In the present study, 1-h bundle therapy, according to the Surviving Sepsis Campaign of 2018, was performed less frequently in women than in men. Among the 1-h bundle components, broad-spectrum antibiotics were administered less frequently in women than in men, whereas adequate fluid resuscitation was performed more frequently in women than in men. Sex differences in adherence to the 1-h bundle therapy persisted in various subgroup analyses. Among the other in-hospital management methods, invasive arterial blood pressure monitoring was performed less frequently in women than in men; however, other in-hospital management methods and survival rates were similar for both the sexes.
The strength of our study is that we simultaneously evaluated the overall 1-h bundle therapy and each of its components, along with various in-hospital managements. Furthermore, our study included patients with sepsis, which was defined using the Sepsis-3 definition, and evaluated sex differences based on the recently proposed 1-h bundle therapy. Most previous studies either included patients with sepsis that was defined using previous definitions6,8,12,13 or evaluated the 3-h bundle therapy7,12. Additionally, we used a multicenter prospective registry and used propensity score matching for unbalanced covariables, including age, comorbidities, infection focus, and severity score. The results of the multivariable logistic regression analysis of the pre-matched and matched cohorts and the results of the subgroup analysis were similar, thus indicating the statistical robustness of the results.
In our study, there was low adherence to the overall 1-h bundle therapy in the emergency department. Although the rate of adherence to the administration of broad-spectrum antibiotics within 1 h was similar to that reported in a previous study17, this rate was the lowest among all components of the bundle therapy. The low adherence to the administration of broad-spectrum antibiotics within 1 h may be attributable to the initial presentation of patients with sepsis in the emergency department. Notably, more than 40% of patients with sepsis were not initially febrile, and approximately 24% of patients with sepsis initially had altered mental status. Therefore, emergency physicians should differentiate these patients from those with other acute and time-sensitive diseases. Performing imaging or laboratory tests to rule out other conditions could potentially delay the administration of broad-spectrum antibiotics in the emergency departments. The patient-to-medical staff ratio and emergency department overcrowding may be additional factors that contribute to the rate of adherence14,18. Prompt administration of broad-spectrum antibiotics to patients with suspected sepsis (even without ruling out other diseases or waiting for the results of other studies), increasing medical staff, and reducing overcrowding may improve adherence to the overall bundle therapy in emergency departments. Continuous efforts to increase adherence to the 1-h bundle therapy, especially focusing on the administration of broad-spectrum antibiotics, are required in emergency departments.
Our results showed sex differences in adherence to the 1-h bundle therapy. Among the bundle therapy components, the administration of broad-spectrum antibiotics was significantly less frequent among women. Similar to the results of our study, a previous study on severe sepsis and septic shock reported that women were less likely to receive 1-h bundle therapy and 1-h antibiotic administration6. Another study reported that antibiotic administration within 3 h was performed less frequently in women with severe sepsis and septic shock12. Previous studies on severe sepsis and septic shock have reported that the time to antibiotic administration was longer in women than in men19,20. Considering the initial presentation of patients with sepsis in our study, altered mental status was more frequent, even after propensity score matching for potential covariables, including severity score and infection focus. A more frequent initial presentation of altered mental status may result in more frequent brain imaging workups in women compared to men. This difference might have contributed to sex differences in bundle therapy adherence for up to 98 min, as observed in our exploratory analysis. Conversely, our study found that adequate fluid resuscitation was performed more frequently in women than in men. Due to this sex difference, more frequent instability of vital signs may occur in men, leading to more frequent invasive arterial blood pressure monitoring. Another explanation for the difference in adequate fluid resuscitation may be differences in body weight. Women tend to have a lower body weight than men; thus, supplementation of 30 mL/kg is easier to achieve in women, even if the same amount of fluid is infused in both sexes. This is supported by a previous study on septic shock which reported that the infused fluid per kilogram was higher in women, although the total amount of fluid was similar between sexes21. To improve adherence to overall 1-h bundle therapy and decrease sex differences, the improvement of broad-spectrum antibiotics administration within 1 h is required in women, whereas the improvement of adequate fluid resuscitation is required in men. However, further studies are needed to determine sex differences in each component of bundle therapy to generalize these results.
Mortality was similar between sexes in the present study. Sex differences in the mortality rates among patients with sepsis remain controversial. Although some studies have reported higher mortality rates among women6,22,23, others have reported higher mortality rates among men7,24,25,26. Furthermore, previous studies have reported no difference between the sexes12,21,27. Possible explanations for these results are described below. Although 1-h bundle therapy was performed less frequently in women, lactate measurement, blood culture before antibiotic administration, and application of vasopressors were well-performed components of bundle therapy in both sexes. Although adequate fluid resuscitation was more prevalent among women, the sex-difference effect of fluid might be compensated for by closer monitoring in men, such as invasive arterial blood pressure monitoring. Regarding sex differences in antibiotic use within 1 h, the protective effect of antibiotics for up to 3 h can lead to reduced sex differences in mortality rates. Although the administration of antibiotics within 1 h was associated with survival in patients with septic shock, this was not associated with survival in patients without septic shock17. Antibiotic administration within 3 h was associated with the survival of patients with sepsis28. Exploratory analysis revealed that the sex difference in bundle therapy reduced after 98 min, and adherence to bundle therapy for up to 3 h showed a survival benefit. As antibiotic administration is a significant contributing factor to adherence to bundle therapy, the protective effect of antibiotics within 3 h may be relevant to the results of the exploratory analysis. The protective effect of 3 h bundle may lead to similar mortality in both sexes. Furthermore, mortality was similar between sexes after balancing for SOFA score, APACHE II score, body temperature, infection focus, comorbidities, and lactate in propensity score matching analysis. The severity of the patients, which can be represented by SOFA score, APACHE II score, or lactate, might be a more contributing factor for mortality. Additionally, other unmeasured factors such as fluid balance or nutritional status during hospital admission might affect the mortality.
Additionally, the proportion of patients with septic shock and those with sepsis without shock can contribute to the sex differences in mortality rates. A previous study on septic shock found no sex-related differences in mortality21. The proportion of patients with septic shock was 17% in a previous study that reported sex-related differences in mortality due to sepsis7. This study also found no sex-related differences in mortality in a subgroup of patients with septic shock. Sex differences in mortality may not have been revealed in our study owing to the high proportion of patients with septic shock. Furthermore, uncollected variables in the ICU or after hospital admission may have contributed to the mortality in patients with sepsis. Therefore, further studies on sex-related differences in mortality rates are required.
This study has several limitations. First, the observational design confers the possibility that some covariables might have been missed and only associations could be identified. Second, although a multicenter prospective registry was used, the study was conducted in a single nation, which limits the generalizability of the results to other nations. Therefore, further multinational studies are warranted. Third, in-hospital managements can affect mortality. In addition, data on in-hospital management and patient status, such as fluid balance or nutritional status in the ICU or general ward, were not collected. Mortality results must be interpreted with caution and further studies are warranted to evaluate sex difference in mortality after adjustment of in-hospital managements. Fourth, as the KoSS registry is an emergency department–based prospective multicenter registry and only patients with acute-onset sepsis who visited the emergency department were included in this study, these results cannot be generalized to patients with delayed-onset sepsis or hospital-acquired sepsis. Fifth, the COVID-19 pandemic might affect clinical practice in the emergency department. We additionally evaluated the differences according to the COVID-19 pandemic in the study cohort. Overall adherence to 1-h bundle therapy was comparable between the COVID pandemic and the period before the COVID pandemic. Among the components of the 1-h bundle therapy, lactate measurement and obtaining blood cultures were less frequently performed, while the vasopressor component was more frequently performed during the COVID pandemic compared to the period before the COVID pandemic (Supplementary Table 3). The sex difference in 1-h bundle therapy existed in both periods. However, the sex difference was smaller during the COVID pandemic (before the COVID pandemic: men 20.8% vs. women 12.5%, p < 0.001; COVID pandemic: men 17.8% vs. women 13.5%, p = 0.043). The decreased sex difference during the COVID pandemic was attributed to decreased lactate measurement and obtaining blood cultures in men, rather than an improvement in adherence to bundle components in women. The COVID pandemic might have delayed lactate measurement and obtaining blood cultures. The sex difference in the overall adherence to 1-h bundle therapy remained similar to the main result after additional adjustment for the COVID pandemic (Supplementary Table 4); however, there may be unmeasured effects of the COVID pandemic on the sex difference in in-hospital management. Therefore, further studies are required.
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