Mechanical ventilation and the daily cost of ICU care.

BACKGROUND: Intensive care units represent one of the largest clinical cost centers in hospitals. Mechanical ventilation accounts for a significant share of this cost. There is a relative dearth of information quantifying the impact of ventilation on daily ICU cost. We thus determine daily costs of ICU care, incremental cost of mechanical ventilation per ICU day, and further differentiate cost by underlying diseases. METHODS: Total ICU costs, length of ICU stay, and duration of mechanical ventilation of all 10,637 adult patients treated in ICUs at a German hospital in 2013 were analyzed for never-ventilated patients (N = 9181), patients ventilated at least 1 day, (N = 1455) and all patients (N = 10,637). Total ICU costs were regressed on the number of ICU days. Finally, costs were analyzed separately by ICD-10 chapter of main diagnosis. RESULTS: Daily non-ventilated costs were €999 (95%CI €924 - €1074), and ventilated costs were €1590 (95%CI €1524 - €1657), a 59% increase. Costs per non-ventilated ICU day differed substantially and were lowest for endocrine, nutritional or metabolic diseases (€844), and highest for musculoskeletal diseases (€1357). Costs per ventilated ICU day were lowest for diseases of the circulatory system (€1439) and highest for cancer patients (€1594). The relative cost increase due to ventilation was highest for diseases of the respiratory system (94%) and even non-systematic for patients with musculoskeletal diseases (13%, p = 0.634). CONCLUSIONS: Results show substantial variability of ICU costs for different underlying diseases and underline mechanical ventilation as an important driver of ICU costs.

The impact of hospital-acquired infections on the patient-level reimbursement-cost relationship in a DRG-based hospital payment system.

Hospital-acquired infections (HAIs) are a common complication in inpatient care. We investigate the incentives to prevent HAIs under the German DRG-based reimbursement system. We analyze the relationship between resource use and reimbursements for HAI in 188,731 patient records from the University Medical Center Freiburg (2011-2014), comparing cases to appropriate non-HAI controls. Resource use is approximated using national standardized costing system data. Reimbursements are the actual payments to hospitals under the G-DRG system. Timing of HAI exposure, cost-clustering within main diagnoses and risk-adjustment are considered. The reimbursement-cost difference of HAI patients is negative (approximately - €4000). While controls on average also have a negative reimbursement-cost difference (approximately - €2000), HAI significantly increase this difference after controlling for confounding and timing of infection (- 1500, p < 0.01). HAIs caused by vancomycin-resistant Enterococci have the most unfavorable reimbursement-cost difference (- €10,800), significantly higher (- €9100, p < 0.05) than controls. Among infection types, pneumonia is associated with highest losses (- €8400 and - €5700 compared with controls, p < 0.05), while cost-reimbursement relationship for Clostridium difficile-associated diarrhea is comparatively balanced (- €3200 and - €500 compared to controls, p = 0.198). From the hospital administration's perspective, it is not the additional costs of HAIs, but rather the cost-reimbursement relationship which guides decisions. Costs exceeding reimbursements for HAI may increase infection prevention and control efforts and can be used to show their cost-effectiveness from the hospital perspective.

Measuring the in-hospital costs of Pseudomonas aeruginosa pneumonia: methodology and results from a German teaching hospital.

BACKGROUND: Pseudomonas aeruginosa-related pneumonia is an ongoing healthcare challenge. Estimating its financial burden is complicated by the time-dependent nature of the disease. METHODS: Two hundred thirty-six cases of Pseudomonas aeruginosa-related pneumonia were recorded at a 2000 bed German teaching hospital between 2011 and 2014. Thirty-five cases (15%) were multidrug-resistant (MDR) Pseudomonas aeruginosa. Hospital- and community-acquired cases were distinguished by main diagnoses and exposure time. The impact of Pseudomonas aeruginosa-related pneumonia on the three endpoints cost, reimbursement, and length of stay was analyzed, taking into account (1) the time-dependent nature of exposure, (2) clustering of costs within diagnostic groups, and (3) additional confounders. RESULTS: Pseudomonas aeruginosa pneumonia is associated with substantial additional costs that are not fully reimbursed. Costs are highest for hospital-acquired cases (€19,000 increase over uninfected controls). However, community-acquired cases are also associated with a substantial burden (€8400 when Pseudomonas aeruginosa pneumonia is the main reason for hospitalization, and €6700 when not). Sensitivity analyses for hospital-acquired cases showed that ignoring or incorrectly adjusting for time-dependency substantially biases results. Furthermore, multidrug-resistance was rare and only showed a measurable impact on the cost of community-acquired cases. CONCLUSIONS: Pseudomonas aeruginosa pneumonia creates a substantial financial burden for hospitals. This is particularly the case for nosocomial infections. Infection control interventions could yield significant cost reductions. However, to evaluate the potential effectiveness of different interventions, the time-dependent aspects of incremental costs must be considered to avoid introduction of bias.

Impact of mechanical ventilation on the daily costs of ICU care: a systematic review and meta regression.

The impact of mechanical ventilation on the daily costs of intensive care unit (ICU) care is largely unknown. We thus conducted a systematic search for studies measuring the daily costs of ICU stays for general populations of adults (age ≥18 years) and the added costs of mechanical ventilation. The relative increase in the daily costs was estimated using random effects meta regression. The results of the analyses were applied to a recent study calculating the excess length-of-stay associated with ICU-acquired (ventilator-associated) pneumonia, a major complication of mechanical ventilation. The search identified five eligible studies including a total of 54 766 patients and ~238 037 patient days in the ICU. Overall, mechanical ventilation was associated with a 25.8% (95% CI 4.7%-51.2%) increase in the daily costs of ICU care. A combination of these estimates with standardised unit costs results in approximate daily costs of a single ventilated ICU day of €1654 and €1580 in France and Germany, respectively. Mechanical ventilation is a major driver of ICU costs and should be taken into account when measuring the financial burden of adverse events in ICU settings.

Costs of hospital-acquired Clostridium difficile infections: an analysis on the effect of time-dependent exposures using routine and surveillance data.

BACKGROUND: Hospital-acquired infections have not only gained increasing attention clinically, but also methodologically, as a time-varying exposure. While methods to appropriately estimate extra length of stay (LOS) have been established and are increasingly used in the literature, proper estimation of cost figures has lagged behind. METHODS: Analysing the additional costs and reimbursements of Clostridium difficile-infections (CDI), we use a within-main-diagnosis-time-to-exposure stratification approach to incorporate time-varying exposures in a regression model, while at the same time accounting for cost clustering within diagnosis groups. RESULTS: We find that CDI is associated with €9000 of extra costs, €7800 of higher reimbursements, and 6.4 days extra length of stay. Using a conventional method, which suffers from time-dependent bias, we derive estimates more than three times as high (€23,000, €8000, 21 days respectively). We discuss our method in the context of recent methodological advances in the estimation of the costs of hospital-acquired infections. CONCLUSIONS: CDI is associated with sizeable in-hospital costs. Neglecting the methodological particularities of hospital-acquired infections can however substantially bias results. As the data needed for an appropriate analysis are collected routinely in most hospitals, we recommend our approach as a feasible way for estimating the economic impact of time-varying adverse events during hospital stay.

In-hospital costs of community-acquired colonization with multidrug-resistant organisms at a German teaching hospital.

BACKGROUND: Antibiotic resistance is a challenge in the management of infectious diseases and can cause substantial cost. Even without the onset of infection, measures must be taken, as patients colonized with multi-drug resistant (MDR) pathogens may transmit the pathogen. We aim to quantify the cost of community-acquired MDR colonizations using routine data from a German teaching hospital. METHODS: All 2006 cases of documented MDR colonization at hospital admission recorded from 2011 to 2014 are matched to 7917 unexposed controls with the same primary diagnosis. Cases with an onset MDR infection are excluded from the analysis. Routine data on costs per case is analysed for three groups of MDR bacteria: Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), and multidrug-resistant gram-negative bacteria (MDR-GN). Multivariate analyses are conducted to adjust for potential confounders. RESULTS: After controlling for main diagnosis group, age, sex, and Charlson Comorbidity Index, MDR colonization is associated with substantial additional costs from the healthcare perspective (€1480.9, 95%CI €1286.4-€1675.5). Heterogeneity between pathogens remains. Colonization with MDR-GN leads to the largest cost increase (€1966.0, 95%CI €1634.6-€2297.4), followed by MRSA with €1651.3 (95%CI €1279.1-€2023.6), and VRE with €879.2 (95%CI €604.1-€1154.2). At the same time, MDR-GN is associated with additional reimbursements of €887.8 (95%CI €722.1-€1053.6), i.e. costs associated with MDR-colonization exceed reimbursement. CONCLUSIONS: Even without the onset of invasive infection, documented MDR-colonization at hospital admission is associated with increased hospital costs, which are not fully covered within the German DRG-based hospital payment system.

Hospital costs associated with psychiatric comorbidities: a retrospective study.

BACKGROUND: Psychiatric comorbidities are relevant for the diagnostic and therapeutic regimes in somatic hospital care. The main aim of this study was to analyse the association between psychiatric comorbidities and hospital costs per inpatient episode. A further aim was to discuss and address the methodological challenges in the estimation of these outcomes based on retrospective data. METHODS: The study included 338,162 inpatient episodes consecutively discharged between 2011 and 2014 at a German university hospital. We used detailed resource use data to calculate day-specific hospital costs. We adjusted analyses for sex, age, somatic comorbidities and main diagnoses. We addressed potential time-related bias in retrospective diagnosis data with sensitivity analyses. RESULTS: Psychiatric comorbidities were associated with an increase in hospital costs per episode of 40% and an increase of reimbursement per episode of 28%, representing marginal effects of 1344 € and 1004 €, respectively. After controlling for length of stay, sensitivity analyses provided a lower bound increase in daily costs and reimbursement of 207 € and 151 €, respectively. CONCLUSION: If differences in hospital costs between patient groups are not adequately accounted for in DRG-systems, perverse incentives are created that can reduce the efficiency of care. Therefore, we suggest intensifying the inclusion of psychiatric comorbidities in the German DRG system. Future research should investigate the appropriate inclusion of psychiatric comorbidities in other health care systems' payment schemes.

Resistance Elasticity of Antibiotic Demand in Intensive Care.

The emergence and spread of antimicrobial resistance (AMR) is still an unresolved problem worldwide. In intensive care units (ICUs), first-line antibiotic therapy is highly standardized and widely empiric while treatment failure because of AMR often has severe consequences. Simultaneously, there is a limited number of reserve antibiotics, whose prices and/or side effects are substantially higher than first-line therapy. This paper explores the implications of resistance-induced substitution effects in ICUs. The extent of such substitution effects is shown in a dynamic fixed effect regression analysis using a panel of 66 German ICUs with monthly antibiotic use and resistance data between 2001 and 2012. Our findings support the hypothesis that demand for reserve antibiotics substantially increases when resistance towards first-line agents rises. For some analyses the lagged effect of resistance is also significant, supporting the conjecture that part of the substitution effect is caused by physicians changing antibiotic choices in empiric treatment by adapting their resistance expectation to new information on resistance prevalence. The available information about resistance rates allows physicians to efficiently balance the trade-off between exacerbating resistance and ensuring treatment success. However, resistance-induced substitution effects are not free of charge. These effects should be considered an indirect burden of AMR. Copyright © 2016 John Wiley & Sons, Ltd.

Herpes simplex virus type 1/adeno-associated virus hybrid vectors mediate site-specific integration at the adeno-associated virus preintegration site, AAVS1, on human chromosome 19.

Herpes simplex virus type 1 (HSV-1)-based amplicon vectors have a large transgene capacity and can efficiently infect many different cell types. One disadvantage of HSV-1 vectors is their instability of transgene expression. By contrast, vectors based on adeno-associated virus (AAV) can either persist in an episomal form or integrate into the host cell genome, thereby supporting long-term gene expression. AAV expresses four rep genes, rep68, -78, -40, and -52. Of those, rep68 or rep78 are sufficient to mediate site-specific integration of the AAV DNA into the host cell genome. The major disadvantage of AAV vectors is the small transgene capacity ( approximately 4.6 kb). In this study, we constructed HSV/AAV hybrid vectors that contained, in addition to the standard HSV-1 amplicon elements, AAV rep68, rep78, both rep68 and -78, or all four rep genes and a reporter gene that was flanked by the AAV inverted terminal repeats (ITRs). Southern blots of Hirt DNA from cells transfected with the hybrid vectors and HSV-1 helper DNA demonstrated that both the AAV elements and the HSV-1 elements were functional in the context of the hybrid vector. All hybrid vectors could be packaged into HSV-1 virions, although those containing rep sequences had lower titers than vectors that did not. Site-specific integration at AAVS1 on human chromosome 19 was directly demonstrated by PCR and sequence analysis of ITR-AAVS1 junctions in hybrid vector-transduced 293 cells. Cell clones that stably expressed the transgene for at least 12 months could easily be isolated without chemical selection. In the majority of these clones, the transgene cassette was integrated at AAVS1, and no sequences outside the ITR cassette, rep in particular, were present as determined by PCR, ITR rescue/replication assays, and Southern analysis. Some of the clones contained random integrations of the transgene cassette alone or together with sequences outside the ITR cassette. These data indicate that the long-term transgene expression observed following transduction with HSV/AAV hybrid vectors is, at least in part, supported by chromosomal integration of the transgene cassette, both randomly and site specifically.