In this study, we demonstrate that in-hospital mortality increases as admission-shock-onset-time increases in patients with sepsis even after adjusting for comorbidities and baseline illness severity. Our study confirms that the timing of shock-onset in patients with sepsis during their hospital stay is independently associated with increased in-hospital mortality. But more importantly, we illustrated that the association between the timing of shock-onset and in-hospital mortality is continuous in nature without clear inflection points and there is a linear relationship between mortality and the time to shock onset during their stay in the hospital.
Our study is the first study to describe the temporal relationship between time to shock onset and mortality in sepsis. In previous studies, 24- and 48- hours from admission to ICU were used as arbitrary cut-offs to dichotomize septic patients into early-onset and late-onset septic shock showed the mortality rate to be 1.5 to 2 times higher in late-onset septic shock [12–14]. The arbitrary dichotomization of time at 24–48 hours implies a change in either patient or disease characteristics at the aforementioned time periods driving the higher mortality in the latter group . In our study, we found mortality increased continuously with time to onset of septic shock from hospital admission implying thereby that mortality associated with this time duration is not a static phenomenon. Other authors have shown the onset of sepsis later during the hospital stay, defined with terms such as hospital-onset sepsis to be associated with higher mortality in comparison to community-acquired sepsis or septic shock [9, 10]. In our subgroup analysis, we found a similar temporal relationship of in-hospital mortality to the onset of septic shock both in patients admitted to ICU with septic shock directly from the emergency department or from other admitting sources confirming that time to onset of septic shock is independently associated with mortality irrespective of where the patient is cared for at septic shock onset.
The higher mortality in septic shock developing later in the course of hospital stay is likely multifactorial. Previous studies have shown the process of care variables including delays in recognition, antibiotic administration, intravenous fluid administration, and non-adherence to bundled care and vasoactive support may be responsible for an increase in mortality in septic shock [12, 20–22]. Patient-specific characteristics including severe comorbidities, underlying debilitation, and the development of organ dysfunction during the hospital course also may play a major role in driving this mortality. A longer hospital stay also puts this patient population at high risk for developing hospital-acquired infections with antibiotic-resistant organisms, which are associated with higher rates of mortality [23–25]. By considering the time to onset of septic shock as a continuous variable, future studies can inform on the specific mechanisms that contribute to this phenomenon.
The most obvious strength of this study is that this is the largest cohort of patients that have been assessed to study outcomes of sepsis based on the timing of septic shock onset [12–14]. In addition, to the best of our knowledge, this is the first study to suggest that the relationship between time to shock onset and mortality does not support the dichotomization of septic shock into “early” and “late”. A previous study using two large national databases reported that patients with initially less severe sepsis made up the majority of sepsis-related deaths while most performance improvement efforts have been focused on the most severely ill patients . Our study also supports the importance of future research to identify patients at high risk for developing septic shock later on in the course of their hospitalization and to identify and develop interventions to prevent the development of septic shock in this cohort.
We acknowledge that this study has limitations which are mainly results of its single-center, retrospective nature and reliance on electronic medical record documentation. To account for the inevitable risk of residual confounding, we performed multivariable analyses adjusting all known or suspected confounders. We also performed multiple imputations for missing values and ran subgroup analysis for a priori identified variables. Since this study was not designed to identify the reason for the delay in vasopressors, a delay in recognition of shock or delay in initiation of vasopressors by the bedside clinician might have resulted in residual confounding. However, we performed multivariable analyses adjusting for all known or suspected confounders and subgroup assessment showcasing similar trends. Therefore, we believe that the finding that the continuous nature of the relationship between admission-shock-onset-time and mortality is still likely to be the case despite these limitations. Secondly, we could not obtain the information on causative pathogens which in turn might have affected mortality . Future analyses should evaluate the change in microbiology patterns in this group of patients and their association with mortality.