The epidemiology and clinical outcomes of ventilator-associated events among 20,769 mechanically ventilated patients at intensive care units: an observational study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection (HAI) in intensive care units (ICUs). Ventilator-associated event (VAE), a more objective definition, has replaced traditional VAP surveillance and is now widely used in the USA. However, the adoption outside the USA is limited. This study aims to describe the epidemiology and clinical outcomes of VAEs in China, based on a prospectively maintained registry. METHODS: An observational study was conducted using an ICU-HAI registry in west China. Patients that were admitted to ICUs and underwent mechanical ventilation (MV) between April 1, 2015, and December 31, 2018, were included. The characteristics and outcomes were compared between patients with and without VAEs. The rates of all VAEs dependent on different ICUs were calculated, and the pathogen distribution of patients with possible VAP (PVAP) was described. RESULTS: A total of 20,769 ICU patients received MV, accounting for 21,723 episodes of mechanical ventilators and 112,697 ventilator-days. In all, we identified 1882 episodes of ventilator-associated condition (VAC) events (16.7 per 1000 ventilator-days), 721 episodes of infection-related ventilator-associated complications (IVAC) events (6.4 per 1000 ventilator-days), and 185 episodes of PVAP events (1.64 per 1000 ventilator-days). The rates of VAC varied across ICUs with the highest incidence in surgical ICUs (23.72 per 1000 ventilator-days). The median time from the start of ventilation to the onset of the first VAC, IVAC, and PVAP was 5 (3-8), 5 (3-9), and 6 (4-13) days, respectively. The median length of hospital stays was 28.00 (17.00-43.00), 30.00 (19.00-44.00), and 30.00 (21.00-46.00) days for the three VAE tiers, which were all longer than that of patients without VAEs (16.00 [12.00-23.00]). The hospital mortality among patients with VAEs was more than three times of those with non-VAEs. CONCLUSIONS: VAE was common in ICU patients with ≥ 4 ventilator days. All tiers of VAEs were highly correlated with poor clinical outcomes, including longer ICU and hospital stays and increased risk of mortality. These findings highlight the importance of VAE surveillance and the development of new strategies to prevent VAEs.

A Novel Algorithm to Analyze Epidemiology and Outcomes of Carbapenem Resistance Among Patients With Hospital-Acquired and Ventilator-Associated Pneumonia: A Retrospective Cohort Study.

BACKGROUND: Carbapenem resistance is a growing concern. Applying a novel algorithm, we examined epidemiology and outcomes of carbapenem resistance among gram-negative pathogens in hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). METHODS: In a retrospective cohort design within the Premier Research database (2009-2016), all hospitalized adult patients with a gram-negative organism in a respiratory or blood culture specimen who fit criteria for HAP/VAP based on International Classification of Diseases, Ninth Revision, Clinical Modification, codes were included in the study. RESULTS: Among 8,969 patients with HAP/VAP, 1,059 isolates (11.8%) were carbapenem-resistant (CR) organisms. Patients with CR organisms were more likely female (41.4% vs 33.2%; P < .001) and medical admissions (33.8% vs 27.4%, P < .001) than those with carbapenem-susceptible (CS) organisms. Patients with carbapenem resistance had higher comorbidity burden than those with carbapenem susceptibility (median [interquartile range] Charlson Comorbidity Index score, 3 [1-4] vs 2 [1-4]; P < .001). Pseudomonas aeruginosa was the most common gram-negative pathogen overall (24.9%) and among CS organisms (23.5%), and was second to Stenotrophomonas maltophilia (44.0%) among CR organisms (35.3%). Acinetobacter baumannii accounted for 11.8% of CR organisms and 2.5% of CS organisms (P < .001). Patients with carbapenem resistance were more likely than those with carbapenem susceptibility to receive inappropriate empiric therapy (25.8% vs 10.0%; P < .001). Carbapenem resistance did not affect adjusted mortality (22.9% CR vs 21.6% CS) or postinfection length of stay (except among survivors of VAP), but it was associated with excess costs ($8,921; 95% CI, 3,864-13,977). CONCLUSIONS: Using administrative data, our novel algorithm identified patients with pneumonia at high risk for death, consistent with HAP/VAP. Among them, carbapenem resistance occurred in 12% of all cases and was associated with substantial excess in hospital costs.

Epidemiology of ICU-acquired pneumonia.

PURPOSE OF REVIEW: Review of the epidemiology of ICU-acquired pneumonia, including both ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) in nonventilated ICU patients, with critical review of the most recent literature in this setting. RECENT FINDINGS: The incidence of ICU-acquired pneumonia, mainly VAP has decrease significantly in recent years possibly due to the generalized implementation of preventive bundles. However, the exact incidence of VAP is difficult to establish due to the diagnostic limitations and the methods employed to report rates. Incidence rates greatly vary based on the studied populations. Data in the literature strongly support the relevance of intubation, not ventilatory support, in the development of HAP in ICU patients, but also that the incidence of HAP in nonintubated patients is not negligible. Despite the fact of a high crude mortality associated with the development of VAP, the overall attributable mortality of this complication was estimated in 13%, with higher mortality rates in surgical patients and those with mid-range severity scores at admission. Mortality is consistently greatest in patients with HAP who require intubation, slightly less in VAP, and least for nonventilated HAP. The economic burden of ICU acquired pneumonia, particularly VAP, is important. The increased costs are mainly related to the longer periods of ventilatory assistance and ICU and hospital stays required by these patients. However, the different impact of VAP on economic burden among countries is largely dependent on the different costs associated with heath care. SUMMARY: VAP has significant impact on mortality mainly in surgical patients and those with mid-range severity scores at admission. The economic burden on ICU-acquired pneumonia depends mainly on the increased length of stay of these patients.

Biomarkers kinetics in the assessment of ventilator-associated pneumonia response to antibiotics - results from the BioVAP study.

PURPOSE: Our aim was to evaluate the role of biomarker kinetics in the assessment of ventilator-associated pneumonia (VAP) response to antibiotics. MATERIALS AND METHODS: We performed a prospective, multicenter, observational study to evaluate in 37 microbiologically documented VAP, the kinetics of C-reactive protein (CRP), procalcitonin (PCT), mid-region fragment of pro-adrenomedullin (MR-proADM). The kinetics of each variable, from day 1 to 6 of therapy, was assessed with a time dependent analysis comparing survivors and non-survivors. RESULTS: During the study period kinetics of CRP as well as its relative changes, CRP-ratio, was significantly different between survivors and non-survivors (p=0.026 and p=0.005, respectively). On day 4 of antibiotic therapy, CRP of survivors was 47% of the initial value while it was 96% in non-survivors. The kinetics of other studied variables did not distinguish between survivors and non-survivors. In survivors the bacterial load also decreased markedly. Adequate initial antibiotic therapy was associated with lower mortality (p=0.025) and faster CRP decrease (p=0.029). CONCLUSIONS: C-reactive protein kinetics can be used to identify VAP patients with poor outcome as soon as four days after the initiation of treatment. (Trial registration - NCT02078999; registered 3 August 2012).

The effectiveness of a bundle in the prevention of ventilator-associated pneumonia

Abstract Objectives The aim of this study was to evaluate the impact of a bundle called FAST HUG in ventilator-associated pneumonia, weigh the healthcare costs of ventilator-associated pneumonia patients in the intensive care unit, and hospital mortality due to ventilator-associated pneumonia. Material and methods The study was performed in a private hospital that has an 8-bed intensive care unit. It was divided into two phases: before implementing FAST HUG, from August 2011 to August 2012 and after the implementation of FAST HUG, from September 2012 to December 2013. An individual form for each patient in the study was filled out by using information taken electronically from the hospital medical records. The following data was obtained from each patient: age, gender, reason for hospitalization, use of three or more antibiotics, length of stay, intubation time, and outcome. Results After the implementation of FAST HUG, there was an observable decrease in the occurrence of ventilator-associated pneumonia (p < 0.01), as well as a reduction in mortality rates (p < 0.01). In addition, the intervention resulted in a significant reduction in intensive care unit hospital costs (p < 0.05). Conclusion The implementation of FAST HUG reduced the number of ventilator-associated pneumonia cases. Thus, decreasing costs, reducing mortality rates and length of stay, which therefore resulted in an improvement to the overall quality of care.

Clarithromycin Leads to Long-Term Survival and Cost Benefit in Ventilator-Associated Pneumonia and Sepsis.

Increasing numbers of admissions for sepsis impose a heavy burden on health care systems worldwide, while novel therapies have proven both expensive and ineffective. We explored the long-term mortality and hospitalization costs after adjunctive therapy with intravenous clarithromycin in ventilator-associated pneumonia (VAP). Two hundred patients with sepsis and VAP were enrolled in a published randomized clinical trial; 100 were allocated to blind treatment with a placebo and another 100 to clarithromycin at 1 g daily for three consecutive days. Long-term mortality was recorded. The hospitalization cost was calculated by direct quantitation of imaging tests, medical interventions, laboratory tests, nonantibiotic drugs and antibiotics, intravenous fluids, and parenteral and enteral nutrition. Quantities were priced by the respective prices defined by the Greek government in 2002. The primary endpoint was 90-day mortality; cumulative hospitalization cost was the secondary endpoint. All-cause mortality rates on day 90 were 60% in the placebo arm and 43% in the clarithromycin arm (P = 0.023); 141 patients were alive on day 28, and mortality rates between days 29 and 90 were 44.4% and 17.4%, respectively (P = 0.001). The mean cumulative costs on day 25 in the placebo group and in the clarithromycin group were €14,701.10 and €13,100.50 per patient staying alive, respectively (P = 0.048). Respective values on day 45 were €26,249.50 and €19,303.10 per patient staying alive (P = 0.011); this was associated with the savings from drugs other than antimicrobials. It is concluded that intravenous clarithromycin for three consecutive days as an adjunctive treatment in VAP and sepsis offers long-term survival benefit along with a considerable reduction in the hospitalization cost. (This study has been registered at ClinicalTrials.gov under registration no. NCT00297674.).

The effectiveness of a bundle in the prevention of ventilator-associated pneumonia.

OBJECTIVES: The aim of this study was to evaluate the impact of a bundle called FAST HUG in ventilator-associated pneumonia, weigh the healthcare costs of ventilator-associated pneumonia patients in the intensive care unit, and hospital mortality due to ventilator-associated pneumonia. MATERIAL AND METHODS: The study was performed in a private hospital that has an 8-bed intensive care unit. It was divided into two phases: before implementing FAST HUG, from August 2011 to August 2012 and after the implementation of FAST HUG, from September 2012 to December 2013. An individual form for each patient in the study was filled out by using information taken electronically from the hospital medical records. The following data was obtained from each patient: age, gender, reason for hospitalization, use of three or more antibiotics, length of stay, intubation time, and outcome. RESULTS: After the implementation of FAST HUG, there was an observable decrease in the occurrence of ventilator-associated pneumonia (p<0.01), as well as a reduction in mortality rates (p<0.01). In addition, the intervention resulted in a significant reduction in intensive care unit hospital costs (p<0.05). CONCLUSION: The implementation of FAST HUG reduced the number of ventilator-associated pneumonia cases. Thus, decreasing costs, reducing mortality rates and length of stay, which therefore resulted in an improvement to the overall quality of care.

A comparison of APACHE II and CPIS scores for the prediction of 30-day mortality in patients with ventilator-associated pneumonia.

OBJECTIVE: The aim of this study was to compare the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the Clinical Pulmonary Infection Score (CPIS) for the prediction of 30-day mortality in patients with ventilator-associated pneumonia (VAP). METHODS: A single-center, prospective cohort study design was employed between January 1, 2010 and January 1, 2014. APACHE II and CPIS scores were determined on the day of VAP diagnosis. Discrimination was tested using receiver-operating characteristic (ROC) curves and the areas under the curve (AUC). Calibration was tested using the Hosmer-Lemeshow statistic. RESULTS: Of 135 patients with VAP, 39 died; the 30-day mortality was 28.9%. APACHE II and CPIS scores were significantly higher in non-survivors compared to survivors (23.1±4.8 vs. 16.7±4.6, p<0.001; 6.8±1.3 vs. 6.2±1.3, p=0.016). APACHE II had excellent discrimination for predicting 30-day mortality in patients with VAP, with AUC 0.808 (95% confidence interval (CI) 0.704-0.912, p<0.001). However, the CPIS score did not have discrimination power for predicting mortality, with AUC 0.612 (95% CI 0.485-0.739, p=0.083). The Hosmer-Lemeshow statistic showed good goodness-of-fit for observed 30-day mortality and APACHE II expected mortality (Chi-square=1.099, p=0.785). However, CPIS expected 30-day mortality did not fit the observed mortality (Chi-square=6.72, p=0.004). CONCLUSIONS: These data suggest that APACHE II is useful for predicting 30-day mortality in patients with VAP, but that the CPIS does not have good discrimination and calibration for predicting mortality.

[Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the Adult Intensive Care Unit]. / Impacto del cobre en la reducción de infecciones intrahospitalarias, mortalidad y gasto en antimicrobianos en una Unidad de Cuidados Intensivo de adultos.

UNLABELLED: We conducted a clinical trial to determine the impact of coating surfaces with copper in reducing hospital-acquired infections, mortality associated with nosocomial infections and antimicrobial costs in the UCI. The study took place at Carlos Van Buren Hospital, Valparaíso, Chile. No differences in the frequency of nosocomial infections were found. Not in rates of ventilator-associated pneumonia (p = 0.9), nor in catheter- associated urinary tract infection (p = 0.9) or in central venous catheter associated bacteremia (p = 0.3). There were no differences in infection-free survival (p = 0.9). There were less costs of antimicrobials in patients in which copper was used. The fact that the sample size was not completed could explain that no significant differences in infections were found. CONCLUSION: The use of copper as a surface in the ICU showed no statistically significant differences in rates of nosocomial infections during the study period, however, these results could be related to the sample size.

Impacto del cobre en la reducción de infecciones intrahospitalarias, mortalidad y gasto en antimicrobianos en una Unidad de Cuidados Intensivo de adultos / Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the Adult Intensive Care Unit

We conducted a clinical trial to determine the impact of coating surfaces with copper in reducing hospital-acquired infections, mortality associated with nosocomial infections and antimicrobial costs in the UCI. The study took place at Carlos Van Buren Hospital, Valparaíso, Chile. No differences in the frequency of nosocomial infections were found. Not in rates of ventilator-associated pneumonia (p = 0.9), nor in catheter- associated urinary tract infection (p = 0.9) or in central venous catheter associated bacteremia (p = 0.3). There were no differences in infection-free survival (p = 0.9). There were less costs of antimicrobials in patients in which copper was used. The fact that the sample size was not completed could explain that no significant differences in infections were found. Conclusion: The use of copper as a surface in the ICU showed no statistically significant differences in rates of nosocomial infections during the study period, however, these results could be related to the sample size.

Introducción: Las infecciones nosocomiales incrementan la mortalidad y costos en las instituciones de salud. El revestimiento con cobre, de superficies de alto contacto en la unidad clínica en torno a los pacientes, reduce la colonización bacteriana de las mismas. Objetivo: Determinar el impacto del revestimiento de las superficies con cobre en la disminución de las infecciones intrahospitalarias, la mortalidad asociada a las infecciones intrahospitalarias y los costos en antimicrobianos en pacientes hospitalizados en UCI adultos en el Hospital Carlos Van Buren. Pacientes y Métodos: Estudio prospectivo, comparativo, mayo de 2011-mayo de 2012. Asignación aleatoria de pacientes adultos ingresados en UCI, que permanecieran al menos por 24 h en dicha unidad, a unidades de aislamiento recubiertas (n: 7) o no recubiertas con cobre (n: 7). Resultados: Ingresaron al estudio 440 pacientes, 217 pacientes (49,3%) en el grupo sin cobre y 223 en el grupo con cobre (50,7%). No se encontraron diferencias en la frecuencia de infecciones intrahospitalarias en ambos grupos. Tampoco se encontraron diferencias significativas en las tasas de neumonía asociada a ventilación mecánica (p = 0,9), infección urinaria asociada a catéter urinario (p = 0,9) y bacteremias asociada a catéter venoso central (p = 0,3). Tampoco se encontraron diferencias en la sobrevida libre de infección (p = 0,9). Se encontró un gasto menor de antimicrobianos en pacientes atendidos en unidades revestidas con cobre. Durante el período del estudio no se completó el tamaño de muestra y las diferencias no significativas podrían deberse a este hecho. Conclusión: El uso del cobre como revestimiento de las superficies hospitalarias en UCI, mostró diferencia en la tasa de bacteriemia asociada a dispositivos venosos, aunque no significativa, y no mostró diferencia en neumonías e infecciones urinarias. Las diferencias no significativas pueden deberse a que no se completó el tamaño de la muestra. Se observó un mayor gasto de antimicrobianos en pacientes de unidades no cobrizadas, lo que plantea una nueva área de investigación.

Healthcare associated infections (HAI) perspectives.

Healthcare associated infections (HAI) are among the major complications of modern medical therapy. The most important HAIs are those related to invasive devices: central line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), ventilator-associated pneumonia (VAP) as well as surgical site infections (SSI). HAIs are associated with significant mortality, morbidities and increasing healthcare cost. The cited case-fatality rate ranges from 2.3% to 14.4% depending on the type of infection. In this mini-review, we shed light on these aspects as well as drivers to decrease HAIs.

European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant hospital-acquired infections worldwide and remains a public health priority in Europe. Nosocomial pneumonia (NP) involving MRSA often affects patients in intensive care units with substantial morbidity, mortality and associated costs. A guideline-based approach to empirical treatment with an antibacterial agent active against MRSA can improve the outcome of patients with MRSA NP, including those with ventilator-associated pneumonia. New methods may allow more rapid or sensitive diagnosis of NP or microbiological confirmation in patients with MRSA NP, allowing early de-escalation of treatment once the pathogen is known. In Europe, available antibacterial agents for the treatment of MRSA NP include the glycopeptides (vancomycin and teicoplanin) and linezolid (available as an intravenous or oral treatment). Vancomycin has remained a standard of care in many European hospitals; however, there is evidence that it may be a suboptimal therapeutic option in critically ill patients with NP because of concerns about its limited intrapulmonary penetration, increased nephrotoxicity with higher doses, as well as the emergence of resistant strains that may result in increased clinical failure. Linezolid has demonstrated high penetration into the epithelial lining fluid of patients with ventilator-associated pneumonia and shown statistically superior clinical efficacy versus vancomycin in the treatment of MRSA NP in a phase IV, randomized, controlled study. This review focuses on the disease burden and clinical management of MRSA NP, and the use of linezolid after more than 10 years of clinical experience.

Tracheostomy timing affects stroke recovery.

BACKGROUND: The timing of tracheostomy in stroke patients unable to protect their airway has become a topic of debate. Proponents for early tracheostomy (ET) cite benefits including less ventilation-associated pneumonia, less sedative drug use, shorter length of stay, and reduced mortality in comparison with late tracheostomy (LT). METHODS: We examined the timing of tracheostomy on stroke patient outcomes across the United States using the Nationwide Inpatient Sample (2008-2010). Independent samples t tests and chi-squared tests were used to make comparisons between early (≤10 days) and late (11-25 days) tracheostomy. Multivariable models, adjusted for confounding factors, investigated outcome measures. RESULTS: In total, 13,165 stroke cases were included in the study (5591 in the ET group and 7574 in the LT group). Patients receiving an ET had a significant reduction in the odds of ventilator-associated pneumonia in comparison with the LT group (OR: .688, P = .026). The length of stay for patients receiving an ET was significantly lower in comparison with the LT group (P < .001) and was associated with an 18% reduction in total hospital costs (P < .001). CONCLUSIONS: Early tracheostomy for stroke patients may reduce the incidence of ventilator-associated pneumonia, thereby shortening the hospital stay and lowering total hospital costs. These relationships warrant further investigation in a large prospective multicenter trial.

Assessment of the implementation of a protocol to reduce ventilator-associated pneumonia in intensive care unit trauma patients.

Ventilator-associated pneumonia (VAP) is the primary hospital-acquired infection contracted by critically ill patients who receive mechanical ventilation. This retrospective study evaluated the efficacy of a multifaceted VAP prevention protocol in an adult trauma population. Ventilator-associated pneumonia was defined according to the National Healthcare Safety Network (2009) criteria. The number of days to onset of VAP in the postprotocol period was longer than the preprotocol period despite a concomitant increase in the number of mechanical ventilation days.

Pentraxin 3 in the assessment of ventilator-associated pneumonia: an early marker of severity.

OBJECTIVES: The aim was to assess the diagnostic and prognostic value of measuring pentraxin 3 (PTX3) together with C-reactive protein (CRP) in patients with ventilator-associated pneumonia (VAP). BACKGROUND: The PTX3 values increase rapidly during multiple inflammatory conditions, but little is known about its characteristics in VAP. METHODS: Measurement of PTX3 and CRP levels in plasma from 136 consecutive patients receiving mechanical ventilation > 48 h in a prospective single center study. RESULTS: A PTX3 threshold of >16.43 ng/ml provided a specificity of 74.0% and a sensitivity of 68.6% for the diagnosis of VAP. PTX3 correlated with severity of sepsis and peaked earlier than CRP in patients with confirmed VAP. Multivariate Cox regression analysis showed PTX3 was the independent predictor for mortality of VAP. CONCLUSIONS: PTX3 was not superior to CRP as a biomarker to diagnose VAP, but it was an early indicator of inflammation and had better prognostic value to predict mortality than CRP.

Long-term survival and healthcare utilization outcomes attributable to sepsis and pneumonia.

BACKGROUND: Hospital associated infections are major problems, which are increasing in incidence and very costly. However, most research has focused only on measuring consequences associated with the initial hospitalization. We explored the long-term consequences of infections in elderly Medicare patients admitted to an intensive care unit (ICU) and discharged alive, focusing on: sepsis, pneumonia, central-line-associated bloodstream infections (CLABSI), and ventilator-associated pneumonia (VAP); the relationships between the infections and long-term survival and resource utilization; and how resource utilization was related to impending death during the follow up period. METHODS: Clinical data and one year pre- and five years post-index hospitalization Medicare records were examined. Hazard ratios (HR) and healthcare utilization incidence ratios (IR) were estimated from state of the art econometric models. Patient demographics (i.e., age, gender, race and health status) and Medicaid status (i.e., dual eligibility) were controlled for in these models. RESULTS: In 17,537 patients, there were 1,062 sepsis, 1,802 pneumonia, 42 CLABSI and 52 VAP cases. These subjects accounted for 62,554 person-years post discharge. The sepsis and CLABSI cohorts were similar as were the pneumonia and VAP cohorts. Infection was associated with increased mortality (sepsis HR = 1.39, P < 0.01; and pneumonia HR = 1.58, P < 0.01) and the risk persisted throughout the follow-up period. Persons with sepsis and pneumonia experienced higher utilization than controls (e.g., IR for long-term care utilization for those with sepsis ranged from 2.67 to 1.93 in years 1 through 5); and, utilization was partially related to impending death. CONCLUSIONS: The infections had significant and lasting adverse consequences among the elderly. Yet, many of these infections may be preventable. Investments in infection prevention interventions are needed in both community and hospitals settings.

Investigating hospital heterogeneity with a multi-state frailty model: application to nosocomial pneumonia disease in intensive care units.

BACKGROUND: Multistate models have become increasingly useful to study the evolution of a patient's state over time in intensive care units ICU (e.g. admission, infections, alive discharge or death in ICU). In addition, in critically-ill patients, data come from different ICUs, and because observations are clustered into groups (or units), the observed outcomes cannot be considered as independent. Thus a flexible multi-state model with random effects is needed to obtain valid outcome estimates. METHODS: We show how a simple multi-state frailty model can be used to study semi-competing risks while fully taking into account the clustering (in ICU) of the data and the longitudinal aspects of the data, including left truncation and right censoring. We suggest the use of independent frailty models or joint frailty models for the analysis of transition intensities. Two distinct models which differ in the definition of time t in the transition functions have been studied: semi-Markov models where the transitions depend on the waiting times and nonhomogenous Markov models where the transitions depend on the time since inclusion in the study. The parameters in the proposed multi-state model may conveniently be computed using a semi-parametric or parametric approach with an existing R package FrailtyPack for frailty models. The likelihood cross-validation criterion is proposed to guide the choice of a better fitting model. RESULTS: We illustrate the use of our approach though the analysis of nosocomial infections (ventilator-associated pneumonia infections: VAP) in ICU, with "alive discharge" and "death" in ICU as other endpoints. We show that the analysis of dependent survival data using a multi-state model without frailty terms may underestimate the variance of regression coefficients specific to each group, leading to incorrect inferences. Some factors are wrongly significantly associated based on the model without frailty terms. This result is confirmed by a short simulation study. We also present individual predictions of VAP underlining the usefulness of dynamic prognostic tools that can take into account the clustering of observations. CONCLUSIONS: The use of multistate frailty models allows the analysis of very complex data. Such models could help improve the estimation of the impact of proposed prognostic features on each transition in a multi-centre study. We suggest a method and software that give accurate estimates and enables inference for any parameter or predictive quantity of interest.

The Sequential Organ Failure Assessment score and copeptin for predicting survival in ventilator-associated pneumonia.

INTRODUCTION: Ventilator-associated pneumonia remains the most common nosocomial infection in the critically ill and contributes to significant morbidity. Eventual decisions regarding withdrawal or maximal therapy are demanding and rely on physicians' experience. Additional objective tools for risk assessment may improve medical judgement. Copeptin, reflecting vasopressin release, as well as the Sequential Organ Failure Assessment (SOFA) score, reflecting the individual degree of organ dysfunction, might qualify for survival prediction in ventilator-associated pneumonia. We investigated the predictive value of the SOFA score and copeptin in ventilator-associated pneumonia. METHODS: One hundred one patients with ventilator-associated pneumonia were prospectively assessed. Death within 28 days after ventilator-associated pneumonia onset was the primary end point. RESULTS: The SOFA score and the copeptin levels at ventilator-associated pneumonia onset were significantly elevated in nonsurvivors (P = .002 and P = .017, respectively). Both markers had different time courses in survivors and nonsurvivors (P < .001 and P = .006). Mean SOFA (average SOFA of 10 days after VAP onset) was superior in predicting 28-day survival as compared with SOFA and copeptin at ventilator-associated pneumonia onset (area under the curve, 0.90 vs 0.73 and 0.67, respectively). CONCLUSIONS: The predictive value of serial-measured SOFA significantly exceeds those of single SOFA and copeptin measurements. Serial SOFA scores accurately predict outcome in ventilator-associated pneumonia.

Guideline-adherent initial intravenous antibiotic therapy for hospital-acquired/ventilator-associated pneumonia is clinically superior, saves lives and is cheaper than non guideline adherent therapy.

INTRODUCTION: Hospital-acquired pneumonia (HAP) often occurring as ventilator-associated pneumonia (VAP) is the most frequent hospital infection in intensive care units (ICU). Early adequate antimicrobial therapy is an essential determinant of clinical outcome. Organisations like the German PEG or ATS/ IDSA provide guidelines for the initial calculated treatment in the absence of pathogen identification. We conducted a retrospective chart review for patients with HAP/VAP and assessed whether the initial intravenous antibiotic therapy (IIAT) was adequate according to the PEG guidelines. MATERIALS AND METHODS: We collected data from 5 tertiary care hospitals. Electronic data filtering identified 895 patients with potential HAP/VAP. After chart review we finally identified 221 patients meeting the definition of HAP/VAP. Primary study endpoints were clinical improvement, survival and length of stay. Secondary endpoints included duration of mechanical ventilation, total costs, costs incurred on the intensive care unit (ICU), costs incurred on general wards and drug costs. RESULTS: We found that 107 patients received adequate initial intravenous antibiotic therapy (IIAT) vs. 114 with inadequate IIAT according to the PEG guidelines. Baseline characteristics of both groups revealed no significant differences and good comparability. Clinical improvement was 64% over all patients and 82% (85/104) in the subpopulation with adequate IIAT while only 47% (48/103) inadequately treated patients improved (p< 0.001). The odds ratio of therapeutic success with GA versus NGA treatment was 5.821 (p<0.001, [95% CI: 2.712-12.497]). Survival was 80% for the total population (n = 221), 86% in the adequately treated (92/107) and 74% in the inadequately treated subpopulation (84/114) (p = 0.021). The odds ratio of mortality for GA vs. NGA treatment was 0.565 (p=0.117, [95% CI: 0.276-1.155]). Adequately treated patients had a significantly shorter length of stay (LOS) (23.9 vs. 28.3 days; p = 0.022), require significantly less hours of mechanical ventilation (175 vs. 274; p = 0.001), incurred lower total costs (EUR 28,033 vs. EUR 36,139, p = 0.006) and lower ICU-related costs (EUR 13,308 vs. EUR 18,666, p = 0.003). Drug costs for the hospital stay were also lower (EUR 4,069 vs. EUR 4,833) yet not significant. The most frequent types of inadequate therapy were monotherapy instead of combination therapy, wrong type of penicillin and wrong type of cephalosporin. DISCUSSION: These findings are consistent with those from other studies analyzing the impact of guideline adherence on survival rates, clinical success, LOS and costs. However, inadequately treated patients had a higher complicated pathogen risk score (CPRS) compared to those who received adequate therapy. This shows that therapy based on local experiences may be sufficient for patients with low CPRS but inadequate for those with high CPRS. Linear regression models showed that single items of the CPRS like extrapulmonary organ failure or late onset had no significant influence on the results. CONCLUSION: Guideline-adherent initial intravenous antibiotic therapy is clinically superior, saves lives and is less expensive than non guideline adherent therapy. Using a CPRS score can be a useful tool to determine the right choice of initial intravenous antibiotic therapy. The net effect on the German healthcare system per year is estimated at up to 2,042 lives and EUR 125,819,000 saved if guideline-adherent initial therapy for HAP/VAP were established in all German ICUs.

Soluble urokinase plasminogen activator receptor (suPAR) for assessment of disease severity in ventilator-associated pneumonia and sepsis.

Urokinase plasminogen activator (uPAR) is a receptor mainly expressed on peripheral blood mononuclear cells and neutrophils. The role of its soluble form, namely suPAR, as a predictor of sepsis outcome in a homogenous cohort of 180 septic patients, was investigated. Blood from 180 patients with ventilator-associated pneumonia (VAP) and sepsis was collected for seven consecutive days. suPAR and PCT were measured in serum by an enzyme immunoassay and an immuno-time-resolved amplified cryptate assay respectively. Neutrophils and monocytes were isolated on day 1 and incubated. suPAR levels greater than 10.5 ng/ml had 80% specificity and 77.6% positive predictive value to discriminate between severe sepsis and sepsis. suPAR levels greater than 12.9 ng/ml had 80% specificity and 76.1% positive predictive value for prognosis of unfavorable outcome. suPAR levels were significantly lower among survivors than among non-survivors over follow-up. Step-wise Cox regression analysis found suPAR as an independent factor related with unfavorable outcome (p: 0.026). Concentrations of suPAR in supernatants of neutrophils of patients with sepsis were greater compared to controls. It is concluded that suPAR is a reliable marker of sepsis severity and a strong independent predictor of unfavorable outcome in VAP and sepsis. Neutrophils are involved in release.