Hrev_master [page 39] [Emergency Care Journal 2023; 19:11655] Emergency Care Journal 2023; volume 19:11655 Abstract For patients with sepsis in the Emergency Department (ED), early risk stratification is important to improve prognosis. The study aimed to evaluate the predictive role of estimated plasma volume (ePVS) on admission to the ED. All sepsis patients who were admitted to our ED in 2021, were included in this prospective study. Multivariate models adjusted for patients’ clinical character- istics were used to assess the contribution of ePVS to the indepen- dent prediction of death at 30 days. A total of 455 septic patients were enrolled and 16.9% of patients died. Patients who survived to 30 days had a mean ePVS of 5.19, while those who died at 30 days had a value of 5.74 (p=0.004). ePVS was an independent risk fac- tor for 30-day mortality with an adjusted OR of 1.211 (95% CI 1.004–1.460, p=0.045). The AUROC of ePVS was 0.619 (95% CI 0.545–0.689). Decision tree analysis showed a predictive role for ePVS in less severe patients. In septic patients, ePVS is an inde- pendent predictor of 30-day mortality and may improve risk pre- diction in less severe patients. Introduction Sepsis is a serious organ dysfunction caused by a dysregulated response to infection.1 Despite advancements in diagnosis and therapeutic therapy, it is associated with high mortality rates and accounts for 30% of in-hospital deaths.1,2 One of the central patho- physiological changes in sepsis is systemic volume dysregulation caused by inflammation-induced endothelial dysfunction and the consequent increase in interstitial permeability; consequently, vol- ume resuscitation with intravenous crystalloids remains the main- stay of acute treatment.1,3,4 However, recent studies suggest that replacement when the microcirculatory system is unable to respond to fluids may worsen prognosis and that new approaches for measuring volume status should be implemented to improve short- and medium-term outcomes.1,5,6 Moreover, as indicated in recent guidelines, the use of vasoactive drugs is crucial in the event of reduced tissue inflow following volemic therapy to improve the patient’s prognosis by ensuring minimal vital organ flow.1 Despite the availability of various tools, designed and applied in ICUs, for assessing tissue and patient perfusion status, the ther- apeutic interventions in ED for suspected hypovolaemia are car- ried out without a precise evaluation of the patient’s plasma vol- ume.1,7-10 Since the relationship between microcirculatory endothe- lial function and interstitial hydration status is finely regulated, such measurements could reveal disruption of this balance and indicate potential states of volume overload or the incapacity to respond to a fluid load.11,12 Correspondence: Gianni Turcato, Department of Internal Medicine, Intermediate Care Unit, Hospital Alto Vicentino (AULSS-7), via Garziere, 43, 36014, Santorso, Italy. E-mail: gianni.turcato@yahoo.it Key words: sepsis; emergency department; septic shock; plasma volume; estimated plasma volume; ePVS; emergency medicine; mortality. Contributions: GT: conceptualization, methodology, investigation, formal analysis, data curation, writing-original draft preparation; AZ: conceptualization, methodology, investigation, formal analysis, data curation, writing-original draft preparation; SS: investigation, writing-original draft preparation; MM: supervision; FB: conceptu- alization, methodology, supervision, writing-original draft prepara- tion, writing - review & editing. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors confirm accuracy. Ethical statements: the study was approved by the local ethics com- mittee (Comitato etico per la sperimentazione clinica, Azienda Sanitaria dell’Alto Adige, Bolzano, Italia, approval number 94- 2020) and was conducted by the Declaration of Helsinki regarding the Ethical Principles for Medical Research Involving Human Subjects. Informed consent: all patients participating in this study signed a written informed consent form for participating in this study. Patient consent for publication: written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article. Availability of data and materials: all data generated or analyzed during this study are included in this published article. Received: 11 August 2023. Accepted: 13 October 2023. Early view: 20 October 2023. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2023 Licensee PAGEPress, Italy Emergency Care Journal 2023; 19:11655 doi:10.4081/ecj.2023.11655 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Estimated plasma volume status can help identify patients with sepsis at risk of death within 30 days in the emergency department Gianni Turcato,1 Arian Zaboli,4 Serena Sibilio,3,4 Michael Mian,2,4,5 Francesco Brigo4 1Department of Internal Medicine, Intermediate Care Unit, Hospital Alto Vicentino (AULSS-7), Santorso; 2Innovation, Research and Teaching Service (SABES-ASDAA), Teaching Hospital of the Paracelsus Medical Private University (PMU), Bolzano; 3Department of Emergency Medicine, Hospital of Merano-Meran (SABES-ASDAA), Merano-Meran, Italy; 4Teaching hospital of Paracelsus Medical Private University, Salzburg, Austria; 5College of Health Care-Professions Claudiana, Bozen, Italy Recently, Duarte et al. suggested estimating plasma volume in patients with heart failure using a simple formula based on hemoglobin and hematocrit. High estimated plasma volume status (ePVS) has been associated with a poor prognosis in patients with heart failure, according to earlier research.13,14 Although studies have demonstrated the prognostic value of ePVS in patients with fever or sepsis in the Intensive Care Unit (ICU), no studies have yet evaluated its prognostic utility in patients with sepsis or septic shock at initial evaluation in the Emergency Department (ED).12,15 Therefore, a prospective observational study was conducted to assess the predictive potential of ePVS in patients with sepsis upon their first admission to the ED. Materials and Methods Design and setting A prospective, observational, single-center study was per- formed in the ED at the Hospital of Merano, Italy (53,000 visits in 2021). The study was conducted between January 1 and December 31, 2021. Patients All patients aged ≥ 18 years were considered for enrolment in the study. This real-world study was performed in the ED during daily clinical activities. Therefore, all patients with suspected infection were initially considered as potentially eligible; in these patients, the study protocol was applied and specific blood tests for suspect- ed infection were carried out. Subsequently, following the recent Surviving Sepsis Campaign Guidelines 2021, after determining the Sequential Organ Failure Assessment (SOFA) score, patients with a suspected or confirmed infection and a SOFA ≥ 2 were enrolled and considered as affected by sepsis.1,16 Other exclusion criteria included: i) vasopressor therapy or invasive ventilation administered before arrival in the ED by healthcare professionals working in the territorial emergency sys- tem; ii) the presence of concomitant major bleeding as assessed by the ED physician; iii) known or suspected pregnancy; iv) fluid infusion ≥ 500 mL before the admission to the ED; v) sepsis or infection due to recent surgery or trauma; vi) predicted survival time of < 24 h after initial ED assessment; vii) tourists or non-res- idents were excluded due to an inability to determine outcomes; viii) transfer from another ED or healthcare facility; ix) study pro- tocol initiated > 3 h after patient arrival in the ED. Data collection and study protocol Each patient with a suspected infection underwent a battery of blood tests as part of their initial evaluation. Complete blood count with differential leucocyte counts, serum electrolytes, renal and hepatic function, serum albumin, C-reactive protein, total biliru- bin, coagulation status, and arterial blood gas were among the analyses performed. By the end of the ED visit, definitive confir- mation of sepsis based on previously established criteria was required for patient enrolment. At the initial examination, the ED physician also collected demographic and clinical information, such as sex, age, medical history, systolic and diastolic blood pres- sure, respiration rate, heart rate, capillary oxygen saturation, and cognitive status. In addition, the Charlson Comorbidity Index (CCI), the National Early Warning Score (NEWS), and the Acute Physiology and Chronic Health Evaluation (APACHE) and SOFA scores were recorded. The ePVS value was determined using hematocrit (Ht) and hemoglobin (Hb) values from the complete blood count performed when the patient arrived in the ED and was calculated using the formula below. Complete blood counts were obtained using a Sysmez analyzer (Sysmex XN-2000, Sysmex Inc. Kobe, Japan). Outcome The primary outcome of the study was death within 30 days after the first evaluation in the ED. Mortality was derived from information provided by the registry office. Statistical analysis Categorical variables were expressed as percentages and num- ber of events relative to the total and univariate comparisons were performed with Fisher’s exact and chi-square tests. Continuous variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR), depending on the underlying distribution. Comparisons were performed with Student’s t-tests, and Mann-Whitney or Kruskal-Wallis tests where appropriate. To assess the discriminatory ability of ePVS, we calculated the area under the receiver operating characteristic (AUROC) curve against 30-day mortality. To evaluate the prognostic ability of ePVS and validate its effect on 30-day mortality, logistic regres- sion models were developed using the CCI (a surrogate of medical history and severity of comorbidities), NEWS (a surrogate of immediate urgency), and SOFA and APACHE scores (surrogates of prognostic severity) as possible clinical confounders. The results of possible independent associations with PVS with 30-day mortality were reported as adjusted odds ratio (OR) with a 95% confidence interval (95% CI). The variables reported in the uni- variate analysis were not included in the multivariate analysis, as the aim of the study was to understand the role of ePVS in predict- ing the risk of death at 30 days in patients with sepsis and not to create a prognostic model. A decision tree analysis was also performed with the same variables to assess the prognostic ability of ePVS on 30-day mor- tality. Decision tree analyses are powerful data-mining analyses that create a non-parametric supervised learning algorithm.17 The decision tree was developed using the chi-square automatic inter- action detection technique. This consists of a hierarchical tree structure comprising a root node, branches, internal nodes, and leaf nodes. At each classification level along the tree, the model identi- fies the most significant predictor using the chi-square test to split the data interactively.17 The root node is at the top of the hierarchy and the data begin to subdivide from this point. Subsequent levels include the parent nodes, which are further subdivided into other nodes at lower levels. Leaf nodes, where further subdivision is not possible, identify subgroups of patients sharing the same risk.17 A 10-fold cross-validation was used to resolve any overfitting. The predictive performance of the decision tree for 30-day mortality was calculated by reporting the estimated correct classifications.17 All results were considered statistically significant for p<0.05. The statistical software packages STATA 16.0 and R were used for the analyses. Ethical statement The study was conducted by the Declaration of Helsinki and approved by the local ethics committee (approval number 94- 2020). Article [Emergency Care Journal 2023; 19:11655] [page 40] Results There were 455 patients with sepsis included in the study (Figure 1). The mean ePVS value in the study cohort was 5.28 (1.53). Patient characteristics for the cohort are listed in Table 1. The mortality rate was 16.9% (77 out of 455 patients died within 30 days). The mean ePVS was 5.19 (1.49) in survivors and 5.74 (1.63; p=0.004) in non-survivors. The characteristics of the non-survivors are reported in Table 2. In the multivariate model adjusted for age, comorbidity (CCI), urgency (NEWS score), and severity (SOFA and APACHE scores), ePVS was an independent risk factor for 30-day mortality, with an adjusted OR of 1.211 (95% CI 1.004–1.460, p=0.045). An ePVS value above the mean (> 5.28) was associated with an adjusted OR of 1.831 (95% CI 1.021–3.286, p=0.042). The discriminatory ability of ePVS for 30-day mortality is shown in Figure 1. The AUROC of ePVS was 0.619 (95% CI 0.545–0.689). According to the Kaplan-Meier analysis, patients with an above-average ePVS had shorter survival (p=0.004, log-rank test) (Figure 2). The decision tree analysis showed that ePVS was effec- tive in predicting 30-day mortality in patients with a low APACHE score (Figure 3), suggesting its prognostic utility in patients with a low apparent risk of mortality. As shown in Figure 3, the APACHE score is unable to correctly identify 15.6% (12/77) of the patients who achieved the study outcome among those with sepsis. In this category of patients, ePVS played an important role, being able to discriminate high-risk patients from low-risk patients. As shown by the decision tree for high-risk patients, the currently available tools (APACHE and NEWS) can accurately identify patients at risk of death at 30 days, whereas ePVS represents a relevant parameter to identify low-risk patients. Discussion In this prospective observational study conducted on patients with sepsis admitted to the ED, ePVS was an independent risk fac- tor for 30-day mortality. To the best of our knowledge, this is the first study to assess a possible predictive role for ePVS obtained Article [page 41] [Emergency Care Journal 2023; 19:11655] Figure 1. Flowchart of patients enrolled in the study. Article [Emergency Care Journal 2023; 19:11655] [page 42] Table 1. Clinical characteristics of patients enrolled in the study, divided by mean ePVS value. Variable ePVS < 5.28 ePVS ≥ 5.28 p Patients, n (%) 268 (58.9) 187 (41.1) Age, years, mean (SD) 74.2 (16.7) 79.4 (13.2) <0.001 Sex, n (%) 0.051 Male 93 (34.7) 82 (43.9) Female 175 (65.3) 105 (56.1) Baseline characteristics, n (%) Ischaemic heart disease 53 (19.8) 45 (24.1) 0.298 Hypertension 175 (65.3) 149 (79.7) 0.001 Diabetes 45 (16.8) 40 (21.4) 0.224 Chronic kidney failure 40 (14.9) 51 (27.3) 0.002 Chronic heart failure 57 (21.3) 57 (30.5) 0.028 Stroke or transient ischemic attack 30 (11.2) 17 (9.1) 0.533 Active tumor 16 (6) 32 (17.1) <0.001 Vital parameters Systolic blood pressure, mean (SD) 123.8 (26.3) 116.3 (25.8) 0.004 Respiratory rate, mean (SD) 22.8 (7.3) 22.9 (7.1) 0.943 Heart rate, median (IQR) 100 (85-113) 96 (80-108) 0.013 Peripheral oxygen saturation, median (IQR) 94 (90-96) 95 (92-97) 0.509 Temperature, median (IQR) 38 (37.2-38.6) 37.9 (37.1-38.5) 0.335 Table 2. Clinical and laboratory characteristics of patients enrolled in the study were divided between dead and undead patients at 30 days. Variable Alive at 30 days Dead at 30 days p Patients, n (%) 378 (83.1) 77 (16.9) Age, years, mean (SD) 74.6 (16.1) 84.9 (8.5) <0.001 Sex, n (%) 0.123 Male 139 (36.8) 36 (46.8) Female 239 (63.2) 41 (53.2) Baseline characteristics, n (%) Ischaemic heart disease 77 (20.1) 22 (28.6) 0.127 Hypertension 258 (68.3) 66 (85.7) 0.001 Diabetes 64 (16.9) 21 (27.3) 0.038 Chronic kidney failure 66 (17.5) 25 (32.5) 0.005 Chronic heart failure 93 (24.6) 21 (27.3) 0.665 Stroke or transient ischemic attack 38 (10.1) 9 (11.7) 0.682 Active tumor 35 (9.3) 13 (16.9) 0.065 Charlson Comorbidity Index, media (SD) 4.7 (2.3) 6.5 (2.1) <0.001 Vital parameters Systolic blood pressure, mean (SD) 123.4 (25.3) 107.6 (27.2) <0.001 Respiratory rate, mean (SD) 22.1 (6.6) 26.5 (8.9) <0.001 Heart rate, median (IQR) 98 (82-110) 102 (84-120) 0.011 Peripheral oxygen saturation, median (IQR) 94 (92-97) 93 (90-96) 0.001 Temperature, median (IQR) 38 (37.3-38.6) 37.6 (36.6-38.3) 0.013 NEWS score, mean (SD) 4.8 (3.4) 8.1 (4.6) <0.001 Blood tests Haemoglobin, g/dL, mean (SD) 12.5 (2.1) 11.7 (2.3) 0.003 Haematocrit, %, mean (SD) 37.9 (6.1) 36.2 (7.1) 0.032 Leukocytes, median (IQR) 11.2 (7.6-14.5) 13.4 (9.6-18.5) 0.003 Platelets, median (IQR) 184 (140-249) 268 (169-369) <0.001 Lactate, median (IQR) 1.5 (1-2.2) 2.3 (1.5-3.4) <0.001 C-reactive protein, median (IQR) 7.2 (2.1-15.3) 13.2 (6.1-20.1) <0.001 Creatinine, median (IQR) 1.24 (0.92-1.66) 1.51 (1.01-2.48) 0.006 Bilirubin, median (IQR) 1.03 (0.66-1.75) 0.86 (0.59-1.27) 0.031 APACHE score, mean (SD) 11.7 (4.6) 16.4 (4.5) <0.001 from blood counts in patients who arrived in the ED with a suspi- cion of sepsis. Furthermore, the decision tree analysis showed that ePVS can have prognostic value also in patients at lower apparent risk (APACHE < 12). Overall, these findings suggest that ePVS could be a promising tool for predicting the prognosis of patients with sepsis in the ED. Furthermore, ePVS has proven to be useful in a comprehensive patient assessment using other laboratory tests and clinical evaluations, making it an excellent tool to support clin- ical decisions. Key aspects of sepsis management include resuscitation with intravenous fluids to restore tissue perfusion, antibiotic therapy, infection control, and the use of vasopressors.1 However, recent studies have shown that a positive fluid balance is associated with a negative outcome in patients with sepsis.6,11,12 Although the exact mechanisms are unknown, previous studies suggest that excessive intravenous fluid resuscitation may result in iatrogenic endothelial damage.18 Increased tissue edema and hypoxia are the results of increased endothelial permeability, which may ultimately cause organ damage.18-20 The treatment and prognostic assessment of patients with sepsis are currently complicated by the lack of a gold- standard method to determine if endothelial damage is present and the capacity for capillary filtration.1 Targeted and individualized therapy is still a long way off due to a lack of diagnostic or clinical tools capable of rapid and non-invasive determination of volume status and response to fluid load.1 Therefore, given the importance of determining volume status, any available additional indication of the patient’s blood volume is likely to be clinically relevant. In previous studies using radiolabelled albumin techniques, ePVS derived from hemoglobin and hematocrit correlated well with plasma volume measured with radioisotopes.13 ePVS is defined as the percentage difference between ideal and actual plas- ma volume; it has been recently proposed as a non-invasive, rapid, and simple method to assess volume status, particularly in patients with acute conditions.12-15 Chen et al. initially proposed a clinical role for ePVS in the prognostic evaluation of patients with heart failure after acute myocardial infarction, reporting that higher Article Figure 2. Kaplan-Meier for 30-day mortality comparing patients who had an ePVS value above or below the mean. Figure 3. Decision tree for 30-day mortality in patients with sepsis. [page 43] [Emergency Care Journal 2023; 19:11655] ePVS was significantly associated with hospitalization or death from cardiovascular causes.21 Furthermore, a decrease in ePVS was correlated with decongestion following effective treatment and with a better cardiovascular outcome.21 High ePVS was recent- ly found to be strongly associated with in-hospital mortality in patients who arrived at the ED with acute dyspnea and acute heart failure.22 Furthermore, among patients admitted to the ED with fever, ePVS was associated with 30-day mortality with an adjusted OR of 2.717 (95% CI 1.103–6.692, p=0.020) and with sepsis or septic shock with an OR of 1.824 (95% CI 1.055–3.154, p=0.030).11 In a subsequent study, Kim et al. found that ePVS was an independent risk factor for in-hospital mortality among sepsis patients admitted to the ICU, with a multivariate OR of 1.39 (95% CI 1.04-1.85, p=0.028), suggesting that ePVS may aid in predict- ing the risk of death.12 An important innovation of the present study is the use of decision tree analysis, a potent statistical technique that overcomes the inherent difficulties of traditional multivariate analyses. High APACHE scores may be sufficient to categorize patients with a poor prognosis. However, among patients with lower APACHE scores which may appear to be less severe cases, ePVS may improve prognostic prediction by providing additional clinical data. Patients with lower APACHE scores who appear clin- ically stable when they enter the ED may already have microcircu- latory changes that, if untreated, could worsen the prognosis. In these patients, the ePVS may thus represent a useful early prognos- tic marker that correlates with initial endothelial dysfunction. Overall, we established that ePVS, a rapid and easy test to administer at the time of ED admission, was independently associ- ated with mortality in sepsis patients and that it plays a role in iden- tifying mortality risk in patients with initially less severe sepsis. Although more studies are required to corroborate these clinical findings, ePVS may eventually be used as a clinical tool in the complex prognostic assessment of sepsis patients. Overall, ePVS, recorded on the patient’s immediate arrival in the ED, was an independent risk factor for 30-day mortality in sep- tic patients. Given its simplicity rapid availability and immediacy, ePVS may be one of the indices that can assist the ED physician in the intricate and sensitive multidimensional assessment to estimate the prognosis and severity of the septic patient in the ED, despite its suboptimal discriminatory ability. The analysis of decision trees further supports this conclusion. Hence, in clinical conditions and patient groups where prognosis and assessment cannot be accom- plished very effectively using the tools that are currently available, ePVS can provide useful additional predictive information. This study has a few limitations. It was conducted in a single center, which could have limited the generalisability of the find- ings. We initially considered all patients with suspicion of infec- tion, as the definition of sepsis is currently linked to the SOFA score; this facilitated the rapid identification of patients who had sepsis. In addition, we excluded patients who were admitted to the Shock Room directly with invasive ventilation or who were administered amines out-of-hospital. This decision was made in agreement with the local committee because it was believed that the study design could not be applied to these patients, even though it may have resulted in the exclusion of patients with sepsis and septic shock. Patients with sepsis and infection caused by a recent surgical procedure or trauma were also excluded. Consequently, only patients with a community infection were considered and recruited in the study, which may have resulted in the exclusion of several sepsis cases. Finally, we did not include COVID-19 patients as they under- went a separate healthcare pathway with specific management dur- ing the study period.23 Conclusions In this preliminary study, the simple and rapid calculation of ePVS based on the first blood count performed on patient arrival in the ED predicts 30-day mortality in patients with sepsis. It also has a useful predictive role in patients with low APACHE scores; if these results are confirmed in further studies, ePVS could prove to be a simple and manageable clinical tool that can facilitate the complex prognostic assessment of patients with sepsis immediate- ly upon arrival in the ED. References 1. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis cam- paign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021;47:1181-1247. 2. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018;392:75-87. 3. Ince C, Mayeux PR, Nguyen T, et al. The endothelium in sep- sis. Shock 2016;45:259-270. 4. Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial Responses in Sepsis. Am J Respir Crit Care Med 2020;202:361-70. 5. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA 2017;318:1233-40. 6. Macdonald SPJ, Keijzers G, Taylor DM, et al. Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial. Intensive Care Med 2018;44:2070-2078. 7. Corradi F, Via G, Tavazzi G. What's new in ultrasound-based assessment of organ perfusion in the critically ill: expanding the bedside clinical monitoring window for hypoperfusion in shock. Intensive Care Med 2020;46:77-9. 8. Corradi F, Brusasco C, Via G, et al. Renal Doppler-Based Assessment of Regional Organ Perfusion in the Critically Ill Patient. Shock (Augusta, Ga.) 2021;55:842–843. 9. 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