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Clin Exp Emerg Med > Volume 10(2); 2023 > Article
Namgung, Ahn, Park, Kwak, Lee, and Won: Mortality among adult patients with sepsis and septic shock in Korea: a systematic review and meta-analysis

Abstract

Objective

To evaluate mortality from sepsis and septic shock in Korea during the past 10 years, we conducted a systematic review and meta-analysis.

Methods

We searched six databases for studies on mortality from sepsis and septic shock in adult patients. Primary outcomes were 28- or 30-day mortality and in-hospital mortality from sepsis and septic shock. To assess the risk of bias, we used the Newcastle-Ottawa Scale and Risk of Bias 2 tools. The protocol is registered in PROSPERO (No. CRD42022365739).

Results

A total of 61 studies were included. The mortality rates from sepsis and septic shock at 28 or 30 days were 22.7% (95% confidence interval [CI], 20.0%–25.6%; I2=89%) and 27.6% (95% CI, 22.3%–33.5%; I2=98%), respectively, according to the Sepsis-3 criteria. Furthermore, in accordance with the Sepsis-3 criteria, the in-hospital mortality rates were 28.1% (95% CI, 25.2%–31.1%; I2=87%) and 34.3% (95% CI, 27.2%–42.2%; I2=97%), respectively.

Conclusion

The mortality rates from sepsis and septic shock in Korea are high. In the case of septic shock, the in-hospital mortality rate is approximately 30%.

INTRODUCTION

Sepsis is a life-threatening multiorgan dysfunction caused by an inappropriate host response to infection [1]. Despite global efforts to minimize its lethality, sepsis remains the leading cause of death in critically ill patients and a burden on patients and healthcare systems worldwide [13]. Through campaigns to reduce the mortality rate of sepsis, experts in various fields have improved the survival rate by defining the Sepsis-3 diagnostic criteria and promoting adherence to recommended treatment protocols [1,4,5]. A total of 48.9 million incident cases and 11.0 million sepsis-related deaths have been reported in 2017, accounting for approximately 20% of global deaths during that time [2]. A recent meta-analysis showed that the pooled mortality rate of sepsis is 19.6% in North America, 23.6% in Europe, 18.7% in Australia, and 29.0% in China [6,7]. The mortality rates differ across countries because of disease severity, study type, period, and region, but different standard care protocols and health care systems also significantly affect the care and prognosis of patients with sepsis [6].
In Korea, previous research analyzing national health insurance data revealed sepsis mortality rates ranging from 17.5% to 30% [810]. However, those studies evaluated sepsis or septic shock based on diagnostic International Classification of Diseases, 10th Revision (ICD-10) codes in insurance records, not the sepsis criteria. Thus, their study populations might differ from the population described by the sepsis criteria and inaccurately depict sepsis mortality. Despite the large number of multicenter and single-center studies on sepsis and septic shock, including some multicenter registries, no previous studies in Korea reflect the overall sepsis fatality rate, to the best of our knowledge. To appropriately determine the mortality rate from sepsis and septic shock in Korea, a systematic review and meta-analysis are required. Therefore, we investigated the sepsis and septic shock mortality rates published for Korea during the past 10 years and analyzed those rates based on the Sepsis-3 criteria.

METHODS

Reporting guidelines and protocol registration

This study adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) and the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guidelines for reporting information from observational studies [11,12]. This review protocol is prospectively registered in PROSPERO (No. CRD42022365739).

Search strategy

We systematically searched the PubMed, Embase, Cochrane Library, KMbase (Korean Medical Database), KoreaMed, and KISS (Korean Studies Information Service System) databases for studies about mortality and the frequency of sepsis and septic shock in adult patients that were published between January 2012 and July 2022. As our search strategy, we combined medical subject headings terms and free terms related to “sepsis,” “septic shock,” and “South Korea” and included Embase subject headings and text words. The detailed search strategy is presented in Supplementary Table 1.

Study selection

We selected studies through title and abstract screening and used the following inclusion criteria: confirmed sepsis, severe sepsis or septic shock in adult patients according to the Sepsis-1, -2, or -3 criteria, and studies conducted in Korea and published between January 1, 2012 and September 23, 2022. We excluded studies with insufficient data and those involving sepsis patients from specific disease groups, reviews, case reports, editorials, letters, conference abstracts, meta-analyses, and animal studies. To prevent duplicate data, we selected studies with the longest study period and largest sample size when we found multiple studies that shared the same registry or institution.

Data extraction

Two reviewers independently extracted the relevant data about the patients in the included studies, and discrepancies between reviewers were discussed and resolved by consensus. We extracted the following variables: publication data; study design and settings; patient information—number of participating centers, patient locations (emergency room, ward, or intensive care unit [ICU]), number of patients, and deaths; sepsis diagnostic criteria; and the time of outcome measurement (28- or 30-day mortality and in-hospital mortality).

Quality assessment of individual studies

The Newcastle-Ottawa Scale, which divides an eight-item score into three domains, was used to evaluate nonrandomized studies [13]. The Risk of Bias 2 tool was used to evaluate randomized controlled trials [14]. Each article was rated based on selection (maximum, four stars), comparability (maximum, two stars), and outcome (maximum, three stars). Both reviewers assessed the 61 included studies independently. Unresolved disagreements between reviewers were resolved by discussion or consultation with a third reviewer.

Statistical analysis

Individual and pooled statistics were calculated as frequencies of sepsis and septic shock diagnosed at admission or during an ICU stay to estimate mortality in the ICU or hospital and to estimate mortality at 28 or 30 days. A random effects model was used to assess mortality for each outcome. Separate analyses were performed in the following subgroups: diagnosed according to Sepsis-3 and non-Sepsis-3 criteria; retrospective and prospective studies; single-center and multicenter studies; and patient location (emergency room, ward, or ICU). Statistical heterogeneity was visually assessed using forest plots and formally assessed using I2. Publication bias was evaluated using a Begg funnel plot. All analyses were performed using the R ver. 4.0.0 (The R Foundation for Statistical Computing) software packages “meta” (ver. 6.1-0) and “metafor” (ver. 3.8-1). A P-value of <0.05 was considered statistically significant.

RESULTS

Study selection

Our database search yielded 4,012 records. From them, 1,271 duplicates were removed, and 2,349 records were excluded in the review of titles and abstracts. Of the remaining 392 records, 331 were also excluded based on the full article review because they had an irrelevant population (n=188), irrelevant outcome (n=46), duplicated data (n=80), animal study (n=10), or experimental study (n=7); details are provided in Supplementary Tables 2 and 3 [1575]. Therefore, 61 studies of sepsis and septic shock mortality are included in this review [1575]. Fig. 1 shows the study flow for the selection process.

Study characteristics

Of the 61 included studies, 26 were prospective cohort studies, 33 were retrospective cohort studies, and two were randomized clinical trials; 46 were single-center studies, and 15 were multicenter studies, nine of which investigated the same two prospective sepsis registries (five used the Korean Shock Society [KoSS] registry [48,50,52,67,75] and four used the Korean Sepsis Alliance [KSA] registry [28,33,59,73]). The KoSS registry was established in 2013 to study patients who went into septic shock in emergency departments (EDs); it has been prospectively collecting data since October 2015 [76]. At the beginning of enrollment, 10 EDs participated, but in the most recent study, which used data up to December 2019, 12 EDs participated [48]. The KSA registry was organized mainly by pulmonologists and critical care medicine physicians from 16 secondary and tertiary hospitals nationwide; this database covers 19 hospitals and includes patients who were diagnosed with sepsis in EDs or hospitals [28].
Data on 28- or 30-day mortality and in-hospital mortality among sepsis patients were extracted from 27 and 17 studies, respectively, and those data for septic shock patients were extracted from 32 and 18 studies, respectively. Table 1 summarizes the characteristics of the included studies [1575].

Sepsis mortality

The studies that examined 28- or 30-day mortality from sepsis analyzed 22,050 patients. The 28- or 30-day mortality from sepsis diagnosed using the Sepsis-3 criteria was 22.7% (95% confidence interval [CI], 20.0%–25.6%; I2=89%) (Table 2 and Fig. 2) [15,17,21,26,27,35,39,42,46,50,5559,69,72]. The range of mortality in the included studies was 14.4% to 40.8%. In addition, the 28- or 30-day mortality rate by including all sepsis criteria was 24.8% (95% CI, 22.1%–27.7%; I2=95%) (Supplementary Fig. 1) [15,17, 20,21,26,27,2931,34,35,39,42,44,46,50,5559,63,69,71,72,74]. In the subgroup analyses, 28- or 30-day mortality from sepsis was 22.6% (95% CI, 19.5%–25.9%; I2=94%) in retrospective cohort studies, 29.1% (95% CI, 23.4%–35.5%; I2=96%) in prospective studies, 23.3% (95% CI, 20.5%–26.5%; I2=93%) in single-center studies, and 31.3% (95% CI, 23.4%–40.4%; I2=98%) in multicenter studies (Table 2).
The studies of in-hospital mortality from sepsis analyzed 11,595 patients. In-hospital mortality from sepsis diagnosed using the Sepsis-3 criteria was 28.1% (95% CI, 25.2%–31.1%; I2=87%) (Table 2 and Fig. 3) [15,17,2628,32,33,39,41,47,50,59,72]. The range of mortality was 15.7% to 47.0%. In addition, in-hospital mortality by including all sepsis criteria was 26.3% (95% CI, 22.6%–30.5%; I2=95%) (Supplementary Fig. 2) [15,17,2628,32,33,39,41,44,47,50,59,63,68,70,72]. In the subgroup analyses, the in-hospital mortality from sepsis was 23.8% (95% CI, 18.2%–30.4%; I2=97%) in retrospective cohort studies, 30.5% (95% CI, 26.1%–35.2%; I2=85%) in prospective studies, 24.8% (95% CI, 17.3%–34.3%; I2=96%) in single-center studies, and 28.1% (95% CI, 25.7%–30.7%; I2=80%) in multicenter studies (Table 2).

Septic shock mortality

The studies for 28- or 30-day mortality from septic shock analyzed 25,101 patients. The 28- or 30-day mortality from septic shock diagnosed using the Sepsis-3 criteria was 27.6% (95% CI, 22.3%–33.5%; I2=98%) (Table 2 and Fig. 4) [15,17,2527,42,46,4850,58,60,67,69,73,75]. The range of mortality was 12.6% to 52.9%. In addition, the 28- or 30-day mortality rate by including all sepsis criteria from septic shock was 25.1% (95% CI, 21.8%–28.8%; I2=97%) (Supplementary Fig. 3) [15,17,19,2427,29,3638,42,46,4851,53,54,58,60-62,6567,69,7375]. In the subgroup analyses, the 28- or 30-day mortality from septic shock was 28.0% (95% CI, 21.1%–36.0%; I2=98%) in retrospective cohort studies, 23.4% (95% CI, 20.1%–27.0%; I2=95%) in prospective studies, 18.0% in the one randomized controlled trial, 24.8% in single-center studies (95% CI, 19.8%–30.7%; I2=98%), and 26.0% in multicenter studies (95% CI, 22.7%–29.6%; I2=93%) (Table 2).
The studies of in-hospital mortality from septic shock analyzed 10,769 patients. In-hospital mortality from septic shock diagnosed using the Sepsis-3 criteria was 34.3% (95% CI, 27.2%–42.2%; I2=97%) (Table 2 and Fig. 5) [15,18,2527,40,45,47,50,52,73,75]. The range of mortality was 21.6% to 50.0%. In addition, in-hospital mortality by including all sepsis criteria from septic shock was 31.4% (95% CI, 26.1%–37.3%; I2=97%) (Supplementary Fig. 4) [15,18,22,23,2527,37,40,43,45,47,50,52,62,64,73,75]. In the subgroup analyses, the in-hospital mortality from septic shock was 34.1% (95% CI, 21.1%–50.2%; I2=99%) in retrospective cohort studies, 29.8% (95% CI, 25.4%–34.7%; I2=93%) in prospective studies, 29.6% (95% CI, 15.8%–48.6%; I2=86%) in randomized controlled trials, 33.3% (95% CI, 24.2%–44.0%; I2=97%) in single-center studies, and 28.6% (95% CI, 23.8%–34.1%; I2=94%) in multicenter studies (Table 2).

Quality assessment

When we used the Newcastle-Ottawa Scale to evaluate the quality of the included articles, we found that 19 studies were of poor quality. The following assessments were derived from the other studies, which were rated as good quality: 24 studies received 9 points, and the others received 7 or 8 points. Using the Risk of Bias 2 for the two randomized controlled trials, one study had low bias, and the other study had high bias (Supplementary Tables 2, 3).

Publication bias

All the funnel plots made to assess the publication bias for each outcome showed symmetry. The funnel plots for sepsis (28- or 30-day and in-hospital mortality) and septic shock (28- or 30-day and in-hospital mortality) are shown in Supplementary Fig. 5.

DISCUSSION

To the best of our knowledge, this is the first meta-analysis to investigate mortality among sepsis and septic shock patients in Korea. We found that the pooled mean of the 28- or 30-day mortality rate and in-hospital mortality rate are 24.8% and 26.3%, respectively, in sepsis patients, and 25.1% and 31.4%, respectively, in septic shock patients. Those data reflect the actual clinical prognosis of sepsis patients classified according to the sepsis criteria used in hospitals. The 28- or 30-day sepsis mortality rate in a national cohort study by Oh et al. [77] is higher than our result at approximately 30%. However, that study used National Health Insurance Service of Korea data and ICD-10 codes to classify sepsis patients; therefore, the diagnosis of sepsis might have been overestimated by including septic shock. Moreover, deaths unrelated to sepsis might have been included in the overall mortality data of that study.
The sepsis mortality rates in the present study are higher than those reported in a recent meta-analysis for the United States (19.6%) and Australia (18.7%), but similar to that in Europe (23.6%) and lower than that in China (29.1%) [6,7]. In contrast, the mortality rate among septic shock patients appears to be similar or lower than that in other countries (North America, 33.7%; Australia, 26.4%; Europe, 32.5%; China, 35.9%) [6,7]. Most of the sepsis studies evaluated in our meta-analysis included sepsis with shock, introducing the possibility of heterogeneity among studies and inaccurately high death rates. In addition, because our study includes research from the past 10 years, our data are based on several sets of sepsis criteria (Sepsis-1, -2, and -3), and that inconsistency could increase heterogeneity. On the other hand, we found clinically relevant results when the Sepsis-3 criteria were used.
Another finding of this study is that in-hospital mortality was higher than 28- or 30-day mortality in sepsis and septic shock patients. This result is consistent with that of previous meta-analyses conducted by Vincent et al. [78] and Liu et al. [7] in Europe, North America, and China. The studies included in this meta-analysis presented their outcomes as either 28- or 30-day mortality or in-hospital mortality, and the study populations differed in their inclusion of sepsis or septic shock patients. In other words, 28- or 30-day mortality and in-hospital mortality were not measured consecutively in the same studies but represent the sum of values extracted from different studies. Therefore, because of the statistical constraints of a meta-analysis, caution is needed in interpreting the result that in-hospital mortality was higher than 28- or 30-day mortality in sepsis and septic shock patients.
We analyzed the mortality rates from sepsis and septic shock after dividing the patients into those diagnosed with the Sepsis-3 criteria and those diagnosed with other criteria. The 28- or 30-day mortality rate and in-hospital mortality rates for septic shock diagnosed according to the Sepsis-3 criteria were 27.6% and 34.3%, respectively, which are higher than those based on the non-Sepsis-3 criteria (28- or 30-day mortality, 22.6%; in-hospital mortality, 26.0%) (Figs. 4, 5) [15,17,18,2527,40,42,4550,52,58,60,67,69,73,75] That finding is consistent with a previous meta-analysis in Europe and North America, which reported that in-hospital septic shock mortality increased significantly, from 39.0% to 52.1%, when the Sepsis-3 criteria were used for diagnosis [78]. The criteria prior to Sepsis-3 defined sepsis as a state with at least two of the four systemic inflammatory response syndrome (SIRS) criteria, which focus solely on the inflammatory response [79,80]. Because the SIRS criteria do not exactly reflect organ dysfunction and life-threatening conditions, the new Sepsis-3 criteria, which were published in 2016, include the Sequential Organ Failure Assessment (SOFA) score and lactate level [1]. Therefore, the increase in septic shock mortality when using the Sepsis-3 criteria could be explained by the advanced disease severity reflected by the change in diagnostic criteria.
Variations in mortality rates among the included studies are likely attributable to differences in the disease severity of the patients. For example, to identify the risk factors of sepsis-associated delirium and their effects on the outcomes of ICU patients, Kim et al. [44] excluded patients with <24 hours of ICU stay or deep or full sedation from their assessment of 28- or 30-day sepsis mortality. Those factors could exacerbate the severity of the patients included, resulting in a higher mortality rate. In addition, Hong et al. [20] excluded patients admitted for hemodialysis or peritoneal dialysis, transferred from other hospitals, or admitted for palliative care. In that case, the mortality rate might have been underreported due to the exclusion of critically ill patients.
It is challenging to generalize the findings of this study to all sepsis patients in Korea. The majority of the research included in this meta-analysis was conducted at tertiary medical institutions or large hospitals, and the sepsis registries include only hospitals with the ability to provide quality care. Thus, data from institutions that are treating sepsis but not reporting their results were not included here. If the outcomes from ineffective-performance medical settings are not considered, the overall results of sepsis treatment might appear to be better than they actually are. Additionally, a recent Korean report indicated that the surviving sepsis campaign had low compliance [81]. Therefore, the mortality rate might increase further when the sepsis outcomes of all medical institutions are considered. Further investigation is needed to examine sepsis outcomes according to the performance level of the medical institution.
This review has several limitations. First, heterogeneity among the studies included in the meta-analysis is very high, all over 95%. One reason for this high heterogeneity is the diversity of study designs included in the analysis. In addition, the definition of sepsis in the included studies was heterogeneous because the new Sepsis-3 criteria were only published in 2016, and that diversity of definitions might have resulted in a wide range of mortality rates. Therefore, we analyzed the mortality rates according to the use of the Sepsis-3 and non-Sepsis-3 criteria. Second, the sepsis criteria were met when patients were included in these studies, but it is possible that critically ill patients might have been only selectively included based on particular domains, such as the lactate level. Third, when several studies were conducted in a single institution or used the same registry during the same study period, we selected only the study with the longest study period and largest sample size because we suspected that the study population might be duplicated. Thus, despite our efforts to include as many studies as possible, we cannot completely rule out the possibility of selection bias. Fourth, despite that attempt to prevent duplicated data, the possibility of duplication between registry studies and single-center studies whose data are included in that registry remains. Fifth, the medical history and care conditions of individual patients, which influence the mortality rate, were not considered. Personal factors were not considered in this study, and our meta-analysis simply confirmed the mortality rate.
In conclusion, our study shows that the mortality rates from sepsis and septic shock in Korea are high. In the case of septic shock, the in-hospital mortality rate is approximately 30%, and that rate was higher when septic shock was diagnosed according to the Sepsis-3 criteria than when it was diagnosed using other criteria.

SUPPLEMENTARY MATERIAL

Supplementary material is available at https://doi.org/10.15441/ceem.23.005.

Supplementary Table 1.

Search strategy
ceem-23-005-supplementary-Table-1.pdf

Supplementary Table 2.

Quality assessment using NewcastleOttawa Scale for cohort studies
ceem-23-005-supplementary-Table-2.pdf

Supplementary Table 3.

Quality assessments using Risk of Bias 2 for randomized controlled trials
ceem-23-005-supplementary-Table-3.pdf

Supplementary Fig. 1.

Forest plot for 28- or 30-day sepsis mortality by including all sepsis criteria.
ceem-23-005-supplementary-Fig-1.pdf

Supplementary Fig. 2.

Forest plot for in-hospital sepsis mortality by including all sepsis criteria.
ceem-23-005-supplementary-Fig-2.pdf

Supplementary Fig. 3.

Forest plot for 28- or 30-day septic shock mortality by including all sepsis criteria.
ceem-23-005-supplementary-Fig-3.pdf

Supplementary Fig. 4.

Forest plot for in-hospital septic shock mortality by including all sepsis criteria.
ceem-23-005-supplementary-Fig-4.pdf

Supplementary Fig. 5.

Funnel plots for each outcome.
ceem-23-005-supplementary-Fig-5.pdf

NOTES

ETHICS STATEMENTS
Not applicable.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
None.
AUTHOR CONTRIBUTIONS
Conceptualization: MN, CA; Data curation: MN, YP, MW; Formal analysis: IYK, JL; Visualization: CA; Writing–original draft: MN, CA; Writing–review & editing: all authors. All authors read and approved the final manuscript.

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44. Kim Y, Jin Y, Jin T, Lee SM. Risk factors and outcomes of sepsis-associated delirium in intensive care unit patients: a secondary data analysis. Intensive Crit Care Nurs 2020; 59:102844.
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45. Kim S, Lee JD, Kim BK, Kim YH, Kim JH. Association between left ventricular systolic dysfunction and mortality in patients with septic shock. J Korean Med Sci 2020; 35:e24.
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47. Kim KH, Cho HJ, Kim SC, Lee J. Prognostic value of estimated plasma volume status in patients with sepsis. J Korean Med Sci 2022; 37:e145.
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48. Kim SM, Ryoo SM, Shin TG, et al. Prognostic factors for late death in septic shock survivors: a multi-center, prospective, registry-based observational study. Intern Emerg Med 2022; 17:865-71.
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49. Kim JS, Ha J, Kim YJ, et al. The impact of myosteatosis percentage on short-term mortality in patients with septic shock. J Clin Med 2022; 11:3031.
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50. Ko BS, Kim K, Choi SH, et al. Prognosis of patients excluded by the definition of septic shock based on their lactate levels after initial fluid resuscitation: a prospective multi-center observational study. Crit Care 2018; 22:47.
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51. Ko DR, Kong T, Lee HS, et al. Usefulness of the thrombotic microangiopathy score as a promising prognostic marker of septic shock for patients in the emergency department. J Clin Med 2019; 8:808.
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52. Ko BS, Choi SH, Kang GH, et al. Time to antibiotics and the outcome of patients with septic shock: a propensity score analysis. Am J Med 2020; 133:485-91.e4.
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53. Lee CM, Kwon OY, Lee JS, Choi HS, Hong HP, Ko YG. Nutritional risk screening as a prognostic factor for emergency department patients with severe sepsis. J Korean Soc Emerg Med 2012; 23:50-5.

54. Lee SH, Jo YH, Kim K, et al. Prognostic importance of hypoalbuminemia in patients with severe sepsis and septic shock. J Korean Soc Emerg Med 2013; 24:599-606.

55. Lee S, Hong DY, Kim JW, et al. Efficacy of red cell distribution width as prognostic factor for Sepsis-3 patients in emergency department. J Korean Soc Emerg Med 2017; 28:255-62.

56. Lee Y, Park HK, Kim WY, Kim MC, Jung W, Ko BS. Muscle mass depletion associated with poor outcome of sepsis in the emergency department. Ann Nutr Metab 2018; 72:336-44.
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57. Lee CU, Jo YH, Lee JH, et al. The index of oxygenation to respiratory rate as a prognostic factor for mortality in sepsis. Am J Emerg Med 2021; 45:426-32.
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58. Lee SG, Song J, Park DW, et al. Prognostic value of lactate levels and lactate clearance in sepsis and septic shock with initial hyperlactatemia: a retrospective cohort study according to the sepsis-3 definitions. Medicine (Baltimore) 2021; 100:e24835.
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59. Lee HY, Lee J, Jung YS, et al. Preexisting clinical frailty is associated with worse clinical outcomes in patients with sepsis. Crit Care Med 2022; 50:780-90.
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60. Oh HJ, Kim SJ, Kim YC, et al. An increased chloride level in hypochloremia is associated with decreased mortality in patients with severe sepsis or septic shock. Sci Rep 2017; 7:15883.
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61. Oh DH, Kim MH, Jeong WY, et al. Risk factors for mortality in patients with low lactate level and septic shock. J Microbiol Immunol Infect 2019; 52:418-25.
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62. Park DW, Chun BC, Kim JM, et al. Epidemiological and clinical characteristics of community-acquired severe sepsis and septic shock: a prospective observational study in 12 university hospitals in Korea. J Korean Med Sci 2012; 27:1308-14.
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63. Park S, Kim DG, Suh GY, et al. Mild hypoglycemia is independently associated with increased risk of mortality in patients with sepsis: a 3-year retrospective observational study. Crit Care 2012; 16:R189.
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64. Park JS, Kim SJ, Lee SW, et al. Initial low oxygen extraction ratio is related to severe organ dysfunction and high in-hospital mortality in severe sepsis and septic shock patients. J Emerg Med 2015; 49:261-7.
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65. Park JE, Shin TG, Jo IJ, et al. Impact of vitamin C and thiamine administration on delirium-free days in patients with septic shock. J Clin Med 2020; 9:193.
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66. Ryoo SM, Ahn S, Kim WY, Lim KS. External validation of the MISSED score to predict mortality in patients with severe sepsis and septic shock in the emergency department. Eur J Emerg Med 2015; 22:327-30.
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67. Ryoo SM, Ahn R, Shin TG, et al. Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients. PLoS One 2019; 14:e0217857.
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68. Song YH, Shin TG, Kang MJ, et al. Predicting factors associated with clinical deterioration of sepsis patients with intermediate levels of serum lactate. Shock 2012; 38:249-54.
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69. Song J, Cho H, Park DW, et al. Vasoactive-inotropic score as an early predictor of mortality in adult patients with sepsis. J Clin Med 2021; 10:495.
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70. Suh SH, Kim CS, Choi JS, Bae EH, Ma SK, Kim SW. Acute kidney injury in patients with sepsis and septic shock: risk factors and clinical outcomes. Yonsei Med J 2013; 54:965-72.
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71. Um YW, Lee JH, Jo YH, Kim J, Kim YJ, Kwon H. Relationship between the time to positivity of blood culture and mortality according to the site of infection in sepsis. J Korean Soc Emerg Med 2018; 29:474-84.

72. Wang GS, You KM, Jo YH, et al. Association of health insurance status with outcomes of sepsis in adult patients: a retrospective cohort study. Int J Environ Res Public Health 2021; 18:5777.
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73. Yeo HJ, Lee YS, Kim TH, et al. Vasopressor initiation within 1hour of fluid loading is associated with increased mortality in septic shock patients: analysis of national registry data. Crit Care Med 2022; 50:e351-60.
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74. Yoo JW, Jung YK, Ju S, et al. Serum vitamin D binding protein level, but not serum total, bioavailable, free vitamin D, is higher in 30-days survivors than in nonsurvivors with sepsis. Medicine (Baltimore) 2020; 99:e20756.
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75. You JS, Park YS, Chung SP, et al. Relationship between time of emergency department admission and adherence to the surviving sepsis campaign bundle in patients with septic shock. Crit Care 2022; 26:43.
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Fig. 1.
Flowchart for included studies. KMbase, Korean Medical Database; KISS, Korean Studies Information Service System.
ceem-23-005f1.jpg
Fig. 2.
Forest plot for 28- or 30-day mortality from sepsis using the Sepsis-3 criteria. CI, confidence interval.
ceem-23-005f2.jpg
Fig. 3.
Forest plot for in-hospital mortality from sepsis using the Sepsis-3 criteria. CI, confidence interval.
ceem-23-005f3.jpg
Fig. 4.
Forest plot for 28- or 30-day mortality from septic shock using the Sepsis-3 criteria. CI, confidence interval.
ceem-23-005f4.jpg
Fig. 5.
Forest plot for in-hospital mortality from septic shock using the Sepsis-3 criteria. CI, confidence interval.
ceem-23-005f5.jpg
Table 1.
Characteristics of the studies included in the systematic review and meta-analysis
Study Study design Study period No. of centers Patient location Cohort screened Outcome Diagnostic criteria Study details
Cha et al. [15] (2022) Retrospective cohort study Nov 2013–May 2017 1 ICU Patients ≥ 18 yr, ICU LOS > 3 day with sepsis and septic shock 30-Day, in-hospital Sepsis-3 Investigation of the effects of nutritional support on clinical prognosis
Cho et al. [16] (2012) Prospective cohort study Sep 2007–Nov 2010 1 General ward, ICU Patients suspected of sepsis in either the general wards or ICU 28-Day Other Assessment of the prognostic power of lysophosphatidylcholine for sepsis
Choi et al. [17] (2020) Retrospective cohort study Mar 2015–Jun 2018 1 ICU Patients > 18 yr, admitted to the medical ICU with sepsis 28-Day, in-hospital Sepsis-3 Clinical value of full-length tryptophanyl-tRNA synthetase for sepsis detection
Choi et al. [18] (2021) Retrospective cohort study Mar 2008–Dec 2017 1 General ward, ICU Patients with septic shock who received rapid response system treatment in hospital wards 28-Day, in-hospital Sepsis-3 Investigation of the effects of the rapid response system on outcomes in patients with septic shock
Chung et al. [19] (2019) Prospective cohort study Mar 2010–Jun 2016 1 ED Patients ≥ 18 yr, with severe sepsis or septic shock 28-Day Other Evaluation of the association between monocyte counts and mortality
Hong et al. [20] (2016) Retrospective cohort study Nov 2012–Sep 2014 1 ED Patients ≥ 18 yr, with sepsis and without dialysis 28-Day Other Assessment of neutrophil gelatinase-associated lipocalin as a prognostic biomarker for hospital mortality in patients with sepsis in EDs
Hong et al. [21] (2020) Retrospective cohort study Sep 2015–Feb 2019 1 ICU Patients ≥ 18 yr, with sepsis or septic shock who underwent echocardiography 28-Day Sepsis-3 Effects of left ventricular dysfunction and fluid balance on the outcomes of patients with sepsis
Huh et al. [22] (2013) RCT Aug 2007–Jan 2009 1 ED Patients ≥ 18 yr, with severe sepsis or septic shock In-hospital Other Comparison of clinical outcomes between intermittent and continuous monitoring of central venous oxygen saturation
Hwang et al. [23] (2018) Retrospective cohort study Aug 2008–Sep 2014 1 ED Patients ≥ 18 yr, diagnosed with severe sepsis or septic shock 28-Day, in-hospital Other Evaluation of the diagnostic value of the qSOFA score for mortality in septic patients
Hwang et al. [24] (2019) Retrospective cohort study Aug 2008–Sep 2016 1 ED Patients ≥ 18 yr, with septic shock 28-Day Other Investigation of the effect of antibiotic timing on the outcomes of sepsis
Hwang et al. [25] (2020) RCT Dec 2018–Jan 2020 6 ED Patients (19–89 yr) with septic shock 28-Day, in-hospital Sepsis-3 Evaluation of the effects of early combination therapy with intravenous vitamin C and thiamine in patients with septic shock
Im et al. [26] (2020) Prospective cohort study Apr 2014–Jan 2019 1 ICU Patients ≥ 19 yr, admitted to the medical ICU with sepsis or septic shock 28-Day, in-hospital Sepsis-3 Association of plasma exosomes with severity of organ failure and mortality in patients with sepsis
Im et al. [27] (2021) Prospective cohort study Apr 2014–Jan 2019 1 ICU Patients ≥ 19 yr, with sepsis admitted to the medical ICU 28-Day, in-hospital Sepsis-3 Evaluation of the association between exosomal CD63 level and clinical outcomes in patients with sepsis
Im et al. [28] (2022) Prospective cohort study Sep 2019–Dec 2020 19a) ED Patients ≥ 19 yr, diagnosed with sepsis or septic shock In-hospital Sepsis-3 Evaluation of the effects of time-to-antibiotics on in-hospital mortality in patients with sepsis
Jang et al. [29] (2016) Retrospective cohort study Jan 2013–Jun 2015 1 ED Patients ≥ 19 yr, suspected to have sepsis and admitted to the ICU 28-Day Other Comparison of the usefulness of the PIRO score and MEDS score in predicting the mortality of septic patients
Jang et al. [30] (2020) Retrospective cohort study Mar 2010–Apr 2017 1 ED Patients ≥ 18 yr, with sepsis or septic shock 28-Day Other Investigation of the association between initial phosphate concentration and mortality in patients with sepsis
Jang et al. [31] (2021) Retrospective cohort study May 2014–Apr 2018 3 ED Patients ≥ 18 yr, with sepsis or septic shock 28-Day Other Investigation of the relationship between the serum total cholesterol concentration and the outcomes of sepsis patients
Jee et al. [32] (2020) Retrospective cohort study Nov 2016–Dec 2016 1 ED Patients ≥ 18 yr, diagnosed with sepsis In-hospital Sepsis-3 Comparison of the mortality rates of patients with early-identified sepsis and late-identified sepsis
Jeon et al. [33] (2019) Retrospective cohort study Jan 2018 19a) ED Patients ≥ 19 yr, with sepsis In-hospital Sepsis-3 Investigation of the characteristics, management, and clinical outcomes of sepsis patients
Jeong et al. [34] (2019) Prospective cohort study Jan 2011–Jun 2017 1 ICU Patients ≥ 18 yr, with sepsis who stayed in the ICU for more than 7 day 28-Day Other Relationship between nutrition intake and mortality in patients with sepsis
Jeong et al. [35] (2020) Retrospective cohort study Jun 2018–Apr 2019 1 ED Patients ≥ 19 yr, with sepsis 30-Day Sepsis-3 Investigation of the efficacy of the albumin-adjusted ischemia-modified albumin level to predict mortality in patients with sepsis
Jung et al. [36] (2019) Prospective cohort study Jun 2012–Dec 2016 1 ED Patients ≥18 yr, with septic shock 28-Day Other Evaluation of relationship between low hemoglobin levels and mortality in patients with septic shock
Kim et al. [37] (2012) Prospective cohort study Jul 2009 25 ICU Patients admitted to an ICU for severe sepsis 28-Day, in-hospital Other Investigation of the influence of full-time intensivist and nurse to patient ratio on the implementation of severe sepsis bundles
Kim et al. [38] (2013) Prospective cohort study Jul 2010–Jan 2011 22 ICU Patients ≥ 18 yr, with severe sepsis or septic shock 28-Day Other Comparison of clinical outcomes between pneumonia and other infections in patients with sepsis
Kim et al. [39] (2017) Retrospective cohort study Dec 2014–Jun 2015 1 ED, ICU Patients diagnosed with sepsis 30-Day, in-hospital Sepsis-3 Investigation of the prognostic utilities of multiple biomarkers for mortality in septic patients
Kim et al. [40] (2019) Retrospective cohort study Sep 2018–Aug 2019 1 ICU Patients ≥ 19 yr, with septic shock who were treated with the vitamin C protocol 28-Day, in-hospital Sepsis-3 To identify septic phenotypes in patients receiving vitamin C, hydrocortisone, and thiamine using temperature and white blood cell count
Kim et al. [41] (2019) Retrospective cohort study Jun 2011–Aug 2017 1 ICU Patients ≥ 18 yr, diagnosed with sepsis who underwent abdominal CT In-hospital Sepsis-3 Investigation of association between skeletal muscle mass and clinical outcomes in patients with sepsis
Kim et al. [42] (2020) Retrospective cohort study Aug 2016–Aug 2017 1 Not mentioned Patients diagnosed with sepsis or septic shock 30-Day Sepsis-3 Investigation of prognostic value of proenkephalin for renal failure and mortality in patients with sepsis
Kim et al. [43] (2020) Retrospective cohort study Jan 2016–Sep 2019 1 ED Patients ≥18 yr, with septic shock In-hospital Other Evaluation of the prognostic value of the inferior vena cava diameter ratio measured on CT in patients with septic shock.
Kim et al. [44] (2020) Prospective cohort study Sep 2009–Jun 2015 1 ICU Patients ≥ 18 yr, ICU LOS > 1 day with sepsis 30-Day, in-hospital Other To identify the risk factors of sepsis-associated delirium and its effects on patient outcomes in ICU patients
Kim et al. [45] (2020) Retrospective cohort study Jan 2015–Jun 2018 1 ICU Patients ≥ 18 yr, with septic shock who underwent echocardiography In-hospital Sepsis-3 Association between left ventricular systolic dysfunction and mortality in patients with septic shock
Kim et al. [46] (2021) Retrospective cohort study Jan 2016–Feb 2019 1 ED Patients ≥ 18 yr, with sepsis 28-Day Sepsis-3 Investigation of the prognostic value of a modified simple scoring system based on the red cell distribution width, delta neutrophil index, and mean platelet volume to platelet count ratio in predicting the mortality of patients with sepsis
Kim et al. [47] (2022) Prospective cohort study Mar 2019–Jun 2020 1 ICU ICU patients with sepsis In-hospital Sepsis-3 Assessment of the prognostic power of estimated plasma volume status in critically ill patients with sepsis
Kim et al. [48] (2022) Retrospective cohort study Oct 2015–Dec 2019 12b) ED Patients ≥ 19 yr, with septic shock 28-Day Sepsis-3 Evaluation of prognostic factors for late death in septic shock survivors
Kim et al. [49] (2022) Prospective cohort study May 2016–May 2020 1 ED Patients ≥18 yr, with suspected or confirmed septic shock 28-Day Sepsis-3 Investigation of the effects of myosteatosis percentage on mortality in patients with septic shock
Ko et al. [50] (2018) Prospective cohort study Oct 2015–Feb 2017 10b) ED Patients ≥ 19 yr, with septic shock 28-Day, in-hospital Sepsis-3 Evaluation of the prognosis of septic shock patients based on their lactate levels after initial fluid resuscitation
Ko et al. [51] (2019) Prospective cohort study Jun 2015–Dec 2016 1 ED Patients ≥ 18 yr, with septic shock 30-Day Other Investigation of the association between the thrombotic microangiopathy score and 30-day mortality among patients with earlystage septic shock
Ko et al. [52] (2020) Prospective cohort study Oct 2015–Dec 2017 10b) ED Patients ≥ 19 yr, with suspected or confirmed infection and evidence of refractory hypotension or hypoperfusion In-hospital Sepsis-3 Evaluation of the association between antibiotic administration timing and in-hospital mortality in septic shock patients
Lee et al. [53] (2012) Retrospective cohort study Jan 2010–Dec 2010 1 ED Patients ≥18 yr, with severe sepsis 28-Day Other Investigation of the association between nutritional risk and mortality in severe sepsis patients
Lee et al. [54] (2013) Prospective cohort study Jul 2008–Jun 2011 1 ED Patients ≥ 18 yr, with severe sepsis or septic shock 28-Day Other Investigation of the association between hypoalbuminemia and mortality in patients with severe sepsis and septic shock
Lee et al. [55] (2017) Retrospective cohort study Oct 2015–Apr 2016 1 ED Patients ≥ 19 yr, with sepsis 30-Day Sepsis-3 Investigation of the efficacy of red cell distribution width as a prognostic factor for Sepsis-3 patients
Lee et al. [56] (2018) Retrospective cohort study Mar 2007–Feb 2016 1 ED Patients ≥18 yr, sepsis who underwent abdominal CT 28-Day Sepsis-3 Evaluation of the association between muscle mass depletion and outcomes in sepsis patients
Lee et al. [57] (2021) Prospective cohort study Mar 2010 – Nov 2017 1 ED Patients ≥ 18 yr, diagnosed with sepsis or septic shock 28-Day Sepsis-3 Investigation of the association among the respiratory rate, oxygenation index, and mortality in patients with sepsis or septic shock
Lee et al. [58] (2021) Retrospective cohort study Jan 2016–Dec 2019 1 ED Patients ≥ 19 yr, with sepsis and septic shock 30-Day Sepsis-3 Investigation of the prognostic value of lactate levels and lactate clearance in sepsis and septic shock with initial hyperlactatemia
Lee et al. [59] (2022) Prospective cohort study Sep 2019–Feb 2020 16a) ED Patients ≥ 19 yr, with sepsis 28-Day, in-hospital Sepsis-3 Investigation of the association between preexisting clinical frailty and clinical outcomes in patients with sepsis
Oh et al. [60] (2017) Retrospective cohort study Jan 2010–Dec 2015 1 ED Patients ≥18 yr, with severe sepsis or septic shock 28-Day Sepsis-3 Assessment of the association between the serum chloride level and mortality in patients with severe sepsis or septic shock
Oh et al. [61] (2019) Retrospective cohort study Nov 2007–Mar 2016 1 ED Patients ≥ 18 yr, with septic shock treated with early goal-directed therapy 28-Day Other Assessment of the prognostic significance of the lactate level in septic shock patients
Park et al. [62] (2012) Prospective cohort study Apr 2005–Feb 2009 12 ED, ICU Patients ≥ 18 yr, with severe sepsis or septic shock 28-Day, in-hospital Other Investigation of clinical outcomes of ICU patients with communityacquired severe sepsis and septic shock
Park et al. [63] (2012) Retrospective cohort study Jan 2008–Dec 2010 1 ICU Patients admitted to the medical ICU for sepsis 30-Day, in-hospital Other Investigation of the association between mild hypoglycemia and hospital mortality
Park et al. [64] (2015) Prospective cohort study Jan 2005–Jun 2007, Dec 2007–Jun 2008 1 ED ED patients with severe sepsis and septic shock In-hospital Other Validation assessment of the low oxygen extraction ratio to predict mortality
Park et al. [65] (2020) Retrospective cohort study Jan 2017–Jul 2018 1 ED Patients ≥ 18 yr, with septic shock 28-Day Other Evaluation of the effects of early combination therapy with vitamin C and thiamine on ICU delirium-free days in patients with septic shock
Ryoo et al. [66] (2015) Prospective cohort study Jan 2010–Dec 2012 1 ED Adult patients with sepsis who received early goal-directed therapy 28-Day Other Validation assessment of the MISSED score to predict mortality in patients with severe sepsis and septic shock
Ryoo et al. [67] (2019) Prospective cohort study Oct 2015–Dec 2017 10b) ED Patients ≥18 yr, with septic shock 28-Day Sepsis-3 Assessment of the prognostic value of lactate normalization
Song et al. [68] (2012) Retrospective cohort study Aug 2008–Jul 2010 1 ED Sepsis patients ≥ 18 yr, without hypotension or hypoperfusion In-hospital Other Investigation of factors for predicting early deterioration in sepsis patients with intermediate levels of serum lactate
Song et al. [69] (2021) Retrospective cohort study Jan 2016–31 Mar 2020 1 ED Patients ≥ 18 yr, with sepsis 30-Day Sepsis-3 Investigation of the association between the vasoactive-inotropic score and mortality in patients with sepsis
Suh et al. [70] (2013) Retrospective cohort study Jan–Dec 2010 1 ED Patients ≥ 18 yr, with sepsis or septic shock excluding chronic renal replacement In-hospital Other Investigation of the clinical characteristics of acute kidney injury in patients with sepsis and septic shock
Um et al. [71] (2018) Prospective cohort study Mar 2010–Sep 2016 1 ED Patients ≥18 yr, with sepsis or septic shock 28-Day Other Evaluation of the relationship between the time to positivity blood culture and mortality in patients with sepsis and septic shock
Wang et al. [72] (2021) Retrospective cohort study Mar 2016–Dec 2018 3 ED Patients ≥18 yr, with sepsis 28-Day, in-hospital Sepsis-3 Association between health insurance status and outcomes of sepsis in adult patients
Yeo et al. [73] (2022) Prospective cohort study Sep 2019–Feb 2020 16a) Not mentioned Patients with septic shock 28-Day, in-hospital Sepsis-3 Evaluation of the effect of administering a vasopressor within 1 hr of first fluid loading on clinical outcomes in septic shock patients
Yoo et al. [74] (2020) Prospective cohort study Mar–Dec 2018 1 ICU Patients with sepsis who were admitted to the medical ICU 30-Day Other Evaluation of the association between 25(OH) D and vitamin D binding protein levels and sepsis mortality
You et al. [75] (2022) Prospective cohort study Nov 2015–Dec 2017 11b) ED Patients >18 yr, with septic shock 28-Day, in-hospital Sepsis-3 Investigation of the rate of compliance with the surviving sepsis campaign 3-hr bundle for nighttime and daytime ED admissions and the clinical effects of compliance on mortality in patients with septic shock

ICU, Intensive care unit; LOS, length of stay; tRNA, transfer RNA; ED, emergency department; RCT, randomized controlled trial; qSOFA, quick Sequential Organ Failure Assessment; PIRO, predisposition, infection, response, and organ dysfunction; MEDS, Mortality in Emergency Department Sepsis; CT, computed tomography; MISSED, Mortality in Severe Sepsis in the Emergency Department.

a) Korean Sepsis Alliance (KSA) registry.

b) Korean Shock Society (KoSS) registry.

Table 2.
Subgroup analyses for sepsis and septic shock
Characteristic Mortality
No. of studies Proportion (95% CI) P-valuea) I2 (%)
Sepsis
 28- or 30-day mortality
  Sepsis criteria
   Sepsis-3 17 22.7 (20.0–25.6) < 0.01 89
   Other 10 29.1 (23.3–35.6) < 0.01 97
  Study design
   Retrospective 17 22.6 (19.5–25.9) < 0.01 94
   Prospective 10 29.1 (23.4–35.5) < 0.01 96
  Included hospital
   Single center 22 23.3 (20.5–26.5) < 0.01 93
   Multicenter 5 31.3 (22.1–27.7) < 0.01 98
 In-hospital mortality
  Sepsis criteria
   Sepsis-3 13 28.1 (25.2–31.1) < 0.01 87
   Other 4 21.6 (9.2–30.5) < 0.01 98
  Study design
   Retrospective 10 23.8 (18.2–30.4) < 0.01 97
   Prospective 7 30.5 (26.1–35.2) < 0.01 85
  Included hospital
   Single center 11 24.8 (17.3–34.3) < 0.01 96
   Multicenter 6 28.1 (25.7–30.7) < 0.01 80
Septic shock
 28- or 30-day mortality
  Sepsis criteria
   Sepsis-3 16 27.6 (22.3–33.5) < 0.01 98
   Other 15 22.6 (18.8–26.8) < 0.01 95
  Study design
   Retrospective 13 28.0 (21.1–36.0) < 0.01 98
   Prospective 17 23.4 (20.1–27.0) < 0.01 95
   Randomized controlled trial 1 18.0 (11.9–26.3) - -
  Included hospital
   Single center 22 24.8 (19.8–30.7) < 0.01 98
   Multicenter 9 26.0 (22.7–29.6) < 0.01 93
 In-hospital mortality
  Sepsis criteria
   Sepsis-3 12 34.3 (27.2–42.2) < 0.01 97
   Other 6 26.0 (19.4–33.9) < 0.01 95
  Study design
   Retrospective 6 34.1 (21.1–50.2) < 0.01 99
   Prospective 10 29.8 (25.4–34.7) < 0.01 93
   Randomized controlled trial 2 29.6 (15.8–48.6) < 0.01 86
  Included hospital
   Single center 11 33.3 (24.2–44.0) < 0.01 97
   Multicenter 7 28.6 (23.8–34.1) < 0.01 94

CI, confidence interval.

a) For heterogeneity.

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