Improved Methods of Sepsis Case Identification and the Effects of Treatment with Low Dose Steroids: A Dissertation

Sepsis is the leading cause of death among critically ill patients and the 10th most common cause of death overall in the United States. The mortality rates increase with severity of the disease, ranging from 15% for sepsis to 60% for septic shock. Patient with sepsis can present varied clinical symptoms depending on the personal predisposition, causal microorganism, organ system involved, and disease severity. To facilitate sepsis diagnosis, the first sepsis consensus definitions was published in 1991 and then updated in 2001. Early recognition of a sepsis patient followed with timely and appropriate treatment and management strategies have been shown to significantly reduce sepsis-related mortality, and allows care to be provided at lower costs. Despite the rapid progress in the knowledge of pathophysiological mechanisms of sepsis and its treatment in the last two decades, identifying patient with sepsis and therapeutic approaches to sepsis and its complications remains challenging to critical care clinicians. Hence, the objectives of this thesis were to 1) evaluate the test characteristics of the two sepsis consensus definitions and delineate the differences in patient profile among patients meeting or not meeting sepsis definitions; 2) determine the relationship between the changes in several physiological parameters before sepsis onset and sepsis, and to determine whether these parameters could be used to identify sepsis in critically ill adults; 3) evaluate the effect of corticosteroids therapy on patient mortality. Data used in this thesis were prospectively collected from an electronic medical record system for all the adult patients admitted into the seven critical care units (ICUs) in a tertiary medical center. Besides analyzing data at the ICU stay level, we investigated patient information in various time frames, including 24-hour, 12-hour, and 6-hour time windows. In the first study of this thesis, the 1991 sepsis definition was found to have a high sensitivity of 94.6%, but a low specificity of 61.0%. The 2001 sepsis definition had a slightly increased sensitivity but a decreased specificity, which was 96.9% and 58.3%, respectively. The areas under the ROC curve for the two consensus definitions were similar, but less than optimal. The sensitivity and area under the ROC curve of both definitions were lower at the 24-hour time window level than those of the unit stay level, though the specificity increased slightly. At the time window level, the 1991 definitions performed slightly better than the 2001 definition. In the second study, minimum systolic blood pressure performed the best, followed by maximum respiratory rate in discriminating sepsis patients from SIRS patients. Maximum heart rate and maximum respiratory rate can differentiate sepsis patients from non-SIRS patients fairly well. The area under ROC of the combination of five physiological parameters was 0.74 and 0.90 for comparing sepsis to non-infectious SIRS patients and comparing sepsis to non-SIRS patients, respectively. Parameters typically performed better in 24-hour windows compared to 6-hour or 12-hour windows. In the third study, significantly increased hospital mortality and ICU mortality were observed in the group treated with low-dose corticosteroids than the control group based on the propensity score matched comparisons, and multivariate logistic regression analyses after adjustment for propensity score alone, covariates, or propensity score (in deciles) and covariates. This thesis advances the existing knowledge by systemically evaluating the test characteristics for the 1991 and 2001 sepsis consensus definitions, delineating physiological signs and symptoms of deterioration in the preceding 24 hours prior to sepsis onset, assessing the prediction performances of single or combined physiological parameters, and examining the use of corticosteroids treatment and survival among septic shock patients. In addition, this thesis sets an innovative example on how to use data from electronic medical records as these surveillance systems are becoming increasingly popular. The results of these studies suggest that a more parsimonious set of definitional criteria for sepsis diagnosis are needed to improve sepsis case identification. In addition, continuously monitored physiological parameters could help to identify patients who show signs of deterioration prior to developing sepsis. Last but not least, caution should be used when considering a recommendation on the use of low dose corticosteroids in clinical practice guidelines for the management of sepsis