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Discussion
Prior reports using administrative data have shown a declining trend in hospital mortality rates for patients with severe sepsis. However, administrative data may be subject to changing trends in coding patterns or hospital discharge patterns that result in biased mortality estimates. Usual care groups from multicenter randomized trials selected prospectively based on modified Consensus severe sepsis definitions may be less likely to differentially misclassify severe sepsis over time than administrative data and provide an alternative data source for estimation of prevailing mortality trends. We determined trends in severe sepsis mortality during the two decades since Consensus sepsis definitions were developed and compared outcomes from multicenter trials with those derived from administrative data. We observed that risk-standardized 28-day severe sepsis mortality declined over the past two decades. We have also shown that temporal trends in severe sepsis mortality derived from administrative claims data ICD-9-CM algorithms are likely accurate.
Our findings have important implications. Severe sepsis mortality rates have declined despite the fact that none of the multicenter trials included in our analysis has yet introduced an efficacious sepsis therapy. Our data do not allow us to ascertain the specific reasons for the improvement in mortality. However, in the absence of novel sepsis therapeutics, mortality declines may be due to improved processes of care. Potentially effective improvements include earlier antibiotic administration, increased use of early goal-directed therapy, improvements in mechanical ventilation strategies, or increased intensivist staffing. To most efficiently target quality improvement interventions, future studies should seek to determine which practice patterns are most strongly associated with outcome improvements in severe sepsis.
Identification of secular trends in severe sepsis mortality has further implications for future conduct of quality improvement studies. Studies that use a "before-and-after" study design to determine the effect of quality improvement interventions in patients with severe sepsis, such as Surviving Sepsis Campaign care bundles, may be confounded by secular trends of declining severe sepsis mortality. Future studies that seek to identify changes in outcomes after introduction of a quality improvement intervention for patients with severe sepsis should account for secular trends in severe sepsis mortality.
Administrative databases are frequently used to assess epidemiological trends in severe sepsis. However, whether trends identified by administrative data are accurate has been a matter of controversy. Lindenauer et al investigated trends in case-fatality rates among hospitalized patients with pneumonia and concluded that putative mortality improvements in patients with pneumonia were likely due to changing ICD-9-CM coding strategies. Hall et al identified that hospital mortality rates may be reduced through earlier discharge of patients to long-term care facilities. Using 28-day mortality data from trial participants prospectively ascertained to meet severe sepsis criteria, our results suggest that administrative data likely accurately reflect secular trends in severe sepsis mortality. Although limited by potential differences between hospital and 28-day mortality, our data suggest that severe sepsis cases selected from administrative data using the Martin definition appear to have outcomes most similar to patients enrolled in clinical trials.
Few other studies have investigated recent trends in severe sepsis mortality outside of administrative data sources. Using a meta-analysis of prior retrospective and prospective studies, Friedman et al showed that mortality rates for patients with septic shock had likely declined from years 1958 to 1997. However, conclusions from Friedman et al are limited by lack of Consensus sepsis definitions prior to 1991, the wide variation in included study designs, use of hospital mortality endpoints, and the lack of data after 1997. Harrison et al identified a decrease in hospital mortality (48.3% vs 44.7%) among patients identified retrospectively with severe sepsis from the multicenter Intensive Care National Audit and Research Centre in the United Kingdom from 1996 to 2004. Additionally, in a 2007 retrospective analysis, the Australian and New Zealand Intensive Care Society found hospital mortality of patients with septic and septic shock to be declining at a rate similar to that of 28-day mortality among international multicenter trial participants.
Our study has several strengths. Participants in multicenter clinical trials were prospectively identified as meeting severe sepsis criteria and thus were less likely to be subject to substantial misclassification bias. Our requirement for use of multicenter trials allowed for selection of generally high-quality international studies with large sample size that reflected a variety of care settings. Furthermore, we used severity-of-illness scores from each clinical trial to adjust for differences in case-mix (e.g., proportion of patients with septic shock) and risk standardize the severe sepsis mortality rates across clinical trials and found that severity of illness among trial participants has not changed substantially over time. In addition, we used previously validated administrative data algorithms to identify severe sepsis in a representative sample of patients hospitalized in the United States. Although our data encompass a greater time span, we identified severe sepsis mortality rates that were similar to prior reports using the NIS.
Our study also has several limitations. First, we excluded clinical trials that were not published in English, which may limit external validity of our findings to studies performed in areas of English fluency. Furthermore, exclusion criteria used in randomized controlled trials may select patients that differ from the underlying population. For example, severe sepsis cases identified from clinical trials had generally lower mortality than patients enrolled in observational studies and were younger than severe sepsis cases identified using administrative data algorithms. Thus, mortality rates from patients enrolled in randomized trials may not provide "gold-standard" estimates of mortality in the underlying population. Second, most of the trials included were conducted multinationally, whereas the administrative data only reflect outcomes for patients with severe sepsis in the United States. However, declines in severe sepsis mortality were similar regardless of trial location. Third, 28-day mortality rates measured in clinical trials likely differ from in-hospital mortality, and although trends are likely similar, the absolute mortality rates may not be comparable between clinical trial and administrative data. Fourth, different algorithms used to identify severe sepsis cases in administrative data selected cases of varying disease severity: the Angus algorithm identified nearly a three-fold larger cohort with substantially lower in-hospital mortality rates and a larger decline in mortality than the Martin definition. Prior single-center chart validation of severe sepsis ICD-9-CM code algorithms shows hospital-level variation in the accuracy of severe sepsis ICD-9-CM coding algorithms. Representative multicenter chart validation studies are necessary to determine the overall sensitivity and specificity of each coding algorithm in the NIS. Given the large difference in sample size between the trials and administrative data, we cannot rule out the possibility that a greater number of trial participants might reveal statistically significant mortality trends when compared with administrative data. Fifth, although the Consensus severe sepsis definition of a suspected infection and presence of acute organ dysfunction was used as inclusion criteria for all trials, the number of acutely dysfunctional organs or systemic inflammatory response syndrome criteria may have differed among trials. The differences in trial inclusion criteria highlight the importance of our use of the SMR to adjust for differences case-mix between trials. That the variation in severity of illness between trials as measured by APACHE II, SAPS II, or LODs scores does not change significantly over time makes it less likely that modification of Consensus sepsis definitions used in some trials affects our finding of a decreasing trend in severe sepsis mortality. Finally, the NIS does not include physiologic variables that would allow calculation of SMR in administrative data. Nonetheless, we have demonstrated that trends in mortality rates are likely comparable between 28-day mortality and hospital mortality measurements.
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