key: cord-0286974-cp7r06en authors: Do, S. N.; Dao, C. X.; Nguyen, T. A.; Nguyen, M. H.; Pham, D. T.; Nguyen, N. T.; Huynh, D. Q.; Hoang, Q. T. A.; Bui, C. V.; Vu, T. D.; Bui, H. N.; Nguyen, H. T.; Hoang, H. B.; Le, T. T. P.; Nguyen, L. T. B.; Duong, P. T.; Nguyen, T. D.; Le, V. H.; Pham, G. T. T.; Bui, G. T. H.; Bui, T. V.; Pham, T. T. N.; Nguyen, C. V.; Nguyen, A. D.; Phua, J.; Li, A. Y.; Luong, C. Q. title: Sequential Organ Failure Assessment (SOFA) score for predicting short-term mortality in patients with sepsis in Vietnamese intensive care units: A multicentre, cross-sectional study date: 2022-05-19 journal: nan DOI: 10.1101/2022.05.18.22275206 sha: 926999473b9de61f893c7fe79c5bd7c5e819591c doc_id: 286974 cord_uid: cp7r06en Objectives: To compare the accuracy of the SOFA and APACHE II scores in predicting short-term mortality among ICU patients with sepsis in an LMIC. Design: A multicentre, cross-sectional study. Setting: A total of 15 adult ICUs from 14 hospitals, of which 5 are central hospitals, and 9 are provincial, district, or private hospitals, throughout Vietnam. Participants: We included all patients aged [≥]18 years who were admitted to ICUs for sepsis and who were still in ICUs from 00:00 hour to 23:59 hour of the study days (i.e., 9th January, 3rd April, 3rd July, and 9th October of 2019). Main outcome measures: Short-term mortality was the main outcome, including hospital and ICU mortality. Results: Of 252 patients, 40.1% died in hospitals, and 33.3% died in ICUs. SOFA (cut-off value [≥]7.5; AUROC: 0.688 [95% CI: 0.618-0.758]; p<0.001) and APACHE II score (cut-off value [≥]20.5; AUROC: 0.689 [95% CI: 0.622-0.756]; p<0.001) both had a poor discriminatory ability for predicting hospital mortality. However, the discriminatory ability for predicting ICU mortality of SOFA (cut-off value [≥]9.5; AUROC: 0.713 [95% CI: 0.643-0.783]; p<0.001) was better and greater than that of APACHE II score (cut-off value [≥]18.5; AUROC: 0.672 [95% CI: 0.603-0.742]; p<0.001). A SOFA score [≥]8 (OR: 2.717; 95% CI: 1.371-5.382) and an APACHE II score [≥]21 (OR: 2.668; 95% CI: 1.338- 5.321) were independently associated with an increased risk of hospital mortality. Additionally, a SOFA score [≥]10 (OR: 2.194; 95% CI: 1.017-4.735) was an independent predictor of ICU mortality, in contrast to an APACHE II score [≥]19, for which this role did not. Conclusions: Both SOFA and APACHE II scores were worthwhile in predicting hospital and ICU mortality among ICU patients with sepsis. However, due to good discrimination for predicting ICU mortality, the SOFA was preferable to the APACHE II score in predicting short-term mortality. Both SOFA and APACHE II scores were worthwhile in predicting hospital and ICU mortality among ICU patients with sepsis. However, due to good discrimination for predicting ICU mortality, the SOFA was preferable to the APACHE II score in predicting short-term mortality. Keyword: APACHE II Score; Emergency Department; Intensive Care Unit; MOSAICS II Study; quick SOFA Score; Sepsis; Septic Shock; Severe Sepsis; SIRS; SOFA Score. • An advantage of the present study was data from multicentre, which had little missing data. • Due to the absence of a national registry of intensive care units (ICUs) to allow systematic recruitment of units, we used a snowball method to identify suitable units, which might have led to the selection of centres with a greater interest in sepsis management. • Due to the study's real-world nature, we did not make a protocol for microbiological investigations. Moreover, we mainly evaluated resources utilized in ICUs; therefore, the data detailing the point-of-care testing and life-sustaining treatments were not available. • To improve the feasibility of conducting the study in busy ICUs, we opted not to collect data on antibiotic resistance and appropriateness. • The sample size was relatively small, which might have led to overfitting in the multivariable prediction model. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Sepsis is a clinical syndrome which has physiologic, biologic, and biochemical abnormalities caused by a dysregulated host response to infection and is a critical global health problem. (1, 2) Sepsis is the most common cause of in-hospital deaths, with most of the burden in lowand middle-income countries (LMICs), and extracts a high economic and social cost; (3) (4) (5) mortality rates remain high at 30-45% and contribute to as much as 20% of all deaths worldwide. (2, 4, 6, 7) There is no reference standard that allows easy, accurate diagnosis and prognosis of sepsis. (1, 8) Although the 1991 International Consensus Definition Task Force proposed the systemic inflammatory response syndrome (SIRS) criteria to identify patients with a septic host response,(9) these criteria do not measure whether the response is injurious, and their utility is limited. (1, 8) . The Acute Physiology and Chronic Health Examination II (APACHE II) score was originally developed for critically ill patients in intensive care units (ICUs).(10) It has 12 physiologic measures and extra points based upon age and the presence of chronic disease.(10) The APACHE II score was shown to have good prognostic value in acutely ill or surgical patients. (10, 11) However, some limitations of the APACHE II score are that (i) it is complex and cumbersome to use, (ii) it does not differentiate between the sterile and infected necrosis, and finally, (iii) it has a poor predictive value at 24 hours. (12) In 2016, the Sepsis-3 Task Force proposed that, for patients with suspected infection, an increase of 2 points or more in the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score could serve as clinical criteria for sepsis. (1) This approach was justified based on content validity (SOFA reflects the facets of organ dysfunction) and predictive validity (the proposed criteria predict downstream events associated with the condition of interest). (13) (14) (15) (16) However, the validity of this score was mainly derived from critically-ill 7 patients with suspected sepsis by interrogating over a million intensive care unit (ICU) electronic health record encounters from ICUs in high-income countries (HICs). (1, 16, 17) Moreover, the patients, pathogens, and clinical capacity to manage sepsis differ considerably between HIC and LMIC settings.(7) Therefore, it's still unclear whether this score could be applied to different types of infection, locations within the hospital, and countries. Vietnam is an LMIC, ranked 15th in the world and 3rd in Southeast Asia by population with 96.462 million people.(18) Vietnam is also a hotspot for emerging infectious diseases in Southeast Asia, including the SARS-CoV,(19) avian influenza A(H5N1), (20, 21) and ongoing global COVID-19 outbreaks(22). Additionally, severe dengue,(23) Streptococcus suis infection,(24) malaria, (25) and increased antibiotic resistance are other major causes of sepsis in ICUs across Vietnam (26, 27) . Despite its recent economic growth spurt,(28) Vietnam is still struggling to provide either enough resources or adequate diagnostic, prognostic and treatment strategies for patients with sepsis in both local and central settings. (29, 30) In addition, within the healthcare system in Vietnam, central hospitals are responsible for receiving patients who have difficulties being treated in local hospital settings.(31) Therefore, the diagnosis, prognosis, and initiation of treatment for patients with sepsis are often delayed. In resource-limited settings, the early identification of infected patients who may go on to develop sepsis or may be at risk of death from sepsis using accurate scoring systems as a way to decrease sepsis-associated mortality. Therefore, this study aimed to investigate the mortality rate and compare the accuracy of the SOFA score and the APACHE II score in predicting short-term mortality in ICU patients with sepsis in Vietnam. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; This multicentre observational, cross-sectional, point prevalence study is part of the Management of Severe sepsis in Asia's Intensive Care unitS II (MOSAICS II) study, (32, 33) which collects data on the management of sepsis in Asia. In this study, we used only data from Vietnam. A total of 15 adult ICUs (excluding predominantly neurosurgical, coronary, and cardiothoracic ICUs) participating in the MOSAICS II study from 14 hospitals, of which 5 are central and 9 are provincial, district, or private hospitals, throughout Vietnam. Each ICU had one or two representatives. Participation was voluntary and unfunded. All patients admitted to participating ICUs on 4 days which represented the different seasons of 2019 (i.e., 9th January, 3rd April, 3rd July, and 9th October) were screened for eligibility; there was no formal sample size calculation. We included all patients, aged ≥ 18 years old, who were admitted to the ICUs for sepsis, and who were still in the ICUs from 00:00 hour to 23 :59 hour of the study days (Fig S1 as shown in in Supplementary file 3). We defined sepsis as infection with a Sequential Organ Failure Assessment (SOFA) score of 2 points or more from baseline (assumed to be 0 for patients without prior organ dysfunction).(1) We used a standardized classification and case record form to collect data on common variables. The data dictionary of the MOSAICS II study is available in Supplementary file 1. Data was entered into the database of the MOSAICS II study by the password-protected online case report forms. We checked the data for implausible outliers and missing fields and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Prior to patient enrolment, representatives completed a questionnaire to describe their centres' characteristics is found in Supplementary file 2. The case report form contained 4 sections which is available in Supplementary file 1. The first section focused on baseline characteristics (demographics, comorbidities, and details of admission). The second section comprised of vital signs upon ICU admission, laboratory parameters, and illness severity scores (e.g., SOFA score,(1) systemic inflammatory response syndrome (SIRS) criteria (34) and the Acute Physiology and Chronic Health Evaluation (APACHE) II score (10) life-sustaining treatments provided during the ICU stay. In addition, each ICU recorded the total number of ICU patients on each study day. We followed all patients till hospital All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; https://doi.org/10.1101/2022.05.18.22275206 doi: medRxiv preprint discharge, short-term death (defined as death in the ICU/hospital), and up to 90 day postenrolment, whichever was earliest. The primary outcome was short-term mortality, which included hospital or ICU mortality. We also examined the following secondary outcomes: ICU and hospital lengths of stay (LOS). We used IBM ® SPSS ® Statistics 22.0 (IBM Corp., Armonk, United States of America) for data analysis. We report data as numbers (no.) and percentages (%) for categorical variables and medians and interquartile ranges (IQRs) or means and standard deviations (SDs) for continuous variables (Tables 1 and 2 , Tables S1 to S14 as shown in Supplementary file 3). Comparisons were made between survival and death in the hospital and ICU for each variable (Tables 1 and 2 , Tables S1 to S14 as shown in Supplementary file 3), using the χ 2 test or Fisher exact test for categorical variables and the Mann-Whitney U test, Kruskal-Wallis test, one-way analysis of variance for continuous variables. Receiver operator characteristic (ROC) curves were plotted and the areas under the receiver operating characteristic curve (AUROC) were calculated to determine the discriminatory ability of the SOFA and APACHE II scores for deaths in the hospital (Fig. 1) and ICU (Fig. 2 ). The cut-off value of the SOFA and the APACHE II scores was determined by the ROC curve analysis. Based on the cut-off value of the scores, the patients were classified into two groups. For the planned primary outcome analysis, we used the Kaplan-Meier time-to-event analysis to estimate the survival functions of ICU patients with sepsis throughout the 60 days of follow-up and the log-rank test to compare survival by the SOFA score groups (Fig. 3 ). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. We assessed factors associated with death in the hospital using logistic regression analysis. To reduce the number of predictors and the multicollinearity issue and resolve the overfitting, we used different ways to select variables as follows: first, we started the variable selection with the univariate analysis of each variable (Table S15 as (Table 3, Table S16 as shown in Supplementary file 3). Similarly, we used these methods of variable selection and analysis for assessing factors associated with death in the ICU (Table 3 , Tables S17 and S18 as shown in Supplementary file 3). We present odds ratios (ORs) and 95% confidence intervals (CIs). For all analyses, significance levels were two-tailed, and we considered p <0.05 as statistically significant. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. Data on 252 patients with sepsis were submitted to the database of the MOSAICS II study (Table S19 as shown in Supplementary file 3). In our study cohort, 64.3% (162/252) were men and the median age was 65 years (IQR: 52-76.75) ( Table 1) . Among the total patients, the median SOFA score was 7 (IQR: 4.75-10) at the time of ICU admission, the median APACHE II score was 18 (IQR: 13-24) over the first 24 hours of ICU admission, and 29.4% (74/252) of patients had septic shock (Table 1) Table 2) . The clinical characteristics, severity of illness, sites of infection and microbiology, compliance with sepsis bundle elements, and life-sustaining treatments during ICU stay were compared between patients who survived and patients who died in the hospital and ICU, as shown in Tables 1 and 2 , and Tables S1 to S14 as shown in Supplementary file 3. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The SOFA score (cut-off value both had a poor discriminatory ability for the hospital mortality (Fig. 1) (Fig. 2) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; Additionally, the estimated Kaplan-Meier survival probabilities (Fig. 3) were better throughout the 60 days of follow-up for the SOFA score of less than 8 points than that for the SOFA score of 8 points and above (cumulative case fatality: 33/140 [23.6%] in the SOFA score of less than 8 points and 64/110 [58.2%] in the SOFA score of 8 points and above, p <0.001 with the log-rank test). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; In the multivariate analysis, a SOFA score of 8 and above (OR: 2.717; 95% CI: 1.371-5.382) and an APACHE II score of 21 and above (OR: 2.668; 95% CI: 1.338-5.321) were independently associated with an increased risk of hospital mortality (Table 3) . Additionally, a SOFA score of 10 and above (OR: 2.801; 95% CI: 1.332-5.891) was independently associated with an increased risk of ICU mortality, in contrast to an APACHE II score of 19 and above, for which this independent association was not observed (Table 3) . Other factors were independently associated with the risk of the hospital and ICU mortalities, as shown in Table 3 and Tables S17 and S18 (as shown in Supplementary file 3). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; (37) and also might be because the patients, pathogens, and clinical capacity to manage sepsis differ considerably between HIC and LMIC settings (7, 33, 37) . In this study, we found a poor ability of both SOFA and APACHE II scores to predict hospital mortality (Fig. 1 ). However, with the SOFA score, the discrimination for predicting ICU mortality was good, and it was better than those of the APACHE II score (Fig. 2) . The APACHE scoring system is among the most widely used, of which there are four versions (APACHE I through IV scores). Although APACHE IV score is the most up-to-date version, some centres still use older versions including APACHE II score. In the present study, despite having a poor discriminatory ability for predicting hospital and ICU mortalities, an APACHE II score of 21 and above was independently associated with an increased risk of deaths in hospitals (Table 3) . However, in contrast to a SOFA score of 10 and above, an APACHE II score of 19 and above was not an independent predictor of ICU mortality (Table 3 ). Previous studies revealed that the APACHE II score had a good prognostic value in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; acutely ill or surgical patients (10, 11) but did not differentiate between the sterile and infected necrotizing pancreatitis and had a poor predictive value for the severity of acute pancreatitis at 24 hours (12). In contrast, the SOFA score was proposed for patients with a suspected infection that an increase of 2 points or more could serve as clinical criteria for sepsis.(1) In ICU patients with suspected infection, discrimination of the SOFA score was good for predicting hospital mortality.(1) However, our study showed that the discriminatory ability of the SOFA score was poor for predicting hospital mortality (Fig. 1) . This difference might be because the burden and causes of sepsis and its management differ considerably between HIC and LMIC settings,(7) which might make the accuracy of critical illness severity scoring systems vary widely in the different countries, particularly between HICs and LMICs. However, our study revealed that the SOFA score had a good discriminatory ability for predicting ICU mortality (Fig. 2) . Moreover, a SOFA score of 8 and above and a score of 10 and above were independently associated with an increased risk of deaths in hospitals and ICUs, respectively (Table 3) . These findings were also supported by Kaplan-Meier time-to-event analyses of which survival probabilities were significantly worse throughout the 60 days of follow-up either for the SOFA score of 8 and above than for the SOFA score of less than 8 (Fig. 3 ) or for the SOFA score of 10 and above than for the SOFA score of less than 10 ( Fig. S5 as shown in Supplementary file 3) . Overall, this study shows that both SOFA and APACHE II scores were worthwhile in predicting hospital and ICU mortalities in ICU patients with sepsis. However, because of having good discrimination for predicting ICU mortality, the SOFA was preferable to the APACHE II score in predicting short-term mortality. Our study has some limitations. First, due to the absence of a national registry of ICUs to allow systematic recruitment of units, we used a snowball method to identify suitable units, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; which might have led to the selection of centres with a greater interest in sepsis management. Therefore, our data are subject to selection bias and might not reflect fully intensive care throughout Vietnam. Second, due to the study's real-world nature, we did not make a protocol for microbiological investigations. Moreover, we mainly evaluated resources utilized in ICUs; therefore, the data detailing the point-of-care testing (e.g., lactate clearance) and life-sustaining treatments (e.g., fluid balance, administration of steroids, and modalities of RRT and MV) were not available. Third, to improve the feasibility of conducting the study in busy ICUs, we opted not to collect data on antibiotic resistance and appropriateness. Finally, although an advantage of the present study was data from the multicentre, which had little missing data, the sample size was relatively small, which might have led to overfitting in the multivariable prediction model. Thus, further studies with larger sample sizes might be needed to consolidate the conclusions. This was a selected cohort of patients with sepsis admitted to the ICUs in Vietnam with high mortality. Both SOFA and APACHE II scores were worthwhile in predicting hospital and ICU mortalities in ICU patients with sepsis; however, due to a good discrimination for predicting ICU mortality, the SOFA score was preferable to the APACHE II score in predicting short-term mortality in ICU patients with sepsis. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Verbal informed consents were directly obtained from patients or, when unavailable, from family members at the ICUs and witnessed by the on-duty medical staff. The Scientific and Ethics Committees of Bach Mai Hospital approved this study (approval number: 2919/QĐ-BM; project code: BM-2017-883-89). We also obtained permission from the heads of institutions and departments of all participating hospitals and their respective institutional review boards wherever available. The study was conducted according to the principles of the Declaration of Helsinki. In this non-intervention study, all collected information has received verbal informed consent from patients or, when unavailable, from family members at the ICUs, and witnessed by the on-duty medical staff. Written informed consent, however, was waived by the Bach Mai Hospital Scientific and Ethics Committees since it was not feasible to undergo such a methodical process of collection when the subject was comprised of an urgent situation in which a patient or a family member's condition was severe or life-threatening. Public notification of the study was made by public posting. All data analyses were based upon datasets kept in password-protected systems, and all final presented data have been made anonymous. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 19, 2022. ; We thank all ED and ICU staff of participating hospitals for their support with this study. We also thank the staff of the Faculty of Public Health at Thai Binh University of Medicine and Pharmacy for their support and statistical advice. Finally, we thank Miss Phuong Thi Tran from the Center for Emergency Medicine of Bach Mai Hospital, Hanoi, Vietnam for her secretarial work with this study. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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