deemed desirable from Society of Hospital Medicine (SHM) benchmarking data. Collaborative interventions included standardized insulin infusion protocols, hypoglycemia prevention bundles, audit and feedback, education, and measure-vention (coupling measurement of patients "off protocol" with concurrent interventions to correct suboptimal care). RESULTS: All sites improved glycemic control. Six reached prespecified levels of improvement of the day-weighted mean BG. The day-weighted mean BG for the cohort decreased by 7.7 mg/dL (95% confidence interval [CI], 7.0 mg/dL to 8.4 mg/dL) to 151.3 mg/dL. Six of nine sites showed improvement in the percent intensive care unit (ICU) days with severe hyperglycemia (any BG >299 mg/dL). ICU severe hyperglycemic days declined from 8.6 to 7.2% for the cohort (relative risk, 0.84; 95% CI, 0.80 to 0.88). Patient days with any BG <70 mg/dL were reduced by 0.4% (95% CI, 0.06% to 0.6%), from 4.5 to 4.1%, for a small but statistically significant reduction in hypoglycemia. Seven of nine sites showed improvement. CONCLUSION: Multihospital improvements in ICU glycemic control, severe hyperglycemia, and hypoglycemia are feasible. Balanced goals for glycemic control and hypoglycemia in the ICU using SHM benchmarks and metrics enhanced successful improvement efforts with good staff acceptance and sustainability. ABBREVIATIONS: BG = blood glucose CMI = case-mix index CY = calendar year DKA = diabetic ketoacidosis EMR = electronic medical record GBMF = Gordon and Betty Moore Foundation ICU = intensive care unit IIP = insulin infusion protocol SHM = Society of z Hospital Medicine.

Hospital delay in South Asian patients with acute ST-elevation myocardial infarction in the UK.

BACKGROUND: South Asians presenting with chest pain in the UK experience disproportionately greater delays with respect to diagnosis and treatment for acute myocardial infarction (AMI). The duration of time between symptom onset and hospital intervention is a critical delay for AMI but there are limited data amongst South Asians. The objectives of this study were to investigate ethnic differences in hospital delay and to look at short-term outcomes in South Asian and White patients presenting with AMI. METHODS: Between 2004 and 2009, data were collected from 672 AMI patients with ST elevation who subsequently received percutaneous coronary intervention at Sandwell and West Birmingham Hospitals NHS Trust (UK). The hospital delay between the onset of symptoms and arrival time (pre-hospital), and between arrival time and intervention (post-hospital) was calculated. RESULTS: South Asians were more likely to be in the upper tertile of hospital delay (pre-hospital odds ratio, OR, 1.44, 95% CI 0.93-2.24, p = 0.06; post-hospital OR 1.83, 95% CI 1.05-3.21, p = 0.015), contributing to an overall hospital delay that was longer (median 314, interquartile range, IQR, 195-679 min) than in Whites (median 240, IQR 182-468 min). Women were more likely to be in the upper tertile for pre-hospital delay than men (p = 0.01) and South Asian ethnicity was an independent predictor of post-hospital delay (p = 0.003). CONCLUSIONS: While the reasons for ethnic differences in AMI-related hospital delay are likely to be multifactorial and complex, there is an urgent need to promote change in both the South Asian patient (delays in arrival) and their treatment (delays in intervention).

Analysis of genetic alterations and clonal proliferation in children treated for acute lymphocytic leukemia.

The development of risk-directed treatment protocols over the last 25 years has resulted in an increase in the survival rates of children treated for cancer. As a consequence, there is a growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapy is unknown. We previously reported that children treated for acute lymphocytic leukemia have significantly elevated somatic mutant frequencies at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in their peripheral T cells. To understand the molecular etiology of the increase in mutant frequencies following chemotherapy, we investigated the HPRT mutation spectra and the extent of clonal proliferation in 562 HPRT T cell mutant isolates of 87 blood samples from 47 subjects at diagnosis, during chemotherapy, and postchemotherapy. We observed a significant increase in the proportion of CpG transitions following treatment (13.6-23.3%) compared with healthy controls (4.0%) and a significant decrease in V(D)J-mediated deletions following treatment (0-6.8%) compared with healthy controls (17.0%). There was also a significant change in the class type percentage of V(D)J-mediated HPRT deletions following treatment. In addition, there was a >5-fold increase in T cell receptor gene usage-defined mean clonal proliferation from diagnosis compared with the completion of chemotherapeutic intervention. These data indicate that unique genetic alterations and extensive clonal proliferation are occurring in children following treatment for acute lymphocytic leukemia that may influence long-term risks for multifactorial diseases, including secondary cancers.

Analysis of microsatellite instability in children treated for acute lymphocytic leukemia with elevated HPRT mutant frequencies.

Survival rates of children treated for cancer have increased dramatically over the last 25 years following the development of risk-directed multi-modality treatment protocols. As a result, there is a rapidly growing population of children and young adult cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. We have previously observed that children treated for acute lymphocytic leukemia (ALL) have significantly increased somatic mutant frequencies (Mfs) (30- to 1300-fold higher) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene in their non-malignant peripheral T cells compared with children at diagnosis or controls. In order to gain insight into the etiology of the observed dramatic increase in Mfs following antineoplastic therapy, we investigated the prevalence of microsatellite instability (MSI), reflective of a defect in DNA mismatch repair (MMR), in children with ALL at diagnosis, during and after chemotherapy and compared them with healthy age-matched controls. MSI analysis using five microsatellite markers was performed on 167 T cell isolates from 40 healthy children and on 842 T cell isolates from 50 patients treated for ALL. High-frequency MSI (MSI-high) was identified in 2 healthy children (5%) and in 2 of 20 ALL subjects at the time of disease recurrence (relapse) (10%). There was no statistically significant difference between the prevalence of MSI-high in patients at the time of ALL relapse and healthy children, nor between the children with ALL at other time points and healthy children. These data indicate that MMR defects, represented by MSI, are not a significant contributor to the elevated HPRT Mfs seen in children treated for ALL. However, in a small number of patients chemotherapy may play a role in the selection of cells with defects in MMR that may have long-term clinical implications.

Genotoxicity of therapeutic intervention in children with acute lymphocytic leukemia.

The survival rates of children treated for cancer have dramatically increased after the development of standardized multiple-modality treatment protocols. As a result, there is a rapidly growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. To study the genotoxic effects of antineoplastic treatment in children, we performed a comparative analysis of the changes in the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT)-reporter gene in children treated for acute lymphocytic leukemia (ALL). We measured HPRT Mfs from 130 peripheral blood samples from 45 children with ALL (13, low risk; 22, standard risk; and 10, high risk) from the time of diagnosis, as well as during and after the completion of therapy. We observed a significant increase in mean HPRT Mfs during each phase of therapy (diagnosis, 1.4 x 10(-6); consolidation, 52.1 x 10(-6); maintenance, 93.2 x 10(-6); and off-therapy, 271.7 x 10(-6)) that were independent of the risk group treatment protocol used. This 200-fold increase in mean somatic Mf remained elevated years after the completion of therapy. We did not observe a significant difference in the genotoxicity of each risk group treatment modality despite differences in the compositional and clinical toxicity associated with these treatment protocols. These findings suggest that combination chemotherapy used to treat children with ALL is quite genotoxic, resulting in an increased somatic mutational load that may result in an elevated risk for the development of multi-factorial diseases, in particular second malignancies.

Comparative analysis of HPRT mutant frequency in children with cancer.

The link between exposure to environmental mutagens and the development of cancer is well established. Yet there is a paucity of data on the relationship between gene-environment interactions and the mechanisms associated with the somatic mutational events involved with malignant transformation, especially in children. To gain insight into somatic mutational mechanisms in children who develop cancer, we determined the background mutant frequency (Mf) in the hypoxanthine phosphoribosyl transferase (HPRT) reporter gene of peripheral blood lymphocytes from pediatric cancer patients at the time of diagnosis and prior to therapeutic intervention. We studied 23 children with hematologic malignancies and 31 children with solid tumors prior to initial therapeutic intervention. Children with solid tumors, specifically sarcomas, and Hodgkin's disease were significantly older and had elevated HPRT Mfs (6.1 x 10(-6) and 3.7 x 10(-6), respectively) at the time of diagnosis, compared to normal controls (2.3 x 10(-6)) and other pediatric tumor groups including children with acute lymphocytic leukemia and non-Hodgkin's lymphoma (ALL/NHL, 1.7 x 10(-6)), central nervous system tumors (CNS, 3.6 x 10(-6)), and neuroblastoma (1.9 x 10(-6)). Of importance is that the significant differences observed in HPRT Mfs between these groups no longer existed after correcting for the effects of age. These data demonstrate that in children who develop cancer there appears to be no significant increase in background HPRT Mf that would indicate significant exposure to genotoxic chemicals or an underlying DNA repair defect resulting in genomic instability. In addition, these data demonstrate the importance of correcting for the effect of age when comparing the frequency of somatic mutations in children and should provide baseline data for future longitudinal biomonitoring studies on the genetic effects of chemotherapy in children treated for cancer.

Mutational spectral analysis at the HPRT locus in healthy children.

There is growing evidence linking somatic mutational events during fetal development and childhood to an increasing number of multifactorial human diseases. Despite this, little is known about the relationship between endogenous and environmentally induced exogenous mutations during human development. Here we describe a comparative spectral analysis of somatic mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene locus in healthy children. We observed an age-specific decrease in the proportion of large alterations and a corresponding increase in the proportion of small alterations with increasing age following birth (P<0.001). The age specific decrease in the proportion of large alterations (67-30%) was mainly due to a decrease in the proportion of aberrant variable (V), diversity (D) and joining (J) (V(D)J) recombinase mediated HPRT deletions (P<0.001). The increase in the proportion of small alterations with age (28-64%) was associated with an increase in transversions from 8% in children at the late stages of fetal development to 31% in children 12-16 years old (P=0.003). Transitions decreased with age, especially at CpG dinucleotides (P=0.010), as transversions increased (P=0.009). These patterns of mutations provide insight into important spontaneous, genotoxic, and site-specific recombinational somatic mutational events associated with the age-specific development of human disease in children as well as adults.