Introduction
Sepsis-3 describes sepsis as a dysregulated host response to infection resulting in life-threatening organ malfunction.1 The most common causes of mortality and morbidity in patients monitored in intensive care are bacterial infections and sepsis.2,3
From data published in 2020, there were 48.9 million cases and 11 million sepsis-related deaths worldwide, representing 20% of all global deaths.4 Determining the progression to sepsis at an early stage and thus reducing mortality rates is of great importance in intensive care patients.
Various biomarkers and scoring systems are currently used to determine the prognosis of patients in intensive care. APACHE II (Acute Physiology and Chronic Health Evaluation II), white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), and lactate are the most important of these. The APACHE II scoring is the gold standard for evaluating high-risk patients in intensive care. This scoring provides information about the prognosis of patients by risk stratifying them. However, sometimes incorrect scores may occur. For example, the APACHE II score is calculated as relatively low in a young patient with severe sepsis but no organ failure.5,6 Biochemistry Laboratory of KSU Application and Research Hospital.
The Society of Critical Care Medicine and the European Society of Intensive Medicine have suggested using the SOFA score to predict mortality in sepsis.1 The use of the quick SOFA (qSOFA) system for out-of-intensive care units (ICU) and pre-hospital periods was recommended by consensus because the SOFA scoring takes time to apply and requires laboratory testing.7 C-reactive protein (CRP) and procalcitonin (PCT) are commonly used to monitor critically ill patients in intensive care.8 However, measuring CRP is not ideal for monitoring sepsis, as its levels can also increase in postoperative conditions, autoimmune diseases, rheumatological disorders, and non-infectious conditions such as myocardial infarction. On the other hand, PCT levels are significantly higher in cases of bacteremia and sepsis. PCT and CRP have low prognostic values on the expected life expectancy of patients with sepsis.9
Although CRP and procalcitonin may not be specific to sepsis, they are useful in identifying critically ill patients who need closer monitoring, enabling earlier diagnosis and treatment.9
No single biomarker of sepsis may be ideal, but many are helpful in terms of at least identifying critically ill patients who need more careful monitoring so that the condition may be diagnosed and treated as soon as possible. Another parameter in the early progression to sepsis is the lactate level. Hyperlactatemia due to tissue hypoxia is observed. Since oxygen delivery to the cells decreases after sepsis develops, lactate values become quite difficult to interpret.
Complete blood count (CBC) is an easily accessible and inexpensive test. The WBC, neutrophil, lymphocyte, platelet (PLT) and mean platelet volume (MPV) values studied in this test and the ratios of these values to each other are used as inflammatory markers. Neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) are some of the most important of these markers. Systemic immune-inflammation index (SII) is an index obtained by calculating with the formula (neutrophil x platelet)/lymphocyte.
Ischemia-modified albumin (IMA) is a biomarker whose level increases secondary to ischemia of the myocardium and skeletal muscle, measured with the albumin cobalt binding test.
Rapid and timely intervention is essential for the successful treatment of sepsis. Therefore, this study aimed to reveal the relationships between patients with mortality by looking at IMA, APACHE II, CRP, PCT, lactate, WBC, NLR, PLR, SII, platelet and lactate/IMA (LIMA) values in sepsis patients followed in the intensive care unit.
Materials and Method
This study was conducted prospectively in a single center over 6 months. Thirty-one patients diagnosed with sepsis were included in the study. The informed consent form was obtained from the patients or their relatives and study permission was obtained. Patients who were considered to have sepsis were ≥ 18 years old and stayed in the intensive care unit for ≥72 hours were included in the study. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) definitions and clinical criteria were used to describe septic shock and multiorgan dysfunction.7
In addition, terminal cancer patients, those who had received massive blood transfusions, ischemic heart disease, and patients with ongoing pregnancy were excluded from the study.
All patients’ general evaluation (age, gender, patient diagnosis, additional diseases), blood biochemistry, complete blood count, arterial blood gas, and APACHE II and SOFA scores were calculated and recorded within the first day of admission to the intensive care unit.
The day the patient was admitted to the intensive care unit was considered day 1.
The values examined on the first day were planned to be compared with the APACHE II criteria, which evaluate many parameters. The values examined on the fifth day were aimed at evaluating the predictive power of mortality after the patient’s clinical deterioration.
To evaluate IMA levels in patients hospitalized in the intensive care unit on days 1 and 5, 8 mL of blood was taken from the peripheral vein into a citrated tube. After the blood was clotted and centrifuged at 3000 g for 10 minutes. The obtained sera were stored at −80 °C until the study day. Serum IMA levels were analyzed colorimetrically using the method developed by Bar et al.10 Complete blood counts were tested in the Biochemistry Laboratory of KSU Application and Research Hospital using SYSMEX XN3000 AND SYSMEX XT 1800i automatic hematology analyzers. Blood gas analyses were performed on the Radiometer ABL 700 device located in the Biochemistry Laboratory of KSU Application and Research Hospital.
Our study was conducted in accordance with the Declaration of Helsinki.
The Ethics Committee of Kahramanmaras sütçü ımam University, School of Medicine approves this study. (Ethics No. 2017/21).
Statistical Analysis
SPSS 25.0 package program (SPSS Inc, Chicago, Illinois, USA) was used to evaluate the statistical data obtained in the study. Continuous data were summarized as mean and standard deviation, while categorical data were summarized as numbers and percentages. Student’s t-test was used to compare continuous variables in independent groups. The chi-square (χ²) test was used to evaluate two categorical independent groups for comparisons between groups. The Receiver operating characteristic (ROC) curve was used to evaluate the predictive power of the markers for appendicitis. According to this method, the sensitivity of 100%, false positivity zero (1-Specifity=0), the area under the curve (AUC) being 1, and the diagnostic value of the AUC value being p<0.05 were accepted as the basic criteria for the best test definition. In determining the cut-off value, the Youden index, which overlaps with the point closest to the upper left corner of the ROC graph and reflects the highest value of the sum of sensitivity and specificity, was used. In investigating the accuracy of the diagnostic test, sensitivity and specificity were calculated with a 95% confidence interval and presented as a table The level of statistical significance was p<0.05.
Results
Thirty-one patients diagnosed with sepsis from the Anesthesia Intensive Care Unit were included in the study. Twenty-one (67.7%) of the patients were male and 10 (32.3%) were female. The mean age of the patients was 76.77±14.92 years (min-max: 30–96 years), and the median (min-max) APACHE II score values at the time of admission to the intensive care unit were 20.5 (12–30).
Of the patients included in the study, 64.5% (n=20) had septic shock on initial admission to the hospital, 35.5% (n=11) had acute renal failure, 16.1% (n=5) had acute liver injury, and 83.9% (n=26) required invasive mechanical ventilation.
The final status of the patients was evaluated as alive and exits, and 18 (58.1%) of the patients ended up as exits). The study included 18 patients, and the mean time to death was determined as 12.6 days. In addition to sepsis, the cases had diabetes mellitus, coronary artery disease, goiter, Alzheimer’s, cerebrovascular disease, arrhythmia, and obesity.
Table 1 presents the first 24 hours and 5th-day IMA, CRP, PCT, lactate, WBC, platelet count, MPV, NLR, PLR, LİMA, and SII values of patients diagnosed with sepsis.
|
Table 1 IMA, CRP, PCT, Lactate, WBC, Platelet Count, NLR, PLR, LIMA and SII Values of Patients Diagnosed with Sepsis in the First 24 hours and on the 5th Day
|
Cut-Off, Sensitivity, Specificity, AUC, 95% confidence interval, and p values of APACHE-II, NLR5, LİMA1, and SII5 values for predicting 28-day mortality of patients diagnosed with sepsis were calculated and presented in Table 2.
 |
Table 2 All Values of Patients Diagnosed with Sepsis Cut-Off, Sensitivity, Specifity, AUC, 95% Confidence Interval and p Values for Predicting 28-Day Mortality
|
ROC curves of patients with sepsis are presented in Figure 1.
 |
Figure 1 ROC curves of patients diagnosed with sepsis.
|
In patients diagnosed with sepsis, APACHE-II was the best statistical indicator in the first 24 hours, and NLR 5th-day values were the second-best statistical indicator. Although statistically significant values were not reached, LİMA1 and SII5 values could also give an idea about 28-day mortality.
Discussion
One of the most important events leading to morbidity and mortality in patients with severe sepsis is the development of global tissue hypoperfusion and oxidative damage. Ischemia-modified albumin (IMA), an albumin produced under ischemic and oxidative conditions, is a marker of oxidative stress and hypoperfusion. Sepsis causes an imbalance between reactive oxygen species and antioxidants.7 Changes in endothelium, neutrophils, macrophages, and mitochondrial signaling pathways during sepsis cause significant oxidative stress.11 Ischemic damage is associated with oxidative stress, and the production of reactive oxygen species affects albumin and produces IMA.12 Mitochondrial dysfunction in sepsis causes increased anaerobic metabolism despite adequate oxygen delivery, which also leads to an increase in lactate levels.13
To our knowledge, this is the first study to compare serum IMA levels with APACHE-II, IMA, CRP, PCT, lactate, WBC, platelet count, MPV, NLR, PLR, LİMA and SII values on different days to predict mortality in patients with sepsis. In previous studies, IMA and APACHE-II were never studied together.
In our study, APACHE-II was found to be the best statistical indicator in the first 24 hours, and NLR values on the 5th day were found to be the second-best statistical indicator in patients with a diagnosis of sepsis. Although statistically significant values were not reached in our study, LİMA1 and SII1 values could also give an idea about 28-day mortality.
Kyoshi et al, in a study examining central line-related bloodstream infection in a general intensive care unit, APACHE-II (OR (95% CI) 1.051 (1.000–1.105), p:0.048) was found to be a prognostic factor in the deterioration of patients.14 In a study investigating the effects of APACHE-II on mortality at 30–60-180 days in oncological patients with sepsis by Kuo et al, APACHE-II (OR (95% CI) 1.07; 1.03–1.11) p <0.001) was found to be statistically significant.15 Suo et al. It was determined that APACHE-II score (AUC:0.568, sen: 61.2%, spe: 62.2, % 95CI:0.512–0.684) and lactate (AUC:0.810, sen:83.3% spe:79.4%, 95CI:0.738–0.882)) values were significant in predicting mortality in patients with sepsis.16 In our study, the APACHE-II score was the most valuable indicator in predicting mortality in patients with sepsis, similar to the literature.
The current meta-analysis of 14 studies by Huang et al, including 11,564 patients with sepsis, showed that NLR was significantly higher in non-survivors than in survivors and that higher NLR was associated with prognosis in patients with sepsis. These results indicate that higher NLR is independently associated with adverse clinical prognosis in patients with sepsis.17 In the study by Hwang et al investigating the relationship between 28-day mortality and NLR in patients with sepsis, it was determined that NLR had a statistically significant predictive power for mortality in patients with sepsis.18 In our study, similar to the literature, NLR value was the most valuable parameter after APACHE-II value in predicting mentality. In the study by Park et al, among 124 patients evaluated, IMA was found to be higher in the non-survivor group than in the survivor group (92.6±8.1 vs 86.8±6.2 U/mL, p<0.001). IMA was found to be associated with 28-day mortality.19 Previous studies evaluating the prognostic value of IMA in patients with sepsis or severe sepsis reported a significant association between IMA and short-term mortality.12 In the study by Prashanth et al, significantly higher IMA levels (p<0.0001) were found in patients with sepsis compared to those without sepsis (0.085±0.234).20 In another study, statistically significantly higher IMA levels were found in patients with sepsis compared to the control group (p <0.0001).21 Yin et al, similarly, in the study conducted by, IMA levels were higher in those who died than in those who survived (p<0.05) and were found to be a strong determinant of 28-day mortality.22 In the study conducted by Yerlikaya et al, serum IMA, CRP, PCT and leukocyte counts were found to be significantly higher in the sepsis group before treatment than in the control group.23 In the study conducted by Cetin et al, the effect of IMA on mortality was investigated in 81 sepsis patients. Serum IMA levels in the patient and control groups were found to be 117.8±85 IU/g and 115.8±134.0 IU/g, respectively (p=0.072). A weak but statistically significant positive correlation was found between IMA and lactate levels (p:0.009). The mortality rate of the patient group on the 28th day was found to be 79%. In this study, similar to our study, it was determined that serum IMA levels were not a prognostic marker in predicting mortality in patients with sepsis.24 In our study, similar to the study by Çetin et al, although IMA levels were high in patients with sepsis, it was not found to be statistically significant. In the study by Choo et al, IMA levels are a useful biomarker for early diagnosis of sepsis/septic shock and its combination with lactate levels may increase the predictive power of early diagnosis of sepsis (AUC IMA: 0.729, AUC IMA and Lactate: 0.815).25 In the study by Bo et al, IMA levels were found to be statistically significantly higher in the non-surviving group than in the surviving group (p<0.001). The predictive power of 28-day mortality in patients with sepsis showed a higher mortality risk compared to other groups in both the group with high IMA and the group with high IMA and lactate (AUC IMA: 0.712, p<0.001; AUC IMA and lactate 0.838, p<0.001).12 In our study, although IMA values increased, they were not found to be statistically significant, and it was predicted that the combined evaluation of LIMA1 values could provide an idea about 28-day mortality. Systemic immune-inflammation index (SII) is an economical and useful parameter based on lymphocyte, neutrophil, and platelet counts and can simultaneously reflect the inflammatory and immune status of patients.26 SII can be used not only to predict death in patients with sepsis but also to increase diagnostic accuracy by combining clinical scores of sepsis severity. A lower SII theoretically indicates that the body may be impaired by severe inflammation or myelosuppression and is generally associated with poor prognosis.27 In the study by Jiang et al, a relationship was found between SII and 28-day mortality (p:0.049) (24). In the study by Mangales et al, in which 267 patients with sepsis were evaluated retrospectively, SII was found to be an independent predictor of sepsis mortality (AUC:0.848, sensitivity was 85.5%, specificity was 71.2% and cut-off was 564).28 In our study, it was found that SII could be useful in predicting 28-day mortality of patients with sepsis, although it was not statistically significant. This study had some limitations. Our study was conducted in a single center with a limited number of patients. These results cannot be generalized to the entire population. IMA may differ according to measurement protocols in each laboratory environment. Results and measurements should be verified before application.
Conclusion
APACHE-II score still maintains its place in predicting mortality in patients with sepsis. No single biomarker has been able to surpass this score, and combined markers such as NLR, LIMA, and SII may help predict mortality. New and large-scale studies are needed on this subject.
Abbreviations
APACHE II, Acute Physiology and Chronic Health Evaluation II; WBC, white blood cell count; CRP, C-reactive protein; PCT, procalcitonin; PLT, platelet; and MPV, mean platelet; NLR, Neutrophil lymphocyte ratio; PLR, platelet lymphocyte ratio; SII, Systemic immune-inflammation index; IMA, Ischemia modified albumin.
Data Sharing Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Informed Consent
This study is approved by the Ethics Committee of kahramanmaras sütçü ımam University, School of Medicine. (Ethics No. 2017/21).
Consent to Participate
Obtained.
Consent for Publication
Obtained.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Shankar-Hari M, Phillips GS, Levy ML, et al. Sepsis definitions task force. developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):775–787. PMID: 26903336; PMCID: PMC4910392. doi:10.1001/jama.2016.0289
2. Alberti C, Brun-Buisson C, Goodman SV, et al. Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients. Am J Respir Crit Care Med. 2003;168(1):77–84. doi:10.1164/rccm.200208-785OC
3. Flaatten H. Epidemiology of sepsis in Norway in 1999. Crit Care. 2004;8(4):180–184. doi:10.1186/cc2867
4. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet. 2020;395(10219):200–211. doi:10.1016/S0140-6736(19)32989-7)
5. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–829. doi:10.1097/00003246-198510000-00009
6. Vincent JL, Donadello K, Schmit X. Biomarkers in the critically ill patient: c-reactive protein. Crit Care Clin. 2011;27(2):241–251. doi:10.1016/j.ccc.2010.12.010
7. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–810. PMID: 26903338; PMCID: PMC4968574. doi:10.1001/jama.2016.0287
8. Schuetz P, Albrich WC, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med. 2011;9(1):107. doi:10.1186/1741-7015-9-107
9. Claeys R, Vinken S, Spapen H, Ver Elst K, Decochez K, Huyghens L. Plasma procalcitonin and c-reactive protein in acute septic shock. Clin Biologic Correlates Crit Care Med. 2002;30:757–762.
10. Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. J Emerg Med. 2000;19(4):311–315. doi:10.1016/S0736-4679(00)00255-9
11. Joffre J, Hellman J. Oxidative stress and endothelial dysfunction in sepsis and acute inflammation. Antioxid Redox Signal. 2021;35(15):1291–1307. doi:10.1089/ars.2021.0027
12. Jin B-Y, Lee S, Kim W, et al. Ischemia-modified albumin lactate, and combination for predicting mortality in patients with septic shock in the emergency department. Biomedicines. 2024;12:1421. doi:10.3390/biomedicines12071421
13. Suetrong B, Walley KR. Lactic acidosis in sepsis: it’s not all anaerobic: implications for diagnosis and management. Chest. 2016;149(1):252–261. doi:10.1378/chest.15-1703
14. Moriyama K, Ando T, Kotani M, et al. Risk factors associated with increased incidences of catheter-related bloodstream infection. Medicine. 2022;101(42):e31160. PMID: 36281147; PMCID: PMC9592381. doi:10.1097/MD.0000000000031160
15. Kuo WK, Hua CC, Yu CC, Liu YC, Huang CY. The cancer control status and APACHE II score are prognostic factors for critically ill patients with cancer and sepsis. J Formos Med Assoc. 2020;119(1 Pt 2):276–281. PMID: 31153724. doi:10.1016/j.jfma.2019.05.012
16. Suo S, Luo L, Song Y, Huang H, Chen X, Liu C. Early diagnosis and prediction of death risk in patients with sepsis by combined detection of serum PCT, BNP, lactic acid, and apache II score. Contrast Media Mol Imaging. 2022 Jul 19;2022:8522842. doi: 10.1155/2022/8522842. Retract Contrast Media Mol Imaging. 2023;2023:9793474. PMID: 35935301; PMCID: PMC9325350. doi:10.1155/2023/9793474
17. Huang Z, Fu Z, Huang W, Huang K. Prognostic value of neutrophil-to-lymphocyte ratio in sepsis: a meta-analysis. Am J Emerg Med. 2020;38(3):641–647. PMID: 31785981. doi:10.1016/j.ajem.2019.10.023
18. Hwang SY, Shin TG, Jo IJ, et al. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically-ill septic patients. Am J Emerg Med. 2017;35(2):234–239. PMID: 27806894. doi:10.1016/j.ajem.2016.10.055
19. Park J, Ahn S, Lee S, et al. Association of ischemia modified albumin with mortality in qSOFA positive sepsis patients by sepsis-3 in the emergency department.Am. J Emerg Med. 2021;44:72–77. PMID: 33582611. doi:10.1016/j.ajem.2021.01.059
20. Prashanth AK, Anand U. Clinical significance of ischemia modified albumin in critically ill patients with sepsis.Indian. J Clin Biochem. 2015;30(2):194–197. doi:10.1007/s12291-014-0434-4
21. Ashok Kumar P, Anand U. Multiple biomarkers to assess the pathophysiological state in critically Ill patients with sepsis. Indian J Clin Biochem. 2016;31(3):310–314. PMID: 27382202; PMCID: PMC4910843. doi:10.1007/s12291-015-0525-x
22. Yin M, Liu X, Chen X, et al. Ischemia-modified albumin is a predictor of short-term mortality in patients with severe sepsis. J Crit Care. 2017;37:7–12. PMID: 27610585. doi:10.1016/j.jcrc.2016.08.005
23. Yerlikaya FH, Kurban S, Mehmetoglu I, et al. Serum ischemia-modified albumin levels at diagnosis and during treatment of late-onset neonatal sepsis. Matern Fetal Neonatal Med. 2014;27(17):1723–1727. doi:10.3109/14767058.2013.876621
24. Cetin M, Oray NC, Bayram B, Calan OG. The prognostic value of ischemia-modified albumin in patients with sepsis. Niger J Clin Pract. 2021;24(5):680–684. doi:10.4103/njcp.njcp_211_20
25. Choo SH, Lim YS, Cho JS, et al. Usefulness of ischemia-modified albumin in the diagnosis of sepsis/septic shock in the emergency department. Clin Exp Emerg Med. 2020;7(3):161–169. PMID: 33028058; PMCID: PMC7550814. doi:10.15441/ceem.19.075
26. Hu B, Yang XR, Xu Y, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20(23):6212–22. doi:10.1158/1078-0432.CCR-14-0442
27. Jiang D, Bian T, Shen Y, Huang Z. Association between admission systemic immune-inflammation index and mortality in critically ill patients with sepsis: a retrospective cohort study based on MIMIC-IV database. Clin Exp Med. 2023;23(7):3641–3650. PMID: 36930382; PMCID: PMC10022570. doi:10.1007/s10238-023-01029-w
28. Mangalesh S, Dudani S, Malik A. The systemic immune-inflammation index in predicting sepsis mortality. Postgrad Med. 2022;135(4):345–351. doi:10.1080/00325481.2022.214053