Relationship Between Nighttime Emergency Department Admission and Adherence to a Sepsis Treatment Bundle

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Following sepsis campaign implementation, this study investigated compliance rates with the Surviving Sepsis Campaign 3-h bundle for daytime and nighttime emergency department (ED) admissions and the clinical impact of compliance on mortality. Methods: We conducted an observational study using data from a prospective, multicenter registry for septic shock provided by the Korean Shock Society from 11 institutions from November 2015 to December 2017. The outcome was the compliance rate with the complete 3-hour treatment bundle according to the time of arrival in the ED. Mediation analysis was conducted to evaluate the proportion of the total effect that could be explained by hospital admission times. Results: A total of 2,247 patients were enrolled. Compared with daytime admission, nighttime admission was associated with higher compliance for the administration of antibiotics within 3-h (adjusted odds ratio (AOR), 1.276; 95% confidence interval (95% CI), 1.050–1.550, p=0.014), vasopressor within 3-h (AOR, 1.235; 95% CI, 1.009–1.512; P=0.031) and for the administration of the complete 3-h bundle (AOR, 1.231; 95% CI, 1.004–1.501; P=0.046), likely as a result of the increased volume of patients admitted during daytime hours. Consequently, daytime hospital admission adversely affected in-hospital and 28-day mortality rates, mediated by decreased compliance with the complete 3-h bundle. Conclusions: Septic shock patients admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted at night. Despite sepsis campaign implementation, factors that decrease bundle compliance should be reconsidered in patients with septic shock. Critical Care & Emergency Medicine Sepsis septic shock off-hour effect Surviving Sepsis Campaign Figures Figure 1 Figure 2 Figure 3 Background Each year, approximately 850,000 adult patients are admitted to the emergency department (ED) in the U.S for sepsis or septic shock [ 1 ]. Although such cases account for nearly 1% of all ED visits, the mortality rate of patients hospitalized with this syndrome is greater than 20% [ 2 , 3 ]. The Surviving Sepsis Campaign (SSC), which aims to improve clinical outcomes in patients being treated for sepsis, has established and endorsed international clinical practice guidelines for the management of sepsis or septic shock [ 4 – 6 ]. These guidelines consist of a bundle that combines treatments for the various components of sepsis, such as rapid fluid resuscitation, timely and appropriate administration of antibiotics following blood sample collection for culture, the use of vasopressors to maintain arterial pressure, and quantification of lactate concentrations [ 7 ]. As improving the quality of care is a fundamental component of medical practice, assuring adherence to evidence-based protocols is crucial [ 8 ]. For sepsis patients, compliance with sepsis treatment bundles has remained the cornerstone for improving quality and clinical outcomes since the publication of the first SSC guidelines [ 5 ]. Owing to certain uncontrollable variables, the off-hour or nighttime effect is usually defined as an increased risk of mortality during off-hour admissions for the treatment of various diseases or conditions [ 9 – 11 ]. For example, many studies have demonstrated the adverse effects of off-hours admissions on diagnosis, treatment, and clinical outcomes in several diseases requiring time-sensitive interventions, such as polytrauma, myocardial infarction, and stroke [ 12 , 13 ]. Compared with daytime hours, medical services in hospitals are commonly reduced at night due to a shortage of staff, the lack of experienced clinicians, diminished access to hospital services and resources, and inadequate subspecialty care [ 12 , 14 , 15 ]. In sepsis, these off-hour characteristics may cause a critical delay in the initial management of the patient or reduced adherence to the sepsis treatment bundle [ 14 , 15 ]. Overall, although off-hour or nighttime admission is significantly associated with increased mortality risk, the associations may vary substantially among different diseases [ 12 ]. Besides the lack of medical and human resources, ED crowding is associated with delays in administering time-critical care processes [ 1 , 16 ]. In patients visiting the ED with sepsis, crowding may also affect the adherence to treatment bundles, some components of which are time-sensitive in nature [ 1 ]. In a multicenter study of sepsis patients in EDs, ED crowding was associated with a delay in initial patient assessments and antibiotic administration [ 1 ]. In addition, the diurnal variation in ED crowding was observed, with the lowest occupancy being from midnight to 10:00 A.M [ 1 ]. Considering these factors, whether nighttime admission can adversely affect timely sepsis bundle management is debatable. Few studies have evaluated the association between timely bundle management and the time of ED visits in patients with sepsis, and conflicting results have been reported [ 17 , 18 ]. Therefore, this large, multicenter study was conducted to investigate the rate of compliance with the SSC 3-h bundle for nighttime and daytime ED admissions and to investigate the clinical impacts of non-compliance on mortality in patients with septic shock. Methods Study design and population We conducted an observational study using a prospective, multicenter registry of septic shock data provided by the Korean Shock Society (KoSS) related to patients treated from November 2015 to December 2017. The KoSS was organized in 2013 by recruiting hospitals that were willing to participate in the consortium voluntarily; it is a collaborative research network developed to better comprehend the results of various studies related to sepsis and to investigate and improve the quality of diagnosis and the management of septic shock patients [ 19 – 21 ]. The KoSS web-based septic shock registry has been prospectively collecting predetermined data pertaining to patients with septic shock who visited the EDs of 11 teaching hospitals throughout South Korea since October 2015 [ 19 – 21 ]. The study design was reviewed and approved by the institutional review boards of the individual participating institutions prior to the initiation of data collection. The protocol and the investigators’ manual for the registry were developed based on a literature review and the consensus of the study investigators [ 19 – 21 ]. All data were collected using standardized web-based electronic case report forms by research coordinators located in each individual institution; this consisted of standard definitions of approximately 200 variables, including clinical characteristics, laboratory and time-related data, therapeutic interventions, and the outcomes of patients treated for septic shock [ 21 ]. The study was performed simultaneously in the 11 institutions following the same protocol. To control the data quality, outliers were primarily filtered by the web-based electronic data entry system [ 19 , 21 ]. Furthermore, the principal investigator and the designated local research coordinator at each participating institution were responsible for verifying data accuracy [ 19 , 21 ]. The quality management committee, which consisted of emergency physicians, local research coordinators, and the investigators in the ED of each participating institution, was established to monitor and review data quality regularly and to relay feedback on the results of the quality management process to the designated local research coordinator and principal investigators using the system’s query function or a telephone call [ 19 , 21 ]. Patients from the septic shock registry who were aged > 18 years and who met the inclusion criteria were enrolled [ 19 – 21 ]. As the implementation of the KoSS registry began prior to the publication of the Sepsis-3 criteria, the inclusion criteria were based on evidence of refractory hypotension or hyperlactatemia in patients with suspected or confirmed infection [ 19 – 21 ]. Hypotension was defined as systolic blood pressure (SBP) < 90 mmHg, a mean arterial pressure 40 mmHg. Refractory hypotension was defined as persistent hypotension based on the same values following an adequate intravenous fluid challenge (20–30 mL/kg or at least 1 L of a crystalloid solution administered over a 30 min period) or as the need for vasopressors following fluid resuscitation [ 19 – 21 ]. Hypoperfusion was defined as a serum lactate concentration of ≥ 4 mmol/L [ 19 – 21 ]; these levels were routinely assessed when the shock was suspected or after a fluid challenge was administered. The following patients were not enrolled in the KoSS registry: patients who did not meet the inclusion criteria within 6 h following ED admission; patients who were transferred from other hospitals without meeting the inclusion criteria upon ED admission or who were transferred from the ED to other hospitals; and patients who signed a “do not attempt resuscitation” order. In 2013, the 6-h septic shock bundle was implemented in South Korea as the standard protocol for sepsis management in EDs of almost all institutions. We also excluded patients who were not provided information about sepsis bundle management or survival outcomes. Data collection We retrieved all the demographic and clinical data of all subjects in this study, including age, sex, past medical history, initial vital signs, laboratory values upon ED admission, Sequential Organ Failure Assessment (SOFA) score, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, therapeutic interventions, and clinical outcomes from the KoSS registry. Compliance with individual components of the sepsis bundle was also recorded in this registry, which included the following procedures: quantification of serum lactate concentration, fluid resuscitation, administration of vasopressors to maintain mean arterial pressure > 65 mmHg, collection of blood samples or other specimens for appropriate culturing, and antibiotic administration. Enrolled patients were classified into two groups based on their time of arrival at the ED, either during the day (09:00 to 19:00) or at night (19:00 to 09:00). In addition, as all the institutions participating in the KoSS are located in Seoul metropolitan area, South Korea, we collected information about patient volume at the time of ED admissions of all 30 emergency medical centers located in Seoul from the Korea National Emergency Department Information System (NEDIS) database. The NEDIS is a nationwide government-run system that collects the clinical and administrative data from all EDs designated by the Ministry of Health and Welfare of Korea. Outcome Measures The outcome measure was defined as the completion of the SSC 3-h treatment bundle, which comprises lactate measurements, blood draws for culturing prior to antibiotic administration, prompt administration of broad-spectrum antibiotics, and appropriate fluid challenge for patients with a mean arterial pressure < 65 mmHg and/or a serum lactate concentration of 4 mmol/L or greater [ 17 ]. The compliance rate with the 3-hour sepsis bundle was calculated according to the time of arrival in the ED. In addition, separate subgroup analyses were conducted to evaluate adherence to the individual components of the complete 3-h sepsis bundle. As compliance with individual components has been shown to independently improve clinical outcomes, the secondary endpoint of this study was to compare patient-centered outcomes, including in-hospital and 28-day mortality rates between patients who did or did not complete individual components of the 3-h sepsis bundle. Statistical analyses Demographic and clinical data are presented as median values with interquartile ranges, means ± standard deviations (SDs), percentages, or frequencies, as appropriate. Continuous variables were compared using two-sample t -tests or Mann–Whitney U tests for parametric and non-parametric variables, respectively. Categorical variables were compared using chi-square or Fisher’s exact tests. Univariate analyses were conducted to evaluate the relationships between clinical characteristics and adherence to individual components of the 3-h sepsis bundle. To identify independent factors affecting compliance with individual components of the bundle, multivariate logistic regression analyses were conducted, integrating the major covariates identified from the univariate analyses (i.e., variables with a p < 0.05). The results are expressed as odds ratios (ORs) and 95% confidential intervals (CIs). Using univariate and multivariate Cox proportional hazards regression analyses, the independent prognostic factors related to in-hospital and 28-day mortality rates were determined based on the compliance rates of individual components of the 3-h sepsis bundle. Kaplan-Meier survival curves and the log-rank test were used to identify significant relationships between the adherence to individual components of the 3-h sepsis bundle, in-hospital mortality, and 28-day mortality. Mediation analysis was performed to evaluate the proportion of the total effect that could be explained by the time of the ED visits (day vs. night). To test the main hypothesis, subjects were classified according to the time of the ED visit or the rate of compliance with the complete 3-h bundle.[ 17 , 22 ] Statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc., Cary, NC) and MedCalc Statistical Software version 16.4.3 (MedCalc Software bvba, Ostend, Belgium). P-values < 0.05 were considered statistically significant. Results Characteristics of Study Subjects During the study period, data from 2,250 patients were registered in the KoSS registry. After exclusion, a total of 2,247 patients with sepsis or septic shock were enrolled in this study. The enrollment and clinical outcome data for patients with septic shock are shown in the flow diagram in Fig. 1 . The eligible patients were stratified based on whether they visited the ED during the day (1,304; 58%) or night (943; 42%). Table 1 shows the comparison of clinical characteristics of the patients with septic shock between those who arrived at the ED during the day or at night. There were no significant differences between the two groups in terms of age, sex, SOFA score, APACHEII score, intensive care unit (ICU) admission rate, or the 28-day or in-hospital mortality rates (Table 1 ). Table 1. Comparison of demographic and clinical characteristics for daytime vs. nighttime admissions of all patients admitted to the emergency department and those with sepsis and septic shock Variables Total Day Night P N = 2247 (100%) N = 1304 (58%) N = 943 (42%) Age (years) 67.9 ± 13.5 68.0 ± 13.3 67.8 ± 13.8 0.721 Male sex [n (%)] 1,314 (58.5) 761 (58.4) 553 (58.6) 0.893 Severity score SOFA score (points) 6.03 ± 3.15 6.04 ± 3.15 6.01 ± 3.15 0.842 APACHE score (points) 19.96 ± 9.10 19.94 ± 9.17 19.98 ± 9.01 0.914 Initial vital sign Systolic blood pressure (mmHg) 89.9 ± 23.4 89.6 ± 22.3 90.3 ± 25.0 0.551 Diastolic blood pressure (mmHg) 54.5 ± 15.9 54.4 ± 15.1 54.7 ± 16.9 0.603 Body temperature ( o C) 37.7 ± 1.3 37.6 ± 1.2 37.7 ± 1.3 0.133 Past medical history [n (%)] Hypertension 927 (41.3) 540 (41.4) 387 (41.0) 0.86 Diabetes mellitus 683 (30.4) 382 (29.3) 301 (31.9) 0.182 Cardiovascular disease 298 (13.3) 180 (13.8) 118 (12.5) 0.373 Cerebraovascular disease 275 (12.2) 165 (12.7) 110 (11.7) 0.481 Chronic lung disease 179 (8.0) 114 (8.7) 65 (6.9) 0.11 Hematologic malignancy 146 (6.5) 85 (6.5) 61 (6.5) 0.962 Metastatic cancer 503 (22.4) 282 (21.6) 221 (23.4) 0.31 Chronic kidney disease 167 (7.43) 95 (7.3) 72 (7.6) 0.755 Chronic liver disease 254 (11.3) 135 (10.4) 119 (12.6) 0.094 Transplantation 41 (1.8) 23 (1.8) 18 (1.9) 0.799 AIDS 6 (0.3) 4 (0.3) 2 (0.2) > 0.999 Source of infection [n (%)] 0.067 GI tract 292 (13.0) 170 (13.0) 122 (12.9) Hepatobiliary or pancreas 403 (17.9) 208 (15.9) 195 (20.7) Respiratory 560 (24.9) 343 (26.3) 217 (23.0) Soft tissue/bone/joint 61 (2.7) 39 (2.99) 22 (2.3) Urinary 422 (18.8) 240 (18.4) 182 (19.3) Mixed 262 (11.7) 148 (11.4) 114 (12.1) Others 112 (5.0) 71 (5.4) 41 (4.4) Unknown 135 (6.0) 85 (6.5) 50 (5.3) Laboratory data White blood cell count (10 3 /µL) 13.14 ± 16.26 13.73 ± 18.10 12.34 ± 13.27 0.035* C-reactive protein (mg/L) 14.55 ± 12.68 15.31 ± 13.42 13.51 ± 11.51 < 0.001* Lactate (mmol/L) 4.40 ± 3.28 4.27 ± 3.18 4.58 ± 3.41 0.038* Albumin (g/dL) 2.977 ± 0.67 2.969 ± 0.68 2.99 ± 0.66 0.492 Creatinine 1.77 ± 1.43 1.805 ± 1.520 1.73 ± 1.30 0.226 Arterial PH 7.42 ± 0.11 7.42 ± 0.11 7.41 ± 0.11 0.534 Clinical outcomes [n (%)] 28-day mortality 452 (20.1) 258 (19.8) 194 (20.6) 0.504 In-hospital mortality 476 (21.2) 270 (20.7) 206 (21.9) 0.514 ICU admission 849 (37.8) 495 (37.9) 354 (37.5) 0.839 Adherence to sepsis bundle [n (%)] Full 3-h bundle 672 (29.9) 365 (27.9) 307 (32.6) 0.02* Antibiotic administration 1,478 (65.8) 828 (63.5) 650 (68.9) 0.005* Lactate measurement 1,904 (85.9) 1,093 (85.2) 811 (86.9) 0.247 Blood culture drawn 1,503 (66.9) 873 (66.9) 630 (66.8) 0.988 Fluid administration 1,619 (72.1) 929 (71.2) 690 (73.1) 0.315 Administration of vasopressors 1,084 (54.7) 602 (52.4) 486 (58.3) 0.01* *P < 0.05 Abbreviations: SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation; AIDS, acquired immunodeficiency syndrome; GI, gastrointestinal; ICU, intensive care unit. The volume of patients admitted to the ED during the day (n = 130.4/h, 5.8%/h) was significantly higher than the volume admitted at night (n = 67.4/h, 3.0%/h; p < 0.001). Association between ED arrival time and compliance with the 3-h sepsis bundle Table 1 shows the rates of compliance with individual components of the sepsis bundle according to the ED arrival time. Patients who arrived at the ED during the night exhibited more frequent compliance with timely antibiotic and vasopressor administration than those who arrived during the day (63.5% vs. 68.9%; p = 0.005, 52.4% vs 58.3%; p = 0.01, for daytime and nighttime arrivals, respectively; p = 0.005), whereas the compliance rates did not differ between groups for the other components of the sepsis bundle. These results affected compliance with the complete 3-hour sepsis bundle (daytime: 27.9% vs. nighttime: 32.6%; p = 0.02). The multivariate logistic regression analysis revealed that, compared with patients who presented during the day, those who presented at night exhibited higher odds of compliance with the administration of antibiotics within 3 h [odds ratio (OR), 1.276; 95% CI, 1.050–1.550, p = 0.014], vasopressors within 3 h (OR, 1.235; 95% CI, 1.009–1.512; p = 0.031) and with the full 3-h bundle (OR, 1.231; 95% CI, 1.004–1.510; p = 0.046), after adjusting for potential confounders (Table 2 , 3 ). Table 2. Multivariate logistic regression analysis to identify variables significantly and independently associated with the 3-h treatment bundle Variable Antibiotic administration < 3H Full 3-h bundle OR (95% CI) P OR (95% CI) P Age (per 1year) 1.004 (0.997–1.012) 0.285 0.999 (0.991–1.007) 0.767 Male sex (vs female) 0.936 (0.769–1.139) 0.51 0.970 (0.788–1.194) 0.772 Admission time Day Reference Reference Night 1.276 (1.050–1.550) 0.014* 1.231 (1.004–1.510) 0.046* Severity score SOFA score (per 1point) 1.033 (0.994–1.072) 0.097 1.029 (0.989–1.070) 0.154 APACHE score (per 1points) 1.005 (0.990–1.020) 0.519 1.005 (0.990–1.021) 0.489 Laboratory data Lactate (per 1mmol/L) 1.022 (0.990–1.056) 0.183 0.999 (0.965–1.033) 0.933 C-reactive protein (per 1mg/L) 1.000 (0.992–1.007) 0.91 0.998 (0.990–1.006) 0.613 Hospital A Reference Reference B 0.359 (0.207–0.626) < 0.001* 8.666 (2.889–25.998) < 0.001* C 1.930 (1.087–3.425) 0.025* 8.227 (2.778–24.365) < 0.001* D 1.151 (0.588–2.255) 0.681 2.787 (0.716–10.852) 0.139 E 1.341 (0.562–3.202) 0.508 1.987 (0.346–11.415) 0.442 F 1.305 (0.737–2.312) 0.362 5.078 (1.649–15.639) 0.005* G 1.283 (0.815–2.020) 0.282 13.617 (4.874–38.041) < 0.001* H 2.007 (1.084–3.716) 0.027* 1.118 (0.271–4.602) 0.877 I 1.456 (0.926–2.289) 0.104 27.447 (9.873–76.305) < 0.001* J 0.613 (0.379–0.991) 0.046* 19.560 (6.901–55.438) < 0.001* K 1.353 (0.734–2.496) 0.333 16.574 (5.528–49.690) < 0.001* *P < 0.05 Abbreviations: SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation. Table 3. Adjusted association between emergency department arrival during nighttime hours and compliance with the 3-hour treatment bundle Compliance with Adjusted† OR (95% CI) P Night admission (vs day admission) Full 3-hour bundle 1.231 (1.004–1.510) 0.046* Antibiotic administration 1.276 (1.050–1.550) 0.014* Lactate measurement 1.118 (0.842–1.483) 0.44 Blood cultures 0.933 (0.736–1.183) 0.567 Fluid administration 1.132 (0.918–1.396) 0.245 Administration of vasopressors 1.235 (1.009–1.512) 0.031* *P < 0.05 Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval. †Adjusted for: age, sex, SOFA score, APACHE score, lactate, C-reactive protein level and hospital. In all institutions, the number of patients admitted to the ED during the day (n = 1,458,104, 5.0%/h) was significantly higher than the number presenting at night (n = 1,467,344, 3.6%/h; p < 0.001) (Fig. 2 ). Association between compliance with the 3-h sepsis bundle and clinical outcomes A total of 452 (20.1%) patients died within 28 days following ED admission and 476 (21.2%) died while hospitalized. In the multivariate Cox proportional hazards regression analyses, the hazard ratios of the intervention bundle for 28-day mortality and in-hospital mortality were 0.704 (95% CI = 0.560–0.884, p = 0.003) and 0.674 (95% CI = 0.539–0.842, p = 0.001), respectively, for the complete 3-h bundle, and 0.775 (95% CI = 0.632–0.950, p = 0.014) and 0.759 (95% CI = 0.622–0.925, p = 0.006), respectively, for the timely administration of antibiotics within 3 h (Table 4). Although daytime and nighttime ED admission did not differ in terms of mortality, timely adherence to the complete 3-h bundle and to antibiotic administration was significantly associated with a decrease in 28-day and in-hospital mortality rates (Table 4). Table 4. Multivariate Cox proportional-hazards regression analysis to identify variables significantly and independently associated with 28-day mortality and hospital mortality rates (A) Variable 28-day mortality HR (95% CI) P HR (95% CI) P Age (per 1year) 1.012 (1.004-1.020) 0.004* 1.013 (1.005-1.021) 0.002* Male sex (vs female) 1.110 (0.907-1.359) 0.311 1.098 (0.897-1.345) 0.364 Severity score SOFA score (per 1points) 1.102 (1.068-1.138) <0.001* 1.105 (1.071-1.141) <0.001* APACHE score (per 1points) 1.048 (1.036-1.060) <0.001* 1.048 (1.036-1.060) <0.001* Laboratory data Lactate (per 1mmol/L) 1.112 (1.086-1.138) <0.001* 1.114 (1.089-1.141) <0.001* C-reactive protein (per 1mg/L) 1.007 (0.999-1.014) 0.087 1.007 (0.999-1.014) 0.082 Adherence to the sepsis bundle Full 3-h bundle 0.704 (0.560-0.884) 0.003* Antibiotic administration < 3H 0.775 (0.632-0.950) 0.014* *P<0.05 (B) Variable Hospital mortality HR (95% CI) P HR (95% CI) P Age (per 1year) 1.010 (1.002-1.018) 0.01* 1.011 (1.004-1.019) 0.0037* Male sex (vs female) 1.112 (0.914-1.354) 0.289 1.100 (0.904-1.339) 0.341 Severity score SOFA score (per 1points) 1.094 (1.060-1.128) <0.001* 1.097 (1.063-1.131) <0.001* APACHE score (per 1points) 1.052 (1.040-1.064) <0.001* 1.052 (1.041-1.064) <0.001* Laboratory data Lactate (per 1mmol/L) 1.111 (1.085-1.136) <0.001* 1.113 (1.087-1.139) <0.001* C-reactive protein (per 1mg/L) 1.007 (1.000-1.014) 0.056 1.007 (1.000-1.014) 0.047* Adherence to the sepsis bundle Full 3-h bundle 0.674 (0.539-0.842) <0.001* Antibiotic administration < 3H 0.759 (0.622-0.925) <0.001* *P<0.05 Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation. Mediation analysis between the time of day and mortality In the mediation analysis with the complete 3-h bundle compliance acting as a mediator, hospital arrival time was associated with in-hospital and 28-day mortality rates. Consequently, it appears that daytime hospital arrivals had an indirect, adverse effect on in-hospital and 28-day mortality rates, mediated solely by decreased compliance with the complete 3-h bundle (Table 5 , Fig. 3 ). Table 5. Compliance with the complete 3-h sepsis bundle as a mediator of the association between nighttime admission and mortality. Variables 28-day mortality Hospital mortality Comparable coefficient (SE) P Comparable coefficient (SE) P Model without mediator Night-time admission à mortality -0.02 (0.029) 0.503 -0.019 (0.028) 0.514 Model with mediator (Compliance of full sepsis bundle) Night-time admission à Sepsis bundle (a) 0.064 (0.026) 0.013* 0.059 (0.025) 0.02* Sepsis bundle à Mortaltiy (b) 0.104 (0.031) 0.001* 0.107 (0.03) < 0.001* Night-time admission à Mortaltiy (c’) -0.025 (0.029) 0.394 -0.024 (0.028) 0.406 Indirect effect (a*b) 0.007 (0.003) 0.039* 0.006 (0.003) 0.045* *P < 0.05 Abbreviations: SE, standard error. Discussion The primary purpose of this study was to evaluate differences in compliance with the 3-h sepsis bundle according to the time of ED admission. The main finding was that patients admitted for septic shock during nighttime hours exhibited higher adherence to timely antibiotic administration and the rapid initiation of vasopressor treatment than those admitted during daytime hours, which resulted in higher compliance with the complete 3-h bundle. These findings remained robust after adjusting for several potential confounders, such as age, sex, disease severity, and the individual hospital where the treatment occurred in the multivariate logistic regression analysis. These findings, which are based on the analysis of prospectively collected multicenter data related to the management of septic shock, contradict those of other diseases in which adverse clinical outcomes and increased mortality risk were shown to be related to nighttime or off-hour effects [ 12 ]. Many factors can be attributed to these off-hour effects, including inadequate staffing of specialists, reduced hospital services, decreased availability of interventions, discontinuity of care, and an overall reduction in the supervision of patients during off-hours [ 9 , 15 ]. Following the implementation of a multidisciplinary critical pathway based on simplified and standardized protocols for treating acute myocardial infarction and ischemic stroke, off-hour effects could be attenuated by improving key steps during the initial management period, such as the door-to-computed tomography- or electrocardiography- time and door-to-balloon or door-to-needle time [ 9 , 23 ]. Although sepsis and septic shock remain associated with higher rates of mortality and morbidity than the aforementioned diseases, the key elements of sepsis care are also early recognition, adoption of bundle care based on systematic evidence, and timely escalation to higher levels of care [ 24 ]. In the years since the establishment of the SSC in 2002, there have been many changes in the management of sepsis, including the implementation of simplified and standardized therapeutic strategies, and comprehensive management may help reduce the marginal benefit related to the expertise of experienced clinicians and subspecialty care providers [ 25 , 26 ]. Most participating institutions in the present study have applied the ‘Code Sepsis’ protocol based on recommendations from the international guidelines and national healthcare authorities. Regardless of hospital arrival times, individual physician characteristics, and experience levels, the sepsis protocol is designed to obligate standardized management [ 26 ]. Thus, the implementation of the sepsis protocol based on the SSC campaign might have mitigated the ‘nighttime effect’ in our study. To date, no obvious association has been demonstrated between the period of treatment and adherence to bundle management in patients with sepsis. Regardless of the implementation of the SSC, organizational factors should be reconsidered to better understand the observed associations and to improve compliance with sepsis treatment guidelines. A retrospective study of 300 consecutive ICU patients reported that compliance with a sepsis 6-h bundle was higher at nighttime, defined based on the hospital arrival time; additionally, the time to address each component of the 6-h bundle was also lower at night than during the day [ 18 ], which is consistent with the present findings. However, that study did not provide information on the precise number of patients treated in each time period, although they suggested that a possible explanation for the findings might be the fact that the lower number of patients entering the ED during nighttime hours had access to the same number of nurses as those entering during daytime [ 18 ]. This higher availability of staff at night might have led to higher rates of compliance with the sepsis bundle management [ 18 ]. Another study by Matsumura et al. reported that nighttime and weekend periods were not associated with increased in-hospital mortality in severe sepsis cases [ 15 ]. They also demonstrated that the amount of time to administer antibiotics was significantly shorter in the nighttime than in the daytime, which may have contributed to reduced off-hour effects in sepsis treatment, and the number of patients with sepsis in the daytime was approximately double the number in the nighttime, reducing the workload of the staff [ 15 ]. In the present study, both the total volume of all patients and the number of patients with sepsis admitted to the ED during the day were higher than the numbers admitted during the night. Several studies have demonstrated that the overcrowding of EDs delays sepsis management [ 1 , 27 ]. For example, in a Korean study, Shin et al. reported that ED crowding significantly decreased compliance with the entire resuscitation bundle, as well as the timely implementation of the bundle elements in patients with severe sepsis and septic shock [ 27 ]. Likewise, a large cohort study conducted by Peltan et al. reported that each 10% increase in the ED occupancy rate was significantly associated with a 4 min delay in the door-to-antibiotic time and a 10% decrease in the probability of initiating antibiotic treatment within 3 h [ 1 ]. Although ED overcrowding indices such as occupancy rates could not be estimated due to the retrospective nature of the present study, we were able to investigate the volume of patients visiting the ED for each time period in Seoul. Despite the fact that most institutions have implemented standard care protocols in the SSC, the number of patients admitted during the daytime was 35% greater than the number of nighttime admissions in the institutions participating in this study, which might explain the decreased adherence to the sepsis 3-h bundle during the daytime. This was consistent with the results of a Portuguese study conducted by Almeida et al. [ 18 ], which showed that decreasing the number of admitted patients led to the higher availability of medical staff, allowing for rapid antibiotic administration and vasopressor infusion. Conversely, in a multicenter, retrospective study, Ranzani et al. reported that patients treated for sepsis during the daytime (defined based on the sepsis identification time) received more frequent lactate measurements, earlier antibiotic administration, and increased compliance with the complete 3-h sepsis bundle [ 17 ]. They hypothesized that a higher turnover rate of staff during night shifts, including displaced staff from other areas to cover the shifts, could affect the association between daytime ED presentation and better sepsis bundle compliance [ 17 ]. In our clinical setting, most of the nursing staff working in emergency departments are subjected to a 'three-shift rotation schedule' (day, evening, and night shifts), and staff members are rarely displaced from other areas to cover night shifts. These institutional differences within various healthcare systems may result in inconsistencies between studies. As the implementation of the sepsis bundle alone cannot guarantee survival in patients with sepsis, continuous effort is required by members in all institutions to mitigate lower rates of compliance with the SSC guidelines and to improve performance. A few studies have reported no significant association between treatment time and mortality rates [ 15 ], and the present study also did not find a significant difference in 28-day mortality rates between daytime and nighttime admissions after adjusting for confounding factors. However, an indirect association was observed between daytime admission and 28-day mortality that was mediated by compliance with the 3-h bundle, with low adherence increasing mortality risk in a manner consistent with the findings of previous studies [ 28 ]. Therefore, increasing the compliance rate of the sepsis bundle during the daytime (defined as the ED arrival time) could improve the prognosis of sepsis patients, although there may be confounding pathways between mediators and mortality that were not evaluated in the present study. This study had several limitations that should be acknowledged. Firstly, although the data were obtained from the prospective multicenter registry using a standardized and predetermined protocol, the data were analyzed retrospectively. Therefore, it was difficult to completely control for potential confounding factors that could increase the risk of selection bias. Secondly, due to the nature of the collected data, it was difficult to clearly determine whether the relationships between the variables were causal. Finally, data on crowding was unavailable and temporal differences in staffing and the specific treatments administered are potential limitations of the study. It may be possible to estimate the trends related to ED crowding in all institutions participating in KoSS data collection based on the number of ED admissions of all 30 emergency medical centers located in Seoul metropolitan area from the Korea NEDIS database. Further prospective, multicenter studies are needed to identify related factors and to verify the association between ED arrival time and adherence to timely sepsis bundle management in patients with sepsis or septic shock. Conclusions Patients experiencing septic shock who were admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted during the nighttime. Both the total number of patients and the number of those with sepsis admitted to the ED during daytime hours may be factors that are responsible for lowering the compliance. Increasing the rate of compliance with the sepsis treatment bundle during the daytime could improve the prognosis of sepsis patients. Despite the implementation of a sepsis treatment campaign, factors that decrease bundle compliance should be reconsidered in patients experiencing septic shock. Abbreviations ED: emergency department; SSC: The Surviving Sepsis Campaign; KoSS: The Korean Shock Society; SBP: systolic blood pressure; SOFA: sequential organ failure assessment; APACHE: acute physiologic assessment and chronic health evaluation; NEDIS: The Korea National Emergency Department Information System; SDs: standard deviations; ORs: odds ratios; CI: confidence interval. Declarations Acknowledgements The authors thank the KoSS participants and participating physicians, investigators and staff for making this research possible. More information about the study and how to access KoSS data is at www. shockkr.com. The following are the investigators of the KoSS study group: Won Young Kim, Seung Mok Ryoo (University of Ulsan College of Medicine, Asan Medical Center), Tae Gun Shin, Sung Yeon Hwang (Samsung Medical Center, Sungkyunkwan University School of Medicine), You Hwan Jo (Seoul National University Bundang Hospital) Sung Phil Chung, Yoon Jung Hwang, Jin Ho Beom, Yoo Seok Park (Yonsei University College of Medicine), Gu Hyun Kang Hallym (University College of Medicine), Sung-Hyuk Choi, Young-Hoon Yoon (Guro Hospital, Korea University Medical Center), Gil Joon Suh (Seoul National University Hospital), Tae Ho Lim, Byuk Sung Ko (College of Medicine, Hanyang University), Kap Su Han (Korea University Anam Hospital), Jong Hwan Shin, Hui Jai Lee, Kyoung Min You (Seoul National University Boramae Medical Center). Authors’ contributions JSY and TK conceptualized and designed the study, interpreted the data, and drafted the article. JSY, YSP, HSL, SJ, WYK and SPC analyzed the data. WYK, TGS, YHJ, GHK, SHC, GJS, BSK, KSH, and JHS reviewed the article and contributed to the discussion. All authors were responsible for interpreting the data and critically revising the article. TK takes responsibility for the paper as a whole. Funding This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (NRF- 2018R1C1B6006159) and a faculty research grant from Yonsei University College of Medicine for 2019 (6-2019-0188). The funder had no role in the execution of this study or interpretation of the results. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approved by the institutional review boards of each participating institute, and informed consent was obtained before data collection. The study has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. 1) Asan Medical Center (2015-1253) 2) Gangnam Sacred Heart Hospital (2015-11-142) 3) Gangnam Severance Hospital (3-2015-0227) 4) Hanyang University Hospital (HYUH 2015-11-013-022) 5) Korea University Anam Hospital (HRPC2016-184) 6) Korea University Kuro Hospital (KUGH15358-001) 7) Samsung Medical Center (SMC2015-09-057-057) 8) Seoul National University Hospital (J-1408-003-599) 9) Seoul National University Bundang Hospital (B-1409/266-401) 10) Severance Hospital (4-2015-0929) 11) Seoul National University Boramae Hospital (IRB-16-2014-36) Consent for publication All authors have read and approved the submission of the manuscript. Competing interests The authors declare that they have no competing interests. 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Intensive Care Med 2018, 44 (6):925-928. Abe T, Kushimoto S, Tokuda Y, Phillips GS, Rhodes A, Sugiyama T, Komori A, Iriyama H, Ogura H, Fujishima S et al : Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: a descriptive analysis of a prospective observational study . Crit Care 2019, 23 (1):360. Spiegel R, Farkas JD, Rola P, Kenny JE, Olusanya S, Marik PE, Weingart SD: The 2018 Surviving Sepsis Campaign's Treatment Bundle: When Guidelines Outpace the Evidence Supporting Their Use . Ann Emerg Med 2019, 73 (4):356-358. Amaral AC, Fowler RA, Pinto R, Rubenfeld GD, Ellis P, Bookatz B, Marshall JC, Martinka G, Keenan S, Laporta D et al : Patient and Organizational Factors Associated With Delays in Antimicrobial Therapy for Septic Shock . Crit Care Med 2016, 44 (12):2145-2153. Yang JM, Park YS, Chung SP, Chung HS, Lee HS, You JS, Lee SH, Park I: Implementation of a clinical pathway based on a computerized physician order entry system for ischemic stroke attenuates off-hour and weekend effects in the ED . Am J Emerg Med 2014, 32 (8):884-889. Bell CM, Redelmeier DA: Mortality among patients admitted to hospitals on weekends as compared with weekdays . The New England journal of medicine 2001, 345 (9):663-668. Cram P, Hillis SL, Barnett M, Rosenthal GE: Effects of weekend admission and hospital teaching status on in-hospital mortality . The American journal of medicine 2004, 117 (3):151-157. Zhou Y, Li W, Herath C, Xia J, Hu B, Song F, Cao S, Lu Z: Off-Hour Admission and Mortality Risk for 28 Specific Diseases: A Systematic Review and Meta-Analysis of 251 Cohorts . Journal of the American Heart Association 2016, 5 (3):e003102. Jneid H, Fonarow GC, Cannon CP, Palacios IF, Kilic T, Moukarbel GV, Maree AO, LaBresh KA, Liang L, Newby LK et al : Impact of time of presentation on the care and outcomes of acute myocardial infarction . Circulation 2008, 117 (19):2502-2509. Raghavan M, Marik PE: Management of sepsis during the early "golden hours" . The Journal of emergency medicine 2006, 31 (2):185-199. Matsumura Y, Nakada TA, Abe T, Ogura H, Shiraishi A, Kushimoto S, Saitoh D, Fujishima S, Mayumi T, Shiino Y et al : Nighttime and non-business days are not associated with increased risk of in-hospital mortality in patients with severe sepsis in intensive care units in Japan: The JAAM FORECAST study . J Crit Care 2019, 52 :97-102. Schull MJ, Vermeulen M, Slaughter G, Morrison L, Daly P: Emergency department crowding and thrombolysis delays in acute myocardial infarction . Ann Emerg Med 2004, 44 (6):577-585. Ranzani OT, Monteiro MB, Besen B, Azevedo LCP: Association of Sepsis Diagnosis at Daytime and on Weekdays with Compliance with the 3-Hour Sepsis Treatment Bundles. A Multicenter Cohort Study . Ann Am Thorac Soc 2020, 17 (8):980-987. Almeida M, Ribeiro O, Aragão I, Costa-Pereira A, Cardoso T: Differences in compliance with Surviving Sepsis Campaign recommendations according to hospital entrance time: day versus night . Crit Care 2013, 17 (2):R79. Ryoo SM, Han KS, Ahn S, Shin TG, Hwang SY, Chung SP, Hwang YJ, Park YS, Jo YH, Chang HL et al : The usefulness of C-reactive protein and procalcitonin to predict prognosis in septic shock patients: A multicenter prospective registry-based observational study . Scientific reports 2019, 9 (1):6579. Ko BS, Choi SH, Kang GH, Shin TG, Kim K, Jo YH, Ryoo SM, Kim YJ, Park YS, Kwon WY et al : Time to Antibiotics and the Outcome of Patients with Septic Shock: A Propensity Score Analysis . The American journal of medicine 2020, 133 (4):485-491.e484. Ryoo SM, Kang GH, Shin TG, Hwang SY, Kim K, Jo YH, Park YS, Choi SH, Yoon YH, Kwon WY et al : Clinical outcome comparison of patients with septic shock defined by the new sepsis-3 criteria and by previous criteria . Journal of thoracic disease 2018, 10 (2):845-853. Kim SH, Park HY, Lee HS, Jung KS, Lee MH, Jhee JH, Kim TH, Lee JE, Kim HJ, Kim BS et al : Association between non-alcoholic fatty liver disease and coronary calcification depending on sex and obesity . Scientific reports 2020, 10 (1):1025. Park YS, Chung SP, You JS, Kim MJ, Chung HS, Hong JH, Lee HS, Wang J, Park I: Effectiveness of a multidisciplinary critical pathway based on a computerised physician order entry system for ST-segment elevation myocardial infarction management in the emergency department: a retrospective observational study . BMJ open 2016, 6 (8):e011429. Labib A: Sepsis Care Pathway 2019 . Qatar medical journal 2019, 2019 (2):4. Hayden GE, Tuuri RE, Scott R, Losek JD, Blackshaw AM, Schoenling AJ, Nietert PJ, Hall GA: Triage sepsis alert and sepsis protocol lower times to fluids and antibiotics in the ED . Am J Emerg Med 2016, 34 (1):1-9. Whitfield PL, Ratliff PD, Lockhart LL, Andrews D, Komyathy KL, Sloan MA, Leslie JC, Judd WR: Implementation of an adult code sepsis protocol and its impact on SEP-1 core measure perfect score attainment in the ED . Am J Emerg Med 2020, 38 (5):879-882. Shin TG, Jo IJ, Choi DJ, Kang MJ, Jeon K, Suh GY, Sim MS, Lim SY, Song KJ, Jeong YK: The adverse effect of emergency department crowding on compliance with the resuscitation bundle in the management of severe sepsis and septic shock . Crit Care 2013, 17 (5):R224. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM: Time to Treatment and Mortality during Mandated Emergency Care for Sepsis . N Engl J Med 2017, 376 (23):2235-2244. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 20 Jul, 2021 Review # 6 received at journal 28 Jun, 2021 Reviewer # 6 agreed at journal 17 Jun, 2021 Review # 5 received at journal 15 Jun, 2021 Reviewer # 5 agreed at journal 15 Jun, 2021 Reviewer # 4 agreed at journal 14 Jun, 2021 Review # 4 received at journal 14 Jun, 2021 Review # 3 received at journal 14 Jun, 2021 Reviewer # 3 agreed at journal 14 Jun, 2021 Review # 2 received at journal 20 May, 2021 Review # 1 received at journal 20 May, 2021 Reviews received at journal 20 May, 2021 Reviewers invited by journal 20 May, 2021 Reviewer # 2 agreed at journal 19 May, 2021 Reviewer # 1 agreed at journal 19 May, 2021 Editor assigned by journal 26 Apr, 2021 Editor invited by journal 26 Apr, 2021 First submitted to journal 26 Apr, 2021 Submission checks completed at journal 26 Apr, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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07:45:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-467514/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-467514/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":8562729,"identity":"fb43876f-57a8-4e63-bcbe-95d3c9f8c2f3","added_by":"auto","created_at":"2021-04-28 18:37:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":898824,"visible":true,"origin":"","legend":"Flow diagram of patient inclusion and exclusion. \nAbbreviations: KoSS, Korean Shock Society.","description":"","filename":"renamed8ed2e.jpg","url":"https://assets-eu.researchsquare.com/files/rs-467514/v1/7338f168c089aae808a34057.jpg"},{"id":8562603,"identity":"2e9ca4b2-97b0-4b56-9a1e-6fb777f50a12","added_by":"auto","created_at":"2021-04-28 18:34:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":666506,"visible":true,"origin":"","legend":"The number of patients admitted to the emergency department (ED) and the compliance rate for the complete 3-h sepsis bundle. The bars indicate the number of patients. The compliance rate for the complete sepsis bundle is shown by the dashed line, and the average 28-day mortality rate in the daytime and nighttime is represented by the solid line. ","description":"","filename":"renamed31f53.jpg","url":"https://assets-eu.researchsquare.com/files/rs-467514/v1/14d44963701014ac74c990cf.jpg"},{"id":8562728,"identity":"5031fe34-91c9-4e2e-8ff9-38b4b24e9a55","added_by":"auto","created_at":"2021-04-28 18:37:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1086115,"visible":true,"origin":"","legend":"Mediation analysis of the association between nighttime emergency department admission and mortality in which compliance with the complete 3-h sepsis bundle is considered as a mediator. ","description":"","filename":"renamed55446.jpg","url":"https://assets-eu.researchsquare.com/files/rs-467514/v1/4012a41a126c2e6c98d4d14c.jpg"},{"id":13689305,"identity":"e95f46a5-2292-4b41-8095-32d13f8970cd","added_by":"auto","created_at":"2021-09-17 12:28:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1495028,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-467514/v1/af7f2253-1c9c-46d2-bec6-440728d46ef7.pdf"}],"financialInterests":"","formattedTitle":"Relationship Between Nighttime Emergency Department Admission and Adherence to a Sepsis Treatment Bundle","fulltext":[{"header":"Background","content":" \u003cp\u003eEach year, approximately 850,000 adult patients are admitted to the emergency department (ED) in the U.S for sepsis or septic shock [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although such cases account for nearly 1% of all ED visits, the mortality rate of patients hospitalized with this syndrome is greater than 20% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The Surviving Sepsis Campaign (SSC), which aims to improve clinical outcomes in patients being treated for sepsis, has established and endorsed international clinical practice guidelines for the management of sepsis or septic shock [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These guidelines consist of a bundle that combines treatments for the various components of sepsis, such as rapid fluid resuscitation, timely and appropriate administration of antibiotics following blood sample collection for culture, the use of vasopressors to maintain arterial pressure, and quantification of lactate concentrations [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. As improving the quality of care is a fundamental component of medical practice, assuring adherence to evidence-based protocols is crucial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. For sepsis patients, compliance with sepsis treatment bundles has remained the cornerstone for improving quality and clinical outcomes since the publication of the first SSC guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOwing to certain uncontrollable variables, the off-hour or nighttime effect is usually defined as an increased risk of mortality during off-hour admissions for the treatment of various diseases or conditions [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. For example, many studies have demonstrated the adverse effects of off-hours admissions on diagnosis, treatment, and clinical outcomes in several diseases requiring time-sensitive interventions, such as polytrauma, myocardial infarction, and stroke [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Compared with daytime hours, medical services in hospitals are commonly reduced at night due to a shortage of staff, the lack of experienced clinicians, diminished access to hospital services and resources, and inadequate subspecialty care [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In sepsis, these off-hour characteristics may cause a critical delay in the initial management of the patient or reduced adherence to the sepsis treatment bundle [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Overall, although off-hour or nighttime admission is significantly associated with increased mortality risk, the associations may vary substantially among different diseases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBesides the lack of medical and human resources, ED crowding is associated with delays in administering time-critical care processes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In patients visiting the ED with sepsis, crowding may also affect the adherence to treatment bundles, some components of which are time-sensitive in nature [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In a multicenter study of sepsis patients in EDs, ED crowding was associated with a delay in initial patient assessments and antibiotic administration [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In addition, the diurnal variation in ED crowding was observed, with the lowest occupancy being from midnight to 10:00 A.M [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsidering these factors, whether nighttime admission can adversely affect timely sepsis bundle management is debatable. Few studies have evaluated the association between timely bundle management and the time of ED visits in patients with sepsis, and conflicting results have been reported [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, this large, multicenter study was conducted to investigate the rate of compliance with the SSC 3-h bundle for nighttime and daytime ED admissions and to investigate the clinical impacts of non-compliance on mortality in patients with septic shock.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eWe conducted an observational study using a prospective, multicenter registry of septic shock data provided by the Korean Shock Society (KoSS) related to patients treated from November 2015 to December 2017. The KoSS was organized in 2013 by recruiting hospitals that were willing to participate in the consortium voluntarily; it is a collaborative research network developed to better comprehend the results of various studies related to sepsis and to investigate and improve the quality of diagnosis and the management of septic shock patients [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The KoSS web-based septic shock registry has been prospectively collecting predetermined data pertaining to patients with septic shock who visited the EDs of 11 teaching hospitals throughout South Korea since October 2015 [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The study design was reviewed and approved by the institutional review boards of the individual participating institutions prior to the initiation of data collection. The protocol and the investigators\u0026rsquo; manual for the registry were developed based on a literature review and the consensus of the study investigators [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. All data were collected using standardized web-based electronic case report forms by research coordinators located in each individual institution; this consisted of standard definitions of approximately 200 variables, including clinical characteristics, laboratory and time-related data, therapeutic interventions, and the outcomes of patients treated for septic shock [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The study was performed simultaneously in the 11 institutions following the same protocol. To control the data quality, outliers were primarily filtered by the web-based electronic data entry system [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Furthermore, the principal investigator and the designated local research coordinator at each participating institution were responsible for verifying data accuracy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The quality management committee, which consisted of emergency physicians, local research coordinators, and the investigators in the ED of each participating institution, was established to monitor and review data quality regularly and to relay feedback on the results of the quality management process to the designated local research coordinator and principal investigators using the system\u0026rsquo;s query function or a telephone call [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients from the septic shock registry who were aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years and who met the inclusion criteria were enrolled [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. As the implementation of the KoSS registry began prior to the publication of the Sepsis-3 criteria, the inclusion criteria were based on evidence of refractory hypotension or hyperlactatemia in patients with suspected or confirmed infection [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Hypotension was defined as systolic blood pressure (SBP)\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg, a mean arterial pressure\u0026thinsp;\u0026lt;\u0026thinsp;70 mmHg, or an SBP decrease\u0026thinsp;\u0026gt;\u0026thinsp;40 mmHg. Refractory hypotension was defined as persistent hypotension based on the same values following an adequate intravenous fluid challenge (20\u0026ndash;30 mL/kg or at least 1 L of a crystalloid solution administered over a 30 min period) or as the need for vasopressors following fluid resuscitation [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Hypoperfusion was defined as a serum lactate concentration of \u0026ge;\u0026thinsp;4 mmol/L [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; these levels were routinely assessed when the shock was suspected or after a fluid challenge was administered.\u003c/p\u003e \u003cp\u003eThe following patients were not enrolled in the KoSS registry: patients who did not meet the inclusion criteria within 6 h following ED admission; patients who were transferred from other hospitals without meeting the inclusion criteria upon ED admission or who were transferred from the ED to other hospitals; and patients who signed a \u0026ldquo;do not attempt resuscitation\u0026rdquo; order. In 2013, the 6-h septic shock bundle was implemented in South Korea as the standard protocol for sepsis management in EDs of almost all institutions. We also excluded patients who were not provided information about sepsis bundle management or survival outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eWe retrieved all the demographic and clinical data of all subjects in this study, including age, sex, past medical history, initial vital signs, laboratory values upon ED admission, Sequential Organ Failure Assessment (SOFA) score, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, therapeutic interventions, and clinical outcomes from the KoSS registry.\u003c/p\u003e \u003cp\u003eCompliance with individual components of the sepsis bundle was also recorded in this registry, which included the following procedures: quantification of serum lactate concentration, fluid resuscitation, administration of vasopressors to maintain mean arterial pressure\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg, collection of blood samples or other specimens for appropriate culturing, and antibiotic administration. Enrolled patients were classified into two groups based on their time of arrival at the ED, either during the day (09:00 to 19:00) or at night (19:00 to 09:00). In addition, as all the institutions participating in the KoSS are located in Seoul metropolitan area, South Korea, we collected information about patient volume at the time of ED admissions of all 30 emergency medical centers located in Seoul from the Korea National Emergency Department Information System (NEDIS) database. The NEDIS is a nationwide government-run system that collects the clinical and administrative data from all EDs designated by the Ministry of Health and Welfare of Korea.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cp\u003eThe outcome measure was defined as the completion of the SSC 3-h treatment bundle, which comprises lactate measurements, blood draws for culturing prior to antibiotic administration, prompt administration of broad-spectrum antibiotics, and appropriate fluid challenge for patients with a mean arterial pressure\u0026thinsp;\u0026lt;\u0026thinsp;65 mmHg and/or a serum lactate concentration of 4 mmol/L or greater [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The compliance rate with the 3-hour sepsis bundle was calculated according to the time of arrival in the ED. In addition, separate subgroup analyses were conducted to evaluate adherence to the individual components of the complete 3-h sepsis bundle. As compliance with individual components has been shown to independently improve clinical outcomes, the secondary endpoint of this study was to compare patient-centered outcomes, including in-hospital and 28-day mortality rates between patients who did or did not complete individual components of the 3-h sepsis bundle.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eDemographic and clinical data are presented as median values with interquartile ranges, means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SDs), percentages, or frequencies, as appropriate. Continuous variables were compared using two-sample \u003cem\u003et\u003c/em\u003e-tests or Mann\u0026ndash;Whitney U tests for parametric and non-parametric variables, respectively. Categorical variables were compared using chi-square or Fisher\u0026rsquo;s exact tests. Univariate analyses were conducted to evaluate the relationships between clinical characteristics and adherence to individual components of the 3-h sepsis bundle. To identify independent factors affecting compliance with individual components of the bundle, multivariate logistic regression analyses were conducted, integrating the major covariates identified from the univariate analyses (i.e., variables with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The results are expressed as odds ratios (ORs) and 95% confidential intervals (CIs). Using univariate and multivariate Cox proportional hazards regression analyses, the independent prognostic factors related to in-hospital and 28-day mortality rates were determined based on the compliance rates of individual components of the 3-h sepsis bundle. Kaplan-Meier survival curves and the log-rank test were used to identify significant relationships between the adherence to individual components of the 3-h sepsis bundle, in-hospital mortality, and 28-day mortality. Mediation analysis was performed to evaluate the proportion of the total effect that could be explained by the time of the ED visits (day vs. night). To test the main hypothesis, subjects were classified according to the time of the ED visit or the rate of compliance with the complete 3-h bundle.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc., Cary, NC) and MedCalc Statistical Software version 16.4.3 (MedCalc Software bvba, Ostend, Belgium). P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eCharacteristics of Study Subjects\u003c/h2\u003e\n\u003cp\u003eDuring the study period, data from 2,250 patients were registered in the KoSS registry. After exclusion, a total of 2,247 patients with sepsis or septic shock were enrolled in this study. The enrollment and clinical outcome data for patients with septic shock are shown in the flow diagram in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eThe eligible patients were stratified based on whether they visited the ED during the day (1,304; 58%) or night (943; 42%). Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the comparison of clinical characteristics of the patients with septic shock between those who arrived at the ED during the day or at night. There were no significant differences between the two groups in terms of age, sex, SOFA score, APACHEII score, intensive care unit (ICU) admission rate, or the 28-day or in-hospital mortality rates (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. \u003c/strong\u003eComparison of demographic and clinical characteristics for daytime vs. nighttime admissions of all patients admitted to the emergency department and those with sepsis and septic shock\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDay\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNight\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;2247 (100%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;1304 (58%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;943 (42%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67.8\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.721\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale sex [n (%)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,314 (58.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e761 (58.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e553 (58.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.893\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSeverity score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA score (points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.03\u0026thinsp;\u0026plusmn;\u0026thinsp;3.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.04\u0026thinsp;\u0026plusmn;\u0026thinsp;3.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.842\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE score (points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.96\u0026thinsp;\u0026plusmn;\u0026thinsp;9.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.94\u0026thinsp;\u0026plusmn;\u0026thinsp;9.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.98\u0026thinsp;\u0026plusmn;\u0026thinsp;9.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.914\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInitial vital sign\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSystolic blood pressure (mmHg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89.9\u0026thinsp;\u0026plusmn;\u0026thinsp;23.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89.6\u0026thinsp;\u0026plusmn;\u0026thinsp;22.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90.3\u0026thinsp;\u0026plusmn;\u0026thinsp;25.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.551\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiastolic blood pressure (mmHg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.5\u0026thinsp;\u0026plusmn;\u0026thinsp;15.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.7\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.603\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBody temperature (\u003csup\u003eo\u003c/sup\u003eC)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.133\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePast medical history [n (%)]\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e927 (41.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e540 (41.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e387 (41.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.86\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e683 (30.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e382 (29.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e301 (31.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.182\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCardiovascular disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e298 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e180 (13.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e118 (12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.373\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCerebraovascular disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e275 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e165 (12.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e110 (11.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.481\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic lung disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e179 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114 (8.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65 (6.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHematologic malignancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e146 (6.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (6.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (6.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.962\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMetastatic cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e503 (22.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e282 (21.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e221 (23.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic kidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e167 (7.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (7.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72 (7.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.755\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic liver disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e254 (11.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135 (10.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e119 (12.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.094\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTransplantation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.799\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAIDS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (0.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (0.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (0.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSource of infection [n (%)]\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.067\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGI tract\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e292 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e170 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e122 (12.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHepatobiliary or pancreas\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e403 (17.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e208 (15.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e195 (20.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRespiratory\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e560 (24.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e343 (26.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e217 (23.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSoft tissue/bone/joint\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (2.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (2.99)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (2.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrinary\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e422 (18.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e240 (18.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e182 (19.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMixed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e262 (11.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148 (11.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114 (12.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112 (5.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71 (5.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135 (6.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (6.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (5.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWhite blood cell count (10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.14\u0026thinsp;\u0026plusmn;\u0026thinsp;16.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.73\u0026thinsp;\u0026plusmn;\u0026thinsp;18.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.34\u0026thinsp;\u0026plusmn;\u0026thinsp;13.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.035*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eC-reactive protein (mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.55\u0026thinsp;\u0026plusmn;\u0026thinsp;12.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.31\u0026thinsp;\u0026plusmn;\u0026thinsp;13.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.51\u0026thinsp;\u0026plusmn;\u0026thinsp;11.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLactate (mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.038*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlbumin (g/dL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.977\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.969\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.492\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.77\u0026thinsp;\u0026plusmn;\u0026thinsp;1.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.805\u0026thinsp;\u0026plusmn;\u0026thinsp;1.520\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.226\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eArterial PH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.534\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcomes [n (%)]\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28-day mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e452 (20.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e258 (19.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e194 (20.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.504\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIn-hospital mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e476 (21.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e270 (20.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e206 (21.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.514\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU admission\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e849 (37.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e495 (37.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e354 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.839\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdherence to sepsis bundle [n (%)]\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFull 3-h bundle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e672 (29.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e365 (27.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e307 (32.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.02*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntibiotic administration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,478 (65.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e828 (63.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e650 (68.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.005*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLactate measurement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,904 (85.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,093 (85.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e811 (86.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.247\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBlood culture drawn\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,503 (66.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e873 (66.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e630 (66.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.988\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFluid administration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,619 (72.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e929 (71.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e690 (73.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.315\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdministration of vasopressors\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1,084 (54.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e602 (52.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e486 (58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eAbbreviations: SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation; AIDS, acquired immunodeficiency syndrome; GI, gastrointestinal; ICU, intensive care unit.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe volume of patients admitted to the ED during the day (n\u0026thinsp;=\u0026thinsp;130.4/h, 5.8%/h) was significantly higher than the volume admitted at night (n\u0026thinsp;=\u0026thinsp;67.4/h, 3.0%/h; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n\u003ch2\u003eAssociation between ED arrival time and compliance with the 3-h sepsis bundle\u003c/h2\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the rates of compliance with individual components of the sepsis bundle according to the ED arrival time. Patients who arrived at the ED during the night exhibited more frequent compliance with timely antibiotic and vasopressor administration than those who arrived during the day (63.5% vs. 68.9%; p\u0026thinsp;=\u0026thinsp;0.005, 52.4% vs 58.3%; p\u0026thinsp;=\u0026thinsp;0.01, for daytime and nighttime arrivals, respectively; p\u0026thinsp;=\u0026thinsp;0.005), whereas the compliance rates did not differ between groups for the other components of the sepsis bundle. These results affected compliance with the complete 3-hour sepsis bundle (daytime: 27.9% vs. nighttime: 32.6%; p\u0026thinsp;=\u0026thinsp;0.02). The multivariate logistic regression analysis revealed that, compared with patients who presented during the day, those who presented at night exhibited higher odds of compliance with the administration of antibiotics within 3 h [odds ratio (OR), 1.276; 95% CI, 1.050\u0026ndash;1.550, p\u0026thinsp;=\u0026thinsp;0.014], vasopressors within 3 h (OR, 1.235; 95% CI, 1.009\u0026ndash;1.512; p\u0026thinsp;=\u0026thinsp;0.031) and with the full 3-h bundle (OR, 1.231; 95% CI, 1.004\u0026ndash;1.510; p\u0026thinsp;=\u0026thinsp;0.046), after adjusting for potential confounders (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. \u003c/strong\u003eMultivariate logistic regression analysis to identify variables significantly and independently associated with the 3-h treatment bundle\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAntibiotic administration\u0026thinsp;\u0026lt;\u0026thinsp;3H\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFull 3-h bundle\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (per 1year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.004 (0.997\u0026ndash;1.012)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.285\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.999 (0.991\u0026ndash;1.007)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.767\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale sex (vs female)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.936 (0.769\u0026ndash;1.139)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.970 (0.788\u0026ndash;1.194)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.772\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdmission time\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.276 (1.050\u0026ndash;1.550)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.014*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.231 (1.004\u0026ndash;1.510)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSeverity score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA score (per 1point)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.033 (0.994\u0026ndash;1.072)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.097\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.029 (0.989\u0026ndash;1.070)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.154\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE score (per 1points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.005 (0.990\u0026ndash;1.020)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.519\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.005 (0.990\u0026ndash;1.021)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.489\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLactate (per 1mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.022 (0.990\u0026ndash;1.056)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.183\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.999 (0.965\u0026ndash;1.033)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.933\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eC-reactive protein (per 1mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000 (0.992\u0026ndash;1.007)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.998 (0.990\u0026ndash;1.006)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.613\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHospital\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.359 (0.207\u0026ndash;0.626)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.666 (2.889\u0026ndash;25.998)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.930 (1.087\u0026ndash;3.425)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.025*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.227 (2.778\u0026ndash;24.365)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.151 (0.588\u0026ndash;2.255)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.681\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.787 (0.716\u0026ndash;10.852)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.139\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.341 (0.562\u0026ndash;3.202)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.508\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.987 (0.346\u0026ndash;11.415)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.442\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.305 (0.737\u0026ndash;2.312)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.362\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.078 (1.649\u0026ndash;15.639)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.005*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.283 (0.815\u0026ndash;2.020)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.282\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.617 (4.874\u0026ndash;38.041)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.007 (1.084\u0026ndash;3.716)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.027*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.118 (0.271\u0026ndash;4.602)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.877\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.456 (0.926\u0026ndash;2.289)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.104\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.447 (9.873\u0026ndash;76.305)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eJ\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.613 (0.379\u0026ndash;0.991)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.560 (6.901\u0026ndash;55.438)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eK\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.353 (0.734\u0026ndash;2.496)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.333\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.574 (5.528\u0026ndash;49.690)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eAbbreviations: SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. \u003c/strong\u003eAdjusted association between emergency department arrival during nighttime hours and compliance with the 3-hour treatment bundle\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCompliance with\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eAdjusted\u0026dagger; OR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eNight admission (vs day admission)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eFull 3-hour bundle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.231 (1.004\u0026ndash;1.510)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eAntibiotic administration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.276 (1.050\u0026ndash;1.550)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.014*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eLactate measurement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.118 (0.842\u0026ndash;1.483)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eBlood cultures\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.933 (0.736\u0026ndash;1.183)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.567\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eFluid administration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.132 (0.918\u0026ndash;1.396)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.245\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eAdministration of vasopressors\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.235 (1.009\u0026ndash;1.512)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.031*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr style=\"height: 13.75px;\"\u003e\n\u003ctd style=\"height: 13.75px;\" colspan=\"3\"\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13px;\"\u003e\n\u003ctd style=\"height: 13px;\" colspan=\"3\"\u003eAbbreviations: OR, odds ratio; 95% CI, 95% confidence interval.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13px;\"\u003e\n\u003ctd style=\"height: 13px;\" colspan=\"3\"\u003e\u0026dagger;Adjusted for: age, sex, SOFA score, APACHE score, lactate, C-reactive protein level and hospital.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn all institutions, the number of patients admitted to the ED during the day (n\u0026thinsp;=\u0026thinsp;1,458,104, 5.0%/h) was significantly higher than the number presenting at night (n\u0026thinsp;=\u0026thinsp;1,467,344, 3.6%/h; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eAssociation between compliance with the 3-h sepsis bundle and clinical outcomes\u003c/h2\u003e\n\u003cp\u003eA total of 452 (20.1%) patients died within 28 days following ED admission and 476 (21.2%) died while hospitalized. In the multivariate Cox proportional hazards regression analyses, the hazard ratios of the intervention bundle for 28-day mortality and in-hospital mortality were 0.704 (95% CI\u0026thinsp;=\u0026thinsp;0.560\u0026ndash;0.884, p\u0026thinsp;=\u0026thinsp;0.003) and 0.674 (95% CI\u0026thinsp;=\u0026thinsp;0.539\u0026ndash;0.842, p\u0026thinsp;=\u0026thinsp;0.001), respectively, for the complete 3-h bundle, and 0.775 (95% CI\u0026thinsp;=\u0026thinsp;0.632\u0026ndash;0.950, p\u0026thinsp;=\u0026thinsp;0.014) and 0.759 (95% CI\u0026thinsp;=\u0026thinsp;0.622\u0026ndash;0.925, p\u0026thinsp;=\u0026thinsp;0.006), respectively, for the timely administration of antibiotics within 3 h (Table\u0026nbsp;4). Although daytime and nighttime ED admission did not differ in terms of mortality, timely adherence to the complete 3-h bundle and to antibiotic administration was significantly associated with a decrease in 28-day and in-hospital mortality rates (Table\u0026nbsp;4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. \u003c/strong\u003eMultivariate Cox proportional-hazards regression analysis to identify variables significantly and independently associated with 28-day mortality and hospital mortality rates\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35.125px;\"\u003e\n\u003ctd style=\"height: 70.125px;\" rowspan=\"2\" width=\"227\"\u003e\n\u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.125px;\" colspan=\"4\" width=\"386\"\u003e\n\u003cp\u003e\u003cstrong\u003e28-day mortality\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eAge (per 1year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.012 (1.004-1.020)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e0.004*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.013 (1.005-1.021)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e0.002*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eMale sex (vs female)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.110 (0.907-1.359)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e0.311\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.098 (0.897-1.345)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e0.364\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003e\u003cstrong\u003eSeverity score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eSOFA score (per 1points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.102 (1.068-1.138)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.105 (1.071-1.141)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eAPACHE score (per 1points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.048 (1.036-1.060)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.048 (1.036-1.060)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eLactate (per 1mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.112 (1.086-1.138)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.114 (1.089-1.141)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eC-reactive protein (per 1mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e1.007 (0.999-1.014)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e0.087\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e1.007 (0.999-1.014)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e0.082\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdherence to the sepsis bundle \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eFull 3-h bundle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e0.704 (0.560-0.884)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e0.003*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"227\"\u003e\n\u003cp\u003eAntibiotic administration \u0026lt; 3H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"127\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"62\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"131\"\u003e\n\u003cp\u003e0.775 (0.632-0.950)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"67\"\u003e\n\u003cp\u003e0.014*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" colspan=\"5\" width=\"227\"\u003e*P\u0026lt;0.05\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e(B)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"228\"\u003e\n\u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" width=\"388\"\u003e\n\u003cp\u003e\u003cstrong\u003eHospital mortality\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eAge (per 1year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.010 (1.002-1.018)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.01*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.011 (1.004-1.019)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.0037*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eMale sex (vs female)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.112 (0.914-1.354)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.289\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.100 (0.904-1.339)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.341\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003e\u003cstrong\u003eSeverity score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eSOFA score (per 1points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.094 (1.060-1.128)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.097 (1.063-1.131)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eAPACHE score (per 1points)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.052 (1.040-1.064)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.052 (1.041-1.064)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eLactate (per 1mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.111 (1.085-1.136)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.113 (1.087-1.139)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eC-reactive protein (per 1mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.007 (1.000-1.014)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.056\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e1.007 (1.000-1.014)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e0.047*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdherence to the sepsis bundle \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eFull 3-h bundle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e0.674 (0.539-0.842)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"228\"\u003e\n\u003cp\u003eAntibiotic administration \u0026lt; 3H\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"127\"\u003e\n\u003cp\u003e0.759 (0.622-0.925)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" width=\"228\"\u003e\n\u003cp\u003e*P\u0026lt;0.05\u003c/p\u003e\n\u003cp\u003eAbbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; SOFA, Sequential Organ Failure Assessment; Acute Physiologic Assessment and Chronic Health Evaluation.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eMediation analysis between the time of day and mortality\u003c/h2\u003e\n\u003cp\u003eIn the mediation analysis with the complete 3-h bundle compliance acting as a mediator, hospital arrival time was associated with in-hospital and 28-day mortality rates. Consequently, it appears that daytime hospital arrivals had an indirect, adverse effect on in-hospital and 28-day mortality rates, mediated solely by decreased compliance with the complete 3-h bundle (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. \u003c/strong\u003eCompliance with the complete 3-h sepsis bundle as a mediator of the association between nighttime admission and mortality.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e28-day mortality\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHospital mortality\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eComparable coefficient (SE)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eComparable coefficient (SE)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel without mediator\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNight-time admission \u0026agrave; mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.02 (0.029)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.503\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.019 (0.028)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.514\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModel with mediator (Compliance of full sepsis bundle)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNight-time admission \u0026agrave; Sepsis bundle (a)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.064 (0.026)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.013*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.059 (0.025)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.02*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSepsis bundle \u0026agrave; Mortaltiy (b)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.104 (0.031)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.107 (0.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNight-time admission \u0026agrave; Mortaltiy (c\u0026rsquo;)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.025 (0.029)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.394\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.024 (0.028)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.406\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIndirect effect (a*b)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.007 (0.003)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.039*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.006 (0.003)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.045*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eAbbreviations: SE, standard error.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eThe primary purpose of this study was to evaluate differences in compliance with the 3-h sepsis bundle according to the time of ED admission. The main finding was that patients admitted for septic shock during nighttime hours exhibited higher adherence to timely antibiotic administration and the rapid initiation of vasopressor treatment than those admitted during daytime hours, which resulted in higher compliance with the complete 3-h bundle. These findings remained robust after adjusting for several potential confounders, such as age, sex, disease severity, and the individual hospital where the treatment occurred in the multivariate logistic regression analysis. These findings, which are based on the analysis of prospectively collected multicenter data related to the management of septic shock, contradict those of other diseases in which adverse clinical outcomes and increased mortality risk were shown to be related to nighttime or off-hour effects [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMany factors can be attributed to these off-hour effects, including inadequate staffing of specialists, reduced hospital services, decreased availability of interventions, discontinuity of care, and an overall reduction in the supervision of patients during off-hours [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Following the implementation of a multidisciplinary critical pathway based on simplified and standardized protocols for treating acute myocardial infarction and ischemic stroke, off-hour effects could be attenuated by improving key steps during the initial management period, such as the door-to-computed tomography- or electrocardiography- time and door-to-balloon or door-to-needle time [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although sepsis and septic shock remain associated with higher rates of mortality and morbidity than the aforementioned diseases, the key elements of sepsis care are also early recognition, adoption of bundle care based on systematic evidence, and timely escalation to higher levels of care [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the years since the establishment of the SSC in 2002, there have been many changes in the management of sepsis, including the implementation of simplified and standardized therapeutic strategies, and comprehensive management may help reduce the marginal benefit related to the expertise of experienced clinicians and subspecialty care providers [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Most participating institutions in the present study have applied the \u0026lsquo;Code Sepsis\u0026rsquo; protocol based on recommendations from the international guidelines and national healthcare authorities. Regardless of hospital arrival times, individual physician characteristics, and experience levels, the sepsis protocol is designed to obligate standardized management [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Thus, the implementation of the sepsis protocol based on the SSC campaign might have mitigated the \u0026lsquo;nighttime effect\u0026rsquo; in our study.\u003c/p\u003e \u003cp\u003eTo date, no obvious association has been demonstrated between the period of treatment and adherence to bundle management in patients with sepsis. Regardless of the implementation of the SSC, organizational factors should be reconsidered to better understand the observed associations and to improve compliance with sepsis treatment guidelines. A retrospective study of 300 consecutive ICU patients reported that compliance with a sepsis 6-h bundle was higher at nighttime, defined based on the hospital arrival time; additionally, the time to address each component of the 6-h bundle was also lower at night than during the day [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], which is consistent with the present findings. However, that study did not provide information on the precise number of patients treated in each time period, although they suggested that a possible explanation for the findings might be the fact that the lower number of patients entering the ED during nighttime hours had access to the same number of nurses as those entering during daytime [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This higher availability of staff at night might have led to higher rates of compliance with the sepsis bundle management [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another study by Matsumura et al. reported that nighttime and weekend periods were not associated with increased in-hospital mortality in severe sepsis cases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. They also demonstrated that the amount of time to administer antibiotics was significantly shorter in the nighttime than in the daytime, which may have contributed to reduced off-hour effects in sepsis treatment, and the number of patients with sepsis in the daytime was approximately double the number in the nighttime, reducing the workload of the staff [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present study, both the total volume of all patients and the number of patients with sepsis admitted to the ED during the day were higher than the numbers admitted during the night. Several studies have demonstrated that the overcrowding of EDs delays sepsis management [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. For example, in a Korean study, Shin et al. reported that ED crowding significantly decreased compliance with the entire resuscitation bundle, as well as the timely implementation of the bundle elements in patients with severe sepsis and septic shock [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Likewise, a large cohort study conducted by Peltan et al. reported that each 10% increase in the ED occupancy rate was significantly associated with a 4 min delay in the door-to-antibiotic time and a 10% decrease in the probability of initiating antibiotic treatment within 3 h [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although ED overcrowding indices such as occupancy rates could not be estimated due to the retrospective nature of the present study, we were able to investigate the volume of patients visiting the ED for each time period in Seoul. Despite the fact that most institutions have implemented standard care protocols in the SSC, the number of patients admitted during the daytime was 35% greater than the number of nighttime admissions in the institutions participating in this study, which might explain the decreased adherence to the sepsis 3-h bundle during the daytime. This was consistent with the results of a Portuguese study conducted by Almeida et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], which showed that decreasing the number of admitted patients led to the higher availability of medical staff, allowing for rapid antibiotic administration and vasopressor infusion. Conversely, in a multicenter, retrospective study, Ranzani et al. reported that patients treated for sepsis during the daytime (defined based on the sepsis identification time) received more frequent lactate measurements, earlier antibiotic administration, and increased compliance with the complete 3-h sepsis bundle [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. They hypothesized that a higher turnover rate of staff during night shifts, including displaced staff from other areas to cover the shifts, could affect the association between daytime ED presentation and better sepsis bundle compliance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In our clinical setting, most of the nursing staff working in emergency departments are subjected to a 'three-shift rotation schedule' (day, evening, and night shifts), and staff members are rarely displaced from other areas to cover night shifts. These institutional differences within various healthcare systems may result in inconsistencies between studies. As the implementation of the sepsis bundle alone cannot guarantee survival in patients with sepsis, continuous effort is required by members in all institutions to mitigate lower rates of compliance with the SSC guidelines and to improve performance.\u003c/p\u003e \u003cp\u003eA few studies have reported no significant association between treatment time and mortality rates [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and the present study also did not find a significant difference in 28-day mortality rates between daytime and nighttime admissions after adjusting for confounding factors. However, an indirect association was observed between daytime admission and 28-day mortality that was mediated by compliance with the 3-h bundle, with low adherence increasing mortality risk in a manner consistent with the findings of previous studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, increasing the compliance rate of the sepsis bundle during the daytime (defined as the ED arrival time) could improve the prognosis of sepsis patients, although there may be confounding pathways between mediators and mortality that were not evaluated in the present study.\u003c/p\u003e \u003cp\u003eThis study had several limitations that should be acknowledged. Firstly, although the data were obtained from the prospective multicenter registry using a standardized and predetermined protocol, the data were analyzed retrospectively. Therefore, it was difficult to completely control for potential confounding factors that could increase the risk of selection bias. Secondly, due to the nature of the collected data, it was difficult to clearly determine whether the relationships between the variables were causal. Finally, data on crowding was unavailable and temporal differences in staffing and the specific treatments administered are potential limitations of the study. It may be possible to estimate the trends related to ED crowding in all institutions participating in KoSS data collection based on the number of ED admissions of all 30 emergency medical centers located in Seoul metropolitan area from the Korea NEDIS database. Further prospective, multicenter studies are needed to identify related factors and to verify the association between ED arrival time and adherence to timely sepsis bundle management in patients with sepsis or septic shock.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003ePatients experiencing septic shock who were admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted during the nighttime. Both the total number of patients and the number of those with sepsis admitted to the ED during daytime hours may be factors that are responsible for lowering the compliance. Increasing the rate of compliance with the sepsis treatment bundle during the daytime could improve the prognosis of sepsis patients. Despite the implementation of a sepsis treatment campaign, factors that decrease bundle compliance should be reconsidered in patients experiencing septic shock.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eED: emergency department; SSC: The Surviving Sepsis Campaign; KoSS: The Korean Shock Society; SBP: systolic blood pressure; SOFA: sequential organ failure assessment; APACHE: acute physiologic assessment and chronic health evaluation; NEDIS: The Korea National Emergency Department Information System; SDs: standard deviations; ORs: odds ratios; CI: confidence interval.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the KoSS participants and participating physicians, investigators and staff for making this research possible. More information about the study and how to access KoSS data is at www. shockkr.com.\u003c/p\u003e\n\u003cp\u003eThe following are the investigators of the KoSS study group: Won Young Kim, Seung Mok Ryoo (University of Ulsan College of Medicine, Asan Medical Center), Tae Gun Shin, Sung Yeon Hwang (Samsung Medical Center, Sungkyunkwan University School of Medicine), You Hwan Jo (Seoul National University Bundang Hospital) Sung Phil Chung, Yoon Jung Hwang, Jin Ho Beom, Yoo Seok Park (Yonsei University College of Medicine), Gu Hyun Kang Hallym (University College of Medicine), Sung-Hyuk Choi, Young-Hoon Yoon (Guro Hospital, Korea University Medical Center), Gil Joon Suh (Seoul National University Hospital), Tae Ho Lim, Byuk Sung Ko (College of Medicine, Hanyang University), Kap Su Han (Korea University Anam Hospital), Jong Hwan Shin, Hui Jai Lee, Kyoung Min You (Seoul National University Boramae Medical Center).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJSY and TK conceptualized and designed the study, interpreted the data, and drafted the article. JSY, YSP, HSL, SJ, WYK and SPC analyzed the data. WYK, TGS, YHJ, GHK, SHC, GJS, BSK, KSH, and JHS reviewed the article and contributed to the discussion. All authors were responsible for interpreting the data and critically revising the article. TK takes responsibility for the paper as a whole.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT \u0026amp; Future Planning (NRF- 2018R1C1B6006159) and a faculty research grant from Yonsei University College of Medicine for 2019 (6-2019-0188). The funder had no role in the execution of this study or interpretation of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review boards of each participating institute, and informed consent was obtained before data collection. The study has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.\u003c/p\u003e\n\u003cp\u003e1) Asan Medical Center (2015-1253)\u003c/p\u003e\n\u003cp\u003e2) Gangnam Sacred Heart Hospital (2015-11-142)\u003c/p\u003e\n\u003cp\u003e3) Gangnam Severance Hospital (3-2015-0227)\u003c/p\u003e\n\u003cp\u003e4) Hanyang University Hospital (HYUH 2015-11-013-022)\u003c/p\u003e\n\u003cp\u003e5) Korea University Anam Hospital (HRPC2016-184)\u003c/p\u003e\n\u003cp\u003e6) Korea University Kuro Hospital (KUGH15358-001)\u003c/p\u003e\n\u003cp\u003e7) Samsung Medical Center (SMC2015-09-057-057)\u003c/p\u003e\n\u003cp\u003e8) Seoul National University Hospital (J-1408-003-599)\u003c/p\u003e\n\u003cp\u003e9) Seoul National University Bundang Hospital (B-1409/266-401)\u003c/p\u003e\n\u003cp\u003e10) Severance Hospital (4-2015-0929)\u003c/p\u003e\n\u003cp\u003e11) Seoul National University Boramae Hospital (IRB-16-2014-36)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the submission of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePeltan ID, Bledsoe JR, Oniki TA, Sorensen J, Jephson AR, Allen TL, Samore MH, Hough CL, Brown SM: \u003cstrong\u003eEmergency Department Crowding Is Associated With Delayed Antibiotics for Sepsis\u003c/strong\u003e. \u003cem\u003eAnn Emerg Med \u003c/em\u003e2019, \u003cstrong\u003e73\u003c/strong\u003e(4):345-355.\u003c/li\u003e\n\u003cli\u003ePruinelli L, Westra BL, Yadav P, Hoff A, Steinbach M, Kumar V, Delaney CW, Simon G: \u003cstrong\u003eDelay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With 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care and outcomes of acute myocardial infarction\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2008, \u003cstrong\u003e117\u003c/strong\u003e(19):2502-2509.\u003c/li\u003e\n\u003cli\u003eRaghavan M, Marik PE: \u003cstrong\u003eManagement of sepsis during the early \"golden hours\"\u003c/strong\u003e. \u003cem\u003eThe Journal of emergency medicine \u003c/em\u003e2006, \u003cstrong\u003e31\u003c/strong\u003e(2):185-199.\u003c/li\u003e\n\u003cli\u003eMatsumura Y, Nakada TA, Abe T, Ogura H, Shiraishi A, Kushimoto S, Saitoh D, Fujishima S, Mayumi T, Shiino Y\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNighttime and non-business days are not associated with increased risk of in-hospital mortality in patients with severe sepsis in intensive care units in Japan: The JAAM FORECAST study\u003c/strong\u003e. \u003cem\u003eJ Crit Care \u003c/em\u003e2019, \u003cstrong\u003e52\u003c/strong\u003e:97-102.\u003c/li\u003e\n\u003cli\u003eSchull MJ, Vermeulen M, Slaughter G, 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bundle in the management of severe sepsis and septic shock\u003c/strong\u003e. \u003cem\u003eCrit Care \u003c/em\u003e2013, \u003cstrong\u003e17\u003c/strong\u003e(5):R224.\u003c/li\u003e\n\u003cli\u003eSeymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM: \u003cstrong\u003eTime to Treatment and Mortality during Mandated Emergency Care for Sepsis\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2017, \u003cstrong\u003e376\u003c/strong\u003e(23):2235-2244.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, septic shock, off-hour effect, Surviving Sepsis Campaign","lastPublishedDoi":"10.21203/rs.3.rs-467514/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-467514/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eNighttime hospital admission is often associated with increased mortality risk in various diseases. Following sepsis campaign implementation, this study investigated compliance rates with the Surviving Sepsis Campaign 3-h bundle for daytime and nighttime emergency department (ED) admissions and the clinical impact of compliance on mortality. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe conducted an observational study using data from a prospective, multicenter registry for septic shock provided by the Korean Shock Society from 11 institutions from November 2015 to December 2017. The outcome was the compliance rate with the complete 3-hour treatment bundle according to the time of arrival in the ED. Mediation analysis was conducted to evaluate the proportion of the total effect that could be explained by hospital admission times.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 2,247 patients were enrolled. Compared with daytime admission, nighttime admission was associated with higher compliance for the administration of antibiotics within 3-h (adjusted odds ratio (AOR), 1.276; 95% confidence interval (95% CI), 1.050–1.550, p=0.014), vasopressor within 3-h (AOR, 1.235; 95% CI, 1.009–1.512; P=0.031) and for the administration of the complete 3-h bundle (AOR, 1.231; 95% CI, 1.004–1.501; P=0.046), likely as a result of the increased volume of patients admitted during daytime hours. Consequently, daytime hospital admission adversely affected in-hospital and 28-day mortality rates, mediated by decreased compliance with the complete 3-h bundle. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eSeptic shock patients admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted at night. Despite sepsis campaign implementation, factors that decrease bundle compliance should be reconsidered in patients with septic shock.\u003c/p\u003e","manuscriptTitle":"Relationship Between Nighttime Emergency Department Admission and Adherence to a Sepsis Treatment Bundle","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-28 18:34:38","doi":"10.21203/rs.3.rs-467514/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-07-21T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-29T00:00:00+00:00","index":6,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-06-18T00:00:00+00:00","index":6,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-16T00:00:00+00:00","index":5,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-06-16T00:00:00+00:00","index":5,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-06-15T01:00:00+00:00","index":4,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-15T00:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-06-15T00:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-06-15T00:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-05-21T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-05-21T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-05-20T14:11:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-05-20T10:12:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-05-20T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-05-20T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2021-04-27T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-04-27T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2021-04-26T23:19:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-04-26T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2a73ccc0-8de6-47bd-98fe-3128e757791a","owner":[],"postedDate":"April 28th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3963988,"name":"Critical Care \u0026 Emergency Medicine"}],"tags":[],"updatedAt":"2022-01-17T06:48:12+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-28 18:34:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-467514","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-467514","identity":"rs-467514","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}