Archives of Academic Emergency Medicine. 2021; 9(1): e44 OR I G I N A L RE S E A RC H Door-to-antibiotic Time and In-hospital Mortality of Elder Patients Presenting to Emergency Department with Sep- sis; a Cross-Sectional Study Siriwimon Tantarattanapong1∗, Thanaporn Hemwej1 1. Department of Emergency Medicine, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand. Received: April 2021; Accepted: May 2021; Published online: 11 June 2021 Abstract: Introduction: The current international sepsis guideline recommends that administration of intravenous broad-spectrum antibiotics should be initiated within 1 hour of emergency department (ED) arrival for sepsis patients. This study aimed to evaluate the association between door-to-antibiotic time and in-hospital mor- tality of these patients. Methods: In this retrospective cross-sectional study, elderly patients (age ≥65 years) diagnosed with sepsis in the ED of a tertiary referral and academic hospital from January to December 2019 were enrolled. Door-to-antibiotic time was defined as the time from ED arrival to antibiotic initiation. The as- sociations of door-to-antibiotic time and each hour delay in first antibiotic initiation with in-hospital mortality were assessed. Results: Six hundred patients with the median age of 78.0 (IQR: 72.0-86.0) were studied (50.8% female). The median door-to-antibiotic time was 51.0 (36.0–89.0) minutes and in-hospital mortality rate was 12.5%. There was no significant difference in the in-hospital mortality rate between door-to-antibiotic time ≤1 hour and >1 hour (13.1% vs. 11.6%, p = 0.726). When considering hour-upon-hour of door-to-antibiotic time, no significant difference in in-hospital mortality was observed (p = 0.866). Factors that led to a delay in door- to-antibiotic time were presenting body temperature <38°C (odds ratio [OR] 3.34; 95% CI, 2.12-5.29; p < 0.001) and age <75 years (OR 1.7; 95% CI, 1.09-2.64; p= 0.019). Conclusion: Door-to-antibiotic time was not associ- ated with in-hospital mortality in elderly sepsis patients in this study. Significant factors that led to a delay in door-to-antibiotic time were no fever, age <75 years, doctor time, and blood sample taking time. Keywords: Anti-Bacterial Agents; Mortality; Emergency Service, Hospital; Quality of Health Care; Sepsis; Aged; Aged, 80 and over Cite this article as: Tantarattanapong S, Hemwej T. Door-to-antibiotic Time and In-hospital Mortality of Elder Patients Presenting to Emer- gency Department with Sepsis; a Cross-Sectional Study. Arch Acad Emerg Med. 2021; 9(1): e44. https://doi.org/10.22037/aaem.v9i1.1266. 1. Introduction Sepsis remains as a public health problem worldwide and is one of the leading causes of death (1). The incidence of sep- sis was 437 cases per 100,000 person-years and has tended to increase as a result of an aging population and more co- morbidities (2). Sepsis is also the major cause of emergency department (ED) visits. The annual incidence of ED sepsis was 0.82% of total ED visits (3). Elderly patients constitute 60% of all sepsis patients (4). Likewise, elderly patients are ∗Corresponding Author: Siriwimon Tantarattanapong; Department of Emer- gency Medicine, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand, 90110. Phone: (66)74- 451705, Fax (66)74-451704, Email: tsiriwimon.er@gmail.com, ORCIDs: https://orcid.org/0000-0002-4792-373X. an increasing proportion of ED visits in the range of 12-24% (5). The characteristics of the elderly, such as unclear complaints, frequent hospital admission, increased cost and more re- sources used for care, and a higher rate of mortality, are dif- ferent compared with younger patients (5). Particularly in institutionalized patients, up to a quarter of the elderly visit the ED with geriatric syndromes (5, 6). Therefore, reaching a diagnosis is challenging for the clinicians because nonspe- cific clinical manifestations of infection are common in such patients (7). Common presentations in the elderly include altered mental status, failure to eat and drink, failure to de- velop fever, lack of pain, functional decline, reduced mobility, falling, fatigue, and urinary incontinence (8). The absence of fever with a disease that is known to cause fever was the most common atypical presentation (9) and was associated with This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Tantarattanapong and T. Hemwej 2 lower rates of ED antibiotic administration and mean intra- venous (IV ) fluid volume, and a higher rate of in-hospital mortality (10). Many studies reported worse outcomes in delayed antibiotic administration in patients with sepsis and septic shock (11- 15). The Surviving Sepsis Campaign (SSC) 2018 (16) strongly recommends initiating administration of IV broad-spectrum antibiotics within 1 hour of ED arrival as well as obtaining blood cultures, assessing serum lactate level, and initiating IV fluid resuscitation and early vasopressor treatment. However, according to the Infectious Diseases Society of America (IDSA) (17), prescribing aggressive antibiotics and administrating antibiotics over a fixed time period may lead to deleterious consequences. Also, some studies and a meta- analysis reported no significant hour-upon-hour increase in sepsis mortality (18-20). Moreover, effective use of SSC pro- tocols to administer antibiotics within 1 hour from ED arrival is challenging, especially in elderly patients. Therefore, what is the appropriate or suitable time for ad- ministration of antibiotics in elderly septic patients in the ED? The aim of this study was to determine whether the time of antibiotic initiation was associated with in-hospital mor- tality. We also aimed to determine the factors that led to delay in antibiotic initiation. 2. Methods 2.1. Study design and setting This single-center retrospective cross-sectional study was conducted in elderly septic patients who visited the ED at Songklanagarind Hospital, which is a tertiary referral and academic hospital on the campus of Prince of Songkla Uni- versity in southern Thailand. Approximately 50,000 patients visit the ED of this hospital each year. Patient data from Jan- uary to December 2019 were retrieved from the hospital elec- tronic medical record database. The Research Ethics Com- mittee of the Faculty of Medicine, Prince of Songkla Univer- sity approved the study (REC 62-425-20-4). 2.2. Participants The study enrolled elderly patients (≥65 years) diagnosed with sepsis at the ED according to the Songklanagarind Hos- pital sepsis protocol, which was developed from the recom- mendation of the SSC (16). Sepsis is defined as having both a suspected infection and an assessment of physiologic pa- rameters using the National Early Warning Score (NEWS) of ≥5 points. In this study, infection was defined as a demon- strated source of infection or positive culture. The exclusion criteria were no sepsis in final diagnosis, referred patients, and incomplete data (e.g., serum lactate level and culture re- sults). 2.3. Data gathering The data obtained from the electronic medical records in- cluded clinical presentation, demographic characteristics, Emergency Severity Index (ESI) triage level, initial NEWS, laboratory results (complete blood count [CBC], lactate val- ues), treatments (antibiotics, IV fluid, oxygen therapy, me- chanical ventilator, vasopressor), sources of infection, ED disposition, length of stay, and hospital outcome. The door-to-antibiotic time was defined as the time from ED arrival to antibiotic initiation. Doctor time was the time elapsed until the doctor examined the patient. Hemoculture time and CBC time were the times when the nurse took blood samples. The time to receive IV fluids, time to receive vaso- pressor, time to start mechanical ventilation, and ED dispo- sition time were recorded by the ED nurse. Fever was defined as body temperature ≥38°C. 2.4. Outcome measurement The primary outcome was the association between the door- to-antibiotic time and in-hospital mortality among elderly patients. The in-hospital mortality rate was calculated in hospitalized sepsis patients. This study also analyzed and compared mortality and door-to-antibiotic time interval as ≤1 hour and each hour interval beyond the first hour. The secondary outcomes were the factors that affected the delay in antibiotic initiation and the most prevalent sources of in- fection in elderly sepsis patients who visited the ED. 2.5. Statistical Analysis The n4Studies was used to calculate the sample size using a two-tailed test based on a study by Tongnoon (21). The final sample size was 534 patients to allow for an expected drop- out rate of 10%. Continuous data are demonstrated as me- dian with interquartile range (IQR) or mean ± standard devia- tion. Categorical data are presented as number and percent- ages. The Pearson’s chi-squared test was performed on cat- egorical data for the primary outcome. The chi-square test was used for the analysis and to compare mortality and door- to-antibiotic time interval at ≤1 hour and at each hour inter- val beyond the first hour. After testing associations, selected variables with p-values <0.2 were introduced into a multiple logistic regression model for secondary outcomes. Odds ra- tios (ORs) for the outcomes and their 95% confidence inter- vals (CIs) were used to identify the significant factors that led to delay in antibiotic initiation. A two-sided p-value <0.05 was considered statistically significant. All statistical analy- ses were performed using R software version 3.5.1 (R Foun- dation for Statistical Computing, Vienna, Austria). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e44 3. Results 3.1. Characteristics of the study population The files of 2,208 elderly patients suspected of infection were reviewed. The patients with no sepsis in the final diagno- sis, initial NEWS <5 points, referred cases, and charts/files with incomplete data were excluded. The flowchart of the enrollment process is shown in Figure 1. A total of 600 pa- tients with the median age of 78.0 (IQR: 72.0-86.0) years were included in the study (50.8% female). The most common sources of infection were pneumonia (38.2%), followed by urinary tract (23.2%), intra-abdominal (16.2%), bacteremia (14.7%), and skin/soft tissue (5.5%). Among intra-abdominal infections, acute gastroenteritis (8.3%), acute cholangitis (4.8%), and acute cholecystitis (1.2%) were the most com- mon. Ninety-one patients (15.2%) had positive hemocul- tures for Escherichia coli (52.7%), Klebsiella pneumoniae (18.7%), Staphylococcus spp. (12.1%), and Streptococcus spp. (12.1%). Frequently prescribed empirical antibiotics were ceftriaxone (64.5%), piperacillin/tazobactam (20.8%), ceftazidime (8%), and carbapenems (4.8%). The percentages of door-to-antibiotic times of ≤1 hour and >1 hour were 59.7% (358/600) and 40.3% (242/600), respec- tively. Table 1 and 2 compared the baseline characters, lab- oratory findings and outcomes between cases with door to antibiotic time of ≤1 and >1 hour. A comparison between the two groups showed that the ≤1-hour group had a signif- icantly higher ESI level and initial NEWS. The median NEWS was 8 points in the ≤1-hour group and 6 points in the >1-hour group. Patients in the ≤1-hour group also had more cere- brovascular diseases as co-morbidities and received more va- sopressor agents and IV fluids in the ED. Patients who com- plained of fever and higher body temperature (BT), and had a change in the Glasgow Coma Scale score from baseline re- ceived antibiotic administration significantly early. Patients who complained of gastrointestinal symptoms received an- tibiotic administration significantly later. 3.2. Primary outcomes The median (IQR) door-to-antibiotic time was 51.0 (36.0–89.0) minutes, and the in-hospital mortality rate was 12.5%. There was no significant difference in the me- dian (IQR) door-to-antibiotic times between the discharged patients and those who died in the hospital, 51.0 (36.0–89.0) vs. 54.0 (41.0-85.0); p = 0.382). Similarly, there was no sig- nificant difference in the in-hospital mortality rate of those with door-to-antibiotic time of ≤1 hour and >1 hour (13.1% vs. 11.6%; p = 0.726). When considering hour-upon-hour of door-to-antibiotic time, no significant difference in the in-hospital mortality rate was observed (p = 0.866). However, the in-hospital mortality rates tended to show a linear in- crease when each extra hour of door-to-antibiotic time was considered independently. The in-hospital mortality rates of door-to-antibiotic times of 1-2 hours, 2-3 hours, and >3 hours were 10.4%, 11.6%, and 14.6%, respectively (Figure 2; p = 0.866). 3.3. Secondary outcomes In multivariate analysis, delays in antibiotic initiation of >1 hour were associated with presenting body temperature <38.0°C (OR 3.34; 95% CI: 2.12-5.29; p < 0.001) and age <75 years (OR 1.70; 95% CI: 1.09-2.64; p = 0.019) (Table 3). 4. Discussion In this retrospective observational study of elderly patients with sepsis in the ED, door-to-antibiotic time was not asso- ciated with in-hospital mortality. Sterling et al. (18) found no significant differences when comparing the antibiotic ad- ministration within 3 hours from ED triage and within 1 hour from septic shock recognition. Door-to-antibiotic time and in-hospital mortality were the main focuses of this study, which showed that each extra hour (relative to door-to-antibiotic time ≤1 hour) was not associated with an increase in the mortality rate. The high- est mortality rate in this study was in the door-to-antibiotic group of >3 hours. Likewise, Peltan et al. (22) found that a door-to-antibiotic time cutoff of 3 hours was associated with mortality, but a cutoff of 1 hour did not show statistical signif- icance. When the door-to-antibiotic times of ≤1 hour and >1 hour were compared, the ≤1-hour group had greater severity of illnesses based on the ESI level and NEWS. For this reason, the door-to-antibiotic time of ≤1 hour had a higher mortality rate than the patients who received antibiotics later. The SSC guideline recommends antibiotic initiation within 1 hour. Nonetheless, many studies showed failure to achieve that goal. For instance, Abe et al. (23) found that 30.5% of cases received antibiotics within 1 hour. Ko et al. (24) re- vealed that the 1-hour target was achieved in 28.6% of septic shock patients treated in the ED. In this study, 59.7% of the patients received antibiotics within 1 hour. The explanation of the differences is that the protocol used to diagnose sep- sis was different from the other reports. The median door- to-antibiotic time in this study was 54 minutes, which was shorter than a former report (119 minutes) (25). The reason was a different set of criteria for a diagnosis of sepsis and our standard care followed the hospital policy. Overall, the in-hospital mortality rate was 12.5%, which dif- fered from the other studies in elderly patients with sepsis. Martin-Loeches et al. (26) found that the overall hospital mortality was 48.8% and Vardi et al. (27) found a 38.4% mor- tality rate in patients older than 85 years. The mortality rate in this study was much lower. The explication is that this study collected data in the ED, while the previous studies col- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Tantarattanapong and T. Hemwej 4 lected data in the intensive care unit (ICU) where the patients had more severe conditions. Atypical presentation accounts for about a third of elderly patients in the ED and a lack of fever is common in the el- derly (9). It was found that 29.7% of elderly patients with sepsis have no fever on arrival. Henning et al. (10) found that afebrile patients with septic shock in the ED had an increased likelihood of in-hospital mortality compared with febrile pa- tients. Similarly, Rumbus (28) reported that septic patients with normothermia had a higher mortality rate (31%) com- pared to those with fever (22%). In this study, no fever (BT <38°C) was an independent factor that led to delay in antibi- otic initiation. Pneumonia, urinary tract infections, and intra-abdominal infections were found to be the three most common sources of infection in elderly patients. This finding was similar to studies previously reported in Thailand (29, 30). Emergency physicians should be careful when evaluating the elderly with sepsis by keeping in mind that most elderly pa- tients have atypical presentations. Age <75 years, body tem- perature <38°C, doctor time, and blood sample taking time were significant factors that led to delay in antibiotic initia- tion. This study showed that door-to-antibiotic time was not as- sociated with in-hospital mortality in elderly sepsis patients. This result supported the IDSA recommendation. For sepsis in elderly patients who present with non-specific symptoms or geriatric syndromes, taking time to perform appropriate investigations may be reasonable, because appropriate and smart antibiotic use is an important issue. 5. Limitations We acknowledge that this study has several limitations. First, this study was retrospective in nature, which resulted in se- lection bias; because patients with incomplete data were ex- cluded. Second, we could not determine the direct cause and effect, which could subject the study to confounding, and there were uncertain factors that possibly made causal inference between antibiotic time and in-hospital mortality. Third, this study used the Songklanagarind Hospital sepsis protocol and criteria for the diagnosis of sepsis that are prob- ably different from other institutions, which may limit gener- alizability. Fourth, the antibiotic times and in-hospital mor- tality were not evaluated to arrive at an adjusted severity of sepsis. Thus, the findings of this study should be applied with caution in septic shock patients. 6. Conclusion Door-to-antibiotic time was not associated with in-hospital mortality in elderly sepsis patients in this study. In addition, a linear association between each hour of delay in first antibi- otic initiation and in-hospital mortality was not observed. 7. Declarations 7.1. Acknowledgments The authors are grateful to Ms. Kingkarn Waiyanak for arti- cle searches and retrieval, Ms. Nannapat Pruphetkaew, Epi- demiology Unit, Faculty of Medicine, Prince of Songkla Uni- versity for statistical assistance, and Glenn K. Shingledecker for his help in editing the manuscript. 7.2. Funding and Support The Faculty of Medicine, Prince of Songkla University funded this research. 7.3. Author contribution Thanaporn Hemwej performed the literature search, study design, data collection, data analysis, data interpretation, and wrote the manuscript. 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Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2021; 9(1): e44 Figure 2: Percentages of in-hospital mortality and door-to-antibiotic time. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Tantarattanapong and T. Hemwej 8 Table 1: Comparing the baseline characteristics between cases with door-to-antibiotic time of ≤ 1 and > 1 hour Characteristics Door-to-antibiotic time (hour) p-value ≤1 (n=358) >1 (n=242) Age (year) 80.0 (73.0- 86.0) 77.0 (70.0-84.0) 0.014 Gender Female 176 (49.2) 129 (53.3) 0.361 Male 182 (50.8) 113 (46.7) ESI levels 1 67 (18.7)) 32 (13.2) <0.001 2 264 (73.7) 143 (59.1) 3 25 (7.0) 66 (27.3) 4 2 (0.6) 1 (0.4) Co-morbidities Diabetes mellitus 127 (35.5) 73 (30.2) 0.206 Hypertension 180 (50.3) 122 (50.4) 1.000 Chronic kidney disease 54 (15.1) 37 (15.3) 1.000 Cerebrovascular disease 115 (32.1) 51 (21.1) 0.004 Heart disease 77 (21.5) 54 (22.3) 0.894 Respiratory disease 57 (15.9) 51 (21.1) 0.133 Malignancy 85 (23.7) 52 (21.5) 0.585 Medication use Systemic steroid 30 (8.4) 14 (5.8) 0.300 Immunosuppressive agents 4 (1.1) 5 (2.1) 0.496 Chemotherapy (within 1 month) 23 (6.4) 15 (6.2) 1.000 Beta blocker 76 (21.2) 41 (16.9) 0.232 Bronchodilator 43 (12.0) 32 (13.2) 0.753 Central acting agents 53 (14.8) 33 (13.6) 0.778 Psychotropic medication 25 (7.0) 15 (6.2) 0.833 Opioids 16 (4.5) 7 (2.9) 0.441 Chief complaint Fever 180 (50.3) 98 (40.5) 0.023 Respiratory tract symptoms 91 (25.4) 62 (25.6) 1.000 Drowsy, stupor, coma 35 (9.8) 26 (10.7) 0.805 Gastrointestinal symptoms 33 (9.2) 41 (16.9) 0.007 Fatigue 12 (3.4) 6 (2.5) 0.711 Fall 3 (0.8) 2 (0.8) 1.000 Presenting vital signs Body temperature (°C) 38.5 (38.0-39.1) 38.1 (37.0-38.8) <0.001 Pulse rate (/ minute) 108.3 ± 20.7 106.0 ± 18.2 0.160 Systolic blood pressure (mmHg) 135.5 ± 31.8 135.4 ± 28.6 0.951 Respiratory rate (/minute) 32.0 (28.0-36.0) 30.0 (26.0-36.0) 0.019 GCS change from baseline 89 (24.9) 41 (16.9) 0.027 Initial NEWS 8 (6-10) 6 (5-8) <0.001 Data are presented as n (%), mean ± standard deviation or median and interquartile range (IQR). ESI: Emergency Severity Index; GCS: Glasgow Coma Scale; NEWS: National Early Warning Score. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2021; 9(1): e44 Table 2: Comparing the laboratory findings and outcomes between cases with door-to-antibiotic time of ≤ 1 and > 1 hour Characteristics Door-to-antibiotic time p-value ≤1 hour(n=358) >1 hour(n=358) ED laboratory findings WBC (1,000/dL) 11.6 (8.2-16.1) 11.4 (8.1-15.9) 0.973 PMN (%) 82.0 (73.3-88) 83.4 (74.8-89.0) 0.087 Band cells (%) 6.0 (2.0-13.0) 3.0 (1.0-11.0) 0.013 Lactate ≥2 mmol/L 145.0 (44.5) 73.0 (38.8) 0.248 ED treatment Vasopressor 34 (9.5) 11 (4.5) 0.036 IV fluid replacement 298 (83.2) 162 (66.9) <0.001 ED length of stay (minute) 265.0 (211.5-350.8) 290.5 (218-369.8) 0.133 ED disposition 0.171 Intensive care unit 30 (8.4) 16 (6.6) Ward 213 (59.5) 125 (51.7) Short-stay observation unit 55 (15.4) 49 (20.2) Discharge 59 (16.5) 50 (20.7) Death in ED 1 (0.3) 2 (0.8) Outcome of admission Discharge 259 (86.9) 168 (88.4) 0.726 Death 39 (13.1) 22 (11.6) Hospitalization (days) 7.0 (3.0–14.0) 6.5 (3.0-11.8) 0.090 Time Door-to-doctor time (minute) 3.0 (0.0–7.0) 6.0 (2.0-14.0) <0.001 Door-to-CBC time (minute) 29.0 (18.2-38.8) 44.0 (29.0–65.0) <0.001 Door-to-lactate time (minute) 19.0 (10.0 -36.0) 36.0 (16.5-83.0) <0.001 Data are presented as n (%), mean ± standard deviation or median and interquartile range (IQR). ED: Emergency department; WBC: white blood cell; PMN: polymorphic neutrophils; IV: intravenous; CBC: complete blood count. Table 3: Multiple logistic regression analysis of factors that led to a delay in antibiotic initiation (>1 hour) Variables Adjusted OR 95% CI p-value No fever (BT <38°C) 3.34 2.12 - 5.29 <0.001 Age <75 years 1.70 1.09 - 2.64 0.019 Door-to-doctor time 1.04 1.01 - 1.06 0.002 Door-to-CBC time 1.04 1.03 - 1.05 <0.001 Door-to-lactate time 1.01 1.00 - 1.01 0.006 OR: odds ratio; CI: confidence interval; BT: body temperature; CBC: complete blood count. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References