Septic shock is sepsis resulting in organ dysfunction through metabolic derangement and hypotension refractory to fluid therapy.1 It represents 20% of all deaths globally and is associated with a 60% mortality rate at 6 months.2,3 Considerable efforts have been made to lessen the impact of sepsis and septic shock; however, there is no approved sepsis-specific medication to date.4,5 Several randomized controlled trials (RCTs) have assessed different treatments for septic shock without clear success in reducing mortality.6 Recent systematic reviews have investigated mortality in patients with severe sepsis and septic shock,7–9 but numerous studies were excluded from these analyses because they did not report a 28-day mortality rate endpoint. Reporting inconsistency of mortality endpoints, and in some cases questionable time frames, can create selection biases that affect external validity of these analyses, clinical practice, or research.6

A preliminary exploration of the literature performed by our group showed heterogeneity in the mortality time frames reported in RCTs,10 with 28-day mortality being the most frequently reported endpoint in RCTs studying critically ill patients with sepsis. The present systematic review was designed to further delineate the mortality time frames used by septic shock RCTs, to identify differences between geographical regions, publication types, and changes over the past decade.

In this systematic review of mortality outcome data extracted from septic shock RCTs published between 2008 and 2019, 28-day mortality was the most commonly reported mortality outcome overall, followed by hospital mortality, ICU mortality, and 90-day mortality. There was, however, substantial interregional variability in the time frames selected for reporting. Few studies from North America, Africa, and Asia reported 90-day mortality as an outcome, whereas 40%–60% of the studies from Europe, South America, and those from multiple countries included this time frame. The variability was also present regardless the study publication type (full-text vs. abstract) and IF.

These results highlight considerable discrepancies in outcome reporting exposing the lack of consensus between clinicians and investigators despite decades of sepsis research. The importance of homogeneity among reported RCTs outcomes and the clinical implications cannot be overstated. Short-term mortality time frames can lead to underestimation of the real problem; at the same time, reports such as 90-day mortality can lead to misallocation of the cause of death or failing to recognize effective therapies due to confounding.145 This reporting variability also reduces the accuracy of meta-analyses limiting our ability to extract meaningful conclusions from the pooled data of septic shock patients.

Although sepsis mortality has been decreasing,6,146 approximately 25% of patients with sepsis are still expected to die within 28 days.6 Because a predefined outcome measure is required to establish whether an intervention is effective, mortality rate is a commonly used endpoint in RCTs of therapeutic interventions for sepsis. Nonetheless, as Vincent suggested in 2004,147 the ideal time at which mortality should be recorded remains uncertain. Many licensing authorities, including the US Food and Drug Administration, consider 28-day all-cause mortality to be a germane time frame for mortality assessments, as this endpoint counterbalances the time needed to assess a given intervention’s impact on mortality against the time in which unrelated events could cloud and confound this impact.147,148 The original sepsis consensus paper published 30 years ago also acknowledged the lack of well-defined endpoints and advocated for the reporting of 28-day and in-hospital mortality.149 Nonetheless, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3) study developed its diagnostic criteria using only in-hospital mortality as a primary outcome.150,151 Furthermore, the current Surviving Sepsis Campaign guidelines do not suggest any specific mortality time frame for explorations of the efficacy of novel treatments for sepsis and septic shock.4 These discrepancies highlight the lack of widely accepted consensus on mortality time frame reporting and sheds light on the need for more standardized reporting.

Different approaches may be considered to establish an optimal time frame for mortality reporting in septic shock RCTs. Early mortality time frames (14 days or less) may be the most suitable endpoints to reflect mortality directly related to septic shock and assess the impact on survival of a studied therapeutic intervention. However, because patients with sepsis and septic shock have a reduced mean life span and a higher risk for long-term mortality,152 a shorter time span for evaluation would leave unrecognized a given intervention’s potential effect on longer-term survival. That said, only 16 (12%) of the included studies reported at least one early mortality endpoint.

Arguments exist for the presentation of alternative mortality endpoints, such as 90-day, 180-day, 6-month, and 12-month mortality rates. While these longer time spans may render the links between interventions and mortality rates more tenuous,148 some authors have questioned the justification for interventions that significantly impact 28-day mortality but do not affect mortality by at least the 3-month mark.147 At longer time points, when the primary insult of septic shock has been overcome, mortality rates may reflect non-sepsis-related causes of death (for instance, cardiovascular disease, stroke, or heart failure) or may reflect the effects of subsequent septic events, such as nosocomial infections, during the ICU or hospital stay.153 This consideration is of paramount importance, as temporality is a basic principle of causal inference and is lost when a late outcome is measured as the effect of an intervention.154 Nevertheless, an intervention that may lead to early recovery or rehabilitation may still impact long-term mortality outcomes. If these outcomes are not measured in clinical trials, a relevant amount of disease information may be ignored. In addition, differential mortality rates may be present among different populations of ICU patients. Assessment of long-term mortality outcomes may thus elucidate the impacts of an intervention in patients with different baseline status (e.g., medical, surgical, oncological).155–159

There are additional key points worthy of discussion. First, it is crucial to consistently define the beginning of the mortality time frame (i.e., when counting begins) when assessing the impact of septic shock on mortality or evaluating the impact of a treatment in an RCT. As stated in the 1992 sepsis consensus paper,149 “the interval between fulfillment of entry criteria and administration of experimental intervention…should be noted” because a lack of clear information on this subject may introduce lead-time bias. Machine learning models for the early detection of sepsis have at times identified a condition consistent with sepsis hours prior to its recognition in the emergency department and ICU, suggesting that, both in patients arriving with clinical sepsis and those developing it while in the hospital, providers may already be working against a significant delay.160–162 Second, the reporting of the causes of death in clinical trials is of paramount importance, as it allows researchers to understand the real effect of an intervention and may shed light on potential long-term events that influence survival and merit further research. A step in that direction was offered by Moskowitz and colleagues,163 who proposed five cause-of-death categories and reported their frequency among patients with sepsis and septic shock. Nonetheless, classifying the cause of death in these patients is challenging, as illustrated by the moderate concordance between the three independent experts in that study.163

With the increasing research emphasis on precision medicine, new sepsis therapies are likely to be developed in the coming years. In actual practice and under research conditions, subpopulations of patients are typically heterogeneous. For this reason, mortality analyses should also consider patient-level differences, not only with regard to clinical and study-related factors, such as patients’ underlying conditions, shock severity, sepsis origins, country of study, or causative pathogen, among others, but also with regard to molecular-level differences. Such studies would illustrate the inherent clinical variability among septic shock patients and septic shock outcomes, which would further justify the use of consistent outcome durations.164,165 For instance, a recent study in Spain with more than 2000 ICU patients identified 3 different types of sepsis secondary to COVID-19 with distinct mortality rates.166 These differences will likely impact the design of clinical trials in the near future.167

This study has limitations. First, we did not divide mortality outcomes into primary or secondary outcomes; thus, we were unable to determine the priority authors gave to their studied outcomes. Second, while we extracted specific data from each study, including the type of intervention and patient characteristics, we were not able to collect information addressing why authors elected to measure one outcome over another. For this reason, factors driving the included trials’ endpoint selections could not be analyzed, representing a gap that requires further attention. Third, our study did not explore the mortality time frames based on study phase or number of patients which could play a role in the variability observed. Fourth, the inclusion of abstracts could also have skewed our findings. Finally, we did not include evidence that emerged during the COVID-19 pandemic because many COVID-19-related studies used an expedited approach that might not reflect the evidence-generating practices used in the sepsis literature over the last decade.

While 28 days was the most widely used time frame for mortality reporting among RCTs involving ICU patients with septic shock, this systematic review found considerable variability in outcome reporting of mortality outcomes. This variability may lead to under or overestimating the problem, failure to recognize the effectiveness of the interventions studied, and further limiting the applicability of RCTs findings and their pooling in meta-analyses. Given the burden of sepsis worldwide, reaching a consensus regarding the mortality time frames in septic shock trials is of paramount importance and long overdue. This consensus should also consider the relevant characteristics of each studied population.

PM, JAC, AL, and JLN conceived the study. ClF developed the search strategy and performed the literature search. PM, JAC, AL, CoF, and NM did the study selection and data extraction for the systematic review. JAC performed the formal analysis. PM, JAC, AL, JB-C, and JLN wrote the first draft of the manuscript. Both AL and JAC contributed equally and have the right to list their name first in their CV. All authors contributed to the interpretation of data and critical revision of the manuscript and approved the final manuscript. All authors confirm the accuracy and integrity of the work.

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Available upon reasonable request.

Preliminary data used in this study were presented virtually at the Society of Critical Care Medicine’s 51th Critical Care Congress; April 2022.

No generative AI or AI-assisted technologies were used in the writing process.

This work is supported by The University of Texas MD Anderson Cancer Center Grant Resources, and the National Institutes of Health/National Cancer Institute under award number P30CA016672. Dr. Lopez-Olivo’s work is supported by the National Cancer Institute (CA237619). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data will be available upon reasonable request.